MULTIMERIC CORONAVIRUS BINDING MOLECULES AND USES THEREOF

SEQUENCE LISTING

The instant application contains a Sequence Listing which has been submitted electronically in ASCII format and is hereby incorporated by reference in its entirety. The ASCII copy, created on Jul. 27, 2021, is named 032US1-Sequence-Listing.txt and is 803,135 bytes in size.

BACKGROUND

Antibodies and antibody-like molecules that can multimerize, such as IgA and IgM antibodies, have emerged as promising drug candidates, e.g., in the fields of immuno-oncology and infectious diseases, allowing for improved specificity, improved avidity, and the ability to bind to multiple binding targets. See, e.g., U.S. Pat. Nos. 9,951,134, 9,938,347, 10,351,631, 10,400,038, and 10,899,935, U.S. Patent Application Publication Nos. US 2019-0100597, US 2018-0009897, US 2019-0330374, US 2019-0330360, US 2019-0338040, US 2019-0338041, US 2019-0185570, US 2018-0265596, US 2018-0118816, US 2018-0118814, and US 2019-0002566, and PCT Publication Nos. WO 2018/187702, and WO 2019/165340, the contents of which are incorporated herein by reference in their entireties.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a single stranded, positive sense enveloped RNA virus. SARS-CoV-2 causes Coronavirus Disease 2019 (COVID-19), which is currently causing a global pandemic. COVID-19 is highly contagious and commonly causes fever, cough, and shortness of breath, and can lead to pneumonia, blood clots, organ failure, and death. The four main structural proteins of the SARS-CoV-2 include spike (S), envelope (E), membrane (M), and nucleic capsid (N).

The trimeric S protein binds the angiotensin-converting enzyme 2 (ACE2) receptor, alters its conformation to a fusogenic protein, which facilitates fusion of the cellular and viral membranes and thereby enables SARS-CoV-2 to enter cells. The S protein comprises two units: S1 and S2, with the S1 domain comprising the receptor-binding domain (RBD). See, e.g., Lan, J., et al., Nature 581:215-220 (2020). The S protein and specifically the RBD are required for entry into cells, which has made the RBD a favored target of potential therapeutic monoclonal antibodies. Unfortunately, even the IgG antibodies having very potent neutralizing activity against the RBD of SARS-CoV-2 need to be administered by infusion at high doses (up to 8 grams per dose) to effectively treat COVID-19 patients (Weinreich, D M, et al., N Engl J Med doi: 10.1056/NEJMoa2035002 12020 (2021); Chen, et al., N Engl J Med doi: 10.1056/NEJMoa2029849 (2021)).

Despite this interest, antibody-dependent enhancement (ADE), also known as antibody-mediated enhancement (AME), of disease caused by SARS-CoV-2 is a concern and has been demonstrated in infections with other coronaviruses. See, e.g., Houser, K. V., et al., PLoS Pathog. 13: Article e1006565 (2017) (MERS-CoV); Weiss, R. C., and F. W. Scott Comp. Immunol. Microbiol. Infect. Dis 4:175-189 (1981) (feline infectious peritonitis virus); and Kam, Y. W., et al., Vaccine 25:729-740 (2007) (SARS-CoV). For example, Kam et al., showed that antibodies against the SARS-CoV S glycoprotein trimer were able to mediate entry of antibody-bound virus into B cells via FcγRII. If Fcγ receptor dependent entry into cells occurs with antibodies against SARS-CoV-2, conventional IgG antibody therapy may make the infection worse than no treatment at all.

In addition to the difficulties in developing therapeutic monoclonal antibodies in general, current practices for treating COVID-19 are severely limited. Remdesivir, convalescent plasma, and hyperimmune globulin have all received FDA emergency use authorizations. However, remdesivir has only been shown to shorten the hospitalization duration a short period of time. Similarly, convalescent plasma and hyperimmune globulin have shown some early signs of improving COVID-19 symptoms, but results are limited, and the plasma is obtained from patients and not manufactured, making it difficult to obtain and scale up and it inherently has lot to lot variations.

Other human coronaviruses also constitute public health risks. Middle East respiratory syndrome coronavirus (MERS-CoV) is endemic in the Middle East but can be transmitted to other countries by travel activity. For example, the introduction of MERS-CoV into the Republic of Korea by an infected traveler resulted in a hospital outbreak of MERS that entailed 186 cases and 38 deaths (Kleine-Weber et al., J. Virol. 2019, 93(2):e01381-18).

There remains an urgent need for therapeutics to treat and/or prevent human coronavirus infections, e.g., SARS, COVID-19, and diseases caused by MERS-CoV.

SUMMARY

Provided herein is a multimeric binding molecule that includes two to six bivalent binding units or variants or fragments thereof, where each binding unit includes two IgM or IgA heavy chain constant regions or multimerizing fragments or variants thereof, each associated with a binding domain, where three to twelve of the binding domains are identical and specifically bind to a human coronavirus, and where the binding molecule is more potent than a bivalent reference IgG antibody that includes two of the binding domains that specifically bind to the human coronavirus. In some embodiments, the human coronavirus is SARS-CoV, MERS-CoV, SARS-CoV-2, variants thereof, derivatives thereof, or any combination thereof.

In some embodiments, the multimeric binding molecule can neutralize infectivity of the human coronavirus at a greater potency than the bivalent reference IgG antibody that includes two of the binding domains that specifically bind to the human coronavirus. In some embodiments, the multimeric binding molecule can neutralize infectivity of the human coronavirus at a lower 50% effective concentration (EC₅₀) than the bivalent reference IgG antibody. In some embodiments, the EC₅₀is at least two-fold, at least five-fold, at least ten-fold, at least fifty-fold, at least 100-fold, at least 500-fold, or at least 1000-fold lower than the EC₅₀of the bivalent reference IgG antibody.

In some embodiments, the binding molecule can inhibit binding of the human coronavirus to its receptor at a lower 50% inhibitory concentration (IC₅₀) than the bivalent reference IgG antibody. In some embodiments, the human coronavirus bound by the multimeric binding molecule is SARS-CoV or SARS-CoV-2 and the receptor is human angiotensin-converting enzyme 2 (ACE2). In some embodiments, the human coronavirus is MERS-CoV and the receptor is human dipeptidyl-peptidase 4 (DPP4).

In some embodiments, the three to twelve binding domains of the multimeric binding molecule of the disclosure bind a human coronavirus structural protein or fragment thereof. In some embodiments the human coronavirus structural protein is a nucleocapsid (N) protein, a membrane (M) protein, an envelope (E) protein, a spike (S) protein, any fragment thereof, any subunit thereof, or any combination thereof. In some embodiments, the human coronavirus structural protein is the S protein, a fragment thereof, or a subunit thereof. In some embodiments, the three to twelve binding domains of the multimeric binding protein specifically bind to the S protein subunit 1 (S1), the S protein receptor binding domain (RBD), the S protein subunit 2 (S2), the S protein furin cleavage site, or any combination thereof. In certain embodiments the three to twelve binding domains of the multimeric binding protein specifically bind to the SARS-CoV-2 RBD.

In some embodiments, the three to twelve identical binding domains of the multimeric binding molecule are immunoglobulin antigen binding domains that include a heavy chain variable region (VH) and a light chain variable region (VL). In some embodiments, each binding unit includes two heavy chains each including a VH and two light chains each including a VL. In some embodiments, the immunoglobulin antigen-binding domains are human or humanized antigen binding domains. In some embodiments, the three to twelve identical binding domains of the multimeric binding molecule are single-domain variable regions (VHH), and where each binding unit includes two heavy chains each including the VHH.

In some embodiments, the three to twelve identical binding domains of the multimeric binding molecule each specifically bind to SARS-CoV-2, and include a heavy chain variable region (VH) and a light chain variable region (VL), where the VH and VL include six immunoglobulin complementarity determining regions HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3, where the HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 include the CDRs of an antibody that includes the VH and VL of SEQ ID NO: 84 and SEQ ID NO: 85, SEQ ID NO: 86 and SEQ ID NO: 87, SEQ ID NO: 88 and SEQ ID NO: 89, SEQ ID NO: 90 and SEQ ID NO: 91, SEQ ID NO: 92 and SEQ ID NO: 93, SEQ ID NO: 94 and SEQ ID NO: 95, SEQ ID NO: 96 and SEQ ID NO: 97, SEQ ID NO: 98 and SEQ ID NO: 99, SEQ ID NO: 100 and SEQ ID NO: 101, SEQ ID NO: 102 and SEQ ID NO: 103, SEQ ID NO: 104 and SEQ ID NO: 105, SEQ ID NO: 106 and SEQ ID NO: 107, SEQ ID NO: 108 and SEQ ID NO: 109, SEQ ID NO: 110 and SEQ ID NO: 111, SEQ ID NO: 112 and SEQ ID NO: 113, SEQ ID NO: 114 and SEQ ID NO: 115, SEQ ID NO: 116 and SEQ ID NO: 117, SEQ ID NO: 118 and SEQ ID NO: 119, SEQ ID NO: 120 and SEQ ID NO: 121, SEQ ID NO: 122 and SEQ ID NO: 123, SEQ ID NO: 124 and SEQ ID NO: 125, SEQ ID NO: 126 and SEQ ID NO: 127, SEQ ID NO: 128 and SEQ ID NO: 129, SEQ ID NO: 130 and SEQ ID NO: 131, SEQ ID NO: 132 and SEQ ID NO: 133, SEQ ID NO: 134 and SEQ ID NO: 135, SEQ ID NO: 136 and SEQ ID NO: 137, SEQ ID NO: 138 and SEQ ID NO: 139, SEQ ID NO: 140 and SEQ ID NO: 141, SEQ ID NO: 142 and SEQ ID NO: 143, SEQ ID NO: 144 and SEQ ID NO: 145, SEQ ID NO: 146 and SEQ ID NO: 147, SEQ ID NO: 148 and SEQ ID NO: 149, SEQ ID NO: 150 and SEQ ID NO: 151, SEQ ID NO: 152 and SEQ ID NO: 153, SEQ ID NO: 154 and SEQ ID NO: 155, SEQ ID NO: 156 and SEQ ID NO: 157, SEQ ID NO: 158 and SEQ ID NO: 159, SEQ ID NO: 160 and SEQ ID NO: 161, SEQ ID NO: 162 and SEQ ID NO: 163, SEQ ID NO: 164 and SEQ ID NO: 165, SEQ ID NO: 166 and SEQ ID NO: 167, SEQ ID NO: 168 and SEQ ID NO: 169, SEQ ID NO: 170 and SEQ ID NO: 171, SEQ ID NO: 172 and SEQ ID NO: 173, SEQ ID NO: 174 and SEQ ID NO: 175, SEQ ID NO: 176 and SEQ ID NO: 177, SEQ ID NO: 178 and SEQ ID NO: 179, SEQ ID NO: 180 and SEQ ID NO: 181, SEQ ID NO: 182 and SEQ ID NO: 183, SEQ ID NO: 184 and SEQ ID NO: 185, SEQ ID NO: 186 and SEQ ID NO: 187, SEQ ID NO: 188 and SEQ ID NO: 189, SEQ ID NO: 190 and SEQ ID NO: 191, SEQ ID NO: 192 and SEQ ID NO: 193, SEQ ID NO: 194 and SEQ ID NO: 195, SEQ ID NO: 196 and SEQ ID NO: 197, SEQ ID NO: 198 and SEQ ID NO: 199, SEQ ID NO: 200 and SEQ ID NO: 201, SEQ ID NO: 202 and SEQ ID NO: 203, SEQ ID NO: 204 and SEQ ID NO: 205, SEQ ID NO: 206 and SEQ ID NO: 207, SEQ ID NO: 208 and SEQ ID NO: 209, SEQ ID NO: 210 and SEQ ID NO: 211, SEQ ID NO: 212 and SEQ ID NO: 213, SEQ ID NO: 214 and SEQ ID NO: 215, SEQ ID NO: 216 and SEQ ID NO: 217, SEQ ID NO: 218 and SEQ ID NO: 219, SEQ ID NO: 220 and SEQ ID NO: 221, SEQ ID NO: 222 and SEQ ID NO: 223, SEQ ID NO: 224 and SEQ ID NO: 225, SEQ ID NO: 226 and SEQ ID NO: 227, SEQ ID NO: 228 and SEQ ID NO: 229, SEQ ID NO: 230 and SEQ ID NO: 231, SEQ ID NO: 232 and SEQ ID NO: 233, SEQ ID NO: 234 and SEQ ID NO: 235, SEQ ID NO: 236 and SEQ ID NO: 237, SEQ ID NO: 238 and SEQ ID NO: 239, SEQ ID NO: 240 and SEQ ID NO: 241, SEQ ID NO: 242 and SEQ ID NO: 243, SEQ ID NO: 244 and SEQ ID NO: 245, SEQ ID NO: 246 and SEQ ID NO: 247, SEQ ID NO: 248 and SEQ ID NO: 249, SEQ ID NO: 250 and SEQ ID NO: 251, SEQ ID NO: 252 and SEQ ID NO: 253, SEQ ID NO: 254 and SEQ ID NO: 255, SEQ ID NO: 256 and SEQ ID NO: 257, SEQ ID NO: 258 and SEQ ID NO: 259, SEQ ID NO: 260 and SEQ ID NO: 261, SEQ ID NO: 264 and SEQ ID NO: 265, SEQ ID NO: 266 and SEQ ID NO: 267, SEQ ID NO: 268 and SEQ ID NO: 269, SEQ ID NO: 270 and SEQ ID NO: 271, SEQ ID NO: 272 and SEQ ID NO: 273, SEQ ID NO: 274 and SEQ ID NO: 275, SEQ ID NO: 276 and SEQ ID NO: 277, SEQ ID NO: 278 and SEQ ID NO: 279, SEQ ID NO: 280 and SEQ ID NO: 281, SEQ ID NO: 282 and SEQ ID NO: 283, SEQ ID NO: 292 and SEQ ID NO: 293, SEQ ID NO: 294 and SEQ ID NO: 295, SEQ ID NO: 296 and SEQ ID NO: 297, SEQ ID NO: 298 and SEQ ID NO: 299, SEQ ID NO: 300 and SEQ ID NO: 301, SEQ ID NO: 302 and SEQ ID NO: 303, SEQ ID NO: 304 and SEQ ID NO: 305, SEQ ID NO: 306 and SEQ ID NO: 307, SEQ ID NO: 308 and SEQ ID NO: 309, SEQ ID NO: 310 and SEQ ID NO: 311, SEQ ID NO: 312 and SEQ ID NO: 313, SEQ ID NO: 314 and SEQ ID NO: 315, SEQ ID NO: 316 and SEQ ID NO: 317, SEQ ID NO: 318 and SEQ ID NO: 319, SEQ ID NO: 320 and SEQ ID NO: 321, SEQ ID NO: 322 and SEQ ID NO: 323, SEQ ID NO: 324 and SEQ ID NO: 325, SEQ ID NO: 326 and SEQ ID NO: 327, SEQ ID NO: 328 and SEQ ID NO: 329, SEQ ID NO: 330 and SEQ ID NO: 331, SEQ ID NO: 332 and SEQ ID NO: 333, SEQ ID NO: 336 and SEQ ID NO: 337, SEQ ID NO: 338 and SEQ ID NO: 339, SEQ ID NO: 340 and SEQ ID NO: 341, SEQ ID NO: 342 and SEQ ID NO: 343, SEQ ID NO: 344 and SEQ ID NO: 345, SEQ ID NO: 348 and SEQ ID NO: 349, SEQ ID NO: 350 and SEQ ID NO: 351, SEQ ID NO: 352 and SEQ ID NO: 353, SEQ ID NO: 354 and SEQ ID NO: 355, SEQ ID NO: 356 and SEQ ID NO: 357, SEQ ID NO: 358 and SEQ ID NO: 359, SEQ ID NO: 362 and SEQ ID NO: 363, SEQ ID NO: 364 and SEQ ID NO: 365, SEQ ID NO: 366 and SEQ ID NO: 367, SEQ ID NO: 368 and SEQ ID NO: 369, SEQ ID NO: 370 and SEQ ID NO: 371, SEQ ID NO: 372 and SEQ ID NO: 373, SEQ ID NO: 374 and SEQ ID NO: 375, SEQ ID NO: 376 and SEQ ID NO: 377, SEQ ID NO: 378 and SEQ ID NO: 379, SEQ ID NO: 380 and SEQ ID NO: 381, SEQ ID NO: 382 and SEQ ID NO: 383, SEQ ID NO: 384 and SEQ ID NO: 385, SEQ ID NO: 386 and SEQ ID NO: 387, SEQ ID NO: 388 and SEQ ID NO: 389, SEQ ID NO: 390 and SEQ ID NO: 391, SEQ ID NO: 392 and SEQ ID NO: 393, SEQ ID NO: 394 and SEQ ID NO: 395, SEQ ID NO: 396 and SEQ ID NO: 397, SEQ ID NO: 398 and SEQ ID NO: 399, SEQ ID NO: 400 and SEQ ID NO: 401, SEQ ID NO: 402 and SEQ ID NO: 403, SEQ ID NO: 404 and SEQ ID NO: 405, SEQ ID NO: 406 and SEQ ID NO: 407, SEQ ID NO: 408 and SEQ ID NO: 409, SEQ ID NO: 410 and SEQ ID NO: 411, SEQ ID NO: 412 and SEQ ID NO: 413, SEQ ID NO: 414 and SEQ ID NO: 415, SEQ ID NO: 416 and SEQ ID NO: 417, SEQ ID NO: 418 and SEQ ID NO: 419, SEQ ID NO: 420 and SEQ ID NO: 421, SEQ ID NO: 422 and SEQ ID NO: 423, SEQ ID NO: 424 and SEQ ID NO: 425, SEQ ID NO: 426 and SEQ ID NO: 427, SEQ ID NO: 428 and SEQ ID NO: 429, SEQ ID NO: 430 and SEQ ID NO: 431, SEQ ID NO: 432 and SEQ ID NO: 433, SEQ ID NO: 434 and SEQ ID NO: 435, SEQ ID NO: 436 and SEQ ID NO: 437, SEQ ID NO: 438 and SEQ ID NO: 439, SEQ ID NO: 440 and SEQ ID NO: 441, SEQ ID NO: 442 and SEQ ID NO: 443, SEQ ID NO: 444 and SEQ ID NO: 445, SEQ ID NO: 446 and SEQ ID NO: 447, SEQ ID NO: 448 and SEQ ID NO: 449, SEQ ID NO: 450 and SEQ ID NO: 451, SEQ ID NO: 452 and SEQ ID NO: 453, SEQ ID NO: 454 and SEQ ID NO: 455, SEQ ID NO: 456 and SEQ ID NO: 457, SEQ ID NO: 458 and SEQ ID NO: 459, SEQ ID NO: 460 and SEQ ID NO: 461, SEQ ID NO: 462 and SEQ ID NO: 463, SEQ ID NO: 464 and SEQ ID NO: 465, SEQ ID NO: 466 and SEQ ID NO: 467, SEQ ID NO: 468 and SEQ ID NO: 469, SEQ ID NO: 470 and SEQ ID NO: 471, SEQ ID NO: 472 and SEQ ID NO: 473, SEQ ID NO: 474 and SEQ ID NO: 475, SEQ ID NO: 476 and SEQ ID NO: 477, SEQ ID NO: 478 and SEQ ID NO: 479, SEQ ID NO: 480 and SEQ ID NO: 481, SEQ ID NO: 482 and SEQ ID NO: 483, SEQ ID NO: 484 and SEQ ID NO: 485, SEQ ID NO: 486 and SEQ ID NO: 487, SEQ ID NO: 488 and SEQ ID NO: 489, SEQ ID NO: 490 and SEQ ID NO: 491, SEQ ID NO: 492 and SEQ ID NO: 493, SEQ ID NO: 494 and SEQ ID NO: 495, SEQ ID NO: 496 and SEQ ID NO: 497, SEQ ID NO: 498 and SEQ ID NO: 499, SEQ ID NO: 500 and SEQ ID NO: 501, SEQ ID NO: 502 and SEQ ID NO: 503, SEQ ID NO: 504 and SEQ ID NO: 505, SEQ ID NO: 506 and SEQ ID NO: 507, SEQ ID NO: 508 and SEQ ID NO: 509, SEQ ID NO: 628 and SEQ ID NO: 629, SEQ ID NO: 630 and SEQ ID NO: 631, SEQ ID NO: 632 and SEQ ID NO: 633, SEQ ID NO: 634 and SEQ ID NO: 635, SEQ ID NO: 636 and SEQ ID NO: 637, SEQ ID NO: 638 and SEQ ID NO: 639, SEQ ID NO: 640 and SEQ ID NO: 641, SEQ ID NO: 642 and SEQ ID NO: 643, SEQ ID NO: 644 and SEQ ID NO: 645, SEQ ID NO: 646 and SEQ ID NO: 647, SEQ ID NO: 648 and SEQ ID NO: 649, SEQ ID NO: 650 and SEQ ID NO: 651, or SEQ ID NO: 652 and SEQ ID NO: 653, respectively with zero, one, or two single amino acid substitutions in one or more of the HCDRs or LCDRs. In some embodiments, the VH and VL of the multimeric binding molecule include amino acid sequences at least 80%, at least 85%, at least 90%, at least 95% or 100% identical to the recited VH and VL amino acid sequences, respectively.

In some embodiments, the three to twelve identical binding domains of the multimeric binding molecule each specifically bind to SARS-CoV-2, and the VH and VL of the multimeric binding molecule include six immunoglobulin complementarity determining regions HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3, where the HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 include the CDRs of an antibody that includes the VH and VL of SEQ ID NO: 86 and SEQ ID NO: 87, SEQ ID NO: 88 and SEQ ID NO: 89, SEQ ID NO: 90 and SEQ ID NO: 91, SEQ ID NO: 92 and SEQ ID NO: 93, SEQ ID NO: 94 and SEQ ID NO: 95, SEQ ID NO: 96 and SEQ ID NO: 97, SEQ ID NO: 98 and SEQ ID NO: 99, SEQ ID NO: 100 and SEQ ID NO: 101, SEQ ID NO: 102 and SEQ ID NO: 103, SEQ ID NO: 106 and SEQ ID NO: 107, SEQ ID NO: 110 and SEQ ID NO: 111, SEQ ID NO: 118 and SEQ ID NO: 119, SEQ ID NO: 128 and SEQ ID NO: 129, SEQ ID NO: 130 and SEQ ID NO: 131, SEQ ID NO: 132 and SEQ ID NO: 133, SEQ ID NO: 134 and SEQ ID NO: 135, SEQ ID NO: 136 and SEQ ID NO: 137, SEQ ID NO: 142 and SEQ ID NO: 143, SEQ ID NO: 146 and SEQ ID NO: 147, SEQ ID NO: 150 and SEQ ID NO: 151, SEQ ID NO: 156 and SEQ ID NO: 157, SEQ ID NO: 160 and SEQ ID NO: 161, SEQ ID NO: 162 and SEQ ID NO: 163, SEQ ID NO: 164 and SEQ ID NO: 165, SEQ ID NO: 166 and SEQ ID NO: 167, SEQ ID NO: 168 and SEQ ID NO: 169, SEQ ID NO: 170 and SEQ ID NO: 171, SEQ ID NO: 172 and SEQ ID NO: 173, SEQ ID NO: 174 and SEQ ID NO: 175, SEQ ID NO: 176 and SEQ ID NO: 177, SEQ ID NO: 180 and SEQ ID NO: 181, SEQ ID NO: 182 and SEQ ID NO: 183, SEQ ID NO: 186 and SEQ ID NO: 187, SEQ ID NO: 188 and SEQ ID NO: 189, SEQ ID NO: 194 and SEQ ID NO: 195, SEQ ID NO: 200 and SEQ ID NO: 201, SEQ ID NO: 206 and SEQ ID NO: 207, SEQ ID NO: 208 and SEQ ID NO: 209, SEQ ID NO: 218 and SEQ ID NO: 219, SEQ ID NO: 220 and SEQ ID NO: 221, SEQ ID NO: 222 and SEQ ID NO: 223, SEQ ID NO: 224 and SEQ ID NO: 225, SEQ ID NO: 228 and SEQ ID NO: 229, SEQ ID NO: 230 and SEQ ID NO: 231, SEQ ID NO: 240 and SEQ ID NO: 241, SEQ ID NO: 244 and SEQ ID NO: 245, SEQ ID NO: 246 and SEQ ID NO: 247, SEQ ID NO: 256 and SEQ ID NO: 257, SEQ ID NO: 258 and SEQ ID NO: 259, SEQ ID NO: 260 and SEQ ID NO: 261, SEQ ID NO: 264 and SEQ ID NO: 265, SEQ ID NO: 266 and SEQ ID NO: 267, SEQ ID NO: 268 and SEQ ID NO: 269, SEQ ID NO: 270 and SEQ ID NO: 271, SEQ ID NO: 272 and SEQ ID NO: 273, SEQ ID NO: 274 and SEQ ID NO: 275, SEQ ID NO: 276 and SEQ ID NO: 277, SEQ ID NO: 278 and SEQ ID NO: 279, SEQ ID NO: 280 and SEQ ID NO: 281, SEQ ID NO: 282 and SEQ ID NO: 283, SEQ ID NO: 292 and SEQ ID NO: 293, SEQ ID NO: 294 and SEQ ID NO: 295, SEQ ID NO: 296 and SEQ ID NO: 297, SEQ ID NO: 298 and SEQ ID NO: 299, SEQ ID NO: 300 and SEQ ID NO: 301, SEQ ID NO: 302 and SEQ ID NO: 303, SEQ ID NO: 304 and SEQ ID NO: 305, SEQ ID NO: 306 and SEQ ID NO: 307, SEQ ID NO: 308 and SEQ ID NO: 309, SEQ ID NO: 310 and SEQ ID NO: 311, SEQ ID NO: 312 and SEQ ID NO: 313, SEQ ID NO: 314 and SEQ ID NO: 315, SEQ ID NO: 316 and SEQ ID NO: 317, SEQ ID NO: 318 and SEQ ID NO: 319, SEQ ID NO: 320 and SEQ ID NO: 321, SEQ ID NO: 322 and SEQ ID NO: 323, SEQ ID NO: 324 and SEQ ID NO: 325, SEQ ID NO: 326 and SEQ ID NO: 327, SEQ ID NO: 328 and SEQ ID NO: 329, SEQ ID NO: 330 and SEQ ID NO: 331, SEQ ID NO: 332 and SEQ ID NO: 333, SEQ ID NO: 336 and SEQ ID NO: 337, SEQ ID NO: 338 and SEQ ID NO: 339, SEQ ID NO: 340 and SEQ ID NO: 341, SEQ ID NO: 342 and SEQ ID NO: 343, SEQ ID NO: 344 and SEQ ID NO: 345, SEQ ID NO: 348 and SEQ ID NO: 349, SEQ ID NO: 350 and SEQ ID NO: 351, SEQ ID NO: 352 and SEQ ID NO: 353, SEQ ID NO: 354 and SEQ ID NO: 355, SEQ ID NO: 356 and SEQ ID NO: 357, SEQ ID NO: 358 and SEQ ID NO: 359, SEQ ID NO: 360 and SEQ ID NO: 361, SEQ ID NO: 362 and SEQ ID NO: 363, SEQ ID NO: 364 and SEQ ID NO: 365, SEQ ID NO: 366 and SEQ ID NO: 367, SEQ ID NO: 368 and SEQ ID NO: 369, SEQ ID NO: 370 and SEQ ID NO: 371, SEQ ID NO: 372 and SEQ ID NO: 373, SEQ ID NO: 374 and SEQ ID NO: 375, SEQ ID NO: 376 and SEQ ID NO: 377, SEQ ID NO: 378 and SEQ ID NO: 379, SEQ ID NO: 380 and SEQ ID NO: 381, SEQ ID NO: 382 and SEQ ID NO: 383, SEQ ID NO: 384 and SEQ ID NO: 385, SEQ ID NO: 386 and SEQ ID NO: 387, SEQ ID NO: 388 and SEQ ID NO: 389, SEQ ID NO: 390 and SEQ ID NO: 391, SEQ ID NO: 392 and SEQ ID NO: 393, SEQ ID NO: 394 and SEQ ID NO: 395, SEQ ID NO: 396 and SEQ ID NO: 397, SEQ ID NO: 398 and SEQ ID NO: 399, SEQ ID NO: 400 and SEQ ID NO: 401, SEQ ID NO: 402 and SEQ ID NO: 403, SEQ ID NO: 404 and SEQ ID NO: 405, SEQ ID NO: 406 and SEQ ID NO: 407, SEQ ID NO: 408 and SEQ ID NO: 409, SEQ ID NO: 410 and SEQ ID NO: 411, SEQ ID NO: 412 and SEQ ID NO: 413, SEQ ID NO: 414 and SEQ ID NO: 415, SEQ ID NO: 416 and SEQ ID NO: 417, SEQ ID NO: 418 and SEQ ID NO: 419, SEQ ID NO: 420 and SEQ ID NO: 421, SEQ ID NO: 422 and SEQ ID NO: 423, SEQ ID NO: 424 and SEQ ID NO: 425, SEQ ID NO: 426 and SEQ ID NO: 427, SEQ ID NO: 428 and SEQ ID NO: 429, SEQ ID NO: 430 and SEQ ID NO: 431, SEQ ID NO: 432 and SEQ ID NO: 433, SEQ ID NO: 434 and SEQ ID NO: 435, SEQ ID NO: 436 and SEQ ID NO: 437, SEQ ID NO: 438 and SEQ ID NO: 439, SEQ ID NO: 440 and SEQ ID NO: 441, SEQ ID NO: 442 and SEQ ID NO: 443, SEQ ID NO: 444 and SEQ ID NO: 445, SEQ ID NO: 446 and SEQ ID NO: 447, SEQ ID NO: 448 and SEQ ID NO: 449, SEQ ID NO: 450 and SEQ ID NO: 451, SEQ ID NO: 452 and SEQ ID NO: 453, SEQ ID NO: 454 and SEQ ID NO: 455, SEQ ID NO: 456 and SEQ ID NO: 457, SEQ ID NO: 458 and SEQ ID NO: 459, SEQ ID NO: 460 and SEQ ID NO: 461, SEQ ID NO: 462 and SEQ ID NO: 463, SEQ ID NO: 464 and SEQ ID NO: 465, SEQ ID NO: 466 and SEQ ID NO: 467, SEQ ID NO: 468 and SEQ ID NO: 469, SEQ ID NO: 470 and SEQ ID NO: 471, SEQ ID NO: 472 and SEQ ID NO: 473, SEQ ID NO: 474 and SEQ ID NO: 475, SEQ ID NO: 476 and SEQ ID NO: 477, SEQ ID NO: 478 and SEQ ID NO: 479, SEQ ID NO: 480 and SEQ ID NO: 481, SEQ ID NO: 482 and SEQ ID NO: 483, SEQ ID NO: 484 and SEQ ID NO: 485, SEQ ID NO: 486 and SEQ ID NO: 487, SEQ ID NO: 488 and SEQ ID NO: 489, SEQ ID NO: 490 and SEQ ID NO: 491, SEQ ID NO: 492 and SEQ ID NO: 493, SEQ ID NO: 494 and SEQ ID NO: 495, SEQ ID NO: 496 and SEQ ID NO: 497, SEQ ID NO: 498 and SEQ ID NO: 499, SEQ ID NO: 500 and SEQ ID NO: 501, SEQ ID NO: 502 and SEQ ID NO: 503, SEQ ID NO: 504 and SEQ ID NO: 505, SEQ ID NO: 506 and SEQ ID NO: 507, SEQ ID NO: 508 and SEQ ID NO: 509, SEQ ID NO: 628 and SEQ ID NO: 629, SEQ ID NO: 632 and SEQ ID NO: 633, SEQ ID NO: 634 and SEQ ID NO: 635, SEQ ID NO: 636 and SEQ ID NO: 637, SEQ ID NO: 638 and SEQ ID NO: 639, SEQ ID NO: 640 and SEQ ID NO: 641, SEQ ID NO: 642 and SEQ ID NO: 643, SEQ ID NO: 644 and SEQ ID NO: 645, SEQ ID NO: 646 and SEQ ID NO: 647, SEQ ID NO: 648 and SEQ ID NO: 649, SEQ ID NO: 650 and SEQ ID NO: 651, or SEQ ID NO: 652 and SEQ ID NO: 653, respectively, with zero, one, or two single amino acid substitutions in one or more HCDRs or LCDRs. In some embodiments, the HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 of the multimeric binding molecule include the CDRs of an antibody that includes the VH and VL of SEQ ID NO: 88 and SEQ ID NO: 89. In some embodiments, the HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 of the multimeric binding molecule include the CDRs of an antibody that includes the VH and VL of SEQ ID NO: 260 and SEQ ID NO: 261. In some embodiments, the HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 of the multimeric binding molecule include the CDRs of an antibody that includes the VH and VL of SEQ ID NO: 264 and SEQ ID NO: 265. In some embodiments, the HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 of the multimeric binding molecule include the CDRs of an antibody that includes the VH and VL of SEQ ID NO: 266 and SEQ ID NO: 267. In some embodiments, the HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 of the multimeric binding molecule include the CDRs of an antibody that includes the VH and VL of SEQ ID NO: 274 and SEQ ID NO: 275, SEQ ID NO: 278, and SEQ ID NO: 279, SEQ ID NO: 280 and SEQ ID NO: 281, or SEQ ID NO: 282 and SEQ ID NO: 283. In some embodiments, the HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 of the multimeric binding molecule include the CDRs of an antibody that includes the VH and VL of SEQ ID NO: 292 and SEQ ID NO: 293. In some embodiments, the VH and VL of the multimeric binding molecule described herein include amino acid sequences at least 80%, at least 85%, at least 90%, at least 95% or 100% identical to the recited VH and VL amino acid sequences, respectively. In some embodiments a bivalent reference IgG antibody that includes two of the binding domains can neutralize SARS-CoV-2.

In some embodiments, the VH and VL of the multimeric binding molecule include six immunoglobulin complementarity determining regions HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3, and where the HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 include the CDRs of an antibody that includes the VH and VL of SEQ ID NO: 260 and SEQ ID NO: 261, SEQ ID NO: 296 and SEQ ID NO: 297, SEQ ID NO: 384 and SEQ ID NO: 385, SEQ ID NO: 628 and SEQ ID NO: 629, SEQ ID NO: 632 and SEQ ID NO: 633, SEQ ID NO: 634 and SEQ ID NO: 635, SEQ ID NO: 636 and SEQ ID NO: 637, SEQ ID NO: 638 and SEQ ID NO: 639, SEQ ID NO: 640 and SEQ ID NO: 641, SEQ ID NO: 642 and SEQ ID NO: 643, SEQ ID NO: 644 and SEQ ID NO: 645, or SEQ ID NO: 646 and SEQ ID NO: 647, respectively. In certain embodiments, the VH and VL include the CDRs of an antibody that includes the VH and VL of SEQ ID NO:384 and SEQ ID NO: 385. In certain embodiments, the VH and VL include the CDRs of an antibody that includes the VH and VL of SEQ ID NO: 646 and SEQ ID NO: 647. In some of these embodiments, the VH and VL of the multimeric binding molecule include amino acid sequences at least 80%, at least 85%, at least 90%, at least 95% or 100% identical to the recited VH and VL amino acid sequences, respectively. In some embodiments, a bivalent reference IgG antibody that includes two of the binding domains can neutralize SARS-CoV and SARS-CoV-2.

In some embodiments, the three to twelve identical binding domains of the multimeric binding molecule each specifically bind to SARS-CoV-2 and each include a single domain variable region (VHH), where the VHH includes three immunoglobulin complementarity determining regions HCDR1, HCDR2, and HCDR3, where the HCDR1, HCDR2, and HCDR3 include the CDRs of an antibody that includes the VHH of SEQ ID NO: SEQ ID NO: 19, SEQ ID NO: 20, SEQ ID NO: 21, SEQ ID NO: 22, SEQ ID NO: 23, SEQ ID NO: 24, SEQ ID NO: 25, SEQ ID NO: 26, SEQ ID NO: 27, SEQ ID NO: 28, SEQ ID NO: 29, SEQ ID NO: 30, SEQ ID NO: 31, SEQ ID NO: 32, SEQ ID NO: 33, SEQ ID NO: 34, SEQ ID NO: 35, SEQ ID NO: 36, SEQ ID NO: 37, SEQ ID NO: 38, SEQ ID NO: 39, SEQ ID NO: 40, SEQ ID NO: 41, SEQ ID NO: 42, SEQ ID NO: 43, SEQ ID NO: 44, SEQ ID NO: 45, SEQ ID NO: 46, SEQ ID NO: 47, SEQ ID NO: 48, SEQ ID NO: 49, SEQ ID NO: 50, SEQ ID NO: 51, SEQ ID NO: 52, SEQ ID NO: 53, SEQ ID NO: 54, SEQ ID NO: 55, SEQ ID NO: 56, SEQ ID NO: 57, SEQ ID NO: 58, SEQ ID NO: 59, SEQ ID NO: 60, SEQ ID NO: 61, SEQ ID NO: 62, SEQ ID NO: 63, SEQ ID NO: 64, SEQ ID NO: 65, SEQ ID NO: 66, SEQ ID NO: 67, SEQ ID NO: 68, SEQ ID NO: 69, SEQ ID NO: 70, SEQ ID NO: 71, SEQ ID NO: 72, SEQ ID NO: 73, SEQ ID NO: 74, SEQ ID NO: 75, SEQ ID NO: 76, SEQ ID NO: 77, SEQ ID NO: 78, SEQ ID NO: 79, SEQ ID NO: 80, SEQ ID NO: 81, SEQ ID NO: 82, or SEQ ID NO:83, with zero, one, or two single amino acid substitutions in one or more of the HCDRs. In some embodiments, the VHH of the multimeric binding molecule includes an amino acid sequence at least 80%, at least 85%, at least 90%, at least 95% or 100% identical to the recited VHH amino acid sequence.

In some embodiments, the three to twelve identical binding domains of the multimeric binding molecule as described herein specifically bind to a human coronavirus that includes an extracellular SARS-CoV-2 RBD-binding fragment of angiotensin-converting enzyme 2 (ACE2).

In some embodiments, the three to twelve identical binding domains of the multimeric binding molecule as described herein each specifically bind to SARS-CoV and include a heavy chain variable region (VH) and a light chain variable region (VL), where the VH and VL include six immunoglobulin complementarity determining regions HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3, and where the HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 include the CDRs of an antibody that includes the VH and VL SEQ ID NO: 84 and SEQ ID NO: 85, SEQ ID NO: 118 and SEQ ID NO: 119, SEQ ID NO: 120 and SEQ ID NO: 121, SEQ ID NO: 138 and SEQ ID NO: 139, SEQ ID NO: 162 and SEQ ID NO: 163, SEQ ID NO: 222 and SEQ ID NO: 223, SEQ ID NO: 236 and SEQ ID NO: 237, SEQ ID NO: 252 and SEQ ID NO: 253, SEQ ID NO: 260 and SEQ ID NO: 261, SEQ ID NO: 262 and SEQ ID NO: 263, SEQ ID NO: 296 and SEQ ID NO: 297, SEQ ID NO: 628 and SEQ ID NO: 629, SEQ ID NO: 632 and SEQ ID NO: 633, SEQ ID NO: 634 and SEQ ID NO: 635, SEQ ID NO: 636 and SEQ ID NO: 637, SEQ ID NO: 638 and SEQ ID NO: 639, SEQ ID NO: 640 and SEQ ID NO: 641, SEQ ID NO: 642 and SEQ ID NO: 643, or SEQ ID NO: 644 and SEQ ID NO: 645. In some embodiments, the VH and VL of the multimeric binding molecule include amino acid sequences at least 80%, at least 85%, at least 90%, at least 95% or 100% identical to the recited VH and VL amino acid sequences, respectively.

In certain embodiments, the VH and VL of the multimeric binding molecule include six immunoglobulin complementarity determining regions HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3, where the HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 include the CDRs of an antibody that includes the VH and VL of SEQ ID NO: 84 and SEQ ID NO: 85, SEQ ID NO: 260 and SEQ ID NO: 261, SEQ ID NO: 262 and SEQ ID NO: 263, SEQ ID NO: 296 and SEQ ID NO: 297, SEQ ID NO: 628 and SEQ ID NO: 629, SEQ ID NO: 632 and SEQ ID NO: 633, SEQ ID NO: 634 and SEQ ID NO: 635, SEQ ID NO: 636 and SEQ ID NO: 637, SEQ ID NO: 638 and SEQ ID NO: 639, SEQ ID NO: 640 and SEQ ID NO: 641, SEQ ID NO: 642 and SEQ ID NO: 643, or SEQ ID NO: 644 and SEQ ID NO: 645. In some embodiments, the VH and VL of the multimeric binding molecule include amino acid sequences at least 80%, at least 85%, at least 90%, at least 95% or 100% identical to the recited VH and VL amino acid sequences, respectively. In some embodiments the bivalent reference IgG antibody that includes two of the binding domains can neutralize SARS-CoV.

In some embodiments, the three to twelve identical binding domains of the multimeric binding molecule each specifically bind to MERS-CoV and include a heavy chain variable region (VH) and a light chain variable region (VL), where the VH and VL include six immunoglobulin complementarity determining regions HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3, and where the HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 include the CDRs of an antibody that includes the VH and VL SEQ ID NO:510 and SEQ ID NO:511, SEQ ID NO:512 and SEQ ID NO:513, SEQ ID NO:514 and SEQ ID NO:515, SEQ ID NO:516 and SEQ ID NO:517, SEQ ID NO:518 and SEQ ID NO:519, SEQ ID NO:520 and SEQ ID NO:521, SEQ ID NO:522 and SEQ ID NO:523, SEQ ID NO:524 and SEQ ID NO:525, SEQ ID NO:526 and SEQ ID NO:527, SEQ ID NO:528 and SEQ ID NO:529, SEQ ID NO:530 and SEQ ID NO:531, SEQ ID NO:532 and SEQ ID NO:533, SEQ ID NO:534 and SEQ ID NO:535, SEQ ID NO:536 and SEQ ID NO:537, SEQ ID NO:538 and SEQ ID NO:539, SEQ ID NO:540 and SEQ ID NO:541, SEQ ID NO:542 and SEQ ID NO:543, SEQ ID NO:544 and SEQ ID NO:545, SEQ ID NO:546 and SEQ ID NO:547, SEQ ID NO:548 and SEQ ID NO:549, SEQ ID NO:550 and SEQ ID NO:551, SEQ ID NO:552 and SEQ ID NO:553, SEQ ID NO:554 and SEQ ID NO:555, SEQ ID NO:556 and SEQ ID NO:557, SEQ ID NO:558 and SEQ ID NO:559, SEQ ID NO:560 and SEQ ID NO:561, SEQ ID NO:562 and SEQ ID NO:563, SEQ ID NO:564 and SEQ ID NO:565, SEQ ID NO:566 and SEQ ID NO:567, SEQ ID NO:568 and SEQ ID NO:569, SEQ ID NO:570 and SEQ ID NO:571, SEQ ID NO:572 and SEQ ID NO:573, SEQ ID NO:574 and SEQ ID NO:575, SEQ ID NO:576 and SEQ ID NO:577, SEQ ID NO:578 and SEQ ID NO:579, SEQ ID NO:580 and SEQ ID NO:581, SEQ ID NO:582 and SEQ ID NO:583, SEQ ID NO:584 and SEQ ID NO:585, SEQ ID NO:586 and SEQ ID NO:587, SEQ ID NO:588 and SEQ ID NO:589, SEQ ID NO:590 and SEQ ID NO:591, SEQ ID NO:592 and SEQ ID NO:593, SEQ ID NO:594 and SEQ ID NO:595, SEQ ID NO:596 and SEQ ID NO:597, SEQ ID NO:598 and SEQ ID NO:599, SEQ ID NO:600 and SEQ ID NO:601, SEQ ID NO:602 and SEQ ID NO:603, SEQ ID NO:604 and SEQ ID NO:605, SEQ ID NO:606 and SEQ ID NO:607, SEQ ID NO:608 and SEQ ID NO:609, SEQ ID NO:610 and SEQ ID NO:611, SEQ ID NO:612 and SEQ ID NO:613, SEQ ID NO:614 and SEQ ID NO:615, SEQ ID NO:616 and SEQ ID NO:617, SEQ ID NO:618 and SEQ ID NO:619, SEQ ID NO:620 and SEQ ID NO:621, SEQ ID NO:622 and SEQ ID NO:623, SEQ ID NO:624 and SEQ ID NO:625, SEQ ID NO:626 and SEQ ID NO:627, or SEQ ID NO:630 and SQ ID NO:631, respectively, with zero, one, or two single amino acid substitutions in one or more of the HCDRs or LCDRs. In some embodiments, the VH and VL of the multimeric binding molecule include amino acid sequences at least 80%, at least 85%, at least 90%, at least 95% or 100% identical to the recited VH and VL amino acid sequences, respectively.

In some embodiments, the HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 of the multimeric binding molecule include the CDRs of an antibody that includes the VH and VL of SEQ ID NO: 510 and SEQ ID NO: 511, SEQ ID NO: 512 and SEQ ID NO: 513, SEQ ID NO: 514 and SEQ ID NO: 515, SEQ ID NO: 516 and SEQ ID NO: 517, SEQ ID NO: 518 and SEQ ID NO: 519, SEQ ID NO: 520 and SEQ ID NO: 521, SEQ ID NO: 522 and SEQ ID NO: 523, SEQ ID NO: 524 and SEQ ID NO: 525, SEQ ID NO: 526 and SEQ ID NO: 527, SEQ ID NO: 528 and SEQ ID NO: 529, SEQ ID NO: 530 and SEQ ID NO: 531, SEQ ID NO: 532 and SEQ ID NO: 533, SEQ ID NO: 534 and SEQ ID NO: 535, SEQ ID NO: 536 and SEQ ID NO: 537, SEQ ID NO: 538 and SEQ ID NO: 539, SEQ ID NO: 540 and SEQ ID NO: 541, SEQ ID NO: 542 and SEQ ID NO: 543, SEQ ID NO: 544 and SEQ ID NO: 545, SEQ ID NO: 546 and SEQ ID NO: 547, SEQ ID NO: 548 and SEQ ID NO: 549, SEQ ID NO: 550 and SEQ ID NO: 551, SEQ ID NO: 552 and SEQ ID NO: 553, SEQ ID NO: 554 and SEQ ID NO: 555, SEQ ID NO: 556 and SEQ ID NO: 557, SEQ ID NO: 558 and SEQ ID NO: 559, SEQ ID NO: 560 and SEQ ID NO: 561, SEQ ID NO: 562 and SEQ ID NO: 563, SEQ ID NO: 564 and SEQ ID NO: 565, SEQ ID NO: 566 and SEQ ID NO: 567, SEQ ID NO: 568 and SEQ ID NO: 569, SEQ ID NO: 574 and SEQ ID NO: 575, SEQ ID NO: 576 and SEQ ID NO: 577, SEQ ID NO: 578 and SEQ ID NO: 579, SEQ ID NO: 580 and SEQ ID NO: 581, SEQ ID NO: 582 and SEQ ID NO: 583, SEQ ID NO: 584 and SEQ ID NO: 585, SEQ ID NO: 586 and SEQ ID NO: 587, SEQ ID NO: 588 and SEQ ID NO: 589, SEQ ID NO: 590 and SEQ ID NO: 591, SEQ ID NO: 592 and SEQ ID NO: 593, SEQ ID NO: 594 and SEQ ID NO: 595, SEQ ID NO: 596 and SEQ ID NO: 597, SEQ ID NO: 598 and SEQ ID NO: 599, SEQ ID NO: 600 and SEQ ID NO: 601, SEQ ID NO: 602 and SEQ ID NO: 603, SEQ ID NO: 604 and SEQ ID NO: 605, SEQ ID NO: 606 and SEQ ID NO: 607, SEQ ID NO: 608 and SEQ ID NO: 609, SEQ ID NO: 610 and SEQ ID NO: 611, SEQ ID NO: 612 and SEQ ID NO: 613, SEQ ID NO: 614 and SEQ ID NO: 615, SEQ ID NO: 616 and SEQ ID NO: 617, SEQ ID NO: 618 and SEQ ID NO: 619, SEQ ID NO: 620 and SEQ ID NO: 621, SEQ ID NO: 622 and SEQ ID NO: 623, SEQ ID NO: 624 and SEQ ID NO: 625, SEQ ID NO: 626 and SEQ ID NO: 627, or SEQ ID NO: 630 and SEQ ID NO: 631, respectively. In some embodiments, the HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 of the multimeric binding molecule include the CDRs of an antibody that includes the VH and VL of SEQ ID NO: 630 and SEQ ID NO: 631, respectively. In some of these embodiments, the VH and VL of the multimeric binding molecule include amino acid sequences at least 80%, at least 85%, at least 90%, at least 95% or 100% identical to the recited VH and VL amino acid sequences, respectively. In some of these embodiments, the bivalent reference IgG antibody that includes two of the binding domains can neutralize MERS-CoV.

In some embodiments, the three to twelve identical binding domains of the multimeric binding molecule include an extracellular MERS-CoV RBD-binding fragment of dipeptidyl peptidase 4 (DPP4).

In some embodiments the multimeric binding molecule can neutralize escape mutants of a bivalent reference IgG antibody that includes two of the binding domains.

In some embodiments, the multimeric binding molecule includes two or four bivalent IgA or IgA-like binding units and a J chain or functional fragment or variant thereof, where each binding unit includes two IgA heavy chain constant regions or multimerizing fragments or variants thereof, each including an IgA Cα3 domain and an IgA tailpiece domain. In some embodiments, the multimeric binding molecule is a dimeric binding molecule that includes two bivalent IgA or IgA-like binding units. In some embodiments, each IgA heavy chain constant region or multimerizing fragment or variant thereof further includes a Cα1 domain, a Cα2 domain, an IgA hinge region, or any combination thereof. In some embodiments, the IgA heavy chain constant regions or multimerizing fragments or variants thereof are human IgA constant regions. In some embodiments, each binding unit of the multimeric binding molecule includes two IgA heavy chains each including a VH situated amino terminal to the IgA constant region or multimerizing fragment thereof, and two immunoglobulin light chains each including a VL situated amino terminal to an immunoglobulin light chain constant region.

In some embodiments, the multimeric binding molecule includes five or six bivalent IgM or IgM-like binding units, where each binding unit includes two IgM heavy chain constant regions or multimerizing fragments or variants thereof, each including an IgM Cμ4 and IgM tailpiece domain. In some embodiments, each IgM heavy chain constant region or multimerizing fragment or variant thereof of the multimeric binding molecule further includes a Cμ1 domain, a Cμ2 domain, a Cμ3 domain, or any combination thereof. In some of these embodiments, the IgM heavy chain constant regions or multimerizing fragments or variants thereof are human IgM constant regions. In some embodiments, the IgM heavy chain constant regions each include the amino acid sequence SEQ ID NO: 1, SEQ ID NO: 2, or a multimerizing fragment or variant thereof. In some embodiments, each binding unit of the multimeric binding molecule includes two IgM heavy chains, each including a VH situated amino terminal to the IgM constant region or fragment thereof, and two immunoglobulin light chains, each including a VL situated amino terminal to an immunoglobulin light chain constant region.

In some embodiments the IgM constant regions of the multimeric binding molecule each include one or more amino acid substitutions corresponding to a wild-type human IgM constant region at position 310, 311, 313, and/or 315 of SEQ ID NO: 1 or SEQ ID NO: 2, and the multimeric binding molecule exhibits reduced complement-dependent cytotoxicity (CDC) activity to cells in the presence of complement, relative to a reference binding molecule that is identical except for the one or more amino acid substitutions. In some embodiments, the IgM constant regions of the multimeric binding molecule each include one or more substitutions corresponding to a wild-type human IgM constant region at positions 46, 209, 272, or 440 of SEQ ID NO: 1 or SEQ ID NO: 2, where the one or more amino acid substitutions prevent asparagine (N)-linked glycosylation. In some of these embodiments, the multimeric binding molecule is pentameric, and further includes a J-chain or functional fragment or variant thereof. In some embodiments, the multimeric binding molecule can transport across vascular endothelial cells via J-chain binding to the polymeric Ig receptor (PIgR). In some embodiments, the multimeric binding molecule further includes a secretory component, or fragment or variant thereof.

In some embodiments the J-chain or functional fragment or variant thereof the multimeric binding molecule that includes five or six bivalent IgM or IgM-like binding units further includes a heterologous polypeptide, where the heterologous polypeptide is directly or indirectly fused to the J-chain or functional fragment or variant thereof. In some embodiments, the heterologous polypeptide is fused to the J-chain or fragment thereof via a peptide linker. In some embodiments, the peptide linker includes at least 5 amino acids, but no more than 25 amino acids. In some embodiments, the peptide linker consists of the amino acid sequence GGGGS (SEQ ID NO: 9), GGGGSGGGGS (SEQ ID NO: 10), GGGGSGGGGSGGGGS (SEQ ID NO: 11), GGGGSGGGGSGGGGSGGGGS (SEQ ID NO: 12), or GGGGSGGGGSGGGGSGGGGSGGGGS (SEQ ID NO: 13).

In some embodiments, the heterologous polypeptide of the multimeric binding molecule that includes five or six bivalent IgM or IgM-like binding units is fused to the N-terminus of the J-chain or fragment or variant thereof, the C-terminus of the J-chain or fragment or variant thereof, or to both the N-terminus and C-terminus of the J-chain or fragment or variant thereof.

In some embodiments, the heterologous polypeptide of the multimeric binding molecule that includes five or six bivalent IgM or IgM-like binding units can influence the absorption, distribution, metabolism and/or excretion (ADME) of the multimeric binding molecule. In some embodiments, the heterologous polypeptide includes an albumin or an albumin binding domain, human serum albumin, or an antigen binding domain. In some embodiments, the antigen binding domain binds to the human coronavirus. In some embodiments, the antigen binding domain binds to a different epitope of the human coronavirus than the three to twelve identical binding domains of the multimeric binding molecule that specifically bind to the human coronavirus. In some embodiments, the antigen binding domain of the heterologous polypeptide is an antibody or antigen-binding fragment thereof. In some of these embodiments, the antigen-binding fragment includes a Fab fragment, a Fab′ fragment, a F(ab′)2 fragment, a Fd fragment, a Fv fragment, a single-chain Fv (scFv) fragment, a disulfide-linked Fv (sdFv) fragment, or any combination thereof. In some embodiments, the antigen-binding fragment is a scFv fragment. In some embodiments, the heterologous polypeptide includes an extracellular SARS-CoV-2 RBD-binding fragment of angiotensin-converting enzyme 2 (ACE2). In some embodiments, the heterologous polypeptide includes an extracellular MERS-COV RBD-binding fragment of dipeptidyl peptidase 4 (DPP4).

In some embodiments, the J-chain or functional fragment or variant thereof of the multimeric binding molecule that includes five or six bivalent IgM or IgM-like binding units further includes an additional heterologous polypeptide, where the additional heterologous polypeptide is directly or indirectly fused to the J-chain or functional fragment or variant thereof. In some embodiments, the additional heterologous polypeptide can influence the absorption, distribution, metabolism and/or excretion (ADME) of the multimeric binding molecule. In some embodiments, the additional heterologous polypeptide includes an albumin, an albumin binding protein, or human serum albumin.

Some embodiments of the disclosure are directed to a composition that includes a multimeric binding molecule as described herein. In some embodiments, the composition includes two or more nonidentical multimeric binding molecules as described herein, where the two or more multimeric binding molecules bind to different epitopes of a single human coronavirus.

Some embodiments of the disclosure are directed to a polynucleotide that includes a nucleic acid sequence that encodes a polypeptide subunit of the binding molecule described herein.

Some embodiments of the disclosure are directed to a vector that includes the polynucleotide as described herein.

Some embodiments of the disclosure are directed to a host cell that includes a polynucleotide of the disclosure, or a vector of the disclosure, where the host cell can express a multimeric binding molecule as described herein.

Some embodiments of the disclosure relate to methods of producing a multimeric binding molecule as described herein, which includes culturing a host cell as described herein, and recovering the multimeric binding molecule. In some embodiments, the method further includes contacting the multimeric binding molecule with a secretory component, or fragment or variant thereof.

Some embodiments as described herein are directed to a method for treating a human coronavirus disease in a subject in need of treatment that includes administering to the subject an effective amount of a multimeric binding molecule as described herein, where the multimeric binding molecule exhibits greater potency than an equivalent amount of a bivalent reference IgG antibody that includes two of the binding domains that specifically bind to the human coronavirus. In some embodiments the human coronavirus disease is coronavirus disease 2019 (COVID-19). In some embodiments, the human coronavirus disease is Middle East Respiratory Syndrome (MERS). In some methods, the subject is human. In some embodiments, the method includes intravenous, subcutaneous, intramuscular, intranasal, and/or inhalation administration of a multimeric binding molecule as described herein.

Some embodiments of the disclosure are directed to a method for preventing a human coronavirus disease in a subject, which includes administering to the subject an effective amount of a multimeric binding molecule as described herein, where the multimeric binding molecule exhibits greater potency than an equivalent amount of a bivalent reference IgG antibody that includes two of the binding domains that specifically bind to the human coronavirus. In some embodiments the human coronavirus disease is coronavirus disease 2019 (COVID-19). In some embodiments, the human coronavirus disease is Middle East Respiratory Syndrome (MERS). In some methods, the subject is human. In some embodiments, the method includes intravenous, subcutaneous, intramuscular, intranasal, and/or inhalation administration of a multimeric binding molecule as described herein.

BRIEF DESCRIPTION OF THE DRAWINGS/FIGURES

FIGS. 1A-1B show binding of CR3022 IgM, IgA1, IgA2m2, and IgG to SARS-CoV-1 (FIG. 1A) or SARS-CoV-2 (FIG. 1B) receptor binding domain (RBD) in an ELISA assay.

FIGS. 2A-2F show the percent inhibition of SARS-CoV-1 pseudovirus by CR3022 IgG1 (FIG. 2A), CR3022 IgA1 (FIG. 2B), CR3022 IgA2m2 (FIG. 2C), CR3022 IgM (FIG. 2D), CR3014 IgG1 (FIG. 2E), and CR3014 IgM (FIG. 2F). The half maximal inhibitory concentration (IC₅₀) is denoted by a dashed line.

FIG. 3 shows the concentration of IgG, IgA1, IgA2m2, and IgM in the apical chamber following pIgR-mediated transcytosis.

FIGS. 4A-4G show binding to SARS-CoV-2 receptor binding domain (RBD) (FIGS. 4A-4D) of IgM or IgG Ab1 (FIG. 4A), IgM or IgG Ab2 (FIG. 4B), IgM or IgG Ab3 (FIG. 4C), IgM or IgG Ab4 (FIG. 4D), IgM or IgG Ab10 (FIG. 4E), IgM or IgG Ab11 (FIG. 4F), and IgM or IgG Ab13 (FIG. 4G) in an ELISA assay.

FIGS. 5A-5D show the percent neutralization of SARS-CoV-2 by IgM or IgG Ab10 (FIG. 5A), IgM or IgG Ab11 (FIG. 5B), IgM or IgG Ab12 (FIG. 5C), IgM or IgG Ab13 (FIG. 5D). The half maximal inhibitory concentration (IC₅₀) is denoted by a dashed line.

FIGS. 6A-6L show the percent neutralization of SARS-CoV-2 pseudovirus by IgM or IgG Ab1 (FIG. 6A), IgM or IgG Ab2 (FIG. 6B), IgM or IgG Ab3 (FIG. 6C), IgM or IgG Ab4 (FIG. 6D), IgM or IgG Ab5 (FIG. 6E), IgM or IgG Ab6 (FIG. 6F), IgM or IgG Ab7 (FIG. 6G), IgM or IgG Ab8 (FIG. 6H), IgM or IgG Ab10 (FIG. 6I), IgM or IgG Ab11 (FIG. 6J), IgM or IgG Ab12 (FIG. 6K), or IgM or IgG Ab13 (FIG. 6L).

DETAILED DESCRIPTION
Definitions

As used herein, the term “a” or “an” entity refers to one or more of that entity; for example, “a binding molecule,” is understood to represent one or more binding molecules. As such, the terms “a” (or “an”), “one or more,” and “at least one” can be used interchangeably herein.

Furthermore, “and/or” where used herein is to be taken as specific disclosure of each of the two specified features or components with or without the other. Thus, the term and/or” as used in a phrase such as “A and/or B” herein is intended to include “A and B,” “A or B,” “A” (alone), and “B” (alone). Likewise, the term “and/or” as used in a phrase such as “A, B, and/or C” is intended to encompass each of the following embodiments: A, B, and C; A, B, or C; A or C; A or B; B or C; A and C; A and B; B and C; A (alone); B (alone); and C (alone).

Unless defined otherwise, technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure is related. For example, the Concise Dictionary of Biomedicine and Molecular Biology, Juo, Pei-Show, 2nd ed., 2002, CRC Press; The Dictionary of Cell and Molecular Biology, 3rd ed., 1999, Academic Press; and the Oxford Dictionary of Biochemistry and Molecular Biology, Revised, 2000, Oxford University Press, provide one of skill with a general dictionary of many of the terms used in this disclosure.

Units, prefixes, and symbols are denoted in their Systeme International de Unites (SI) accepted form. Numeric ranges are inclusive of the numbers defining the range. Unless otherwise indicated, amino acid sequences are written left to right in amino to carboxy orientation. The headings provided herein are not limitations of the various embodiments or embodiments of the disclosure, which can be had by reference to the specification as a whole. Accordingly, the terms defined immediately below are more fully defined by reference to the specification in its entirety.

As used herein, the term “polypeptide” is intended to encompass a singular “polypeptide” as well as plural “polypeptides,” and refers to a molecule composed of monomers (amino acids) linearly linked by amide bonds (also known as peptide bonds). The term “polypeptide” refers to any chain or chains of two or more amino acids and does not refer to a specific length of the product. Thus, peptides, dipeptides, tripeptides, oligopeptides, “protein,” “amino acid chain,” or any other term used to refer to a chain or chains of two or more amino acids are included within the definition of “polypeptide,” and the term “polypeptide” can be used instead of any of these terms. The term “polypeptide” is also intended to refer to the products of post-expression modifications of the polypeptide, including without limitation glycosylation, acetylation, phosphorylation, amidation, and derivatization by known protecting/blocking groups, proteolytic cleavage, or modification by non-naturally occurring amino acids. A polypeptide can be derived from a biological source or produced by recombinant technology but is not necessarily translated from a designated nucleic acid sequence. It can be generated in any manner, including by chemical synthesis.

A polypeptide as disclosed herein can be of a size of about 3 or more, 5 or more, 10 or more, 20 or more, 25 or more, 50 or more, 75 or more, 100 or more, 200 or more, 500 or more, 1,000 or more, or 2,000 or more amino acids. Polypeptides can have a defined three-dimensional structure, although they do not necessarily have such structure. Polypeptides with a defined three-dimensional structure are referred to as folded, and polypeptides which do not possess a defined three-dimensional structure, but rather can adopt many different conformations and are referred to as unfolded. As used herein, the term glycoprotein refers to a protein coupled to at least one carbohydrate moiety that is attached to the protein via an oxygen-containing or a nitrogen-containing side chain of an amino acid, e.g., a serine or an asparagine. Asparagine (N)-linked glycans are described in more detail elsewhere in this disclosure.

By an “isolated” polypeptide or a fragment, variant, or derivative thereof is intended a polypeptide that is not in its natural milieu. No particular level of purification is required. For example, an isolated polypeptide can be removed from its native or natural environment. Recombinantly produced polypeptides and proteins expressed in host cells are considered isolated as disclosed herein, as are native or recombinant polypeptides which have been separated, fractionated, or partially or substantially purified by any suitable technique.

As used herein, the term “a non-naturally occurring polypeptide” or any grammatical variants thereof, is a conditional definition that explicitly excludes, but only excludes, those forms of the polypeptide that are, or might be, determined or interpreted by a judge or an administrative or judicial body, to be “naturally-occurring.”

Other polypeptides disclosed herein are fragments, derivatives, analogs, or variants of the foregoing polypeptides, and any combination thereof. The terms “fragment,” “variant,” “derivative” and “analog” as disclosed herein include any polypeptides which retain at least some of the properties of the corresponding native antibody or polypeptide, for example, specifically binding to an antigen. Fragments of polypeptides include, for example, proteolytic fragments, as well as deletion fragments, in addition to specific antibody fragments discussed elsewhere herein. Variants of, e.g., a polypeptide include fragments as described above, and also polypeptides with altered amino acid sequences due to amino acid substitutions, deletions, or insertions. In certain embodiments, variants can be non-naturally occurring. Non-naturally occurring variants can be produced using art-known mutagenesis techniques. Variant polypeptides can comprise conservative or non-conservative amino acid substitutions, deletions, or additions. Derivatives are polypeptides that have been altered so as to exhibit additional features not found on the original polypeptide. Examples include fusion proteins. As used herein a “derivative” of a polypeptide can also refer to a subject polypeptide having one or more amino acids chemically derivatized by reaction of a functional side group. Also included as “derivatives” are those polypeptides that contain one or more derivatives of the twenty standard amino acids. For example, 4-hydroxyproline can be substituted for proline; 5-hydroxylysine can be substituted for lysine; 3-methylhistidine can be substituted for histidine; homoserine can be substituted for serine; and omithine can be substituted for lysine.

A “conservative amino acid substitution” is one in which one amino acid is replaced with another amino acid having a similar side chain. Families of amino acids having similar side chains have been defined in the art, including basic side chains (e.g., lysine, arginine, histidine), acidic side chains (e.g., aspartic acid, glutamic acid), uncharged polar side chains (e.g., asparagine, glutamine, serine, threonine, tyrosine, cysteine), nonpolar side chains (e.g., glycine, alanine, valine, leucine, isoleucine, proline, phenylalanine, methionine, tryptophan), beta-branched side chains (e.g., threonine, valine, isoleucine) and aromatic side chains (e.g., tyrosine, phenylalanine, tryptophan, histidine). For example, substitution of a phenylalanine for a tyrosine is a conservative substitution. In certain embodiments, conservative substitutions in the sequences of the polypeptides, binding molecules, and antibodies of the present disclosure do not abrogate the binding of the polypeptide, binding molecule, or antibody containing the amino acid sequence, to the antigen to which the antibody binds. Methods of identifying nucleotide and amino acid conservative substitutions which do not eliminate antigen-binding are well-known in the art (see, e.g., Brummell et al., Biochem. 32: 1180-1 187 (1993); Kobayashi et al., Protein Eng. 12:879-884 (1999); and Burks et al., Proc. Natl. Acad. Sci. USA 94: 412-417 (1997)).

The term “polynucleotide” is intended to encompass a singular nucleic acid as well as plural nucleic acids and refers to an isolated nucleic acid molecule or construct, e.g., messenger RNA (mRNA), cDNA, or plasmid DNA (pDNA). A polynucleotide can comprise a conventional phosphodiester bond or a non-conventional bond (e.g., an amide bond, such as found in peptide nucleic acids (PNA)). The terms “nucleic acid” or “nucleic acid sequence” refer to any one or more nucleic acid segments, e.g., DNA or RNA fragments, present in a polynucleotide.

By an “isolated” nucleic acid or polynucleotide is intended any form of the nucleic acid or polynucleotide that is separated from its native environment. For example, gel-purified polynucleotide, or a recombinant polynucleotide encoding a polypeptide contained in a vector would be considered to be “isolated.” Also, a polynucleotide segment, e.g., a PCR product, which has been engineered to have restriction sites for cloning is considered to be “isolated.” Further examples of an isolated polynucleotide include recombinant polynucleotides maintained in heterologous host cells or purified (partially or substantially) polynucleotides in a non-native solution such as a buffer or saline. Isolated RNA molecules include in vivo or in vitro RNA transcripts of polynucleotides, where the transcript is not one that would be found in nature. Isolated polynucleotides or nucleic acids further include such molecules produced synthetically. In addition, polynucleotide or a nucleic acid can be or can include a regulatory element such as a promoter, ribosome binding site, or a transcription terminator.

As used herein, the term “a non-naturally occurring polynucleotide” or any grammatical variants thereof, is a conditional definition that explicitly excludes, but only excludes, those forms of the nucleic acid or polynucleotide that are, or might be, determined or interpreted by a judge, or an administrative or judicial body, to be “naturally-occurring.”

As used herein, a “coding region” is a portion of nucleic acid which consists of codons translated into amino acids. Although a “stop codon” (TAG, TGA, or TAA) is not translated into an amino acid, it can be considered to be part of a coding region, but any flanking sequences, for example promoters, ribosome binding sites, transcriptional terminators, introns, and the like, are not part of a coding region. Two or more coding regions can be present in a single polynucleotide construct, e.g., on a single vector, or in separate polynucleotide constructs, e.g., on separate (different) vectors. Furthermore, any vector can contain a single coding region, or can comprise two or more coding regions, e.g., a single vector can separately encode an immunoglobulin heavy chain variable region and an immunoglobulin light chain variable region. In addition, a vector, polynucleotide, or nucleic acid can include heterologous coding regions, either fused or unfused to another coding region. Heterologous coding regions include without limitation, those encoding specialized elements or motifs, such as a secretory signal peptide or a heterologous functional domain.

In certain embodiments, the polynucleotide or nucleic acid is DNA. In the case of DNA, a polynucleotide comprising a nucleic acid which encodes a polypeptide normally can include a promoter and/or other transcription or translation control elements operably associated with one or more coding regions. An operable association is when a coding region for a gene product, e.g., a polypeptide, is associated with one or more regulatory sequences in such a way as to place expression of the gene product under the influence or control of the regulatory sequence(s). Two DNA fragments (such as a polypeptide coding region and a promoter associated therewith) are “operably associated” if induction of promoter function results in the transcription of mRNA encoding the desired gene product and if the nature of the linkage between the two DNA fragments does not interfere with the ability of the expression regulatory sequences to direct the expression of the gene product or interfere with the ability of the DNA template to be transcribed. Thus, a promoter region would be operably associated with a nucleic acid encoding a polypeptide if the promoter was capable of effecting transcription of that nucleic acid. The promoter can be a cell-specific promoter that directs substantial transcription of the DNA in predetermined cells. Other transcription control elements, besides a promoter, for example enhancers, operators, repressors, and transcription termination signals, can be operably associated with the polynucleotide to direct cell-specific transcription.

A variety of transcription control regions are known to those skilled in the art. These include, without limitation, transcription control regions that function in vertebrate cells, such as, but not limited to, promoter and enhancer segments from cytomegaloviruses (the immediate early promoter, in conjunction with intron A), simian virus 40 (the early promoter), and retroviruses (such as Rous sarcoma virus). Other transcription control regions include those derived from vertebrate genes such as actin, heat shock protein, bovine growth hormone and rabbit β-globin, as well as other sequences capable of controlling gene expression in eukaryotic cells. Additional suitable transcription control regions include tissue-specific promoters and enhancers as well as lymphokine-inducible promoters (e.g., promoters inducible by interferons or interleukins).

Similarly, a variety of translation control elements are known to those of ordinary skill in the art. These include, but are not limited to ribosome binding sites, translation initiation and termination codons, and elements derived from picornaviruses (particularly an internal ribosome entry site, or IRES, also referred to as a CITE sequence).

In other embodiments, a polynucleotide can be RNA, for example, in the form of messenger RNA (mRNA), transfer RNA, or ribosomal RNA.

Polynucleotide and nucleic acid coding regions can be associated with additional coding regions which encode secretory or signal peptides, which direct the secretion of a polypeptide encoded by a polynucleotide as disclosed herein. According to the signal hypothesis, proteins secreted by mammalian cells have a signal peptide or secretory leader sequence which is cleaved from the mature protein once export of the growing protein chain across the rough endoplasmic reticulum has been initiated. Those of ordinary skill in the art are aware that polypeptides secreted by vertebrate cells can have a signal peptide fused to the N-terminus of the polypeptide, which is cleaved from the complete or “full length” polypeptide to produce a secreted or “mature” form of the polypeptide. In certain embodiments, the native signal peptide, e.g., an immunoglobulin heavy chain or light chain signal peptide is used, or a functional derivative of that sequence that retains the ability to direct the secretion of the polypeptide that is operably associated with it. Alternatively, a heterologous mammalian signal peptide, or a functional derivative thereof, can be used. For example, the wild-type leader sequence can be substituted with the leader sequence of human tissue plasminogen activator (TPA) or mouse β-glucuronidase.

As used herein, the term “binding molecule” refers in its broadest sense to a molecule that specifically binds to a receptor or target, e.g., an epitope or an antigenic determinant. As described further herein, a binding molecule can comprise one of more “binding domains,” e.g., “antigen-binding domains” described herein. A non-limiting example of a binding molecule is an antibody or antibody-like molecule as described in detail herein that retains antigen-specific binding. In certain embodiments a “binding molecule” comprises an antibody or antibody-like or antibody-derived molecule as described in detail herein.

As used herein, the terms “binding domain” or “antigen-binding domain” (can be used interchangeably) refer to a region of a binding molecule, e.g., an antibody or antibody-like, or antibody-derived molecule, that is necessary and sufficient to specifically bind to a target, e.g., an epitope, a polypeptide, a cell, or an organ. For example, an “Fv,” e.g., a heavy chain variable region and a light chain variable region of an antibody, either as two separate polypeptide subunits or as a single chain, is considered to be a “binding domain.” Other antigen-binding domains include, without limitation, a single domain heavy chain variable region (VHH) of an antibody derived from a camelid species, or six immunoglobulin complementarity determining regions (CDRs) expressed in a fibronectin scaffold. A “binding molecule,” e.g., an “antibody” as described herein can include one, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, or more “antigen-binding domains.”

The terms “antibody” and “immunoglobulin” can be used interchangeably herein. An antibody (or a fragment, variant, or derivative thereof as disclosed herein, e.g., an IgM-like antibody) includes at least the variable domain of a heavy chain (e.g., from a camelid species) or at least the variable domains of a heavy chain and a light chain. Basic immunoglobulin structures in vertebrate systems are relatively well understood. See, e.g., Harlow et al., Antibodies: A Laboratory Manual, (Cold Spring Harbor Laboratory Press, 2nd ed. 1988). Unless otherwise stated, the term “antibody” encompasses anything ranging from a small antigen-binding fragment of an antibody to a full sized antibody, e.g., an IgG antibody that includes two complete heavy chains and two complete light chains, an IgA antibody that includes four complete heavy chains and four complete light chains and includes a J-chain and/or a secretory component, or an IgM-derived binding molecule, e.g., an IgM antibody or IgM-like antibody, that includes ten or twelve complete heavy chains and ten or twelve complete light chains and optionally includes a J-chain or functional fragment or variant thereof.

The term “immunoglobulin” comprises various broad classes of polypeptides that can be distinguished biochemically. Those skilled in the art will appreciate that heavy chains are classified as gamma, mu, alpha, delta, or epsilon, (γ, μ, α, δ, ε) with some subclasses among them (e.g., γ1-γ4 or α1-α2)). It is the nature of this chain that determines the “isotype” of the antibody as IgG, IgM, IgA IgD, or IgE, respectively. The immunoglobulin subclasses (subtypes) e.g., IgG₁, IgG₂, IgG₃, IgG₄, IgA₁, IgA₂, etc. are well characterized and are known to confer functional specialization. Modified versions of each of these immunoglobulins are readily discernible to the skilled artisan in view of the instant disclosure and, accordingly, are within the scope of this disclosure.

Light chains are classified as either kappa or lambda (κ, λ). Each heavy chain class can be bound with either a kappa or lambda light chain. In general, the light and heavy chains are covalently bonded to each other, and the “tail” portions of the two heavy chains are bonded to each other by covalent disulfide linkages or non-covalent linkages when the immunoglobulins are expressed, e.g., by hybridomas, B cells or genetically engineered host cells. In the heavy chain, the amino acid sequences run from an N-terminus at the forked ends of the Y configuration to the C-terminus at the bottom of each chain. The basic structure of certain antibodies, e.g., IgG antibodies, includes two heavy chain subunits and two light chain subunits covalently connected via disulfide bonds to form a “Y” structure, also referred to herein as an “H2L2” structure, or a “binding unit.”

The term “binding unit” is used herein to refer to the portion of a binding molecule, e.g., an antibody, antibody-like molecule, or antibody-derived molecule, antigen-binding fragment thereof, or multimerizing fragment thereof, which corresponds to a standard “H2L2” immunoglobulin structure, i.e., two heavy chains or fragments thereof and two light chains or fragments thereof. In certain embodiments, e.g., where the binding molecule is a bivalent IgG antibody or antigen-binding fragment thereof, the terms “binding molecule” and “binding unit” are equivalent. Such binding molecules are also referred to herein as “monomeric.” In other embodiments, e.g., where the binding molecule is a “multimeric binding molecule,” e.g., a dimeric or tetrameric IgA antibody, a dimeric or tetrameric IgA-like antibody, a dimeric or tetrameric IgA-derived binding molecule, a pentameric or hexameric IgM antibody, a pentameric or hexameric IgM-like antibody, or a pentameric or hexameric IgM-derived binding molecule or any derivative thereof, the binding molecule comprises two or more “binding units.” Two in the case of an IgA dimer, four in the case of an IgA tetramer, or five or six in the case of an IgM pentamer or hexamer, respectively. A binding unit need not include full-length antibody heavy and light chains, but will typically be bivalent, i.e., will include two “antigen-binding domains,” as defined above. As used herein, certain binding molecules provided in this disclosure are “dimeric,” and include two bivalent binding units that include IgA constant regions or multimerizing fragments thereof. Certain binding molecules provided in this disclosure are “pentameric” or “hexameric,” and include five or six bivalent binding units that include IgM constant regions or multimerizing fragments or variants thereof. A binding molecule, e.g., an antibody or antibody-like molecule or antibody-derived binding molecule, comprising two or more, e.g., two, five, or six binding units, is referred to herein as “multimeric.”

The term “J-chain” as used herein refers to the J-chain of IgM or IgA antibodies of any animal species, any functional fragment thereof, derivative thereof, and/or variant thereof, including a mature human J-chain, the amino acid sequence of which is presented as SEQ ID NO: 7. Various J-chain variants and modified J-chain derivatives are disclosed herein. As persons of ordinary skill in the art will recognize, “a functional fragment” or “a functional variant” includes those fragments and variants that can associate with IgM heavy chain constant regions to form a pentameric IgM antibody or can associate with IgA heavy chain constant regions to form a dimeric IgA antibody.

The term “modified J-chain” is used herein to refer to a derivative of a J-chain polypeptide comprising a heterologous moiety, e.g., a heterologous polypeptide, e.g., an extraneous binding domain or functional domain introduced into or attached to the J-chain sequence. The introduction can be achieved by any means, including direct or indirect fusion of the heterologous polypeptide or other moiety or by attachment through a peptide or chemical linker. The term “modified human J-chain” encompasses, without limitation, the human J-chain comprising the amino acid sequence of SEQ ID NO: 7 or functional fragment thereof, or functional variant thereof, modified by the introduction of a heterologous moiety, e.g., a heterologous polypeptide, e.g., an extraneous binding domain. In certain embodiments the heterologous moiety does not interfere with efficient polymerization of IgM into a pentamer or IgA into a multimer, e.g., a dimer or tetramer, and binding of such polymers to a target. Exemplary modified J-chains can be found, e.g., in U.S. Pat. Nos. 9,951,134, 10,400,038, and 10,618,978, and in U.S. Patent Application Publication No. US-2019-0185570, each of which is incorporated herein by reference in its entirety.

As used herein the term “IgM-derived binding molecule” refers collectively to native IgM antibodies, IgM-like antibodies, as well as other IgM-derived binding molecules comprising non-antibody binding and/or functional domains instead of an antibody antigen binding domain or subunit thereof, and any fragments, e.g., multimerizing fragments, variants, or derivatives thereof.

As used herein, the term “IgM-like antibody” refers generally to a variant antibody or antibody-derived binding molecule that still retains the ability to form hexamers or pentamers, e.g., in association with a J-chain. An IgM-like antibody or other IgM-derived binding molecule typically includes at least the Cμ4-tp domains of the IgM constant region but can include heavy chain constant region domains from other antibody isotypes, e.g., IgG, from the same species or from a different species. An IgM-like antibody or other IgM-derived binding molecule can likewise be an antibody fragment in which one or more constant regions are deleted, as long as the IgM-like antibody is capable of forming hexamers and/or pentamers. Thus, an IgM-like antibody or other IgM-derived binding molecule can be, e.g., a hybrid IgM/IgG antibody or can be a “multimerizing fragment” of an IgM antibody.

As used herein the term “IgA-derived binding molecule” refers collectively to native IgA antibodies, IgA-like antibodies, as well as other IgA-derived binding molecules comprising non-antibody binding and/or functional domains instead of an antibody antigen binding domain or subunit thereof, and any fragments, e.g., multimerizing fragments, variants, or derivatives thereof.

As used herein, the term “IgA-like antibody” refers generally to a variant antibody or antibody-derived binding molecule that still retains the ability to form multimers, e.g., dimers, trimers, tetramers, and/or pentamers e.g., dimers and/or tetramers, e.g., in association with a J-chain. An IgA-like antibody or other IgA-derived binding molecule typically includes at least the Cα3-tp domains of the IgA constant region but can include heavy chain constant region domains from other antibody isotypes, e.g., IgG, from the same species or from a different species. An IgA-like antibody or other IgA-derived binding molecule can likewise be an antibody fragment in which one or more constant regions are deleted, as long as the IgA-like antibody can form multimers, e.g., dimers and/or tetramers. Thus, an IgA-like antibody or other IgA-derived binding molecule can be, e.g., a hybrid IgA/IgG antibody or can be a “multimerizing fragment” of an IgA antibody.

The terms “valency,” “bivalent,” “multivalent” and grammatical equivalents, refer to the number of binding domains, e.g., antigen-binding domains in given binding molecule, e.g., antibody, antibody-derived, or antibody-like molecule, or in a given binding unit. As such, the terms “bivalent”, “tetravalent”, and “hexavalent” in reference to a given binding molecule, e.g., an IgM antibody, IgM-like antibody, other IgM-derived binding molecule, or multimerizing fragment thereof, denote the presence of two antigen-binding domains, four antigen-binding domains, and six antigen-binding domains, respectively. A typical IgM antibody, IgM-like antibody, or other IgM-derived binding molecule, where each binding unit is bivalent, can have 10 or 12 valencies. A bivalent or multivalent binding molecule, e.g., antibody or antibody-derived molecule, can be monospecific, i.e., all of the antigen-binding domains are the same, or can be bispecific or multispecific, e.g., where two or more antigen-binding domains are different, e.g., bind to different epitopes on the same antigen, or bind to entirely different antigens.

The term “epitope” includes any molecular determinant capable of specific binding to an antigen-binding domain of an antibody, antibody-like, or antibody-derived molecule. In certain embodiments, an epitope can include chemically active surface groupings of molecules such as amino acids, sugar side chains, phosphoryl groups, or sulfonyl groups, and, in certain embodiments, can have three-dimensional structural characteristics, and or specific charge characteristics. An epitope is a region of a target that is bound by an antigen-binding domain of an antibody.

The term “target” is used in the broadest sense to include substances that can be bound by a binding molecule, e.g., antibody, antibody-like, or antibody-derived molecule. A target can be, e.g., a polypeptide, a nucleic acid, a carbohydrate, a lipid, or other molecule, or a minimal epitope on such molecule. Moreover, a “target” can, for example, be a cell, an organ, or an organism, e.g., an animal, plant, microbe, or virus, that comprises an epitope that can be bound by a binding molecule, e.g., antibody, antibody-like, or antibody-derived molecule.

Both the light and heavy chains of antibodies, antibody-like, or antibody-derived molecules are divided into regions of structural and functional homology. The terms “constant” and “variable” are used functionally. In this regard, it will be appreciated that the variable domains of both the variable light (VL) and variable heavy (VH) chain portions determine antigen recognition and specificity. Conversely, the constant region domains of the light chain (CL) and the heavy chain (e.g., CH1, CH2, CH3, or CH4) confer biological properties such as secretion, transplacental mobility, Fc receptor binding, complement binding, and the like. By convention, the numbering of the constant region domains increases as they become more distal from the antigen-binding site or amino-terminus of the antibody. The N-terminal portion is a variable region and at the C-terminal portion is a constant region; the CH3 (or CH4, e.g., in the case of IgM) and CL domains actually comprise the carboxy-terminus of the heavy and light chain, respectively.

A “full length IgM antibody heavy chain” is a polypeptide that includes, in N-terminal to C-terminal direction, an antibody heavy chain variable domain (VH), an antibody heavy chain constant domain 1 (CM1 or Cμ1), an antibody heavy chain constant domain 2 (CM2 or Cμ2), an antibody heavy chain constant domain 3 (CM3 or Cμ3), and an antibody heavy chain constant domain 4 (CM4 or Cμ4) that can include a tailpiece.

A “full length IgA antibody heavy chain” is a polypeptide that includes, in N-terminal to C-terminal direction, an antibody heavy chain variable domain (VH), an antibody heavy chain constant domain 1 (CA1 or Cα1), an IgA hinge region, an antibody heavy chain constant domain 2 (CA2 or Cα2), and an antibody heavy chain constant domain 3 (CA3 or Cα3) that can include an IgA tailpiece.

As indicated above, variable region(s) allow a binding molecule, e.g., antibody, antibody-like, or antibody-derived molecule, to selectively recognize and specifically bind epitopes on antigens. That is, the VL domain and VH domain, or subset of the complementarity determining regions (CDRs), of a binding molecule, e.g., an antibody, antibody-like, or antibody-derived molecule, combine to form the antigen-binding domain. More specifically, an antigen-binding domain can be defined by three CDRs on each of the VH and VL chains. Certain antibodies form larger structures. For example, IgA can form a molecule that includes two H2L2 binding units and a J-chain covalently connected via disulfide bonds, which can be further associated with a secretory component, and IgM can form a pentameric or hexameric molecule that includes five or six H2L2 binding units and optionally a J-chain covalently connected via disulfide bonds.

The six “complementarity determining regions” or “CDRs” present in an antibody antigen-binding domain are short, non-contiguous sequences of amino acids that are specifically positioned to form the antigen-binding domain as the antibody assumes its three-dimensional configuration in an aqueous environment. The remainder of the amino acids in the antigen-binding domain, referred to as “framework” regions, show less inter-molecular variability. The framework regions largely adopt a β-sheet conformation and the CDRs form loops which connect, and in some cases form part of, the β-sheet structure. Thus, framework regions act to form a scaffold that provides for positioning the CDRs in correct orientation by inter-chain, non-covalent interactions. The antigen-binding domain formed by the positioned CDRs defines a surface complementary to the epitope on the immunoreactive antigen. This complementary surface promotes the non-covalent binding of the antibody to its cognate epitope. The amino acids that make up the CDRs and the framework regions, respectively, can be readily identified for any given heavy or light chain variable region by one of ordinary skill in the art, since they have been defined in various different ways (see, “Sequences of Proteins of Immunological Interest,” Kabat, E., et al., U.S. Department of Health and Human Services, (1983); and Chothia and Lesk, J. Mol. Biol., 196:901-917 (1987), which are incorporated herein by reference in their entireties).

In the case where there are two or more definitions of a term which is used and/or accepted within the art, the definition of the term as used herein is intended to include all such meanings unless explicitly stated to the contrary. A specific example is the use of the term “complementarity determining region” (“CDR”) to describe the non-contiguous antigen combining sites found within the variable region of both heavy and light chain polypeptides. These particular regions have been described, for example, by Kabat et al., U.S. Dept. of Health and Human Services, “Sequences of Proteins of Immunological Interest” (1983) and by Chothia et al., J. Mol. Biol. 196:901-917 (1987), which are incorporated herein by reference. The Kabat and Chothia definitions include overlapping or subsets of amino acids when compared against each other. Nevertheless, application of either definition (or other definitions known to those of ordinary skill in the art) to refer to a CDR of an antibody or variant thereof is intended to be within the scope of the term as defined and used herein, unless otherwise indicated. The appropriate amino acids which encompass the CDRs as defined by each of the above cited references are set forth below in Table 1 as a comparison. The exact amino acid numbers which encompass a particular CDR will vary depending on the sequence and size of the CDR. Those skilled in the art can routinely determine which amino acids comprise a particular CDR given the variable region amino acid sequence of the antibody.

TABLE 1

CDR Definitions*

Kabat
Chothia

VH CDR1
31-35
26-32

VH CDR2
50-65
52-58

VH CDR3
95-102
95-102

VL CDR1
24-34
26-32

VL CDR2
50-56
50-52

VL CDR3
89-97
91-96

*Numbering of all CDR definitions in Table 1 is according to the numbering conventions set forth by Kabat et al. (see below).

Antibody variable domains can also be analyzed, e.g., using the IMGT information system (imgt.cines.fr) (IMGT®/V-Quest) to identify variable region segments, including CDRs. (See, e.g., Brochet et al., Nucl. Acids Res. 36:W503-508, 2008). IMGT uses a different numbering system than Kabat. See, e.g., Lefranc, M.-P. et al., Dev. Comp. Immunol. 27:55-77 (2003). Correspondences are listed, for example, at imgt.org/IMGTScientificChart/Numbering/CDR1-IMGTgaps.html.

Kabat et al. also defined a numbering system for variable domain sequences that is applicable to any antibody. One of ordinary skill in the art can unambiguously assign this system of “Kabat numbering” to any variable domain sequence, without reliance on any experimental data beyond the sequence itself. As used herein, “Kabat numbering” refers to the numbering system set forth by Kabat et al., U.S. Dept. of Health and Human Services, “Sequence of Proteins of Immunological Interest” (1983). Unless use of the Kabat numbering system is explicitly noted, however, consecutive numbering is used for all amino acid sequences in this disclosure.

The Kabat numbering system for the human IgM constant domain can be found in Kabat, et. al. “Tabulation and Analysis of Amino acid and nucleic acid Sequences of Precursors, V-Regions, C-Regions, J-Chain, T-Cell Receptors for Antigen, T-Cell Surface Antigens, 0-2 Microglobulins, Major Histocompatibility Antigens, Thy-1, Complement, C-Reactive Protein, Thymopoietin, Integrins, Post-gamma Globulin, α-2 Macroglobulins, and Other Related Proteins,” U.S. Dept. of Health and Human Services (1991). IgM constant regions can be numbered sequentially (i.e., amino acid #1 starting with the first amino acid of the constant region, or by using the Kabat numbering scheme. A comparison of the numbering of two alleles of the human IgM constant region sequentially (presented herein as SEQ ID NO: 1 (allele IGHM*03) and SEQ ID NO: 2 (allele IGHM*04)) and by the Kabat system is set out below. The underlined amino acid residues are not accounted for in the Kabat system (“X,” double underlined below, can be serine (S) (SEQ ID NO: 1) or glycine (G) (SEQ ID NO: 2)): Sequential (SEQ ID NO: 1 or SEQ ID NO: 2)/KABAT numbering key for IgM heavy chain

1/127 GSASAPTLFP LVSCENSPSD TSSVAVGCLA QDFLPDSITF SWKYKNNSDI

51/176 SSTRGFPSVL RGGKYAATSQ VLLPSKDVMQ GTDEHVVCKV QHPNGNKEKN

101/226 VPLPVIAELP PKVSVFVPPR DGFFGNPRKS KLICQATGFS PRQIQVSWLR

151/274 EGKQVGSGVT TDQVQAEAKE SGPTTYKVTS TLTIKESDWL XQSMFTCRVD

201/324 HRGLTFQQNA SSMCVPDQDT AIRVFAIPPS FASIFLTKST KLTCLVTDLT

251/374 TYDSVTISWT RQNGEAVKTH TNISESHPNA TFSAVGEASI CEDDWNSGER

301/424 FTCTVTHTDL PSPLKQTISR PKGVALHRPD VYLLPPAREQ LNLRESATIT

351/474 CLVTGFSPAD VFVQWMQRGQ PLSPEKYVTS APMPEPQAPG RYFAHSILTV

401/524 SEEEWNTGET YTCVVAHEAL PNRVTERTVD KSTGKPTLYN VSLVMSDTAG

451/574 TCY

Binding molecules, e.g., antibodies, antibody-like, or antibody-derived molecules, antigen-binding fragments, variants, or derivatives thereof, and/or multimerizing fragments thereof include, but are not limited to, polyclonal, monoclonal, human, humanized, or chimeric antibodies, single chain antibodies, epitope-binding fragments, e.g., Fab, Fab′ and F(ab′)₂, Fd, Fvs, single-chain Fvs (scFv), single-chain antibodies, disulfide-linked Fvs (sdFv), fragments comprising either a VL or VH domain, fragments produced by a Fab expression library. ScFv molecules are known in the art and are described, e.g., in U.S. Pat. No. 5,892,019.

By “specifically binds,” it is generally meant that a binding molecule, e.g., an antibody or fragment, variant, or derivative thereof binds to an epitope via its antigen-binding domain, and that the binding entails some complementarity between the antigen-binding domain and the epitope. According to this definition, a binding molecule, e.g., antibody, antibody-like, or antibody-derived molecule, is said to “specifically bind” to an epitope when it binds to that epitope, via its antigen-binding domain more readily than it would bind to a random, unrelated epitope. The term “specificity” is used herein to qualify the relative affinity by which a certain binding molecule binds to a certain epitope. For example, binding molecule “A” can be deemed to have a higher specificity for a given epitope than binding molecule “B,” or binding molecule “A” can be said to bind to epitope “C” with a higher specificity than it has for related epitope “D.”

A binding molecule, e.g., an antibody or fragment, variant, or derivative thereof disclosed herein can be said to bind a target antigen with an off rate (k(off)) of less than or equal to 5×10⁻²sec⁻¹, 10⁻²sec⁻¹, 5×10⁻³sec⁻¹, 10⁻³sec⁻¹, 5×10⁻⁴sec⁻¹, 10⁻⁴sec⁻¹, 5×10⁻⁵sec⁻¹, or 10⁻⁵sec⁻¹5×10⁻⁶sec⁻¹, 10⁻⁶sec⁻¹, 5×10⁻⁷sec⁻¹or 10⁻⁷sec⁻¹.

A binding molecule, e.g., an antibody or antigen-binding fragment, variant, or derivative disclosed herein can be said to bind a target antigen with an on rate (k(on)) of greater than or equal to 10³M⁻¹sec⁻¹, 5×10³M⁻¹sec⁻¹, 10⁴M⁻¹sec⁻¹, 5×10⁴M⁻¹sec⁻¹, 10⁵M⁻¹sec⁻¹, 5×10⁵M⁻¹sec⁻¹, 10⁶M⁻¹sec⁻¹, or 5×10⁶M⁻¹sec⁻¹or 10⁷M⁻¹sec⁻¹.

A binding molecule, e.g., an antibody or fragment, variant, or derivative thereof is said to competitively inhibit binding of a reference antibody or antigen-binding fragment to a given epitope if it preferentially binds to that epitope to the extent that it blocks, to some degree, binding of the reference antibody or antigen-binding fragment to the epitope. Competitive inhibition can be determined by any method known in the art, for example, competition ELISA assays. A binding molecule can be said to competitively inhibit binding of the reference antibody or antigen-binding fragment to a given epitope by at least 90%, at least 80%, at least 70%, at least 60%, or at least 50%.

As used herein, the term “affinity” refers to a measure of the strength of the binding of an individual epitope with one or more antigen-binding domains, e.g., of an immunoglobulin molecule. See, e.g., Harlow et al., Antibodies: A Laboratory Manual, (Cold Spring Harbor Laboratory Press, 2nd ed. 1988) at pages 27-28. As used herein, the term “avidity” refers to the overall stability of the complex between a population of antigen-binding domains and an antigen. See, e.g., Harlow at pages 29-34. Avidity is related to both the affinity of individual antigen-binding domains in the population with specific epitopes, and also the valencies of the immunoglobulins and the antigen. For example, the interaction between a bivalent monoclonal antibody and an antigen with a highly repeating epitope structure, such as a polymer, would be one of high avidity. An interaction between a bivalent monoclonal antibody with a receptor present at a high density on a cell surface would also be of high avidity.

Binding molecules, e.g., antibodies or fragments, variants, or derivatives thereof as disclosed herein can also be described or specified in terms of their cross-reactivity. As used herein, the term “cross-reactivity” refers to the ability of a binding molecule, e.g., an antibody or fragment, variant, or derivative thereof, specific for one antigen, to react with a second antigen; a measure of relatedness between two different antigenic substances. Thus, a binding molecule is cross reactive if it binds to an epitope other than the one that induced its formation. The cross-reactive epitope generally contains many of the same complementary structural features as the inducing epitope, and in some cases, can actually fit better than the original.

A binding molecule, e.g., an antibody or fragment, variant, or derivative thereof can also be described or specified in terms of their binding affinity to an antigen. For example, a binding molecule can bind to an antigen with a dissociation constant or K_Dno greater than 5×10⁻²M, 10⁻²M, 5×10⁻³M, 10⁻³M, 5×10⁻⁴M, 10⁻⁴M, 5×10⁻⁵M, 10⁻⁵M, 5×10⁻⁶M, 10⁻⁶M, 5×10⁻⁷M, 10⁻⁷M, 5×10⁻⁸M, 10⁻⁸M, 5×10⁻⁹M, 10⁻⁹M, 5×10⁻¹⁰M, 10⁻¹⁰M, 5×10⁻¹¹M, 10⁻¹¹M, 5×10⁻¹²M, 10⁻¹²M, 5×10⁻¹³M, 10⁻¹³M, 5×10⁻¹⁴M, 10⁻¹⁴M, 5×10⁻¹⁵M, or 10⁻¹⁵M.

“Antigen-binding antibody fragments” including single-chain antibodies or other antigen-binding domains can exist alone or in combination with one or more of the following: hinge region, CH1, CH2, CH3, or CH4 domains, J-chain, or secretory component. Also included are antigen-binding fragments that can include any combination of variable region(s) with one or more of a hinge region, CH1, CH2, CH3, or CH4 domains, a J-chain, or a secretory component. Binding molecules, e.g., antibodies, or antigen-binding fragments thereof can be from any animal origin including birds and mammals. The antibodies can be human, murine, donkey, rabbit, goat, guinea pig, camel, llama, horse, or chicken antibodies. In another embodiment, the variable region can be condricthoid in origin (e.g., from sharks). As used herein, “human” antibodies include antibodies having the amino acid sequence of a human immunoglobulin and include antibodies isolated from human immunoglobulin libraries or from animals transgenic for one or more human immunoglobulins and can in some instances express endogenous immunoglobulins and some not, as described infra and, for example in, U.S. Pat. No. 5,939,598 by Kucherlapati et al. According to embodiments of the present disclosure, an IgM antibody, IgM-like antibody, or other IgM-derived binding molecule as provided herein can include an antigen-binding fragment of an antibody, e.g., a scFv fragment, so long as the IgM antibody, IgM-like antibody, or other IgM-derived binding molecule is able to form a multimer, e.g., a hexamer or a pentamer, and an IgA antibody, IgA-like antibody, or other IgA-derived binding molecule as provided herein can include an antigen-binding fragment of an antibody, e.g., a scFv fragment, so long as the IgA antibody, IgA-like antibody, or other IgA-derived binding molecule is able to form a multimer, e.g., a dimer and/or a tetramer. As used herein such a fragment comprises a “multimerizing fragment.”

As used herein, the term “heavy chain subunit” includes amino acid sequences derived from an immunoglobulin heavy chain, a binding molecule, e.g., an antibody, antibody-like, or antibody-derived molecule comprising a heavy chain subunit can include at least one of: a VH domain, a CH1 domain, a hinge (e.g., upper, middle, and/or lower hinge region) domain, a CH2 domain, a CH3 domain, a CH4 domain, or a variant or fragment thereof. For example, a binding molecule, e.g., an antibody, antibody-like, or antibody-derived molecule, or fragment, e.g., multimerizing fragment, variant, or derivative thereof can include without limitation, in addition to a VH domain: a CH1 domain; a CH1 domain, a hinge, and a CH2 domain; a CH1 domain and a CH3 domain; a CH1 domain, a hinge, and a CH3 domain; or a CH1 domain, a hinge domain, a CH2 domain, and a CH3 domain. In certain embodiments a binding molecule, e.g., an antibody, antibody-like, or antibody-derived molecule, or fragment, e.g., multimerizing fragment, variant, or derivative thereof can include, in addition to a VH domain, a CH3 domain and a CH4 domain; or a CH3 domain, a CH4 domain, and a J-chain. Further, a binding molecule, e.g., an antibody, antibody-like, or antibody-derived molecule, for use in the disclosure can lack certain constant region portions, e.g., all or part of a CH2 domain. It will be understood by one of ordinary skill in the art that these domains (e.g., the heavy chain subunit) can be modified such that they vary in amino acid sequence from the original immunoglobulin molecule. According to embodiments of the present disclosure, an IgM antibody, IgM-like antibody, or other IgM-derived binding molecule as provided herein comprises sufficient portions of an IgM heavy chain constant region to allow the IgM antibody, IgM-like antibody, or other IgM-derived binding molecule to form a multimer, e.g., a hexamer or a pentamer. As used herein such a fragment comprises a “multimerizing fragment.” According to embodiments of the present disclosure, an IgA antibody, IgA-like antibody, or other IgA-derived binding molecule as provided herein comprises sufficient portions of an IgA heavy chain constant region to allow the IgA antibody, IgA-like antibody, or other IgA-derived binding molecule to form a multimer, e.g., a dimer or a tetramer. As used herein such a fragment comprises a “multimerizing fragment.”

As used herein, the term “light chain subunit” includes amino acid sequences derived from an immunoglobulin light chain. The light chain subunit includes at least a VL, and can further include a CL (e.g., Cκ or Cλ) domain.

Binding molecules, e.g., antibodies, antibody-like molecules, antibody-derived molecules, antigen-binding fragments, variants, or derivatives thereof, or multimerizing fragments thereof can be described or specified in terms of the epitope(s) or portion(s) of a target, e.g., a target antigen that they recognize or specifically bind. The portion of a target antigen that specifically interacts with the antigen-binding domain of an antibody is an “epitope,” or an “antigenic determinant.” A target antigen can comprise a single epitope or at least two epitopes, and can include any number of epitopes, depending on the size, conformation, and type of antigen.

As used herein, the term “hinge region” includes the portion of a heavy chain molecule that joins the CH1 domain to the CH2 domain in IgG, IgA, and IgD heavy chains, and provides flexibility to the molecule.

As used herein the term “disulfide bond” includes the covalent bond formed between two sulfur atoms, e.g., in cysteine residues of a polypeptide. The amino acid cysteine comprises a thiol group that can form a disulfide bond or bridge with a second thiol group. Disulfide bonds can be “intra-chain,” i.e., linking to cysteine residues in a single polypeptide or polypeptide subunit, or can be “inter-chain,” i.e., linking two separate polypeptide subunits, e.g., an antibody heavy chain and an antibody light chain, to antibody heavy chains, or an IgM or IgA antibody heavy chain constant region and a J-chain.

As used herein, the term “reference antibody” refers to an antibody with function similar to a multimeric binding molecule provided by this disclosure, e.g., an antibody functionally interacting with the target protein of interest that can include similar or identical antigen-binding domains. Reference antibodies may be monoclonal or polyclonal antibodies. In a particular embodiment, a “reference antibody” is a single-binding unit antibody with identical binding domains to a corresponding multimeric binding molecule as provided herein, e.g., a multimeric antibody with two, four, five, or six binding units.

As used herein, the term “chimeric antibody” refers to an antibody in which the immunoreactive region or site is obtained or derived from a first species and the constant region (which can be intact, partial, or modified) is obtained from a second species. In some embodiments the target binding region or site will be from a non-human source (e.g., mouse or primate) and the constant region is human.

The terms “multispecific antibody” or “bispecific antibody” refer to an antibody, antibody-like, or antibody-derived molecule that has antigen-binding domains for two or more different epitopes within a single antibody molecule. Other binding molecules in addition to the canonical antibody structure can be constructed with two binding specificities. Epitope binding by bispecific or multispecific antibodies can be simultaneous or sequential. Triomas and hybrid hybridomas are two examples of cell lines that can secrete bispecific antibodies. Bispecific antibodies can also be constructed by recombinant means. (Strohlein and Heiss, Future Oncol. 6:1387-94 (2010); Mabry and Snavely, IDrugs. 13:543-9 (2010)). A bispecific antibody can also be a diabody.

As used herein, the term “engineered antibody” refers to an antibody in which a variable domain, constant region, and/or J-chain is altered by at least partial replacement of one or more amino acids. In certain embodiments entire CDRs from an antibody of known specificity can be grafted into the framework regions of a heterologous antibody. Although alternate CDRs can be derived from an antibody of the same class or even subclass as the antibody from which the framework regions are derived, CDRs can also be derived from an antibody of different class, e.g., from an antibody from a different species. An engineered antibody in which one or more “donor” CDRs from a non-human antibody of known specificity are grafted into a human heavy or light chain framework region is referred to herein as a “humanized antibody.” In certain embodiments not all of the CDRs are replaced with the complete CDRs from the donor variable region and yet the antigen-binding capacity of the donor can still be transferred to the recipient variable domains. Given the explanations set forth in, e.g., U.S. Pat. Nos. 5,585,089, 5,693,761, 5,693,762, and 6,180,370, it will be well within the competence of those skilled in the art, either by carrying out routine experimentation or by trial-and-error testing, to obtain a functional engineered or humanized antibody.

As used herein the term “engineered” includes manipulation of nucleic acid or polypeptide molecules by synthetic means (e.g., by recombinant techniques, in vitro peptide synthesis, by enzymatic or chemical coupling of peptides, nucleic acids, or glycans, or some combination of these techniques).

As used herein, the terms “linked,” “fused” or “fusion” or other grammatical equivalents can be used interchangeably. These terms refer to the joining together of two more elements or components, by whatever means including chemical conjugation or recombinant means. An “in-frame fusion” refers to the joining of two or more polynucleotide open reading frames (ORFs) to form a continuous longer ORF, in a manner that maintains the translational reading frame of the original ORFs. Thus, a recombinant fusion protein is a single protein containing two or more segments that correspond to polypeptides encoded by the original ORFs (which segments are not normally so joined in nature.) Although the reading frame is thus made continuous throughout the fused segments, the segments can be physically or spatially separated by, for example, in-frame linker sequence. For example, polynucleotides encoding the CDRs of an immunoglobulin variable region can be fused, in-frame, but be separated by a polynucleotide encoding at least one immunoglobulin framework region or additional CDR regions, as long as the “fused” CDRs are co-translated as part of a continuous polypeptide.

In the context of polypeptides, a “linear sequence” or a “sequence” is an order of amino acids in a polypeptide in an amino to carboxyl terminal direction in which amino acids that neighbor each other in the sequence are contiguous in the primary structure of the polypeptide. A portion of a polypeptide that is “amino-terminal” or “N-terminal” to another portion of a polypeptide is that portion that comes earlier in the sequential polypeptide chain. Similarly, a portion of a polypeptide that is “carboxy-terminal” or “C-terminal” to another portion of a polypeptide is that portion that comes later in the sequential polypeptide chain. For example, in a typical antibody, the variable domain is “N-terminal” to the constant region, and the constant region is “C-terminal” to the variable domain.

The term “expression” as used herein refers to a process by which a gene produces a biochemical, for example, a polypeptide. The process includes any manifestation of the functional presence of the gene within the cell including, without limitation, gene knockdown as well as both transient expression and stable expression. It includes without limitation transcription of the gene into RNA, e.g., messenger RNA (mRNA), and the translation of such mRNA into polypeptide(s). If the final desired product is a biochemical, expression includes the creation of that biochemical and any precursors. Expression of a gene produces a “gene product.” As used herein, a gene product can be either a nucleic acid, e.g., a messenger RNA produced by transcription of a gene, or a polypeptide that is translated from a transcript. Gene products described herein further include nucleic acids with post transcriptional modifications, e.g., polyadenylation, or polypeptides with post translational modifications, e.g., methylation, glycosylation, the addition of lipids, association with other protein subunits, proteolytic cleavage, and the like.

The terms “neutralizing” or “neutralize” as used herein refer to the ability of a therapeutic, e.g., a therapeutic antibody, to reduce and/or prevent viral infectivity. The term “infectivity” as used herein refers to the ability of the virus to do one or more of attach to cells, enter cells, release its nucleic acid, replicate its nucleic acid, and synthesize viral proteins, and package its nucleic acid into new virions that can be released from the infected cell. A virus can be neutralized, e.g., by a therapeutic antibody, via the antibody's ability to specifically bind to the virion and inhibit its ability to attach to a host cell receptor, thereby preventing entry into the host cell.

The terms “potent” or “potency” as used herein refer to the amount required to produce an effect, e.g., the amount of a binding molecule required to neutralize infectivity of a human coronavirus. In some embodiments, the potency is measured as the 50% effective concentration (EC₅₀) or 50% inhibitory concentration (IC₅₀) to neutralize or otherwise block infectivity (e.g., block attachment of the virus to the cellular receptor) of the human coronavirus, or therapeutic protection of a subject infected with a human coronavirus, measured, e.g., as a 50% effective dose (ED₅₀), or prophylactic protection of a subject susceptible to human infection, measured, e.g., as a 50% effective dose (ED₅₀). As used herein in the context of virus neutralization, the terms “50% effective concentration (EC₅₀)” and “50% inhibitory concentration (IC₅₀)” can be used interchangeably.

As used herein, a “human coronavirus” or “H-CoV” is a virus of the family Coronaviridae that is capable of infecting humans. Some coronaviruses can be traced to zoonotic sources, e.g., bats. Certain betacoronaviruses can cause severe respiratory syndromes in humans and include, without limitation, SARS-CoV, MERS-CoV, and SARS-CoV-2. See, e.g., Sadia, A., and Basra, M. A. R., Drug Dev. Res. DOI: 10.1002/ddr.21710 (2020). The terms “SARS-CoV” and “SARS-CoV-1” are used interchangeably herein. Included herein are existing strains of human corona viruses, including but not limited to H-CoV strains 229E, NL63, OCH3, and HKV1. Further included are emerging variant strains of known human coronaviruses and escape variants including the 20H, 20I, 21A (Delta) Delta Plus, 21B (Kappa), 21D (Eta), and B.1.1.318 variants. Of particular relevance are emerging variants that are resistant to established therapeutics.

The phrase “structural protein” of a virus as used herein refer to a protein that is a component of a mature assembled viral particle and includes naturally-occurring variants. The four main structural proteins of the SARS-CoV and SARS-CoV-2 viruses include spike (S), envelope (E), membrane (M), and nucleic capsid (N). See, e.g., Sadia and Basra M. A. R., Drug Dev. Res. DOI: 10.1002/ddr.21710 (2020).

The phrases “emerging variant”, “escape mutant” or “escape variant” as used herein refer to strains of a human coronavirus comprising one or more mutations, such as a substitution, addition, or deletion, that reduces or prevents neutralization by a treatment or prophylactic, such as an antibody treatment or prophylaxis. An exemplary escape variant is a variant of an initial strain of SARS-CoV-2 that arises following contact of the initial strain of SARS-CoV-2, or cells infected with the initial strain of SARS-CoV-2, with an antibody capable of neutralizing the initial strain of SARS-CoV-2, where the escape variant is more resistant to neutralization by the antibody or is no longer capable of being neutralized by the antibody. SARS-CoV-2 escape variants can include one or more mutations, such as an amino acid substitutions, additions, or deletions, typically in the spike (S) protein, and typically in the receptor binding domain (RBD) of the S protein. Known SARS-CoV-2 escape variants that may be treated by compositions and methods described herein include, but are not limited to, 20I/501Y.V1 VOC 202012/01 (also referred to as B.1.1.7), 20H/501Y.V2 (also referred to as B.1.351), Delta variant (also referred to as B.1.617.2), Delta Plus, 20H, 20I, 21A (Delta) Delta Plus, 21B (Kappa), 21D (Eta), and B.1.1.318 variants and P.1 variants.

MERS escape variants or escape mutants can include one or more mutations, such as an amino acid substitutions, additions, or deletions, typically in the spike (S) protein, and typically in the receptor binding domain (RBD) of the S protein. Such mutants may be resistant to treatment, including immunotherapies. For example, mutations in the MERS-CoV spike (S) protein can result in reduced binding to DPP4. D510G and I528T mutations reduce S protein binding to DPP4, which can reduce levels of viral entry into cells having low levels of DPP4 (Kleine-Weber et al., J. Virol. 2019).

Terms such as “treating” or “treatment” or “to treat” or “alleviating” or “to alleviate” refer to therapeutic measures that cure, slow down, lessen symptoms of, lessen the severity of symptoms of, and/or halt or slow the progression of an existing diagnosed pathologic condition or disorder. Terms such as “prevent,” “prevention,” “avoid,” “deterrence,” “prophylactic,” and the like refer to prophylactic or preventative measures that can prevent the development of, or can reduce the symptoms of, a targeted pathologic condition or disorder in a subject who has not yet contracted the targeted pathologic condition or disorder. The targeted pathologic condition or disorder can be, for example, COVID-19. Thus, “those in need of treatment” can include those already infected with the human coronavirus, as well as those who wish to prevent infection, or reduce or alleviate symptoms associated with an infection should they become infected.

The terms “protect,” “protection,” “protective,” and other related terms, as used herein, refer to the ability of a therapeutic or prophylactic agent to confer a desirable effect on a subject diagnosed with or susceptible to an infectious disease resulting from a human coronavirus infection, such as COVID-19. Protection can include, for example, alleviation of or a reduction in infection-related symptoms in a subject infected with a human coronavirus, such as SARS-CoV-2, such that, for example, the subject does not need to be hospitalized or put on a ventilator. Protection can also include, for example, preventing healthcare workers, family members, or other contacts of infected patients from becoming infected with the human coronavirus, e.g., SARS-CoV-2, or if they do become infected, reducing the symptoms related to infection. As it applies to a therapeutic or prophylactic animal model, “protection” can include a lower 50% effective dose (ED₅₀) among a group of animal subjects challenged with the therapeutic agent either before or after challenge with the human coronavirus. Data points that can be used to measure ED₅₀vary, e.g., with the animal model or the amount of human coronavirus used to challenge the animal subjects. Data points can include, e.g., measurement of the virus titer in the lungs of the animals, weight loss, death, or disease symptoms such as fever or difficulty breathing.

The terms “antibody-dependent enhancement” and “ADE” refer to the situation where the binding of an antibody or related binding molecule can increase infectivity of an infectious virus, including coronaviruses. See, e.g., Wen, J., et al., Int. J. Infect. Dis. 100:483-489 (2020).

As used herein the terms “serum half-life” or “plasma half-life” refer to the time it takes (e.g., in minutes, hours, or days) following administration for the serum or plasma concentration of a drug, e.g., a binding molecule such as an antibody, antibody-like, or antibody-derived molecule or fragment, e.g., multimerizing fragment thereof as described herein, to be reduced by 50%. Two half-lives can be described: the alpha half-life, a half-life, or t_1/2α, which is the rate of decline in plasma concentrations due to the process of drug redistribution from the central compartment, e.g., the blood in the case of intravenous delivery, to a peripheral compartment (e.g., a tissue or organ), and the beta half-life, β half-life, or t_1/2β which is the rate of decline due to the processes of excretion or metabolism.

As used herein the term “area under the plasma drug concentration-time curve” or “AUC” reflects the actual body exposure to drug after administration of a dose of the drug and is expressed in mg*h/L. This area under the curve can be measured, e.g., from time 0 (t₀) to infinity (∞) and is dependent on the rate of elimination of the drug from the body and the dose administered.

As used herein, the term “mean residence time” or “MRT” refers to the average length of time the drug remains in the body.

By “subject” or “individual” or “animal” or “patient” is meant any subject. In certain embodiments the subject is a mammalian subject, for whom diagnosis, prognosis, or therapy is desired. Mammalian subjects include humans, domestic animals, farm animals, and zoo, sports, or pet animals such as dogs, cats, guinea pigs, rabbits, rats, mice, horses, swine, cows, bears, and so on.

As used herein, as the term “a subject that would benefit from therapy” refers to a subset of subjects, from amongst all prospective subjects, which would benefit from administration of a given therapeutic agent, e.g., a binding molecule such as an antibody, comprising one or more antigen-binding domains. Such binding molecules, e.g., antibodies, can be used, e.g., for a diagnostic procedure and/or for treatment or prevention of a disease.

Human Coronavirus, e.g., SARS-CoV-1, SARS-CoV-2, and MERS-CoV Binding Molecules

Provided herein are multimeric binding molecules comprising two to six bivalent binding units or variants or fragments thereof, where each binding unit comprises two IgA or IgM heavy chain constant regions or multimerizing fragments or variants thereof, each associated with a binding domain, where three to twelve of the binding domains are identical and specifically bind to a human coronavirus-, e.g., HCoV-229, HCoV-OC43, HCov-NL63, HCoV-HKU1, SARS-CoV, MERS-CoV, or SARS-CoV-2, any derivative or variant thereof, e.g., any naturally-occurring or non-naturally-occurring mutant (e.g., an escape mutant or emerging variant), or any combination thereof. The provided binding molecules can be used to treat or prevent human severe respiratory diseases caused by human coronaviruses, e.g., Coronavirus Disease 2019 (COVID-19).

In some embodiments, the binding molecules comprise three to twelve identical binding domains of the multimeric binding molecule that specifically bind to a human coronavirus comprise one or more heavy chain variable region (VH) and/or light chain variable region (VL) sequences or fragments thereof derived from antibodies with capacity to neutralize one or more human coronaviruses that are published in the Coronavirus Antibody Database (CoV-AbDAB), opig.stats.ox.ac.uk/webapps/covabdab/.

In some embodiments, the bivalent reference IgG antibody can bind SARS-CoV. In some embodiments, the bivalent reference IgG antibody can bind SARS-CoV-2. In some embodiments the bivalent reference antibody can bind MERS-CoV. In some embodiments, the bivalent reference molecule can bind more than one type of human coronavirus. In some embodiments, the bivalent reference IgG antibody can bind both SARS-CoV-2 and SARS-CoV. In some embodiments the bivalent reference antibody can bind SARS-CoV2, SARS-COV-1, and MERS-CoV. The ability of an antibody to bind a human coronavirus can readily be determined by one of skill in the art, such as by measuring binding in vitro using a technique such as enzyme-linked immunosorbent assay (ELISA). In some embodiments, the binding is determined at a specific concentration or within a range of concentrations of reference IgG antibody, e.g., at 0.1 nM, 1 nM, or 0.1 nM to 10 nM.

In some embodiments, the bivalent reference IgG antibody can neutralize a human coronavirus. In some embodiments, the bivalent reference IgG antibody can neutralize SARS-CoV-2. In some embodiments, the bivalent reference IgG antibody can neutralize SARS-CoV. In some embodiments the bivalent reference antibody can neutralize MERS-CoV. In some embodiments, the bivalent reference molecule can neutralize more than one type of human coronavirus. In some embodiments, the bivalent reference IgG antibody can neutralize SARS-CoV and SARS-CoV-2. In some embodiments, the bivalent reference IgG antibody can neutralize SARS-CoV-2 and cannot neutralize SARS-CoV. In some embodiments, the bivalent reference IgG antibody can neutralize SARS-CoV and cannot neutralize SARS-CoV-2. In some embodiments the bivalent reference antibody can neutralize SARS-CoV2, SARS-CoV, and MERS-CoV. In some embodiments the bivalent reference antibody can neutralize SARS-CoV2 and MERS-CoV.

In some embodiments, the provided binding molecule comprises two to six bivalent binding units or variants or multimerizing fragments thereof has greater avidity than the corresponding IgG reference antibody.

The ability of an antibody to neutralize a human coronavirus can readily be determined by one of skill in the art, such as by measuring infectivity in vitro using a viral or pseudoviral infectivity assay, such as an assay adapted from Richman et al. (PNAS, 2003, 100(7): 4144-4149) or described in Yuan et al., Science 10.1126/science.abb7269; (2020) or Muruato et al. (2020, Nat Comm. 11(1):4059. doi: 10.1038/s41467-020-17892-0). In some embodiments, the neutralization is determined at a specific concentration or within a range of concentrations of reference IgG antibody, e.g., at 0.1 nm, 1 nM, or 0.1 nM to 10 nM.

In certain embodiments, the greater potency of the provided multimeric binding molecule relative to the reference IgG can be measured, e.g., as inhibition of binding of the human coronavirus to its receptor, e.g., the SARS-CoV or SARS-CoV-2 spike protein binding to angiotensin-converting enzyme 2 (ACE2), at a lower 50% effective concentration (EC₅₀) or lower 50% inhibitory concentration (IC₅₀) than that of the bivalent reference IgG antibody. In certain embodiments the provided multimeric binding molecule can inhibit binding of the human coronavirus to its receptor, e.g., SARS-CoV or SARS-CoV-2 spike protein binding to ACE2 under conditions where the bivalent reference IgG antibody cannot inhibit binding. In certain embodiments, the greater potency of the provided multimeric binding molecule relative to the reference IgG can be measured, e.g., as inhibition of binding to the MERS-CoV spike protein binding of dipeptidyl-peptidase 4 (DPP4), at a lower EC₅₀than the bivalent reference IgG antibody. In certain embodiments the provided multimeric binding molecule can inhibit binding of MERS-CoV-spike protein binding to DPP4 under conditions where the bivalent reference IgG antibody cannot inhibit binding. In certain embodiments, the provided multimeric binding molecule can neutralize the human coronavirus, e.g., SARS-CoV, SARS-CoV-2, or MERS-CoV, at a lower EC₅₀than the bivalent reference IgG antibody. In certain embodiments, the provided multimeric binding molecule can neutralize the human coronavirus, e.g., SARS-CoV, SARS-CoV-2, or MERS-CoV under conditions where the bivalent reference IgG antibody cannot neutralize the respective human coronavirus. In certain embodiments, the provided multimeric binding molecule can protect infected animals, or prevent infection in uninfected animals in a therapeutic animal model at a lower 50% effective dose (ED₅₀) than the bivalent reference IgG antibody. In certain embodiments, the provided multimeric binding molecule can protect infected animals, or prevent infection in uninfected animals in a therapeutic animal model under conditions where the bivalent reference IgG antibody cannot protect. In certain embodiments, the provided multimeric binding molecule can comprise any combination of the foregoing properties.

In certain embodiments, the provided multimeric binding molecule can neutralize infectivity of a human coronavirus, e.g., SARS-CoV, SARS-CoV-2, or MERS-CoV, at a lower EC₅₀than the bivalent reference IgG antibody. In certain embodiments, the provided multimeric binding molecule can neutralize infectivity of a human coronavirus, e.g., SARS-CoV, SARS-CoV-2, or MERS-CoV under conditions where the bivalent reference IgG antibody cannot neutralize. In certain embodiments, the EC₅₀of the provided multimeric binding molecule is at least two-fold, at least five-fold, at least ten-fold, at least fifty-fold, at least 100-fold, at least 500-fold, or at least 1000-fold, or at least 10,000-fold lower than the EC₅₀of the bivalent reference IgG antibody. The EC₅₀can be measured either as mass per volume, e.g., μg/ml, or as the number of molecules present, e.g., moles/liter. In certain embodiments, the conditions where the bivalent reference IgG antibody cannot neutralize comprise neutralization of an antibody-resistant variant of a human coronavirus, e.g., SARS-CoV, SARS-CoV-2, or MERS-CoV. In certain embodiments, the antibody resistant variant of the human coronavirus, e.g., SARS-CoV, SARS-CoV-2, or MERS-CoV, comprises an “escape mutant” of a human coronavirus, e.g., SARS-CoV, SARS-CoV-2, or MERS-CoV virus that arose following contact with the bivalent reference IgG antibody. By “the human coronavirus, e.g., a SARS-CoV, SARS-CoV-2, or MERS-CoV virus that arose following contact with the bivalent reference IgG antibody” is meant a variant SARS-CoV-2 or MERS-CoV virus that arises in response to selective pressure. For example, an escape mutant can arise during an in vitro neutralization assay in which SARS-CoV-2 virus is contacted with the bivalent reference IgG antibody and then used to infect ACE2-expressing host cells, or during in in vivo infection of a subject animal, where the subject animal is administered the bivalent reference IgG antibody either prior to or subsequent to the virus infection. During viral replication in the host cells or subject animal mutations may arise that confer resistance to the bivalent reference IgG antibody.

In some embodiments the provided multimeric binding molecule can confer protection against a human coronavirus, e.g., SARS-CoV, SARS-CoV-2, or MERS-CoV, infection in a therapeutic or prophylactic animal model at a lower 50% effective dose (ED₅₀) than the bivalent reference IgG antibody, or wherein the binding molecule can confer protection against the human coronavirus, e.g., SARS-CoV, SARS-CoV-2, or MERS-CoV, infection in a therapeutic or prophylactic animal model under conditions where the bivalent reference IgG antibody cannot protect. As used herein, measurements of “protection” against the human coronavirus, e.g., SARS-CoV, SARS-CoV-2, or MERS-CoV, infection in an animal model can include a reduced human coronavirus, e.g., SARS-CoV, SARS-CoV-2, or MERS-CoV viral load in the subject animals, e.g., in the animals' lungs, survival of the subject animals from an otherwise lethal human coronavirus infection, and/or a reduction of symptoms typical of the human coronavirus infection in the animal model, e.g., weight loss, fever, difficulty breathing, or neurological symptoms. The ED₅₀can be measured either as mass per volume, e.g., μg/ml, or as the number of molecules present, e.g., moles/liter. In certain embodiments, the conditions where the bivalent reference IgG antibody cannot protect comprises a virus challenge with an antibody-resistant variant of a human coronavirus, e.g., SARS-CoV, SARS-CoV-2, or MERS-CoV. In certain embodiments, the antibody resistant variant of the human coronavirus comprises an “escape mutant” of a human coronavirus that arose following contact with a bivalent reference IgG antibody.

In some embodiments the multimeric binding molecule reduces, inhibits, or blocks the human coronavirus from binding to its receptor at a lower EC₅₀than the bivalent reference IgG antibody or reduces, inhibits, or blocks the human coronavirus from binding to its receptor under conditions where the bivalent reference IgG antibody cannot reduce, inhibit, or block the human coronavirus from binding to its receptor. In certain embodiments, the receptor is expressed on the surface of a cell, e.g., a cultured host cell, e.g., a Vero cell, or a cell in a susceptible subject, e.g., a human subject. In some embodiments, the binding molecule inhibits human coronavirus binding to its receptor at a lower 50% effective concentration (EC₅₀) than the bivalent reference IgG antibody. In some embodiments, the EC₅₀is at least two-fold, at least three-fold, at least four-fold, at least five-fold, at least ten-fold, at least twenty-fold, at least thirty-fold, at least forty-fold, or at least fifty-fold lower than the EC₅₀of the bivalent reference IgG antibody.

In some embodiments, the multimeric binding molecule binds a cell surface receptor involved in the attachment of the human coronavirus to a cell, a prerequisite for viral infection of the cell. In some embodiments, the human coronavirus is SARS-CoV (also referred to herein as SARS-CoV1), SARS-CoV-2, or human coronavirus NL63/HCoV-NL63, and the multimeric binding molecule reduces, inhibits, or blocks the human coronavirus from binding to its receptor, ACE2. An exemplary precursor human ACE2 amino acid sequence (UniprotKB Q9BYF1) is presented as SEQ ID NO: 14. As provided by UniprotKB, the signal peptide comprises amino acids 1 to 17 of SEQ ID NO: 14, the mature protein comprises amino acids 18 to 805 of SEQ ID NO: 2, the extracellular domain comprises amino acids 18 to 740 of SEQ ID NO: 14, the transmembrane domain comprises amino acids 741 to 761 of SEQ ID NO: 14, and the cytoplasmic domain comprises amino acids 762 to 805 of SEQ ID NO: 14. Amino acids 30-41, 82-84, and 353-357 of SEQ ID NO: 14 are reported to interact with the SARS-CoV spike protein. See Zhang, C., et al., EMBO J. 24:1634-1643 (2005).

In some embodiments, the human coronavirus is HCoV-229, and the multimeric binding molecule reduces, inhibits, or blocks the human coronavirus from binding to its receptor, aminopeptidase N (hAPN), also known as CD13.

In some embodiments, the human coronavirus is HCoV-OC43, and the multimeric binding molecule reduces, inhibits, or blocks the human coronavirus from binding to its receptor, n-acetyl-9-O-acetylneuraminic acid.

In some embodiments, the human coronavirus is HCoV-HKU1, and the multimeric binding molecule reduces, inhibits, or blocks the human coronavirus from binding to its receptor, O-acetylated sialic acid.

In some embodiments, the human coronavirus is MERS-CoV, and the multimeric binding molecule reduces, inhibits, or blocks the human coronavirus from binding to its receptor, dipeptidyl-peptidase 4 (DPP4), also known as CD26. An exemplary version of human DPP4 has the UniProtKB accession number P27487.

In some embodiments the multimeric binding molecule reduces, inhibits, or blocks the SARS-CoV or the SARS-CoV-2 S protein from binding to ACE2 at a lower EC₅₀than the bivalent reference IgG antibody or reduces, inhibits, or blocks the SARS-CoV or the SARS-CoV-2 S protein from binding to ACE2 under conditions where the bivalent reference IgG antibody cannot reduce, inhibit, or block the SARS-CoV or the SARS-CoV-2 S protein from binding to ACE2. In certain embodiments the ACE2 is human ACE2, e.g., amino acids 18 to 805 of SEQ ID NO: 14. In certain embodiments, ACE2 is expressed on the surface of a cell, e.g., a cultured host cell, e.g., a Vero cell, or a cell in a susceptible subject, e.g., a human subject. In some embodiments, the binding molecule inhibits SARS-CoV-2 binding to its receptor, e.g., ACE2, at a lower 50% effective concentration (EC₅₀) than the bivalent reference IgG antibody. In some embodiments, the EC₅₀is at least two-fold, at least three-fold, at least four-fold, at least five-fold, at least ten-fold, at least twenty-fold, at least thirty-fold, at least forty-fold, or at least fifty-fold lower than the EC₅₀of the bivalent reference IgG antibody.

In some embodiments the multimeric binding molecule reduces, inhibits, or blocks the MERS-CoV S protein from binding to DPP4/CD26 at a lower EC₅₀than the bivalent reference IgG antibody or reduces, inhibits, or blocks the MERS-CoV S protein from binding to DPP4/CD26 under conditions where the bivalent reference IgG antibody cannot reduce, inhibit, or block the MERS-CoV S protein from binding to DPP4/CD26. In certain embodiments the DPP4/CD26 is human DPP4/CD26. In certain embodiments, DPP4/CD26 is expressed on the surface of a cell, e.g., a cultured host cell, e.g., a Vero cell, or a cell in a susceptible subject, e.g., a human subject. In some embodiments, the binding molecule inhibits MERS-CoV binding to its receptor, e.g., DPP4/CD26, at a lower 50% effective concentration (EC₅₀) than the bivalent reference IgG antibody. In some embodiments, the EC₅₀is at least two-fold, at least three-fold, at least four-fold, at least five-fold, at least ten-fold, at least twenty-fold, at least thirty-fold, at least forty-fold, or at least fifty-fold lower than the EC₅₀of the bivalent reference IgG antibody.

Human coronaviruses are known to develop one or more mutations overtime that may alter the behavior of the virus. For example, SARS-CoV-2 has developed a spike mutant (D614G) that is believed to be more infectious than the original SARS-CoV-2 strain that does not contain this mutation (Korber et al. Cell 2020, DOI: 10.1016/j.cell.2020.06.043). D510G and I528T mutations in the MERS-CoV spike (S) protein can result in reduced binding to its receptor, DPP4, resulting in a reduction in a reduction in levels of viral entry into cells having low levels of DPP4 (Kleine-Weber et al., J. Virol. 2019).

A reference precursor SARS-CoV S protein (UniProtKB—P59594 (SPIKE_SARS)) is presented herein as SEQ ID NO: 16. Myriad variant SARS CoV S proteins have been sequenced and are available in the literature but share the common structure of SEQ ID NO: 16. As reported in UniProtKB, the signal peptide of the precursor SARS-CoV S protein corresponds to amino acids 1 to 13 of SEQ ID NO: 16, the mature SARS-CoV S protein corresponds to amino acids 14 to 1255 of SEQ ID NO: 16, the S1 region of the SARS-CoV S protein corresponds to amino acids 14 to 667 of SEQ ID NO: 16, the S2 region of the SARS-CoV S protein corresponds to amino acids 668 to 1255 of SEQ ID NO: 16, the receptor binding domain (RBD) of the SARS-CoV S protein corresponds to amino acids 306 to 527 of SEQ ID NO: 16 (underlined below), the receptor binding motif of the SARS-CoV S protein corresponds to amino acids 424 to 494 of SEQ ID NO: 16, the extracellular domain of the SARS-CoV S protein corresponds to amino acids 14 to 1195 of SEQ ID NO: 16, the transmembrane domain of the SARS-CoV S protein corresponds to amino acids 1196 to 1216 of SEQ ID NO: 16, and the cytoplasmic domain of the SARS-CoV S protein corresponds to amino 1214 to 1255 of SEQ ID NO: 16. As persons of ordinary skill in the art will recognize, the RBD of various SARS-CoV S proteins present in the environment have mutated so an RBD that “corresponds” to amino acids 306 to 527 of SEQ ID NO: 16 may not be identical to amino acids 306 to 527 of SEQ ID NO: 16. The TMPRSS2 or furin cleavage site between the S1 and S2 subunits is between amino acids 667 and 668 of SEQ ID NO: 16.

SEQ ID NO: 16: SARS-CoV Spike Protein, UniProt: P59594

1 MEIFLLFLTL TSGSDLDRCT TFDDVQAPNY TQHTSSMRGV YYPDEIFRSD TLYLTQDLFL

61 PFYSNVTGFH TINHTFGNPV IPFKDGIYFA ATEKSNVVRG WVFGSTMNNK SQSVIIINNS

121 TNVVIRACNF ELCDNPFFAV SKPMGTQTHT MIFDNAFNCT FEYISDAFSL DVSEKSGNFK

181 HLREFVFKNK DGFLYVYKGY QPIDVVRDLP SGFNTLKPIF KLPLGINITN FRAILTAFSP

241 AQDIWGTSAA AYFVGYLKPT TFMLKYDENG TITDAVDCSQ NPLAELKCSV KSFEIDKGIY

301 QTSNFRVVPS GDVVRFPNIT NLCPFGEVFN ATKFPSVYAW ERKKISNCVA DYSVLYNSTF

361 FSTFKCYGVS ATKLNDLCFS NVYADSFVVK GDDVRQIAPG QTGVIADYNY KLPDDFMGCV

421 LAWNTRNIDA TSTGNYNYKY RYLRHGKLRP FERDISNVPF SPDGKPCTPP ALNCYWPLND

481 YGFYTTTGIG YQPYRVVVLS FELLNAPATV CGPKLSTDLI KNQCVNFNFN GLTGTGVLTP

541 SSKRFQPFQQ FGRDVSDFTD SVRDPKTSEI LDISPCSFGG VSVITPGTNA SSEVAVLYQD

601 VNCTDVSTAI HADQLTPAWR IYSTGNNVFQ TQAGCLIGAE HVDTSYECDI PIGAGICASY

661 HTVSLLRSTS QKSIVAYTMS LGADSSIAYS NNTIAIPTNF SISITTEVMP VSMAKTSVDC

721 NMYICGDSTE CANLLLQYGS FCTQLNRALS GIAAEQDRNT REVFAQVKQM YKTPTLKYFG

781 GFNFSQILPD PLKPTKRSFI EDLLFNKVTL ADAGFMKQYG ECLGDINARD LICAQKFNGL

841 TVLPPLLTDD MIAAYTAALV SGTATAGWTF GAGAALQIPF AMQMAYRFNG IGVTQNVLYE

901 NQKQIANQFN KAISQIQESL TTTSTALGKL QDVVNQNAQA LNTLVKQLSS NFGAISSVLN

961 DILSRLDKVE AEVQIDRLIT GRLQSLQTYV TQQLIRAAEI RASANLAATK MSECVLGQSK

1021 RVDFCGKGYH LMSFPQAAPH GVVFLHVTYV PSQERNFTTA PAICHEGKAY FPREGVFVFN

1081 GTSWFITQRN FFSPQIITTD NTFVSGNCDV VIGIINNTVY DPLQPELDSF KEELDKYFKN

1141 HTSPDVDLGD ISGINASVVN IQKEIDRLNE VAKNLNESLI DLQELGKYEQ YIKWPWYVWL

1201 GFIAGLIAIV MVTILLCCMT SCCSCLKGAC SCGSCCKFDE DDSEPVLKGV KLHYT

A reference precursor SARS-CoV-2 S protein (UniProtKB—P0DTC2 (SPIKE_SARS2)) is presented herein as SEQ ID NO: 17. Myriad variant SARS CoV-2 S proteins have been sequenced and are available in the literature but share the common structure of SEQ ID NO: 17. As reported in UniProtKB, the signal peptide of the precursor SARS-CoV-2 S protein corresponds to amino acids 1 to 12 of SEQ ID NO: 17, the mature SARS-CoV-2 S protein corresponds to amino acids 13 to 1273 of SEQ ID NO: 17, the S1 region of the SARS-CoV-2 S protein corresponds to amino acids 13 to 685 of SEQ ID NO: 17, the S2 region of the SARS-CoV-2 S protein corresponds to amino acids 686 to 1273 of SEQ ID NO: 17, the receptor binding domain (RBD) of the SARS-CoV-2 S protein corresponds to amino acids 319 to 541 of SEQ ID NO: 17 (underlined below, Yan, R. et al., Science 367:1444-1448 (2020)), the receptor binding motif of the SARS-CoV-2 S protein corresponds to amino acids 437 to 508 of SEQ ID NO: 17, the extracellular domain of the SARS-CoV-2 S protein corresponds to amino acids 13 to 1213 of SEQ ID NO: 17, the transmembrane domain of the SARS-CoV-2 S protein corresponds to amino acids 1214 to 1234 of SEQ ID NO: 17, and the cytoplasmic domain of the SARS-CoV-2 S protein corresponds to amino 1235 to 1273 of SEQ ID NO: 17. As persons of ordinary skill in the art will recognize, the RBD of various SARS-CoV-2 S proteins present in the environment have mutated so an RBD that “corresponds” to amino acids 319 to 541 of SEQ ID NO: 17 may not be identical to amino acids 319 to 541 of SEQ ID NO: 17. The TMPRSS2 or furin cleavage site between the S1 and S2 subunits is between amino acids 685 and 686 of SEQ ID NO: 17 (Hoffmann, M. et al., Cell 181:271-280 (2020)).

SEQ ID NO: 17: SARS-CoV-2 Spike Protein, UniProt: P0DTC2

1 MFVFLVLLPL VSSQCVNLTT RTQLPPAYTN SFTRGVYYPD KVFRSSVLHS TQDLFLPFFS

61 NVTWFHAIHV SGTNGTKRFD NPVLPFNDGV YFASTEKSNI IRGWIFGTTL DSKTQSLLIV

121 NNATNVVIKV CEFQFCNDPF LGVYYHKNNK SWMESEFRVY SSANNCTFEY VSQPFLMDLE

181 GKQGNFKNLR EFVFKNIDGY FKIYSKHTPI NLVRDLPQGF SALEPLVDLP IGINITRFQT

241 LLALHRSYLT PGDSSSGWTA GAAAYYVGYL QPRTFLLKYN ENGTITDAVD CALDPLSETK

301 CTLKSFTVEK GIYQTSNFRV QPTESIVRFP NITNLCPFGE VFNATRFASV YAWNRKRISN

361 CVADYSVLYN SASFSTFKCY GVSPIKLNDL CFTNVYADSF VIRGDEVRQI APGQTGKIAD

421 YNYKLPDDFT GCVIAWNSNN LDSKVGGNYN YLYRLFRKSN LKPFERDIST EIYQAGSTPC

481 NGVEGFNCYF PLQSYGFQPT NGVGYQPYRV VVLSFELLHA PATVCGPKKS TNLVKNKCVN

541 FNFNGLTGTG VLTESNKKFL PFQQFGRDIA DTTDAVRDPQ TLEILDITPC SFGGVSVITP

601 GINTSNQVAV LYQDVNCTEV PVAIHADQLT PTWRVYSTGS NVFQTRAGCL IGAEHVNNSY

661 ECDIPIGAGI CASYQTQTNS PRRAPSVASQ SIIAYTMSLG AENSVAYSNN SIAIPTNFTI

721 SVTTEILPVS MTKTSVDCTM YICGDSTECS NLLLQYGSFC TQLNRALTGI AVEQDKNTQE

781 VFAQVKQIYK TPPIKDFGGF NFSQILPDPS KPSKRSFIED LLFNKVTLAD AGFIKQYGDC

841 LGDIAARDLI CAQKENGLTV LPPLLTDEMI AQYTSALLAG TITSGWTFGA GAALQIPFAM

901 QMAYRFNGIG VTQNVLYENQ KLIANQFNSA IGKIQDSLSS TASALGKLQD VVNQNAQALN

961 TLVKQLSSNF GAISSVLNDI LSRLDKVEAE VQIDRLITGR LQSLQTYVTQ QLIRAAEIRA

1021 SANLAATKMS ECVLGQSKRV DFCGKGYHLM SFPQSAPHGV VFLHVTYVPA QEKNFTTAPA

1081 ICHDGKAHFP REGVFVSNGT HWFVTQRNFY EPQIITTDNT FVSGNCDVVI GIVNNTVYDP

1141 LQPELDSFKE ELDKYFKNHT SPDVDLGDIS GINASVVNIQ KEIDRLNEVA KNLNESLIDL

1201 QELGKYEQYI KWPWYIWLGF IAGLIAIVMV TIMLCCMTSC CSCLKGCCSC GSCCKFDEDD

1261 SEPVLKGVKL HYT

A reference precursor MERS-CoV S protein (UniProtKB—K9N5Q8 (SPIKE_MERS1)) is presented herein as SEQ ID NO: 18. Myriad variant MERS-CoV S proteins have been sequenced and are available in the literature but share the common structure of SEQ ID NO: 18. As reported in UniProtKB, the signal peptide of the precursor MERS-CoV S protein corresponds to amino acids 1 to 17 of SEQ ID NO: 18, the mature MERS-CoV S protein corresponds to amino acids 18 to 1353 of SEQ ID NO: 18, the S1 region of the MERS-CoV S protein corresponds to amino acids 18 to 751 of SEQ ID NO: 18, the S2 region of the MERS-CoV S protein corresponds to amino acids 752 to 1353 of SEQ ID NO: 18, the receptor binding domain (RBD) of the MERS-CoV S protein corresponds to amino acids 367 to 606 of SEQ ID NO: 18 (underlined below, Wang, et al., Cell Res. 23:986-993 (2013)), the extracellular domain of the MERS-CoV S protein corresponds to amino acids 18 to 1296 of SEQ ID NO: 18, the transmembrane domain of the MERS-CoV S protein corresponds to amino acids 1297 to 1317 of SEQ ID NO: 18, and the cytoplasmic domain of the MERS-CoV S protein corresponds to amino 1318 to 1353 of SEQ ID NO: 18. As persons of ordinary skill in the art will recognize, the RBD of various MERS-CoV S proteins present in the environment have mutated so an RBD that “corresponds” to amino acids 367 to 606 of SEQ ID NO: 18 may not be identical to amino acids 367 to 606 of SEQ ID NO: 18. The furin cleavage site between the S1 and S2 subunits is between amino acids 751 and 752 of SEQ ID NO: 18.

SEQ ID NO: 18: MERS-CoV Spike Protein, UniProt: K9N5Q8

1 MIHSVFLLMF LLTPTESYVD VGPDSVKSAC IEVDIQQTFF DKTWPRPIDV SKADGIIYPQ

61 GRTYSNITIT YQGLFPYQGD HGDMYVYSAG HATGTTPQKL FVANYSQDVK QFANGFVVRI

121 GAAANSTGTV IISPSTSATI RKIYPAFMLG SSVGNFSDGK MGRFFNHTLV LLPDGCGTLL

181 RAFYCILEPR SGNHCPAGNS YTSFATYHTP ATDCSDGNYN RNASLNSFKE YFNLRNCTFM

241 YTYNITEDEI LEWFGITQTA QGVHLFSSRY VDLYGGNMFQ FATLPVYDTI KYYSIIPHSI

301 RSIQSDRKAW AAFYVYKLQP LTFLLDFSVD GYIRRAIDCG FNDLSQLHCS YESFDVESGV

361 YSVSSFEAKP SGSVVEQAEG VECDFSPLLS GTPPQVYNFK RLVFTNCNYN LTKLLSLFSV

421 NDFTCSQISP AAIASNCYSS LILDYFSYPL SMKSDLSVSS AGPISQFNYK QSFSNPTCLI

481 LATVPHNLTT ITKPLKYSYI NKCSRFLSDD RTEVPQLVNA NQYSPCVSIV PSTVWEDGDY

541 YRKQLSPLEG GGWLVASGST VAMTEQLQMG FGITVQYGTD TNSVCPKLEF ANDTKIASQL

601 GNCVEYSLYG VEGRGVFQNC TAVGVRQQRF VYDAYQNLVG YYSDDGNYYC LRACVSVPVS

661 VIYDKETKTH ATLFGSVACE HISSTMSQYS RSTRSMLKRR DSTYGPLQTP VGCVLGLVNS

721 SLFVEDCKLP LGQSLCALPD TPSTLTPRSV RSVPGEMRLA SIAFNHPIQV DQLNSSYFKL

781 SIPTNFSFGV TQEYIQTTIQ KVTVDCKQYV CNGFQKCEQL LREYGQFCSK INQALHGANL

841 RQDDSVRNLF ASVKSSQSSP IIPGFGGDFN LTLLEPVSIS TGSRSARSAI EDLLFDKVTI

901 ADPGYMQGYD DCMQQGPASA RDLICAQYVA GYKVLPPLMD VNMEAAYTSS LLGSIAGVGW

961 TAGLSSFAAI PFAQSIFYRL NGVGITQQVL SENQKLIANK FNQALGAMQT GETTTNEAFH

1021 KVQDAVNNNA QALSKLASEL SNTFGAISAS IGDIIQRLDV LEQDAQIDRL INGRLTTLNA

1081 FVAQQLVRSE SAALSAQLAK DKVNECVKAQ SKRSGFCGQG THIVSFVVNA PNGLYFMHVG

1141 YYPSNHIEVV SAYGLCDAAN PTNCIAPVNG YFIKTNNTRI VDEWSYTGSS FYAPEPITSL

1201 NTKYVAPQVT YQNISTNLPP PLLGNSTGID FQDELDEFFK NVSTSIPNFG SLTQINTTLL

1261 DLTYEMLSLQ QVVKALNESY IDLKELGNYT YYNKWPWYIW LGFIAGLVAL ALCVFFILCC

1321 TGCGTNCMGK LKCNRCCDRY EEYDLEPHKV HVH

Human coronaviruses are known to develop one or more mutations, particularly in the receptor binding domain (RBD) of the spike (S) protein over time that may alter the behavior of the virus. The SARS-CoV-2 variants are identified, for example, by nomenclature referred to as “pango” lineages (Rambaut, A., et al., Nature Microbiol. 5:1403-1407 (2020)), and have been assigned Greek letter nomenclature by the World Health Organization (who.int/en/activities/tracking-SARS-CoV-2-variants/). SARS CoV-2 variants of clinical relevance are cataloged by the Centers for Disease Control, e.g., at cdc.gov/coronavirus/2019-ncov/variants/variant-info.html (last visited Jul. 5, 2021). The CDC catalog is updated regularly. Those of skill in the art will understand that these lineages do not correspond to exact sequences and are generally characterized by the amino acid variations noted below, particularly in the RBD region, but may be mixtures and may include additional or fewer amino acid deletions, insertions, and/or substitutions relative to SEQ ID NO: 17.

For example, the pango lineage B.1.1.7 or WHO “Alpha” variant first identified in the UK includes an RBD substitution of tyrosine (Y) for asparagine (N) at a position corresponding to amino acid 501 in SEQ ID NO: 17, and can include additional spike protein alterations such as amino acid deletions at positions corresponding to amino acids 69, 70, and 144 of SEQ ID NO: 17, and amino acid substitutions A570D, D614G, P681H, T716I, S982A, D1118H corresponding to the indicated positions in SEQ ID NO: 17. By “an amino acid corresponding to amino acid 501 in SEQ ID NO: 17 (and other spike protein mutations described herein) is meant the amino acid in the sequence of any given SARS-CoV-2 spike protein, which is homologous to N501 in SEQ ID NO: 17. Variant viruses carrying this “N501Y” mutation have been shown to be more highly transmissible than the non-variant virus. See Leung, K., et al., Euro Surveill. 26:2002106. doi: 10.2807/1560-7917.ES.2020.26.1.2002106 (2021).

The pango lineage B.1.351 or WHO “Beta” variant first identified in South Africa includes K417N, E484K and N501Y RBD substitutions corresponding to the indicated positions in SEQ ID NO: 17 and can include additional spike protein substitutions such as D80A, D215G, D614G, and A701V and amino acid deletions corresponding to amino acids 241-243 (all positions corresponding to SEQ ID NO: 17). This variant is likewise believed to be more highly transmissible. See Wibmer, C K et al., Nature Med.: 27:622-625, doi: 10.1038/s41591-021-01285-x (2021).

The pango lineage P.1 or WHO “Gamma” variant first identified in Brazil includes K417T, E484K, and N501Y RBD substitutions corresponding to the indicated positions in SEQ ID NO: 17 and can include additional spike protein substitutions such as L18F, T20N, P26S, D138Y, R190S, D614G, H655Y, and T10271 (all positions corresponding to SEQ ID NO: 17). This variant again is believed to be more highly transmissible. See Faria, Nuno R., et al., Virological (2021) (available at icpcovid.com, visited Feb. 19, 2021). Additionally, a SARS-CoV-2 variant with a D614G mutation is believed to have increased infectivity and transmissibility (Korber B., et al., Cell 182:812-827 (2020)).

The pango lineage B.1.525 or WHO “Eta” variant first identified in Nigeria includes an E484K RBD substitution corresponding to the indicated position in SEQ ID NO: 17 and can include additional spike protein alterations such as amino acid deletions at positions corresponding to amino acids 69, 70, and 144 of SEQ ID NO: 17, and spike protein substitutions Q52R, A67V, D614G, Q677H, F888L (all positions corresponding to SEQ ID NO: 17).

The pango lineage B.1.617.1 or WHO “Kappa” variant first identified in India includes L452R and E484Q RBD substitutions corresponding to the indicated positions in SEQ ID NO: 17 and can include spike protein substitutions such as G142D, E154K, D614G, P681R, Q1071H, and H1101D (all positions corresponding to SEQ ID NO: 17).

The pango lineage B.1.617.2 or WHO “Delta” variant first identified in India includes L452R and T478K RBD substitutions corresponding to the indicated positions in SEQ ID NO: 17 and can include additional spike protein substitutions such as T19R, G142D, D614G, P681R, and D950N (all positions corresponding to SEQ ID NO: 17). A newly-emerging Delta variant, designated “Delta Plus” or Pango lineage B.1.617.2/AY.1 further includes a K417N substitution corresponding to SEQ ID NO: 17.

The pango lineage B.1.617.2.v2 variant first identified in India includes L452R and T478K RBD substitutions corresponding to the indicated positions in SEQ ID NO: 17 and can include additional spike protein alterations such as amino acid deletions at positions corresponding to amino acids 157 and 158 of SEQ ID NO: 17, and spike protein substitutions such as T19R, G142D, E156G, D614G, P681R, and D950N (all positions corresponding to SEQ ID NO: 17).

The pango lineage B.1.618 variant first identified in India includes an E484K RBD substitution corresponding to the indicated position in SEQ ID NO: 17 and can include additional spike protein alterations such as amino acid deletions at positions corresponding to amino acids 145 and 146 of SEQ ID NO: 17, and spike protein substitutions such as H49Y and D614G (all positions corresponding to SEQ ID NO: 17).

Of particular concern is the potential development of escape mutations that can reduce or prevent neutralization by a therapy, such as an antibody therapy. The multimeric binding molecules disclosed herein may be able to maintain the ability to bind and neutralize strains of the human coronavirus that are escape mutants for the corresponding IgG antibody. Additionally, the multimeric binding molecules disclosed herein may be less prone to generating escape mutants. Accordingly, in certain embodiments, the human coronavirus, e.g., SARS-CoV-2, is a reference IgG antibody escape mutant.

Prevalent SARS-CoV-2 escape mutations include, without limitation, N439K, Y453F, S477N, and N501Y, which are four prevalent RBD mutations in circulation and are associated with resistance to several neutralizing mAbs (Thomson, E. C., et al. Cell 184: 1171-1187 (2021); Liu, Z., et al. bioRxiv doi: 10.2139/ssrn.3725763 (2020); Weisblum, Y., et al., eLife 9:e61312 doi: 10.7554/eLife.61312 (Oct. 28, 2020); Hayashi et al. medRxiv doi: 10.1101/2021.01.28.21250577). Other RBD mutations are associated with resistance to three approved mAbs, Bamlanivimab (E484K, F490S, Q493R, S494P), Casivirivimab (REGN-10933, K417E, Y453F, L455F, G476S, F486V, Q493K) and Imdevimab (REGN-10987, K444Q, V445A, G446V) (Fact Sheet for Health Care Providers Emergency Use Authorization (EUA) of Bamlanivimab, (2020); Fact Sheet for Health Care Providers Emergency Use Authorization (EUA) Of Casirivimab and Imdevimab, (2020), both available at fda.gov (visited Jan. 25, 2021).

Exemplary escape mutations in the SARS-CoV S protein corresponding to SEQ ID NO: 16 that block neutralization by selected SARS-CoV antibodies are identified, e.g., in Rockx, B., et al. J. Infect. Dis. 201:946-955 (2010), and Sui, et al., J. Virol. 88:13769-13780 (2014).

Exemplary MERS-CoV escape mutations in the MERS-CoV S protein corresponding to SEQ ID NO: 18 that block neutralization by selected MERS-CoV antibodies are identified, e.g., in Kleine Weber et al., J. Virol. 93(2):e01381-18 (2019).

Antibody-dependent enhancement (ADE) of diseases caused by human coronaviruses is a concern (Houser, K. V., et al., PLoS Pathog. 13: Article e1006565 (2017) (MERS-CoV); Weiss, R. C., and F. W. Scott Comp. Immunol. Microbiol. Infect. Dis 4:175-189 (1981) (feline infectious peritonitis virus); and Kam, Y. W., et al., Vaccine 25:729-740 (2007) (SARS-CoV)). It is believed that Fcγ receptors may mediate antibody dependent entry into cells (Kam et al., supra). Fcγ receptors do not bind IgA or IgM antibodies. Accordingly, the multimeric binding molecules disclosed herein can have a reduced risk of ADE than the reference IgG antibody. In some embodiments, the multimeric binding molecule cannot cause ADE.

As the terms “SARS” and “MERS” imply, infection with SARS-CoV, SARS-CoV-2, and MERS-CoV often leads to severe respiratory symptoms. These respiratory symptoms make the respiratory mucosa an important tissue to target for any molecule developed to treat or prevent SARS, COVID-19, or MERS; however, the epithelium often prevents the transcytosis of therapeutics such as IgG antibodies. By contrast, polymeric immunoglobulin receptors (pIgR) on the epithelium bind the J-chain of IgA and IgM antibodies and transports the molecules across the epithelia to the mucosa. During this process, the process, the extracellular region of pIgR is cleaved and is then termed the secretory component. Accordingly, in some embodiments, the multimeric binding molecule can transport across vascular endothelial cells via J-chain binding to the polymeric Ig receptor (PIgR). It is believed that recombinant secretory component can also facilitate transcytosis of J-chain comprising molecules to the mucosa. Accordingly, in some embodiments, the multimeric binding molecule comprises a secretory component, or fragment or variant thereof. In some embodiments, the multimeric binding molecule comprises a secretory component.

In certain embodiments, the binding molecule is more potent than a bivalent reference IgG antibody comprising two of the human coronavirus, e.g., SARS-CoV, SARS-CoV-2 or MERS-CoV, binding domains. In some embodiments, the binding molecule neutralizes human coronavirus, e.g., SARS-CoV, SARS-CoV-2 or MERS-CoV infectivity at a lower 50% effective concentration (EC₅₀) than the bivalent reference IgG antibody. In some embodiments, the EC₅₀is at least two-fold, at least three-fold, at least four-fold, at least five-fold, at least ten-fold, at least twenty-fold, at least thirty-fold, at least forty-fold, at least fifty-fold, at least seventy-five-fold, at least 100-fold, at least 200-fold, at least 300-fold, at least 400-fold, at least 500-fold, at least 750-fold or at least 1000-fold lower than the EC₅₀of the bivalent reference IgG antibody.

In some embodiments, the multimeric binding molecule reduces, inhibits, or blocks the human coronavirus, e.g., SARS-CoV or SARS-CoV-2 from binding to its receptor, e.g., angiotensin-converting enzyme 2 (ACE2). In some embodiments, the multimeric binding molecule reduces, inhibits, or blocks the human coronavirus, e.g., MERS-CoV binding to its receptor, e.g., dipeptidyl peptidase 4 (DPP4). In some embodiments, the multimeric binding molecule reduces, inhibits, or blocks the human coronavirus binding to its receptor more than a bivalent reference IgG antibody comprising two of the human coronavirus, e.g., SARS-CoV, SARS-CoV-2 or MERS-CoV, binding domains. In some embodiments, the multimeric binding molecule reduces, inhibits, or blocks SARS-CoV or SARS-CoV2 binding to ACE2 more than a bivalent reference IgG antibody comprising two of the human coronavirus, e.g., SARS-CoV or SARS-CoV-2, binding domains. In some embodiments, the multimeric binding molecule reduces, inhibits, or blocks MERS-CoV binding to DPP4 more than a bivalent reference IgG antibody comprising two of the human coronavirus, e.g., MERS-CoV, binding domains. In some embodiments, the binding molecule inhibits human coronavirus, e.g., SARS-CoV-2 binding to its receptor, e.g., ACE2, at a lower 50% inhibitory concentration (IC₅₀) than the bivalent reference IgG antibody. In some embodiments, the binding molecule inhibits human coronavirus, e.g., MERS-CoV binding to its receptor, e.g., DPP4, at a lower 50% inhibitory concentration (IC₅₀) than the bivalent reference IgG antibody. In some embodiments, the IC₅₀is at least two-fold, at least three-fold, at least four-fold, at least five-fold, at least ten-fold, at least twenty-fold, at least thirty-fold, at least forty-fold, at least fifty-fold, at least seventy-five-fold, at least 100-fold, at least 200-fold, at least 300-fold, at least 400-fold, at least 500-fold, at least 750-fold or at least 1000-fold lower than the IC₅₀of the bivalent reference IgG antibody.

In some embodiments, the multimeric binding molecules are dimeric and comprise two bivalent binding units or variants or fragments thereof. In some embodiments, the multimeric binding molecules are dimeric, comprise two bivalent binding units or variants or fragments thereof, and further comprise a J-chain or functional fragment or variant thereof as described herein. In some embodiments, the multimeric binding molecules are dimeric, comprise two bivalent binding units or variants or fragments thereof, and further comprise a J-chain or functional fragment or variant thereof as described herein, where each binding unit comprises two IgA heavy chain constant regions or multimerizing fragments or variants thereof.

In some embodiments, the multimeric binding molecules are tetrameric and comprise four bivalent binding units or variants or fragments thereof. In some embodiments, the multimeric binding molecules are tetrameric, comprise four bivalent binding units or variants or fragments thereof, and further comprise a J-chain or functional fragment or variant thereof as described herein. In some embodiments, the multimeric binding molecules are tetrameric, comprise four bivalent binding units or variants or fragments thereof, and further comprise a J-chain or functional fragment or variant thereof as described herein, where each binding unit comprises two IgA heavy chain constant regions or multimerizing fragments or variants thereof.

In some embodiments, the multimeric binding molecules are pentameric and comprise five bivalent binding units or variants or fragments thereof. In some embodiments, the multimeric binding molecules are pentameric and comprise five bivalent binding units or variants or fragments thereof, and further comprise a J-chain or functional fragment or variant thereof as described herein. In some embodiments, the multimeric binding molecules are pentameric and comprise five bivalent binding units or variants or fragments thereof, and further comprise a J-chain or functional fragment or variant thereof as described herein, where each binding unit comprises two IgM heavy chain constant regions or multimerizing fragments or variants thereof.

In some embodiments, the multimeric binding molecules are hexameric and comprise six bivalent binding units or variants or fragments thereof. In some embodiments, the multimeric binding molecules are hexameric and comprise six bivalent binding units or variants or fragments thereof, and where each binding unit comprises two IgM heavy chain constant regions or multimerizing fragments or variants thereof.

In certain embodiments, heavy chain constant regions in the provided binding molecules are each associated with a binding domain, e.g., an antibody antigen-binding domain, e.g., a scFv, a VHH or the VH subunit of an antibody antigen-binding domain. The multimeric binding molecule disclosed herein can comprise three to twelve binding domains that are human coronavirus, e.g., SARS-CoV, SARS-CoV-2 or MERS-CoV binding domains. In some embodiments, the multimeric binding molecule, such as an IgA antibody, an IgA-like antibody, or an IgA-derived binding molecule comprises three to eight binding domains that specifically bind to the human coronavirus, e.g., SARS-CoV, SARS-CoV-2 or MERS-CoV. In some embodiments, the multimeric binding molecule, such as an IgA antibody, an IgA-like antibody, or an IgA-derived binding molecule comprises four binding domains that specifically bind to the human coronavirus, e.g., SARS-CoV, SARS-CoV-2 or MERS-CoV. In some embodiments, the multimeric binding molecule, such as an IgA antibody, an IgA-like antibody, or an IgA-derived binding molecule comprises eight binding domains that specifically bind to the human coronavirus, e.g., SARS-CoV, SARS-CoV-2 or MERS-CoV. In some embodiments, the multimeric binding molecule, such as an IgM antibody, an IgM-like antibody, or an IgM-derived binding molecule comprises ten or twelve binding domains that specifically bind to the human coronavirus, e.g., SARS-CoV, SARS-CoV-2 or MERS-CoV.

In certain embodiments, the provided multimeric binding molecule is multispecific, e.g., bispecific, trispecific, or tetraspecific, where two or more binding domains associated with the heavy chain constant regions of the binding molecule specifically bind to different targets. In certain embodiments, the binding domains of the multimeric binding molecule all specifically bind to the human coronavirus, e.g., SARS-CoV, SARS-CoV-2 or MERS-CoV. In certain embodiments, the binding domains of the multimeric binding molecule are identical. In such cases, the multimeric binding molecule can still be bispecific, if, for example, a binding domain with a different specificity is part of a modified J-chain as described elsewhere herein. In certain embodiments, the binding domains are antibody-derived antigen-binding domains, e.g., a scFv associated with the heavy chain constant regions or a VH subunit of an antibody binding domain associated with the heavy chain constant regions.

For example, in some embodiments, the provided multimeric binding molecule binds a conserved, or highly conserved, cryptic receptor binding domain epitope and cross-reacts or binds spike protein epitopes of all human corona viruses. See, e.g., Tortorici et al., Nature, (2021) doi: 10.1038/s41586-021-03817-4. In some embodiments, the multimeric binding protein that binds all human coronaviruses comprise a heavy chain variable region (VH) and a light chain variable region (VL), wherein the VH and VL comprise six immunoglobulin complementarity determining regions HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 comprise the CDRs of an antibody comprising the VH and VL of SEQ ID NOS:384 and 385. In some embodiments the multimeric binding protein that binds all human coronaviruses is an IgM antibody. In some embodiments the IgM antibody comprises a modified or variant J-chain. In some embodiments the multimeric binding protein that binds all human coronaviruses is an IgA antibody.

In certain embodiments, each binding unit comprises two heavy chains each comprising a VH situated amino terminal to the heavy chain constant region, and two immunoglobulin light chains each comprising a light chain variable domain (VL) situated amino terminal to an immunoglobulin light chain constant region, e.g., a kappa or lambda constant region. The provided VH and VL combine to form an antigen-binding domain that specifically binds to the target. In certain embodiments each antigen-binding domain of each binding molecule binds to the human coronavirus, e.g., SARS-CoV, SARS-CoV-2 or MERS-CoV. In certain embodiments, each antigen-binding domain of each binding molecule is identical.

In certain embodiments, the three to twelve identical binding domains of the multimeric binding molecule that bind to SARS-CoV-2, comprise a heavy chain variable region (VH) and a light chain variable region (VL), where the VH and VL comprise six immunoglobulin complementarity determining regions HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3, where the HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 comprise the CDRs of an antibody comprising the VH and VL of any of SEQ ID NO: 84 and SEQ ID NO: 85, SEQ ID NO: 86 and SEQ ID NO: 87, SEQ ID NO: 88 and SEQ ID NO: 89, SEQ ID NO: 90 and SEQ ID NO: 91, SEQ ID NO: 92 and SEQ ID NO: 93, SEQ ID NO: 94 and SEQ ID NO: 95, SEQ ID NO: 96 and SEQ ID NO: 97, SEQ ID NO: 98 and SEQ ID NO: 99, SEQ ID NO: 100 and SEQ ID NO: 101, SEQ ID NO: 102 and SEQ ID NO: 103, SEQ ID NO: 104 and SEQ ID NO: 105, SEQ ID NO: 106 and SEQ ID NO: 107, SEQ ID NO: 108 and SEQ ID NO: 109, SEQ ID NO: 110 and SEQ ID NO: 111, SEQ ID NO: 112 and SEQ ID NO: 113, SEQ ID NO: 114 and SEQ ID NO: 115, SEQ ID NO: 116 and SEQ ID NO: 117, SEQ ID NO: 118 and SEQ ID NO: 119, SEQ ID NO: 120 and SEQ ID NO: 121, SEQ ID NO: 122 and SEQ ID NO: 123, SEQ ID NO: 124 and SEQ ID NO: 125, SEQ ID NO: 126 and SEQ ID NO: 127, SEQ ID NO: 128 and SEQ ID NO: 129, SEQ ID NO: 130 and SEQ ID NO: 131, SEQ ID NO: 132 and SEQ ID NO: 133, SEQ ID NO: 134 and SEQ ID NO: 135, SEQ ID NO: 136 and SEQ ID NO: 137, SEQ ID NO: 138 and SEQ ID NO: 139, SEQ ID NO: 140 and SEQ ID NO: 141, SEQ ID NO: 142 and SEQ ID NO: 143, SEQ ID NO: 144 and SEQ ID NO: 145, SEQ ID NO: 146 and SEQ ID NO: 147, SEQ ID NO: 148 and SEQ ID NO: 149, SEQ ID NO: 150 and SEQ ID NO: 151, SEQ ID NO: 152 and SEQ ID NO: 153, SEQ ID NO: 154 and SEQ ID NO: 155, SEQ ID NO: 156 and SEQ ID NO: 157, SEQ ID NO: 158 and SEQ ID NO: 159, SEQ ID NO: 160 and SEQ ID NO: 161, SEQ ID NO: 162 and SEQ ID NO: 163, SEQ ID NO: 164 and SEQ ID NO: 165, SEQ ID NO: 166 and SEQ ID NO: 167, SEQ ID NO: 168 and SEQ ID NO: 169, SEQ ID NO: 170 and SEQ ID NO: 171, SEQ ID NO: 172 and SEQ ID NO: 173, SEQ ID NO: 174 and SEQ ID NO: 175, SEQ ID NO: 176 and SEQ ID NO: 177, SEQ ID NO: 178 and SEQ ID NO: 179, SEQ ID NO: 180 and SEQ ID NO: 181, SEQ ID NO: 182 and SEQ ID NO: 183, SEQ ID NO: 184 and SEQ ID NO: 185, SEQ ID NO: 186 and SEQ ID NO: 187, SEQ ID NO: 188 and SEQ ID NO: 189, SEQ ID NO: 190 and SEQ ID NO: 191, SEQ ID NO: 192 and SEQ ID NO: 193, SEQ ID NO: 194 and SEQ ID NO: 195, SEQ ID NO: 196 and SEQ ID NO: 197, SEQ ID NO: 198 and SEQ ID NO: 199, SEQ ID NO: 200 and SEQ ID NO: 201, SEQ ID NO: 202 and SEQ ID NO: 203, SEQ ID NO: 204 and SEQ ID NO: 205, SEQ ID NO: 206 and SEQ ID NO: 207, SEQ ID NO: 208 and SEQ ID NO: 209, SEQ ID NO: 210 and SEQ ID NO: 211, SEQ ID NO: 212 and SEQ ID NO: 213, SEQ ID NO: 214 and SEQ ID NO: 215, SEQ ID NO: 216 and SEQ ID NO: 217, SEQ ID NO: 218 and SEQ ID NO: 219, SEQ ID NO: 220 and SEQ ID NO: 221, SEQ ID NO: 222 and SEQ ID NO: 223, SEQ ID NO: 224 and SEQ ID NO: 225, SEQ ID NO: 226 and SEQ ID NO: 227, SEQ ID NO: 228 and SEQ ID NO: 229, SEQ ID NO: 230 and SEQ ID NO: 231, SEQ ID NO: 232 and SEQ ID NO: 233, SEQ ID NO: 234 and SEQ ID NO: 235, SEQ ID NO: 236 and SEQ ID NO: 237, SEQ ID NO: 238 and SEQ ID NO: 239, SEQ ID NO: 240 and SEQ ID NO: 241, SEQ ID NO: 242 and SEQ ID NO: 243, SEQ ID NO: 244 and SEQ ID NO: 245, SEQ ID NO: 246 and SEQ ID NO: 247, SEQ ID NO: 248 and SEQ ID NO: 249, SEQ ID NO: 250 and SEQ ID NO: 251, SEQ ID NO: 252 and SEQ ID NO: 253, SEQ ID NO: 254 and SEQ ID NO: 255, SEQ ID NO: 256 and SEQ ID NO: 257, SEQ ID NO: 258 and SEQ ID NO: 259, SEQ ID NO: 260 and SEQ ID NO: 261, SEQ ID NO: 264 and SEQ ID NO: 265, SEQ ID NO: 266 and SEQ ID NO: 267, SEQ ID NO: 268 and SEQ ID NO: 269, SEQ ID NO: 270 and SEQ ID NO: 271, SEQ ID NO: 272 and SEQ ID NO: 273, SEQ ID NO: 274 and SEQ ID NO: 275, SEQ ID NO: 276 and SEQ ID NO: 277, SEQ ID NO: 278 and SEQ ID NO: 279, SEQ ID NO: 280 and SEQ ID NO: 281, SEQ ID NO: 282 and SEQ ID NO: 283, SEQ ID NO: 284 and SEQ ID NO: 285, SEQ ID NO: 286 and SEQ ID NO: 287, SEQ ID NO: 288 and SEQ ID NO: 289, SEQ ID NO: 290 and SEQ ID NO: 291, SEQ ID NO: 292 and SEQ ID NO: 293, SEQ ID NO: 294 and SEQ ID NO: 295, SEQ ID NO: 296 and SEQ ID NO: 297, SEQ ID NO: 298 and SEQ ID NO: 299, SEQ ID NO: 300 and SEQ ID NO: 301, SEQ ID NO: 302 and SEQ ID NO: 303, SEQ ID NO: 304 and SEQ ID NO: 305, SEQ ID NO: 306 and SEQ ID NO: 307, SEQ ID NO: 308 and SEQ ID NO: 309, SEQ ID NO: 310 and SEQ ID NO: 311, SEQ ID NO: 312 and SEQ ID NO: 313, SEQ ID NO: 314 and SEQ ID NO: 315, SEQ ID NO: 316 and SEQ ID NO: 317, SEQ ID NO: 318 and SEQ ID NO: 319, SEQ ID NO: 320 and SEQ ID NO: 321, SEQ ID NO: 322 and SEQ ID NO: 323, SEQ ID NO: 324 and SEQ ID NO: 325, SEQ ID NO: 326 and SEQ ID NO: 327, SEQ ID NO: 328 and SEQ ID NO: 329, SEQ ID NO: 330 and SEQ ID NO: 331, SEQ ID NO: 332 and SEQ ID NO: 333, SEQ ID NO: 336 and SEQ ID NO: 337, SEQ ID NO: 338 and SEQ ID NO: 339, SEQ ID NO: 340 and SEQ ID NO: 341, SEQ ID NO: 342 and SEQ ID NO: 343, SEQ ID NO: 344 and SEQ ID NO: 345, SEQ ID NO: 348 and SEQ ID NO: 349, SEQ ID NO: 350 and SEQ ID NO: 351, SEQ ID NO: 352 and SEQ ID NO: 353, SEQ ID NO: 354 and SEQ ID NO: 355, SEQ ID NO: 356 and SEQ ID NO: 357, SEQ ID NO: 358 and SEQ ID NO: 359, SEQ ID NO: 362 and SEQ ID NO: 363, SEQ ID NO: 364 and SEQ ID NO: 365, SEQ ID NO: 366 and SEQ ID NO: 367, SEQ ID NO: 368 and SEQ ID NO: 369, SEQ ID NO: 370 and SEQ ID NO: 371, SEQ ID NO: 372 and SEQ ID NO: 373, SEQ ID NO: 374 and SEQ ID NO: 375, SEQ ID NO: 376 and SEQ ID NO: 377, SEQ ID NO: 378 and SEQ ID NO: 379, SEQ ID NO: 380 and SEQ ID NO: 381, SEQ ID NO: 382 and SEQ ID NO: 383, SEQ ID NO: 384 and SEQ ID NO: 385, SEQ ID NO: 386 and SEQ ID NO: 387, SEQ ID NO: 388 and SEQ ID NO: 389, SEQ ID NO: 390 and SEQ ID NO: 391, SEQ ID NO: 392 and SEQ ID NO: 393, SEQ ID NO: 394 and SEQ ID NO: 395, SEQ ID NO: 396 and SEQ ID NO: 397, SEQ ID NO: 398 and SEQ ID NO: 399, SEQ ID NO: 400 and SEQ ID NO: 401, SEQ ID NO: 402 and SEQ ID NO: 403, SEQ ID NO: 404 and SEQ ID NO: 405, SEQ ID NO: 406 and SEQ ID NO: 407, SEQ ID NO: 408 and SEQ ID NO: 409, SEQ ID NO: 410 and SEQ ID NO: 411, SEQ ID NO: 412 and SEQ ID NO: 413, SEQ ID NO: 414 and SEQ ID NO: 415, SEQ ID NO: 416 and SEQ ID NO: 417, SEQ ID NO: 418 and SEQ ID NO: 419, SEQ ID NO: 420 and SEQ ID NO: 421, SEQ ID NO: 422 and SEQ ID NO: 423, SEQ ID NO: 424 and SEQ ID NO: 425, SEQ ID NO: 426 and SEQ ID NO: 427, SEQ ID NO: 428 and SEQ ID NO: 429, SEQ ID NO: 430 and SEQ ID NO: 431, SEQ ID NO: 432 and SEQ ID NO: 433, SEQ ID NO: 434 and SEQ ID NO: 435, SEQ ID NO: 436 and SEQ ID NO: 437, SEQ ID NO: 438 and SEQ ID NO: 439, SEQ ID NO: 440 and SEQ ID NO: 441, SEQ ID NO: 442 and SEQ ID NO: 443, SEQ ID NO: 444 and SEQ ID NO: 445, SEQ ID NO: 446 and SEQ ID NO: 447, SEQ ID NO: 448 and SEQ ID NO: 449, SEQ ID NO: 450 and SEQ ID NO: 451, SEQ ID NO: 452 and SEQ ID NO: 453, SEQ ID NO: 454 and SEQ ID NO: 455, SEQ ID NO: 456 and SEQ ID NO: 457, SEQ ID NO: 458 and SEQ ID NO: 459, SEQ ID NO: 460 and SEQ ID NO: 461, SEQ ID NO: 462 and SEQ ID NO: 463, SEQ ID NO: 464 and SEQ ID NO: 465, SEQ ID NO: 466 and SEQ ID NO: 467, SEQ ID NO: 468 and SEQ ID NO: 469, SEQ ID NO: 470 and SEQ ID NO: 471, SEQ ID NO: 472 and SEQ ID NO: 473, SEQ ID NO: 474 and SEQ ID NO: 475, SEQ ID NO: 476 and SEQ ID NO: 477, SEQ ID NO: 478 and SEQ ID NO: 479, SEQ ID NO: 480 and SEQ ID NO: 481, SEQ ID NO: 482 and SEQ ID NO: 483, SEQ ID NO: 484 and SEQ ID NO: 485, SEQ ID NO: 486 and SEQ ID NO: 487, SEQ ID NO: 488 and SEQ ID NO: 489, SEQ ID NO: 490 and SEQ ID NO: 491, SEQ ID NO: 492 and SEQ ID NO: 493, SEQ ID NO: 494 and SEQ ID NO: 495, SEQ ID NO: 496 and SEQ ID NO: 497, SEQ ID NO: 498 and SEQ ID NO: 499, SEQ ID NO: 500 and SEQ ID NO: 501, SEQ ID NO: 502 and SEQ ID NO: 503, SEQ ID NO: 504 and SEQ ID NO: 505, SEQ ID NO: 506 and SEQ ID NO: 507, SEQ ID NO: 508 and SEQ ID NO: 509, SEQ ID NO: 628 and SEQ ID NO: 629, SEQ ID NO: 630 and SEQ ID NO: 631, SEQ ID NO: 632 and SEQ ID NO: 633, SEQ ID NO: 634 and SEQ ID NO: 635, SEQ ID NO: 636 and SEQ ID NO: 637, SEQ ID NO: 638 and SEQ ID NO: 639, SEQ ID NO: 640 and SEQ ID NO: 641, SEQ ID NO: 642 and SEQ ID NO: 643, or SEQ ID NO: 644 SEQ ID NO: 645, SEQ ID NO: 646 and SEQ ID NO: 647, SEQ ID NO: 648 and SEQ ID NO: 649, SEQ ID NO: 650 and SEQ ID NO: 651, or SEQ ID NO: 652 and SEQ ID NO: 653, respectively with zero, one, or two single amino acid substitutions in one or more of the HCDRs or LCDRs.

In certain embodiments, the three to twelve identical binding domains of the multimeric binding molecule that specifically bind to a human coronavirus, e.g., SARS-CoV-2, comprise a heavy chain variable region (VH) and a light chain variable region (VL), where the VH and VL comprise six immunoglobulin complementarity determining regions HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3, where the HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 comprise the CDRs of an antibody comprising the VH and VL of SEQ ID NO: 86 and SEQ ID NO: 87, SEQ ID NO: 88 and SEQ ID NO: 89, SEQ ID NO: 90 and SEQ ID NO: 91, SEQ ID NO: 92 and SEQ ID NO: 93, SEQ ID NO: 94 and SEQ ID NO: 95, SEQ ID NO: 96 and SEQ ID NO: 97, SEQ ID NO: 98 and SEQ ID NO: 99, SEQ ID NO: 100 and SEQ ID NO: 101, SEQ ID NO: 102 and SEQ ID NO: 103, SEQ ID NO: 106 and SEQ ID NO: 107, SEQ ID NO: 110 and SEQ ID NO: 111, SEQ ID NO: 118 and SEQ ID NO: 119, SEQ ID NO: 128 and SEQ ID NO: 129, SEQ ID NO: 130 and SEQ ID NO: 131, SEQ ID NO: 132 and SEQ ID NO: 133, SEQ ID NO: 134 and SEQ ID NO: 135, SEQ ID NO: 136 and SEQ ID NO: 137, SEQ ID NO: 142 and SEQ ID NO: 143, SEQ ID NO: 146 and SEQ ID NO: 147, SEQ ID NO: 150 and SEQ ID NO: 151, SEQ ID NO: 156 and SEQ ID NO: 157, SEQ ID NO: 160 and SEQ ID NO: 161, SEQ ID NO: 162 and SEQ ID NO: 163, SEQ ID NO: 164 and SEQ ID NO: 165, SEQ ID NO: 166 and SEQ ID NO: 167, SEQ ID NO: 168 and SEQ ID NO: 169, SEQ ID NO: 170 and SEQ ID NO: 171, SEQ ID NO: 172 and SEQ ID NO: 173, SEQ ID NO: 174 and SEQ ID NO: 175, SEQ ID NO: 176 and SEQ ID NO: 177, SEQ ID NO: 180 and SEQ ID NO: 181, SEQ ID NO: 182 and SEQ ID NO: 183, SEQ ID NO: 186 and SEQ ID NO: 187, SEQ ID NO: 188 and SEQ ID NO: 189, SEQ ID NO: 194 and SEQ ID NO: 195, SEQ ID NO: 200 and SEQ ID NO: 201, SEQ ID NO: 206 and SEQ ID NO: 207, SEQ ID NO: 208 and SEQ ID NO: 209, SEQ ID NO: 218 and SEQ ID NO: 219, SEQ ID NO: 220 and SEQ ID NO: 221, SEQ ID NO: 222 and SEQ ID NO: 223, SEQ ID NO: 224 and SEQ ID NO: 225, SEQ ID NO: 228 and SEQ ID NO: 229, SEQ ID NO: 230 and SEQ ID NO: 231, SEQ ID NO: 240 and SEQ ID NO: 241, SEQ ID NO: 244 and SEQ ID NO: 245, SEQ ID NO: 246 and SEQ ID NO: 247, SEQ ID NO: 256 and SEQ ID NO: 257, SEQ ID NO: 258 and SEQ ID NO: 259, SEQ ID NO: 260 and SEQ ID NO: 261, SEQ ID NO: 264 and SEQ ID NO: 265, SEQ ID NO: 266 and SEQ ID NO: 267, SEQ ID NO: 268 and SEQ ID NO: 269, SEQ ID NO: 270 and SEQ ID NO: 271, SEQ ID NO: 272 and SEQ ID NO: 273, SEQ ID NO: 274 and SEQ ID NO: 275, SEQ ID NO: 276 and SEQ ID NO: 277, SEQ ID NO: 278 and SEQ ID NO: 279, SEQ ID NO: 280 and SEQ ID NO: 281, SEQ ID NO: 282 and SEQ ID NO: 283, SEQ ID NO: 284 and SEQ ID NO: 285, SEQ ID NO: 286 and SEQ ID NO: 287, SEQ ID NO: 288 and SEQ ID NO: 289, SEQ ID NO: 290 and SEQ ID NO: 291, SEQ ID NO: 292 and SEQ ID NO: 293, SEQ ID NO: 294 and SEQ ID NO: 295, SEQ ID NO: 296 and SEQ ID NO: 297, SEQ ID NO: 298 and SEQ ID NO: 299, SEQ ID NO: 300 and SEQ ID NO: 301, SEQ ID NO: 302 and SEQ ID NO: 303, SEQ ID NO: 304 and SEQ ID NO: 305, SEQ ID NO: 306 and SEQ ID NO: 307, SEQ ID NO: 308 and SEQ ID NO: 309, SEQ ID NO: 310 and SEQ ID NO: 311, SEQ ID NO: 312 and SEQ ID NO: 313, SEQ ID NO: 314 and SEQ ID NO: 315, SEQ ID NO: 316 and SEQ ID NO: 317, SEQ ID NO: 318 and SEQ ID NO: 319, SEQ ID NO: 320 and SEQ ID NO: 321, SEQ ID NO: 322 and SEQ ID NO: 323, SEQ ID NO: 324 and SEQ ID NO: 325, SEQ ID NO: 326 and SEQ ID NO: 327, SEQ ID NO: 328 and SEQ ID NO: 329, SEQ ID NO: 330 and SEQ ID NO: 331, SEQ ID NO: 332 and SEQ ID NO: 333, SEQ ID NO: 336 and SEQ ID NO: 337, SEQ ID NO: 338 and SEQ ID NO: 339, SEQ ID NO: 340 and SEQ ID NO: 341, SEQ ID NO: 342 and SEQ ID NO: 343, SEQ ID NO: 344 and SEQ ID NO: 345, SEQ ID NO: 348 and SEQ ID NO: 349, SEQ ID NO: 350 and SEQ ID NO: 351, SEQ ID NO: 352 and SEQ ID NO: 353, SEQ ID NO: 354 and SEQ ID NO: 355, SEQ ID NO: 356 and SEQ ID NO: 357, SEQ ID NO: 358 and SEQ ID NO: 359, SEQ ID NO: 360 and SEQ ID NO: 361, SEQ ID NO: 362 and SEQ ID NO: 363, SEQ ID NO: 364 and SEQ ID NO: 365, SEQ ID NO: 366 and SEQ ID NO: 367, SEQ ID NO: 368 and SEQ ID NO: 369, SEQ ID NO: 370 and SEQ ID NO: 371, SEQ ID NO: 372 and SEQ ID NO: 373, SEQ ID NO: 374 and SEQ ID NO: 375, SEQ ID NO: 376 and SEQ ID NO: 377, SEQ ID NO: 378 and SEQ ID NO: 379, SEQ ID NO: 380 and SEQ ID NO: 381, SEQ ID NO: 382 and SEQ ID NO: 383, SEQ ID NO: 384 and SEQ ID NO: 385, SEQ ID NO: 386 and SEQ ID NO: 387, SEQ ID NO: 388 and SEQ ID NO: 389, SEQ ID NO: 390 and SEQ ID NO: 391, SEQ ID NO: 392 and SEQ ID NO: 393, SEQ ID NO: 394 and SEQ ID NO: 395, SEQ ID NO: 396 and SEQ ID NO: 397, SEQ ID NO: 398 and SEQ ID NO: 399, SEQ ID NO: 400 and SEQ ID NO: 401, SEQ ID NO: 402 and SEQ ID NO: 403, SEQ ID NO: 404 and SEQ ID NO: 405, SEQ ID NO: 406 and SEQ ID NO: 407, SEQ ID NO: 408 and SEQ ID NO: 409, SEQ ID NO: 410 and SEQ ID NO: 411, SEQ ID NO: 412 and SEQ ID NO: 413, SEQ ID NO: 414 and SEQ ID NO: 415, SEQ ID NO: 416 and SEQ ID NO: 417, SEQ ID NO: 418 and SEQ ID NO: 419, SEQ ID NO: 420 and SEQ ID NO: 421, SEQ ID NO: 422 and SEQ ID NO: 423, SEQ ID NO: 424 and SEQ ID NO: 425, SEQ ID NO: 426 and SEQ ID NO: 427, SEQ ID NO: 428 and SEQ ID NO: 429, SEQ ID NO: 430 and SEQ ID NO: 431, SEQ ID NO: 432 and SEQ ID NO: 433, SEQ ID NO: 434 and SEQ ID NO: 435, SEQ ID NO: 436 and SEQ ID NO: 437, SEQ ID NO: 438 and SEQ ID NO: 439, SEQ ID NO: 440 and SEQ ID NO: 441, SEQ ID NO: 442 and SEQ ID NO: 443, SEQ ID NO: 444 and SEQ ID NO: 445, SEQ ID NO: 446 and SEQ ID NO: 447, SEQ ID NO: 448 and SEQ ID NO: 449, SEQ ID NO: 450 and SEQ ID NO: 451, SEQ ID NO: 452 and SEQ ID NO: 453, SEQ ID NO: 454 and SEQ ID NO: 455, SEQ ID NO: 456 and SEQ ID NO: 457, SEQ ID NO: 458 and SEQ ID NO: 459, SEQ ID NO: 460 and SEQ ID NO: 461, SEQ ID NO: 462 and SEQ ID NO: 463, SEQ ID NO: 464 and SEQ ID NO: 465, SEQ ID NO: 466 and SEQ ID NO: 467, SEQ ID NO: 468 and SEQ ID NO: 469, SEQ ID NO: 470 and SEQ ID NO: 471, SEQ ID NO: 472 and SEQ ID NO: 473, SEQ ID NO: 474 and SEQ ID NO: 475, SEQ ID NO: 476 and SEQ ID NO: 477, SEQ ID NO: 478 and SEQ ID NO: 479, SEQ ID NO: 480 and SEQ ID NO: 481, SEQ ID NO: 482 and SEQ ID NO: 483, SEQ ID NO: 484 and SEQ ID NO: 485, SEQ ID NO: 486 and SEQ ID NO: 487, SEQ ID NO: 488 and SEQ ID NO: 489, SEQ ID NO: 490 and SEQ ID NO: 491, SEQ ID NO: 492 and SEQ ID NO: 493, SEQ ID NO: 494 and SEQ ID NO: 495, SEQ ID NO: 496 and SEQ ID NO: 497, SEQ ID NO: 498 and SEQ ID NO: 499, SEQ ID NO: 500 and SEQ ID NO: 501, SEQ ID NO: 502 and SEQ ID NO: 503, SEQ ID NO: 504 and SEQ ID NO: 505, SEQ ID NO: 506 and SEQ ID NO: 507, SEQ ID NO: 508 and SEQ ID NO: 509, SEQ ID NO: 628 and SEQ ID NO: 629, SEQ ID NO: 632 and SEQ ID NO: 633, SEQ ID NO: 634 and SEQ ID NO: 635, SEQ ID NO: 636 and SEQ ID NO: 637, SEQ ID NO: 638 and SEQ ID NO: 639, SEQ ID NO: 640 and SEQ ID NO: 641, SEQ ID NO: 642 and SEQ ID NO: 643, SEQ ID NO: 644 and SEQ ID NO: 645, SEQ ID NO: 646 and SEQ ID NO: 647, SEQ ID NO: 648 and SEQ ID NO: 649, SEQ ID NO: 650 and SEQ ID NO: 651, or SEQ ID NO: 652 and SEQ ID NO: 653, respectively with zero, one, or two single amino acid substitutions in one or more of the HCDRs or LCDRs, wherein the bivalent reference IgG antibody comprising two of the binding domains that specifically bind to the human coronavirus can neutralize SARS-CoV-2.

In certain embodiments, the three to twelve identical binding domains of the multimeric binding molecule that bind to SARS-CoV, comprise a heavy chain variable region (VH) and a light chain variable region (VL), where the VH and VL comprise six immunoglobulin complementarity determining regions HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3, where the HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 comprise the CDRs of an antibody comprising the VH and VL of any of SEQ ID NO: 84 and SEQ ID NO: 85, SEQ ID NO: 118 and SEQ ID NO: 119, SEQ ID NO: 120 and SEQ ID NO: 121, SEQ ID NO: 138 and SEQ ID NO: 139, SEQ ID NO: 162 and SEQ ID NO: 163, SEQ ID NO: 222 and SEQ ID NO: 223, SEQ ID NO: 236 and SEQ ID NO: 237, SEQ ID NO: 252 and SEQ ID NO: 253, SEQ ID NO: 260 and SEQ ID NO: 261, SEQ ID NO: 262 and SEQ ID NO: 263, SEQ ID NO: 296 and SEQ ID NO: 297, SEQ ID NO: 384 and SEQ ID NO: 385, SEQ ID NO: 628 and SEQ ID NO: 629, SEQ ID NO: 632 and SEQ ID NO: 633, SEQ ID NO: 634 and SEQ ID NO: 635, SEQ ID NO: 636 and SEQ ID NO: 637, SEQ ID NO: 638 and SEQ ID NO: 639, SEQ ID NO: 640 and SEQ ID NO: 641, SEQ ID NO: 642 and SEQ ID NO: 643, SEQ ID NO: 644 and SEQ ID NO: 645, or SEQ ID NO: 646 and SEQ ID NO: 647, respectively with zero, one, or two single amino acid substitutions in one or more of the HCDRs or LCDRs.

In certain embodiments, the three to twelve identical binding domains of the multimeric binding molecule that specifically bind to a human coronavirus, e.g., SARS-CoV, comprise a heavy chain variable region (VH) and a light chain variable region (VL), where the VH and VL comprise six immunoglobulin complementarity determining regions HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3, where the HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 comprise the CDRs of an antibody comprising the VH and VL of SEQ ID NO: 84 and SEQ ID NO: 85, SEQ ID NO: 260 and SEQ ID NO: 261, SEQ ID NO: 262 and SEQ ID NO: 263, SEQ ID NO: 296 and SEQ ID NO: 297, SEQ ID NO: 384 and SEQ ID NO: 385, SEQ ID NO: 628 and SEQ ID NO: 629, SEQ ID NO: 632 and SEQ ID NO: 633, SEQ ID NO: 634 and SEQ ID NO: 635, SEQ ID NO: 636 and SEQ ID NO: 637, SEQ ID NO: 638 and SEQ ID NO: 639, SEQ ID NO: 640 and SEQ ID NO: 641, SEQ ID NO: 642 and SEQ ID NO: 643, SEQ ID NO: 644 and SEQ ID NO: 645, or SEQ ID NO: 646 and SEQ ID NO: 647, respectively with zero, one, or two single amino acid substitutions in one or more of the HCDRs or LCDRs, wherein the bivalent reference IgG antibody comprising two of the binding domains that specifically bind to the human coronavirus can neutralize SARS-CoV.

In certain embodiments, the three to twelve identical binding domains of the multimeric binding molecule that bind to MERS-CoV, comprise a heavy chain variable region (VH) and a light chain variable region (VL), where the VH and VL comprise six immunoglobulin complementarity determining regions HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3, where the HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 comprise the CDRs of an antibody comprising the VH and VL of any of SEQ ID NO: 510 and SEQ ID NO: 511, SEQ ID NO: 512 and SEQ ID NO: 513, SEQ ID NO: 514 and SEQ ID NO: 515, SEQ ID NO: 516 and SEQ ID NO: 517, SEQ ID NO: 518 and SEQ ID NO: 519, SEQ ID NO: 520 and SEQ ID NO: 521, SEQ ID NO: 522 and SEQ ID NO: 523, SEQ ID NO: 524 and SEQ ID NO: 525, SEQ ID NO: 526 and SEQ ID NO: 527, SEQ ID NO: 528 and SEQ ID NO: 529, SEQ ID NO: 530 and SEQ ID NO: 531, SEQ ID NO: 532 and SEQ ID NO: 533, SEQ ID NO: 534 and SEQ ID NO: 535, SEQ ID NO: 536 and SEQ ID NO: 537, SEQ ID NO: 538 and SEQ ID NO: 539, SEQ ID NO: 540 and SEQ ID NO: 541, SEQ ID NO: 542 and SEQ ID NO: 543, SEQ ID NO: 544 and SEQ ID NO: 545, SEQ ID NO: 546 and SEQ ID NO: 547, SEQ ID NO: 548 and SEQ ID NO: 549, SEQ ID NO: 550 and SEQ ID NO: 551, SEQ ID NO: 552 and SEQ ID NO: 553, SEQ ID NO: 554 and SEQ ID NO: 555, SEQ ID NO: 556 and SEQ ID NO: 557, SEQ ID NO: 558 and SEQ ID NO: 559, SEQ ID NO: 560 and SEQ ID NO: 561, SEQ ID NO: 562 and SEQ ID NO: 563, SEQ ID NO: 564 and SEQ ID NO: 565, SEQ ID NO: 566 and SEQ ID NO: 567, SEQ ID NO: 568 and SEQ ID NO: 569, SEQ ID NO: 570 and SEQ ID NO: 571, SEQ ID NO: 572 and SEQ ID NO: 573, SEQ ID NO: 574 and SEQ ID NO: 575, SEQ ID NO: 576 and SEQ ID NO: 577, SEQ ID NO: 578 and SEQ ID NO: 579, SEQ ID NO: 580 and SEQ ID NO: 581, SEQ ID NO: 582 and SEQ ID NO: 583, SEQ ID NO: 584 and SEQ ID NO: 585, SEQ ID NO: 586 and SEQ ID NO: 587, SEQ ID NO: 588 and SEQ ID NO: 589, SEQ ID NO: 590 and SEQ ID NO: 591, SEQ ID NO: 592 and SEQ ID NO: 593, SEQ ID NO: 594 and SEQ ID NO: 595, SEQ ID NO: 596 and SEQ ID NO: 597, SEQ ID NO: 598 and SEQ ID NO: 599, SEQ ID NO: 600 and SEQ ID NO: 601, SEQ ID NO: 602 and SEQ ID NO: 603, SEQ ID NO: 604 and SEQ ID NO: 605, SEQ ID NO: 606 and SEQ ID NO: 607, SEQ ID NO: 608 and SEQ ID NO: 609, SEQ ID NO: 610 and SEQ ID NO: 611, SEQ ID NO: 612 and SEQ ID NO: 613, SEQ ID NO: 614 and SEQ ID NO: 615, SEQ ID NO: 616 and SEQ ID NO: 617, SEQ ID NO: 618 and SEQ ID NO: 619, SEQ ID NO: 620 and SEQ ID NO: 621, SEQ ID NO: 622 and SEQ ID NO: 623, SEQ ID NO: 624 and SEQ ID NO: 625, SEQ ID NO: 626 and SEQ ID NO: 627, or SEQ ID NO: 630 and SEQ ID NO: 631, respectively with zero, one, or two single amino acid substitutions in one or more of the HCDRs or LCDRs.

In certain embodiments, the three to twelve identical binding domains of the multimeric binding molecule that specifically bind to a human coronavirus, e.g., MERS-CoV, comprise a heavy chain variable region (VH) and a light chain variable region (VL), where the VH and VL comprise six immunoglobulin complementarity determining regions HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3, where the HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 comprise the CDRs of an antibody comprising the VH and VL of SEQ ID NO: 510 and SEQ ID NO: 511, SEQ ID NO: 512 and SEQ ID NO: 513, SEQ ID NO: 514 and SEQ ID NO: 515, SEQ ID NO: 516 and SEQ ID NO: 517, SEQ ID NO: 518 and SEQ ID NO: 519, SEQ ID NO: 520 and SEQ ID NO: 521, SEQ ID NO: 522 and SEQ ID NO: 523, SEQ ID NO: 524 and SEQ ID NO: 525, SEQ ID NO: 526 and SEQ ID NO: 527, SEQ ID NO: 528 and SEQ ID NO: 529, SEQ ID NO: 530 and SEQ ID NO: 531, SEQ ID NO: 532 and SEQ ID NO: 533, SEQ ID NO: 534 and SEQ ID NO: 535, SEQ ID NO: 536 and SEQ ID NO: 537, SEQ ID NO: 538 and SEQ ID NO: 539, SEQ ID NO: 540 and SEQ ID NO: 541, SEQ ID NO: 542 and SEQ ID NO: 543, SEQ ID NO: 544 and SEQ ID NO: 545, SEQ ID NO: 546 and SEQ ID NO: 547, SEQ ID NO: 548 and SEQ ID NO: 549, SEQ ID NO: 550 and SEQ ID NO: 551, SEQ ID NO: 552 and SEQ ID NO: 553, SEQ ID NO: 554 and SEQ ID NO: 555, SEQ ID NO: 556 and SEQ ID NO: 557, SEQ ID NO: 558 and SEQ ID NO: 559, SEQ ID NO: 560 and SEQ ID NO: 561, SEQ ID NO: 562 and SEQ ID NO: 563, SEQ ID NO: 564 and SEQ ID NO: 565, SEQ ID NO: 566 and SEQ ID NO: 567, SEQ ID NO: 568 and SEQ ID NO: 569, SEQ ID NO: 574 and SEQ ID NO: 575, SEQ ID NO: 576 and SEQ ID NO: 577, SEQ ID NO: 578 and SEQ ID NO: 579, SEQ ID NO: 580 and SEQ ID NO: 581, SEQ ID NO: 582 and SEQ ID NO: 583, SEQ ID NO: 584 and SEQ ID NO: 585, SEQ ID NO: 586 and SEQ ID NO: 587, SEQ ID NO: 588 and SEQ ID NO: 589, SEQ ID NO: 590 and SEQ ID NO: 591, SEQ ID NO: 592 and SEQ ID NO: 593, SEQ ID NO: 594 and SEQ ID NO: 595, SEQ ID NO: 596 and SEQ ID NO: 597, SEQ ID NO: 598 and SEQ ID NO: 599, SEQ ID NO: 600 and SEQ ID NO: 601, SEQ ID NO: 602 and SEQ ID NO: 603, SEQ ID NO: 604 and SEQ ID NO: 605, SEQ ID NO: 606 and SEQ ID NO: 607, SEQ ID NO: 608 and SEQ ID NO: 609, SEQ ID NO: 610 and SEQ ID NO: 611, SEQ ID NO: 612 and SEQ ID NO: 613, SEQ ID NO: 614 and SEQ ID NO: 615, SEQ ID NO: 616 and SEQ ID NO: 617, SEQ ID NO: 618 and SEQ ID NO: 619, SEQ ID NO: 620 and SEQ ID NO: 621, SEQ ID NO: 622 and SEQ ID NO: 623, SEQ ID NO: 624 and SEQ ID NO: 625, SEQ ID NO: 626 and SEQ ID NO: 627, or SEQ ID NO: 630 and SEQ ID NO: 631, respectively with zero, one, or two single amino acid substitutions in one or more of the HCDRs or LCDRs, wherein the bivalent reference IgG antibody comprising two of the binding domains that specifically bind to the human coronavirus can neutralize MERS-CoV.

In certain embodiments, the three to twelve identical binding domains of the multimeric binding molecule that specifically bind to a human coronavirus, e.g., SARS-CoV or SARS-CoV-2, comprise a heavy chain variable region (VH) and a light chain variable region (VL), where the VH and VL comprise six immunoglobulin complementarity determining regions HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3, where the HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 comprise the CDRs of an antibody comprising the VH and VL of SEQ ID NO: 118 and SEQ ID NO: 119, SEQ ID NO: 162 and SEQ ID NO: 163, SEQ ID NO: 222 and SEQ ID NO: 223, SEQ ID NO: 260 and SEQ ID NO: 261, SEQ ID NO: 296 and SEQ ID NO: 297, SEQ ID NO: 384 and SEQ ID NO: 385, SEQ ID NO: 628 and SEQ ID NO: 629, SEQ ID NO: 632 and SEQ ID NO: 633, SEQ ID NO: 634 and SEQ ID NO: 635, SEQ ID NO: 636 and SEQ ID NO: 637, SEQ ID NO: 638 and SEQ ID NO: 639, SEQ ID NO: 640 and SEQ ID NO: 641, SEQ ID NO: 642 and SEQ ID NO: 643, SEQ ID NO: 644 and SEQ ID NO: 645, or SEQ ID NO: 646 and SEQ ID NO: 647, respectively with zero, one, or two single amino acid substitutions in one or more of the HCDRs or LCDRs, wherein the bivalent reference IgG antibody comprising two of the binding domains that specifically bind to the human coronavirus can neutralize SARS-CoV-2 and can bind SARS-CoV.

In certain embodiments, the three to twelve identical binding domains of the multimeric binding molecule that specifically bind to at least two human coronaviruses, e.g., SARS-CoV and SARS-CoV-2, comprise a heavy chain variable region (VH) and a light chain variable region (VL), where the VH and VL comprise six immunoglobulin complementarity determining regions HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3, where the HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 comprise the CDRs of an antibody comprising the VH and VL of SEQ ID NO: 260 and SEQ ID NO: 261, SEQ ID NO: 296 and SEQ ID NO: 297, SEQ ID NO: 384 and SEQ ID NO: 385, SEQ ID NO: 628 and SEQ ID NO: 629, SEQ ID NO: 632 and SEQ ID NO: 633, SEQ ID NO: 634 and SEQ ID NO: 635, SEQ ID NO: 636 and SEQ ID NO: 637, SEQ ID NO: 638 and SEQ ID NO: 639, SEQ ID NO: 640 and SEQ ID NO: 641, SEQ ID NO: 642 and SEQ ID NO: 643, SEQ ID NO: 644 and SEQ ID NO: 645, or SEQ ID NO: 646 and SEQ ID NO: 647, respectively with zero, one, or two single amino acid substitutions in one or more of the HCDRs or LCDRs, wherein the bivalent reference IgG antibody comprising two of the binding domains that specifically bind to the human coronavirus can neutralize SARS-CoV and SARS-CoV-2.

In certain embodiments, the three to twelve identical binding domains of the multimeric binding molecule that specifically bind to a human coronavirus, e.g., SARS-CoV-2, comprise an antibody VH and a VL, wherein the VH and VL comprise amino acid sequences at least 80%, at least 85%, at least 90%, at least 95% or 100% identical to SEQ ID NO: 84 and SEQ ID NO: 85, SEQ ID NO: 86 and SEQ ID NO: 87, SEQ ID NO: 88 and SEQ ID NO: 89, SEQ ID NO: 90 and SEQ ID NO: 91, SEQ ID NO: 92 and SEQ ID NO: 93, SEQ ID NO: 94 and SEQ ID NO: 95, SEQ ID NO: 96 and SEQ ID NO: 97, SEQ ID NO: 98 and SEQ ID NO: 99, SEQ ID NO: 100 and SEQ ID NO: 101, SEQ ID NO: 102 and SEQ ID NO: 103, SEQ ID NO: 104 and SEQ ID NO: 105, SEQ ID NO: 106 and SEQ ID NO: 107, SEQ ID NO: 108 and SEQ ID NO: 109, SEQ ID NO: 110 and SEQ ID NO: 111, SEQ ID NO: 112 and SEQ ID NO: 113, SEQ ID NO: 114 and SEQ ID NO: 115, SEQ ID NO: 116 and SEQ ID NO: 117, SEQ ID NO: 118 and SEQ ID NO: 119, SEQ ID NO: 120 and SEQ ID NO: 121, SEQ ID NO: 122 and SEQ ID NO: 123, SEQ ID NO: 124 and SEQ ID NO: 125, SEQ ID NO: 126 and SEQ ID NO: 127, SEQ ID NO: 128 and SEQ ID NO: 129, SEQ ID NO: 130 and SEQ ID NO: 131, SEQ ID NO: 132 and SEQ ID NO: 133, SEQ ID NO: 134 and SEQ ID NO: 135, SEQ ID NO: 136 and SEQ ID NO: 137, SEQ ID NO: 138 and SEQ ID NO: 139, SEQ ID NO: 140 and SEQ ID NO: 141, SEQ ID NO: 142 and SEQ ID NO: 143, SEQ ID NO: 144 and SEQ ID NO: 145, SEQ ID NO: 146 and SEQ ID NO: 147, SEQ ID NO: 148 and SEQ ID NO: 149, SEQ ID NO: 150 and SEQ ID NO: 151, SEQ ID NO: 152 and SEQ ID NO: 153, SEQ ID NO: 154 and SEQ ID NO: 155, SEQ ID NO: 156 and SEQ ID NO: 157, SEQ ID NO: 158 and SEQ ID NO: 159, SEQ ID NO: 160 and SEQ ID NO: 161, SEQ ID NO: 162 and SEQ ID NO: 163, SEQ ID NO: 164 and SEQ ID NO: 165, SEQ ID NO: 166 and SEQ ID NO: 167, SEQ ID NO: 168 and SEQ ID NO: 169, SEQ ID NO: 170 and SEQ ID NO: 171, SEQ ID NO: 172 and SEQ ID NO: 173, SEQ ID NO: 174 and SEQ ID NO: 175, SEQ ID NO: 176 and SEQ ID NO: 177, SEQ ID NO: 178 and SEQ ID NO: 179, SEQ ID NO: 180 and SEQ ID NO: 181, SEQ ID NO: 182 and SEQ ID NO: 183, SEQ ID NO: 184 and SEQ ID NO: 185, SEQ ID NO: 186 and SEQ ID NO: 187, SEQ ID NO: 188 and SEQ ID NO: 189, SEQ ID NO: 190 and SEQ ID NO: 191, SEQ ID NO: 192 and SEQ ID NO: 193, SEQ ID NO: 194 and SEQ ID NO: 195, SEQ ID NO: 196 and SEQ ID NO: 197, SEQ ID NO: 198 and SEQ ID NO: 199, SEQ ID NO: 200 and SEQ ID NO: 201, SEQ ID NO: 202 and SEQ ID NO: 203, SEQ ID NO: 204 and SEQ ID NO: 205, SEQ ID NO: 206 and SEQ ID NO: 207, SEQ ID NO: 208 and SEQ ID NO: 209, SEQ ID NO: 210 and SEQ ID NO: 211, SEQ ID NO: 212 and SEQ ID NO: 213, SEQ ID NO: 214 and SEQ ID NO: 215, SEQ ID NO: 216 and SEQ ID NO: 217, SEQ ID NO: 218 and SEQ ID NO: 219, SEQ ID NO: 220 and SEQ ID NO: 221, SEQ ID NO: 222 and SEQ ID NO: 223, SEQ ID NO: 224 and SEQ ID NO: 225, SEQ ID NO: 226 and SEQ ID NO: 227, SEQ ID NO: 228 and SEQ ID NO: 229, SEQ ID NO: 230 and SEQ ID NO: 231, SEQ ID NO: 232 and SEQ ID NO: 233, SEQ ID NO: 234 and SEQ ID NO: 235, SEQ ID NO: 236 and SEQ ID NO: 237, SEQ ID NO: 238 and SEQ ID NO: 239, SEQ ID NO: 240 and SEQ ID NO: 241, SEQ ID NO: 242 and SEQ ID NO: 243, SEQ ID NO: 244 and SEQ ID NO: 245, SEQ ID NO: 246 and SEQ ID NO: 247, SEQ ID NO: 248 and SEQ ID NO: 249, SEQ ID NO: 250 and SEQ ID NO: 251, SEQ ID NO: 252 and SEQ ID NO: 253, SEQ ID NO: 254 and SEQ ID NO: 255, SEQ ID NO: 256 and SEQ ID NO: 257, SEQ ID NO: 258 and SEQ ID NO: 259, SEQ ID NO: 260 and SEQ ID NO: 261, SEQ ID NO: 264 and SEQ ID NO: 265, SEQ ID NO: 266 and SEQ ID NO: 267, SEQ ID NO: 268 and SEQ ID NO: 269, SEQ ID NO: 270 and SEQ ID NO: 271, SEQ ID NO: 272 and SEQ ID NO: 273, SEQ ID NO: 274 and SEQ ID NO: 275, SEQ ID NO: 276 and SEQ ID NO: 277, SEQ ID NO: 278 and SEQ ID NO: 279, SEQ ID NO: 280 and SEQ ID NO: 281, SEQ ID NO: 282 and SEQ ID NO: 283, SEQ ID NO: 284 and SEQ ID NO: 285, SEQ ID NO: 286 and SEQ ID NO: 287, SEQ ID NO: 288 and SEQ ID NO: 289, SEQ ID NO: 290 and SEQ ID NO: 291, SEQ ID NO: 292 and SEQ ID NO: 293, SEQ ID NO: 294 and SEQ ID NO: 295, SEQ ID NO: 296 and SEQ ID NO: 297, SEQ ID NO: 298 and SEQ ID NO: 299, SEQ ID NO: 300 and SEQ ID NO: 301, SEQ ID NO: 302 and SEQ ID NO: 303, SEQ ID NO: 304 and SEQ ID NO: 305, SEQ ID NO: 306 and SEQ ID NO: 307, SEQ ID NO: 308 and SEQ ID NO: 309, SEQ ID NO: 310 and SEQ ID NO: 311, SEQ ID NO: 312 and SEQ ID NO: 313, SEQ ID NO: 314 and SEQ ID NO: 315, SEQ ID NO: 316 and SEQ ID NO: 317, SEQ ID NO: 318 and SEQ ID NO: 319, SEQ ID NO: 320 and SEQ ID NO: 321, SEQ ID NO: 322 and SEQ ID NO: 323, SEQ ID NO: 324 and SEQ ID NO: 325, SEQ ID NO: 326 and SEQ ID NO: 327, SEQ ID NO: 328 and SEQ ID NO: 329, SEQ ID NO: 330 and SEQ ID NO: 331, SEQ ID NO: 332 and SEQ ID NO: 333, SEQ ID NO: 336 and SEQ ID NO: 337, SEQ ID NO: 338 and SEQ ID NO: 339, SEQ ID NO: 340 and SEQ ID NO: 341, SEQ ID NO: 342 and SEQ ID NO: 343, SEQ ID NO: 344 and SEQ ID NO: 345, SEQ ID NO: 348 and SEQ ID NO: 349, SEQ ID NO: 350 and SEQ ID NO: 351, SEQ ID NO: 352 and SEQ ID NO: 353, SEQ ID NO: 354 and SEQ ID NO: 355, SEQ ID NO: 356 and SEQ ID NO: 357, SEQ ID NO: 358 and SEQ ID NO: 359, SEQ ID NO: 362 and SEQ ID NO: 363, SEQ ID NO: 364 and SEQ ID NO: 365, SEQ ID NO: 366 and SEQ ID NO: 367, SEQ ID NO: 368 and SEQ ID NO: 369, SEQ ID NO: 370 and SEQ ID NO: 371, SEQ ID NO: 372 and SEQ ID NO: 373, SEQ ID NO: 374 and SEQ ID NO: 375, SEQ ID NO: 376 and SEQ ID NO: 377, SEQ ID NO: 378 and SEQ ID NO: 379, SEQ ID NO: 380 and SEQ ID NO: 381, SEQ ID NO: 382 and SEQ ID NO: 383, SEQ ID NO: 384 and SEQ ID NO: 385, SEQ ID NO: 386 and SEQ ID NO: 387, SEQ ID NO: 388 and SEQ ID NO: 389, SEQ ID NO: 390 and SEQ ID NO: 391, SEQ ID NO: 392 and SEQ ID NO: 393, SEQ ID NO: 394 and SEQ ID NO: 395, SEQ ID NO: 396 and SEQ ID NO: 397, SEQ ID NO: 398 and SEQ ID NO: 399, SEQ ID NO: 400 and SEQ ID NO: 401, SEQ ID NO: 402 and SEQ ID NO: 403, SEQ ID NO: 404 and SEQ ID NO: 405, SEQ ID NO: 406 and SEQ ID NO: 407, SEQ ID NO: 408 and SEQ ID NO: 409, SEQ ID NO: 410 and SEQ ID NO: 411, SEQ ID NO: 412 and SEQ ID NO: 413, SEQ ID NO: 414 and SEQ ID NO: 415, SEQ ID NO: 416 and SEQ ID NO: 417, SEQ ID NO: 418 and SEQ ID NO: 419, SEQ ID NO: 420 and SEQ ID NO: 421, SEQ ID NO: 422 and SEQ ID NO: 423, SEQ ID NO: 424 and SEQ ID NO: 425, SEQ ID NO: 426 and SEQ ID NO: 427, SEQ ID NO: 428 and SEQ ID NO: 429, SEQ ID NO: 430 and SEQ ID NO: 431, SEQ ID NO: 432 and SEQ ID NO: 433, SEQ ID NO: 434 and SEQ ID NO: 435, SEQ ID NO: 436 and SEQ ID NO: 437, SEQ ID NO: 438 and SEQ ID NO: 439, SEQ ID NO: 440 and SEQ ID NO: 441, SEQ ID NO: 442 and SEQ ID NO: 443, SEQ ID NO: 444 and SEQ ID NO: 445, SEQ ID NO: 446 and SEQ ID NO: 447, SEQ ID NO: 448 and SEQ ID NO: 449, SEQ ID NO: 450 and SEQ ID NO: 451, SEQ ID NO: 452 and SEQ ID NO: 453, SEQ ID NO: 454 and SEQ ID NO: 455, SEQ ID NO: 456 and SEQ ID NO: 457, SEQ ID NO: 458 and SEQ ID NO: 459, SEQ ID NO: 460 and SEQ ID NO: 461, SEQ ID NO: 462 and SEQ ID NO: 463, SEQ ID NO: 464 and SEQ ID NO: 465, SEQ ID NO: 466 and SEQ ID NO: 467, SEQ ID NO: 468 and SEQ ID NO: 469, SEQ ID NO: 470 and SEQ ID NO: 471, SEQ ID NO: 472 and SEQ ID NO: 473, SEQ ID NO: 474 and SEQ ID NO: 475, SEQ ID NO: 476 and SEQ ID NO: 477, SEQ ID NO: 478 and SEQ ID NO: 479, SEQ ID NO: 480 and SEQ ID NO: 481, SEQ ID NO: 482 and SEQ ID NO: 483, SEQ ID NO: 484 and SEQ ID NO: 485, SEQ ID NO: 486 and SEQ ID NO: 487, SEQ ID NO: 488 and SEQ ID NO: 489, SEQ ID NO: 490 and SEQ ID NO: 491, SEQ ID NO: 492 and SEQ ID NO: 493, SEQ ID NO: 494 and SEQ ID NO: 495, SEQ ID NO: 496 and SEQ ID NO: 497, SEQ ID NO: 498 and SEQ ID NO: 499, SEQ ID NO: 500 and SEQ ID NO: 501, SEQ ID NO: 502 and SEQ ID NO: 503, SEQ ID NO: 504 and SEQ ID NO: 505, SEQ ID NO: 506 and SEQ ID NO: 507, SEQ ID NO: 508 and SEQ ID NO: 509, SEQ ID NO: 628 and SEQ ID NO: 629, SEQ ID NO: 630 and SEQ ID NO: 631, SEQ ID NO: 632 and SEQ ID NO: 633, SEQ ID NO: 634 and SEQ ID NO: 635, SEQ ID NO: 636 and SEQ ID NO: 637, SEQ ID NO: 638 and SEQ ID NO: 639, SEQ ID NO: 640 and SEQ ID NO: 641, SEQ ID NO: 642 and SEQ ID NO: 643, SEQ ID NO: 644 and SEQ ID NO: 645, SEQ ID NO: 646 and SEQ ID NO: 647, SEQ ID NO: 648 and SEQ ID NO: 649, SEQ ID NO: 650 and SEQ ID NO: 651, or SEQ ID NO: 652 and SEQ ID NO: 653, respectively.

In certain embodiments, the three to twelve identical binding domains of the multimeric binding molecule that specifically bind to a human coronavirus, e.g., SARS-CoV-2, comprise an antibody VH and a VL, where the VH and VL comprise amino acid sequences at least 80%, at least 85%, at least 90%, at least 95% or 100% identical to SEQ ID NO: 86 and SEQ ID NO: 87, SEQ ID NO: 88 and SEQ ID NO: 89, SEQ ID NO: 90 and SEQ ID NO: 91, SEQ ID NO: 92 and SEQ ID NO: 93, SEQ ID NO: 94 and SEQ ID NO: 95, SEQ ID NO: 96 and SEQ ID NO: 97, SEQ ID NO: 98 and SEQ ID NO: 99, SEQ ID NO: 100 and SEQ ID NO: 101, SEQ ID NO: 102 and SEQ ID NO: 103, SEQ ID NO: 106 and SEQ ID NO: 107, SEQ ID NO: 110 and SEQ ID NO: 111, SEQ ID NO: 118 and SEQ ID NO: 119, SEQ ID NO: 128 and SEQ ID NO: 129, SEQ ID NO: 130 and SEQ ID NO: 131, SEQ ID NO: 132 and SEQ ID NO: 133, SEQ ID NO: 134 and SEQ ID NO: 135, SEQ ID NO: 136 and SEQ ID NO: 137, SEQ ID NO: 142 and SEQ ID NO: 143, SEQ ID NO: 146 and SEQ ID NO: 147, SEQ ID NO: 150 and SEQ ID NO: 151, SEQ ID NO: 156 and SEQ ID NO: 157, SEQ ID NO: 160 and SEQ ID NO: 161, SEQ ID NO: 162 and SEQ ID NO: 163, SEQ ID NO: 164 and SEQ ID NO: 165, SEQ ID NO: 166 and SEQ ID NO: 167, SEQ ID NO: 168 and SEQ ID NO: 169, SEQ ID NO: 170 and SEQ ID NO: 171, SEQ ID NO: 172 and SEQ ID NO: 173, SEQ ID NO: 174 and SEQ ID NO: 175, SEQ ID NO: 176 and SEQ ID NO: 177, SEQ ID NO: 180 and SEQ ID NO: 181, SEQ ID NO: 182 and SEQ ID NO: 183, SEQ ID NO: 186 and SEQ ID NO: 187, SEQ ID NO: 188 and SEQ ID NO: 189, SEQ ID NO: 194 and SEQ ID NO: 195, SEQ ID NO: 200 and SEQ ID NO: 201, SEQ ID NO: 206 and SEQ ID NO: 207, SEQ ID NO: 208 and SEQ ID NO: 209, SEQ ID NO: 218 and SEQ ID NO: 219, SEQ ID NO: 220 and SEQ ID NO: 221, SEQ ID NO: 222 and SEQ ID NO: 223, SEQ ID NO: 224 and SEQ ID NO: 225, SEQ ID NO: 228 and SEQ ID NO: 229, SEQ ID NO: 230 and SEQ ID NO: 231, SEQ ID NO: 240 and SEQ ID NO: 241, SEQ ID NO: 244 and SEQ ID NO: 245, SEQ ID NO: 246 and SEQ ID NO: 247, SEQ ID NO: 256 and SEQ ID NO: 257, SEQ ID NO: 258 and SEQ ID NO: 259, SEQ ID NO: 260 and SEQ ID NO: 261, SEQ ID NO: 264 and SEQ ID NO: 265, SEQ ID NO: 266 and SEQ ID NO: 267, SEQ ID NO: 268 and SEQ ID NO: 269, SEQ ID NO: 270 and SEQ ID NO: 271, SEQ ID NO: 272 and SEQ ID NO: 273, SEQ ID NO: 274 and SEQ ID NO: 275, SEQ ID NO: 276 and SEQ ID NO: 277, SEQ ID NO: 278 and SEQ ID NO: 279, SEQ ID NO: 280 and SEQ ID NO: 281, SEQ ID NO: 282 and SEQ ID NO: 283, SEQ ID NO: 284 and SEQ ID NO: 285, SEQ ID NO: 286 and SEQ ID NO: 287, SEQ ID NO: 288 and SEQ ID NO: 289, SEQ ID NO: 290 and SEQ ID NO: 291, SEQ ID NO: 292 and SEQ ID NO: 293, SEQ ID NO: 294 and SEQ ID NO: 295, SEQ ID NO: 296 and SEQ ID NO: 297, SEQ ID NO: 298 and SEQ ID NO: 299, SEQ ID NO: 300 and SEQ ID NO: 301, SEQ ID NO: 302 and SEQ ID NO: 303, SEQ ID NO: 304 and SEQ ID NO: 305, SEQ ID NO: 306 and SEQ ID NO: 307, SEQ ID NO: 308 and SEQ ID NO: 309, SEQ ID NO: 310 and SEQ ID NO: 311, SEQ ID NO: 312 and SEQ ID NO: 313, SEQ ID NO: 314 and SEQ ID NO: 315, SEQ ID NO: 316 and SEQ ID NO: 317, SEQ ID NO: 318 and SEQ ID NO: 319, SEQ ID NO: 320 and SEQ ID NO: 321, SEQ ID NO: 322 and SEQ ID NO: 323, SEQ ID NO: 324 and SEQ ID NO: 325, SEQ ID NO: 326 and SEQ ID NO: 327, SEQ ID NO: 328 and SEQ ID NO: 329, SEQ ID NO: 330 and SEQ ID NO: 331, SEQ ID NO: 332 and SEQ ID NO: 333, SEQ ID NO: 336 and SEQ ID NO: 337, SEQ ID NO: 338 and SEQ ID NO: 339, SEQ ID NO: 340 and SEQ ID NO: 341, SEQ ID NO: 342 and SEQ ID NO: 343, SEQ ID NO: 344 and SEQ ID NO: 345, SEQ ID NO: 348 and SEQ ID NO: 349, SEQ ID NO: 350 and SEQ ID NO: 351, SEQ ID NO: 352 and SEQ ID NO: 353, SEQ ID NO: 354 and SEQ ID NO: 355, SEQ ID NO: 356 and SEQ ID NO: 357, SEQ ID NO: 358 and SEQ ID NO: 359, SEQ ID NO: 360 and SEQ ID NO: 361, SEQ ID NO: 362 and SEQ ID NO: 363, SEQ ID NO: 364 and SEQ ID NO: 365, SEQ ID NO: 366 and SEQ ID NO: 367, SEQ ID NO: 368 and SEQ ID NO: 369, SEQ ID NO: 370 and SEQ ID NO: 371, SEQ ID NO: 372 and SEQ ID NO: 373, SEQ ID NO: 374 and SEQ ID NO: 375, SEQ ID NO: 376 and SEQ ID NO: 377, SEQ ID NO: 378 and SEQ ID NO: 379, SEQ ID NO: 380 and SEQ ID NO: 381, SEQ ID NO: 382 and SEQ ID NO: 383, SEQ ID NO: 384 and SEQ ID NO: 385, SEQ ID NO: 386 and SEQ ID NO: 387, SEQ ID NO: 388 and SEQ ID NO: 389, SEQ ID NO: 390 and SEQ ID NO: 391, SEQ ID NO: 392 and SEQ ID NO: 393, SEQ ID NO: 394 and SEQ ID NO: 395, SEQ ID NO: 396 and SEQ ID NO: 397, SEQ ID NO: 398 and SEQ ID NO: 399, SEQ ID NO: 400 and SEQ ID NO: 401, SEQ ID NO: 402 and SEQ ID NO: 403, SEQ ID NO: 404 and SEQ ID NO: 405, SEQ ID NO: 406 and SEQ ID NO: 407, SEQ ID NO: 408 and SEQ ID NO: 409, SEQ ID NO: 410 and SEQ ID NO: 411, SEQ ID NO: 412 and SEQ ID NO: 413, SEQ ID NO: 414 and SEQ ID NO: 415, SEQ ID NO: 416 and SEQ ID NO: 417, SEQ ID NO: 418 and SEQ ID NO: 419, SEQ ID NO: 420 and SEQ ID NO: 421, SEQ ID NO: 422 and SEQ ID NO: 423, SEQ ID NO: 424 and SEQ ID NO: 425, SEQ ID NO: 426 and SEQ ID NO: 427, SEQ ID NO: 428 and SEQ ID NO: 429, SEQ ID NO: 430 and SEQ ID NO: 431, SEQ ID NO: 432 and SEQ ID NO: 433, SEQ ID NO: 434 and SEQ ID NO: 435, SEQ ID NO: 436 and SEQ ID NO: 437, SEQ ID NO: 438 and SEQ ID NO: 439, SEQ ID NO: 440 and SEQ ID NO: 441, SEQ ID NO: 442 and SEQ ID NO: 443, SEQ ID NO: 444 and SEQ ID NO: 445, SEQ ID NO: 446 and SEQ ID NO: 447, SEQ ID NO: 448 and SEQ ID NO: 449, SEQ ID NO: 450 and SEQ ID NO: 451, SEQ ID NO: 452 and SEQ ID NO: 453, SEQ ID NO: 454 and SEQ ID NO: 455, SEQ ID NO: 456 and SEQ ID NO: 457, SEQ ID NO: 458 and SEQ ID NO: 459, SEQ ID NO: 460 and SEQ ID NO: 461, SEQ ID NO: 462 and SEQ ID NO: 463, SEQ ID NO: 464 and SEQ ID NO: 465, SEQ ID NO: 466 and SEQ ID NO: 467, SEQ ID NO: 468 and SEQ ID NO: 469, SEQ ID NO: 470 and SEQ ID NO: 471, SEQ ID NO: 472 and SEQ ID NO: 473, SEQ ID NO: 474 and SEQ ID NO: 475, SEQ ID NO: 476 and SEQ ID NO: 477, SEQ ID NO: 478 and SEQ ID NO: 479, SEQ ID NO: 480 and SEQ ID NO: 481, SEQ ID NO: 482 and SEQ ID NO: 483, SEQ ID NO: 484 and SEQ ID NO: 485, SEQ ID NO: 486 and SEQ ID NO: 487, SEQ ID NO: 488 and SEQ ID NO: 489, SEQ ID NO: 490 and SEQ ID NO: 491, SEQ ID NO: 492 and SEQ ID NO: 493, SEQ ID NO: 494 and SEQ ID NO: 495, SEQ ID NO: 496 and SEQ ID NO: 497, SEQ ID NO: 498 and SEQ ID NO: 499, SEQ ID NO: 500 and SEQ ID NO: 501, SEQ ID NO: 502 and SEQ ID NO: 503, SEQ ID NO: 504 and SEQ ID NO: 505, SEQ ID NO: 506 and SEQ ID NO: 507, SEQ ID NO: 508 and SEQ ID NO: 509, SEQ ID NO: 628 and SEQ ID NO: 629, SEQ ID NO: 632 and SEQ ID NO: 633, SEQ ID NO: 634 and SEQ ID NO: 635, SEQ ID NO: 636 and SEQ ID NO: 637, SEQ ID NO: 638 and SEQ ID NO: 639, SEQ ID NO: 640 and SEQ ID NO: 641, SEQ ID NO: 642 and SEQ ID NO: 643, SEQ ID NO: 644 and SEQ ID NO: 645, SEQ ID NO: 646 and SEQ ID NO: 647, SEQ ID NO: 648 and SEQ ID NO: 649, SEQ ID NO: 650 and SEQ ID NO: 651, or SEQ ID NO: 652 and SEQ ID NO: 653, respectively, wherein the bivalent reference IgG antibody comprising two of the binding domains that specifically bind to the human coronavirus can neutralize SARS-CoV-2.

In certain embodiments, the three to twelve identical binding domains of the multimeric binding molecule that specifically bind to a human coronavirus, e.g., SARS-CoV, comprise an antibody VH and a VL, where the VH and VL comprise amino acid sequences at least 80%, at least 85%, at least 90%, at least 95% or 100% identical to SEQ ID NO: 84 and SEQ ID NO: 85, SEQ ID NO: 118 and SEQ ID NO: 119, SEQ ID NO: 120 and SEQ ID NO: 121, SEQ ID NO: 138 and SEQ ID NO: 139, SEQ ID NO: 162 and SEQ ID NO: 163, SEQ ID NO: 222 and SEQ ID NO: 223, SEQ ID NO: 236 and SEQ ID NO: 237, SEQ ID NO: 252 and SEQ ID NO: 253, SEQ ID NO: 260 and SEQ ID NO: 261, SEQ ID NO: 262 and SEQ ID NO: 263, SEQ ID NO: 296 and SEQ ID NO: 297, SEQ ID NO: 384 and SEQ ID NO: 385, SEQ ID NO: 628 and SEQ ID NO: 629, SEQ ID NO: 632 and SEQ ID NO: 633, SEQ ID NO: 634 and SEQ ID NO: 635, SEQ ID NO: 636 and SEQ ID NO: 637, SEQ ID NO: 638 and SEQ ID NO: 639, SEQ ID NO: 640 and SEQ ID NO: 641, SEQ ID NO: 642 and SEQ ID NO: 643, SEQ ID NO: 644 and SEQ ID NO: 645, or SEQ ID NO: 646 and SEQ ID NO: 647, respectively.

In certain embodiments, the three to twelve identical binding domains of the multimeric binding molecule that specifically bind to a human coronavirus, e.g., SARS-CoV, comprise an antibody VH and a VL, where the VH and VL comprise amino acid sequences at least 80%, at least 85%, at least 90%, at least 95% or 100% identical to SEQ ID NO: 84 and SEQ ID NO: 85, SEQ ID NO: 260 and SEQ ID NO: 261, SEQ ID NO: 262 and SEQ ID NO: 263, SEQ ID NO: 296 and SEQ ID NO: 297, SEQ ID NO: 384 and SEQ ID NO: 385, SEQ ID NO: 628 and SEQ ID NO: 629, SEQ ID NO: 632 and SEQ ID NO: 633, SEQ ID NO: 634 and SEQ ID NO: 635, SEQ ID NO: 636 and SEQ ID NO: 637, SEQ ID NO: 638 and SEQ ID NO: 639, SEQ ID NO: 640 and SEQ ID NO: 641, SEQ ID NO: 642 and SEQ ID NO: 643, SEQ ID NO: 644 and SEQ ID NO: 645, or SEQ ID NO: 646 and SEQ ID NO: 647, respectively, wherein the bivalent reference IgG antibody comprising two of the binding domains that specifically bind to the human coronavirus can neutralize SARS-CoV.

In certain embodiments, the three to twelve identical binding domains of the multimeric binding molecule that specifically bind to a human coronavirus, e.g., MERS-CoV, comprise an antibody VH and a VL, where the VH and VL comprise amino acid sequences at least 80%, at least 85%, at least 90%, at least 95% or 100% identical to SEQ ID NO: 510 and SEQ ID NO: 511, SEQ ID NO: 512 and SEQ ID NO: 513, SEQ ID NO: 514 and SEQ ID NO: 515, SEQ ID NO: 516 and SEQ ID NO: 517, SEQ ID NO: 518 and SEQ ID NO: 519, SEQ ID NO: 520 and SEQ ID NO: 521, SEQ ID NO: 522 and SEQ ID NO: 523, SEQ ID NO: 524 and SEQ ID NO: 525, SEQ ID NO: 526 and SEQ ID NO: 527, SEQ ID NO: 528 and SEQ ID NO: 529, SEQ ID NO: 530 and SEQ ID NO: 531, SEQ ID NO: 532 and SEQ ID NO: 533, SEQ ID NO: 534 and SEQ ID NO: 535, SEQ ID NO: 536 and SEQ ID NO: 537, SEQ ID NO: 538 and SEQ ID NO: 539, SEQ ID NO: 540 and SEQ ID NO: 541, SEQ ID NO: 542 and SEQ ID NO: 543, SEQ ID NO: 544 and SEQ ID NO: 545, SEQ ID NO: 546 and SEQ ID NO: 547, SEQ ID NO: 548 and SEQ ID NO: 549, SEQ ID NO: 550 and SEQ ID NO: 551, SEQ ID NO: 552 and SEQ ID NO: 553, SEQ ID NO: 554 and SEQ ID NO: 555, SEQ ID NO: 556 and SEQ ID NO: 557, SEQ ID NO: 558 and SEQ ID NO: 559, SEQ ID NO: 560 and SEQ ID NO: 561, SEQ ID NO: 562 and SEQ ID NO: 563, SEQ ID NO: 564 and SEQ ID NO: 565, SEQ ID NO: 566 and SEQ ID NO: 567, SEQ ID NO: 568 and SEQ ID NO: 569, SEQ ID NO: 570 and SEQ ID NO: 571, SEQ ID NO: 572 and SEQ ID NO: 573, SEQ ID NO: 574 and SEQ ID NO: 575, SEQ ID NO: 576 and SEQ ID NO: 577, SEQ ID NO: 578 and SEQ ID NO: 579, SEQ ID NO: 580 and SEQ ID NO: 581, SEQ ID NO: 582 and SEQ ID NO: 583, SEQ ID NO: 584 and SEQ ID NO: 585, SEQ ID NO: 586 and SEQ ID NO: 587, SEQ ID NO: 588 and SEQ ID NO: 589, SEQ ID NO: 590 and SEQ ID NO: 591, SEQ ID NO: 592 and SEQ ID NO: 593, SEQ ID NO: 594 and SEQ ID NO: 595, SEQ ID NO: 596 and SEQ ID NO: 597, SEQ ID NO: 598 and SEQ ID NO: 599, SEQ ID NO: 600 and SEQ ID NO: 601, SEQ ID NO: 602 and SEQ ID NO: 603, SEQ ID NO: 604 and SEQ ID NO: 605, SEQ ID NO: 606 and SEQ ID NO: 607, SEQ ID NO: 608 and SEQ ID NO: 609, SEQ ID NO: 610 and SEQ ID NO: 611, SEQ ID NO: 612 and SEQ ID NO: 613, SEQ ID NO: 614 and SEQ ID NO: 615, SEQ ID NO: 616 and SEQ ID NO: 617, SEQ ID NO: 618 and SEQ ID NO: 619, SEQ ID NO: 620 and SEQ ID NO: 621, SEQ ID NO: 622 and SEQ ID NO: 623, SEQ ID NO: 624 and SEQ ID NO: 625, SEQ ID NO: 626 and SEQ ID NO: 627, or SEQ ID NO: 630 and SEQ ID NO: 631, respectively.

In certain embodiments, the three to twelve identical binding domains of the multimeric binding molecule that specifically bind to a human coronavirus, e.g., MERS-CoV, comprise an antibody VH and a VL, where the VH and VL comprise amino acid sequences at least 80%, at least 85%, at least 90%, at least 95% or 100% identical to SEQ ID NO: 510 and SEQ ID NO: 511, SEQ ID NO: 512 and SEQ ID NO: 513, SEQ ID NO: 514 and SEQ ID NO: 515, SEQ ID NO: 516 and SEQ ID NO: 517, SEQ ID NO: 518 and SEQ ID NO: 519, SEQ ID NO: 520 and SEQ ID NO: 521, SEQ ID NO: 522 and SEQ ID NO: 523, SEQ ID NO: 524 and SEQ ID NO: 525, SEQ ID NO: 526 and SEQ ID NO: 527, SEQ ID NO: 528 and SEQ ID NO: 529, SEQ ID NO: 530 and SEQ ID NO: 531, SEQ ID NO: 532 and SEQ ID NO: 533, SEQ ID NO: 534 and SEQ ID NO: 535, SEQ ID NO: 536 and SEQ ID NO: 537, SEQ ID NO: 538 and SEQ ID NO: 539, SEQ ID NO: 540 and SEQ ID NO: 541, SEQ ID NO: 542 and SEQ ID NO: 543, SEQ ID NO: 544 and SEQ ID NO: 545, SEQ ID NO: 546 and SEQ ID NO: 547, SEQ ID NO: 548 and SEQ ID NO: 549, SEQ ID NO: 550 and SEQ ID NO: 551, SEQ ID NO: 552 and SEQ ID NO: 553, SEQ ID NO: 554 and SEQ ID NO: 555, SEQ ID NO: 556 and SEQ ID NO: 557, SEQ ID NO: 558 and SEQ ID NO: 559, SEQ ID NO: 560 and SEQ ID NO: 561, SEQ ID NO: 562 and SEQ ID NO: 563, SEQ ID NO: 564 and SEQ ID NO: 565, SEQ ID NO: 566 and SEQ ID NO: 567, SEQ ID NO: 568 and SEQ ID NO: 569, SEQ ID NO: 574 and SEQ ID NO: 575, SEQ ID NO: 576 and SEQ ID NO: 577, SEQ ID NO: 578 and SEQ ID NO: 579, SEQ ID NO: 580 and SEQ ID NO: 581, SEQ ID NO: 582 and SEQ ID NO: 583, SEQ ID NO: 584 and SEQ ID NO: 585, SEQ ID NO: 586 and SEQ ID NO: 587, SEQ ID NO: 588 and SEQ ID NO: 589, SEQ ID NO: 590 and SEQ ID NO: 591, SEQ ID NO: 592 and SEQ ID NO: 593, SEQ ID NO: 594 and SEQ ID NO: 595, SEQ ID NO: 596 and SEQ ID NO: 597, SEQ ID NO: 598 and SEQ ID NO: 599, SEQ ID NO: 600 and SEQ ID NO: 601, SEQ ID NO: 602 and SEQ ID NO: 603, SEQ ID NO: 604 and SEQ ID NO: 605, SEQ ID NO: 606 and SEQ ID NO: 607, SEQ ID NO: 608 and SEQ ID NO: 609, SEQ ID NO: 610 and SEQ ID NO: 611, SEQ ID NO: 612 and SEQ ID NO: 613, SEQ ID NO: 614 and SEQ ID NO: 615, SEQ ID NO: 616 and SEQ ID NO: 617, SEQ ID NO: 618 and SEQ ID NO: 619, SEQ ID NO: 620 and SEQ ID NO: 621, SEQ ID NO: 622 and SEQ ID NO: 623, SEQ ID NO: 624 and SEQ ID NO: 625, SEQ ID NO: 626 and SEQ ID NO: 627, or SEQ ID NO: 630 and SEQ ID NO: 631, respectively, wherein the bivalent reference IgG antibody comprising two of the binding domains that specifically bind to the human coronavirus can neutralize MERS-CoV.

In certain embodiments, the three to twelve identical binding domains of the multimeric binding molecule that specifically bind to a human coronavirus, e.g., SARS-CoV or SARS-CoV-2, comprise an antibody VH and a VL, where the VH and VL comprise amino acid sequences at least 80%, at least 85%, at least 90%, at least 95% or 100% identical to SEQ ID NO: 118 and SEQ ID NO: 119, SEQ ID NO: 162 and SEQ ID NO: 163, SEQ ID NO: 222 and SEQ ID NO: 223, SEQ ID NO: 260 and SEQ ID NO: 261, SEQ ID NO: 296 and SEQ ID NO: 297, SEQ ID NO: 384 and SEQ ID NO: 385, SEQ ID NO: 628 and SEQ ID NO: 629, SEQ ID NO: 632 and SEQ ID NO: 633, SEQ ID NO: 634 and SEQ ID NO: 635, SEQ ID NO: 636 and SEQ ID NO: 637, SEQ ID NO: 638 and SEQ ID NO: 639, SEQ ID NO: 640 and SEQ ID NO: 641, SEQ ID NO: 642 and SEQ ID NO: 643, SEQ ID NO: 644 and SEQ ID NO: 645, or SEQ ID NO: 646 and SEQ ID NO: 647, respectively, wherein the bivalent reference IgG antibody comprising two of the binding domains that specifically bind to the human coronavirus can neutralize SARS-CoV-2 and can bind SARS-CoV.

In certain embodiments, the three to twelve identical binding domains of the multimeric binding molecule that specifically bind to a human coronavirus, e.g., SARS-CoV or SARS-CoV-2, comprise an antibody VH and a VL, where the VH and VL comprise amino acid sequences at least 80%, at least 85%, at least 90%, at least 95% or 100% identical to SEQ ID NO: 260 and SEQ ID NO: 261, SEQ ID NO: 296 and SEQ ID NO: 297, SEQ ID NO: 384 and SEQ ID NO: 385, SEQ ID NO: 628 and SEQ ID NO: 629, SEQ ID NO: 632 and SEQ ID NO: 633, SEQ ID NO: 634 and SEQ ID NO: 635, SEQ ID NO: 636 and SEQ ID NO: 637, SEQ ID NO: 638 and SEQ ID NO: 639, SEQ ID NO: 640 and SEQ ID NO: 641, SEQ ID NO: 642 and SEQ ID NO: 643, SEQ ID NO: 644 and SEQ ID NO: 645, or SEQ ID NO: 646 and SEQ ID NO: 647, respectively with zero, one, or two single amino acid substitutions in one or more of the HCDRs or LCDRs, wherein the bivalent reference IgG antibody comprising two of the binding domains that specifically bind to the human coronavirus can neutralize SARS-CoV and SARS-CoV-2.

In certain embodiments, the three to twelve SARS-CoV2-binding domains comprise a single domain variable region (a “nanobody” or VHH), where the VHH comprises three immunoglobulin complementarity determining regions HCDR1, HCDR2, and HCDR3, where the HCDR1, HCDR2, and HCDR3 the CDRs of an antibody comprising the VHH of SEQ ID NO: 19, SEQ ID NO: 20, SEQ ID NO: 21, SEQ ID NO: 22, SEQ ID NO: 23, SEQ ID NO: 24, SEQ ID NO: 25, SEQ ID NO: 26, SEQ ID NO: 27, SEQ ID NO: 28, SEQ ID NO: 29, SEQ ID NO: 30, SEQ ID NO: 31, SEQ ID NO: 32, SEQ ID NO: 33, SEQ ID NO: 34, SEQ ID NO: 35, SEQ ID NO: 36, SEQ ID NO: 37, SEQ ID NO: 38, SEQ ID NO: 39, SEQ ID NO: 40, SEQ ID NO: 41, SEQ ID NO: 42, SEQ ID NO: 43, SEQ ID NO: 44, SEQ ID NO: 45, SEQ ID NO: 46, SEQ ID NO: 47, SEQ ID NO: 48, SEQ ID NO: 49, SEQ ID NO: 50, SEQ ID NO: 51, SEQ ID NO: 52, SEQ ID NO: 53, SEQ ID NO: 54, SEQ ID NO: 55, SEQ ID NO: 56, SEQ ID NO: 57, SEQ ID NO: 58, SEQ ID NO: 59, SEQ ID NO: 60, SEQ ID NO: 61, SEQ ID NO: 62, SEQ ID NO: 63, SEQ ID NO: 64, SEQ ID NO: 65, SEQ ID NO: 66, SEQ ID NO: 67, SEQ ID NO: 68, SEQ ID NO: 69, SEQ ID NO: 70, SEQ ID NO: 71, SEQ ID NO: 72, SEQ ID NO: 73, SEQ ID NO: 74, SEQ ID NO: 75, SEQ ID NO: 76, SEQ ID NO: 77, SEQ ID NO: 78, SEQ ID NO: 79, SEQ ID NO: 80, SEQ ID NO: 81, SEQ ID NO: 82, or SEQ ID NO: 83 with zero, one, or two single amino acid substitutions in one or more of the HCDRs. In certain embodiments, the three to twelve SARS-CoV2-binding domains comprise a single domain variable region (VHH), where the VHH comprises three immunoglobulin complementarity determining regions HCDR1, HCDR2, and HCDR3, where the HCDR1, HCDR2, and HCDR3 the CDRs of an antibody comprising the VHH of SEQ ID NO: 83 with zero, one, or two single amino acid substitutions in one or more of the HCDRs.

In certain embodiments, the three to twelve SARS-CoV2-binding domains of the binding molecule comprise an antibody VHH, where the VHH comprises an amino acid sequence at least 80%, at least 85%, at least 90%, at least 95% or 100% identical to SEQ ID NO: 19, SEQ ID NO: 20, SEQ ID NO: 21, SEQ ID NO: 22, SEQ ID NO: 23, SEQ ID NO: 24, SEQ ID NO: 25, SEQ ID NO: 26, SEQ ID NO: 27, SEQ ID NO: 28, SEQ ID NO: 29, SEQ ID NO: 30, SEQ ID NO: 31, SEQ ID NO: 32, SEQ ID NO: 33, SEQ ID NO: 34, SEQ ID NO: 35, SEQ ID NO: 36, SEQ ID NO: 37, SEQ ID NO: 38, SEQ ID NO: 39, SEQ ID NO: 40, SEQ ID NO: 41, SEQ ID NO: 42, SEQ ID NO: 43, SEQ ID NO: 44, SEQ ID NO: 45, SEQ ID NO: 46, SEQ ID NO: 47, SEQ ID NO: 48, SEQ ID NO: 49, SEQ ID NO: 50, SEQ ID NO: 51, SEQ ID NO: 52, SEQ ID NO: 53, SEQ ID NO: 54, SEQ ID NO: 55, SEQ ID NO: 56, SEQ ID NO: 57, SEQ ID NO: 58, SEQ ID NO: 59, SEQ ID NO: 60, SEQ ID NO: 61, SEQ ID NO: 62, SEQ ID NO: 63, SEQ ID NO: 64, SEQ ID NO: 65, SEQ ID NO: 66, SEQ ID NO: 67, SEQ ID NO: 68, SEQ ID NO: 69, SEQ ID NO: 70, SEQ ID NO: 71, SEQ ID NO: 72, SEQ ID NO: 73, SEQ ID NO: 74, SEQ ID NO: 75, SEQ ID NO: 76, SEQ ID NO: 77, SEQ ID NO: 78, SEQ ID NO: 79, SEQ ID NO: 80, SEQ ID NO: 81, SEQ ID NO: 82, or SEQ ID NO: 83 such as the amino acid sequences at least 80%, at least 85%, at least 90%, at least 95% or 100% identical to SEQ ID NO: 83.

In certain embodiments, the three to twelve identical binding domains of the multimeric binding molecule that specifically bind to a human coronavirus, e.g., SARS-CoV or SARS-CoV-2, comprise an extracellular SARS-CoV or SARS-CoV-2 RBD-binding fragment of angiotensin-converting enzyme 2 (ACE2). In certain embodiments, the three to twelve human coronavirus binding domains, e.g., SARS-CoV-2-binding domains of the binding molecule comprise an extracellular SARS-CoV or SARS-CoV-2 RBD-binding fragment of SEQ ID NO: 14. In certain embodiments, the three to twelve human coronavirus binding domains, e.g., SARS-CoV-2-binding domains, of the binding molecule comprise an amino acid sequence at least 80%, at least 85%, at least 90%, at least 95% or 100% identical to amino acids 18 to 740 of SEQ ID NO: 14. In certain embodiments the multimeric binding molecule is a pentameric or hexameric binding molecule comprising three to twelve IgM, IgM-like, or IgM-derived heavy chains each comprising at least the Cμ3, Cμ4, and tailpiece (tp) domains corresponding to an IgM heavy chain, e.g., a human IgM heavy chain fused to an extracellular domain of ACE2, e.g., human ACE2, e.g., an amino acid sequence at least 80%, at least 85%, at least 90%, at least 95% or 100% identical to amino acids 18 to 740 of SEQ ID NO: 14. In certain embodiments the heavy chains comprise the Cμ3, Cμ4, and tailpiece (tp) domains corresponding to an IgM heavy chain, e.g., a human IgM heavy chain with a modified human IgG1 hinge region fused to the N-terminus where the cysteine at position 7 of the human IgG1 hinge region is substituted with serine, e.g., amino acids 724 to 741 of SEQ ID NO: 15 (VEPKSSD KTHTCPPCPA P). In certain embodiments the binding molecule is engineered to reduce or eliminate complement-mediated cytotoxicity, e.g., comprising amino acid substitutions P311A, P313S corresponding to the positions in SEQ ID NO: 1 and SEQ ID NO: 2, or comprising the amino acid substitution K315D corresponding to the position in SEQ ID NO: 1 and SEQ ID NO: 2. In certain embodiments the multimeric binding molecule comprises ten or twelve heavy chains comprising the amino acid sequence SEQ ID NO: 15.

In certain embodiments, the three to twelve identical binding domains of the multimeric binding molecule that specifically bind to a human coronavirus, e.g., SARS-CoV-1, comprise a heavy chain variable region (VH) and a light chain variable region (VL), where the VH and VL comprise six immunoglobulin complementarity determining regions HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3, where the HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 comprise the CDRs of an antibody comprising the VH and VL of SEQ ID NO: 84 and SEQ ID NO: 85, or SEQ ID NO: 262 and SEQ ID NO: 263, respectively, with zero, one, or two single amino acid substitutions in one or more of the HCDRs or LCDRs.

In certain embodiments, the three to twelve identical binding domains of the multimeric binding molecule that specifically bind to a human coronavirus, e.g., SARS-CoV-1, comprise an antibody VH and a VL, where the VH and VL comprise amino acid sequences at least 80%, at least 85%, at least 90%, at least 95% or 100% identical to SEQ ID NO: 84 and SEQ ID NO: 85, or SEQ ID NO: 262 and SEQ ID NO: 263, respectively.

In certain embodiments, the three to twelve identical binding domains of the multimeric binding molecule that specifically bind to a human coronavirus, e.g., SARS-CoV-2, comprise a heavy chain variable region (VH) and a light chain variable region (VL), where the VH and VL comprise six immunoglobulin complementarity determining regions HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3, where the HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 comprise the CDRs of an antibody comprising the VH and VL of SEQ ID NO: 256 and SEQ ID NO: 257, respectively, with zero, one, or two single amino acid substitutions in one or more of the HCDRs or LCDRs.

In certain embodiments, the three to twelve identical binding domains of the multimeric binding molecule that specifically bind to a human coronavirus, e.g., SARS-CoV-2, comprise a heavy chain variable region (VH) and a light chain variable region (VL), where the VH and VL comprise six immunoglobulin complementarity determining regions HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3, where the HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 comprise the CDRs of an antibody comprising the VH and VL of SEQ ID NO: 260 and SEQ ID NO: 261, respectively, with zero, one, or two single amino acid substitutions in one or more of the HCDRs or LCDRs.

In certain embodiments, the three to twelve identical binding domains of the multimeric binding molecule that specifically bind to a human coronavirus, e.g., SARS-CoV-2, comprise a heavy chain variable region (VH) and a light chain variable region (VL), where the VH and VL comprise six immunoglobulin complementarity determining regions HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3, where the HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 comprise the CDRs of an antibody comprising the VH and VL of SEQ ID NO: 264 and SEQ ID NO: 265, or SEQ ID NO: 266 and SEQ ID NO: 267, respectively, with zero, one, or two single amino acid substitutions in one or more of the HCDRs or LCDRs.

In certain embodiments, the three to twelve identical binding domains of the multimeric binding molecule that specifically bind to a human coronavirus, e.g., SARS-CoV-2, comprise a heavy chain variable region (VH) and a light chain variable region (VL), where the VH and VL comprise six immunoglobulin complementarity determining regions HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3, where the HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 comprise the CDRs of an antibody comprising the VH and VL of SEQ ID NO: 88 and SEQ ID NO: 89, respectively, with zero, one, or two single amino acid substitutions in one or more of the HCDRs or LCDRs.

In certain embodiments, the three to twelve identical binding domains of the multimeric binding molecule that specifically bind to a human coronavirus, e.g., SARS-CoV-2, comprise a heavy chain variable region (VH) and a light chain variable region (VL), where the VH and VL comprise six immunoglobulin complementarity determining regions HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3, where the HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 comprise the CDRs of an antibody comprising the VH and VL of SEQ ID NO: 268 and SEQ ID NO: 269, respectively, with zero, one, or two single amino acid substitutions in one or more of the HCDRs or LCDRs.

In certain embodiments, the three to twelve identical binding domains of the multimeric binding molecule that specifically bind to a human coronavirus, e.g., SARS-CoV-2, comprise a heavy chain variable region (VH) and a light chain variable region (VL), where the VH and VL comprise six immunoglobulin complementarity determining regions HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3, where the HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 comprise the CDRs of an antibody comprising the VH and VL of SEQ ID NO: 270 and SEQ ID NO: 271, respectively, with zero, one, or two single amino acid substitutions in one or more of the HCDRs or LCDRs.

In certain embodiments, the three to twelve identical binding domains of the multimeric binding molecule that specifically bind to a human coronavirus, e.g., SARS-CoV-2, comprise a heavy chain variable region (VH) and a light chain variable region (VL), where the VH and VL comprise six immunoglobulin complementarity determining regions HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3, where the HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 comprise the CDRs of an antibody comprising the VH and VL of SEQ ID NO: 272 and SEQ ID NO: 273, SEQ ID NO: 274 and SEQ ID NO: 275, SEQ ID NO: 276 and SEQ ID NO: 277, SEQ ID NO: 278 and SEQ ID NO: 279, SEQ ID NO: 280 and SEQ ID NO: 281, SEQ ID NO: 282 and SEQ ID NO: 283, respectively, with zero, one, or two single amino acid substitutions in one or more of the HCDRs or LCDRs.

In certain embodiments, the three to twelve identical binding domains of the multimeric binding molecule that specifically bind to a human coronavirus, e.g., SARS-CoV-2, comprise a heavy chain variable region (VH) and a light chain variable region (VL), where the VH and VL comprise six immunoglobulin complementarity determining regions HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3, where the HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 comprise the CDRs of an antibody comprising the VH and VL of SEQ ID NO: 284 and SEQ ID NO: 285, SEQ ID NO: 286 and SEQ ID NO: 287, SEQ ID NO: 288 and SEQ ID NO: 289, SEQ ID NO: 290 and SEQ ID NO: 291, respectively, with zero, one, or two single amino acid substitutions in one or more of the HCDRs or LCDRs.

In certain embodiments, the three to twelve identical binding domains of the multimeric binding molecule that specifically bind to a human coronavirus, e.g., SARS-CoV-2, comprise a heavy chain variable region (VH) and a light chain variable region (VL), where the VH and VL comprise six immunoglobulin complementarity determining regions HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3, where the HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 comprise the CDRs of an antibody comprising the VH and VL of SEQ ID NO: 292 and SEQ ID NO: 293, respectively, with zero, one, or two single amino acid substitutions in one or more of the HCDRs or LCDRs.

In certain embodiments, the three to twelve identical binding domains of the multimeric binding molecule that specifically bind to a human coronavirus, e.g., SARS-CoV and SARS-CoV-2, comprise a heavy chain variable region (VH) and a light chain variable region (VL), where the VH and VL comprise six immunoglobulin complementarity determining regions HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3, where the HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 comprise the CDRs of an antibody comprising the VH and VL of SEQ ID NO: 384 and SEQ ID NO: 385, respectively, with zero, one, or two single amino acid substitutions in one or more of the HCDRs or LCDRs.

In certain embodiments, the three to twelve identical binding domains of the multimeric binding molecule that specifically bind to a human coronavirus, e.g., SARS-CoV and SARS-CoV-2, comprise an antibody VH and a VL, where the VH and VL comprise amino acid sequences at least 80%, at least 85%, at least 90%, at least 95% or 100% identical to SEQ ID NO: 384 and SEQ ID NO: 385, respectively.

In certain embodiments, the three to twelve identical binding domains of the multimeric binding molecule that specifically bind to a human coronavirus, e.g., SARS-CoV and SARS-CoV-2, comprise a heavy chain variable region (VH) and a light chain variable region (VL), where the VH and VL comprise six immunoglobulin complementarity determining regions HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3, where the HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 comprise the CDRs of an antibody comprising the VH and VL of SEQ ID NO: 646 and SEQ ID NO: 647, respectively, with zero, one, or two single amino acid substitutions in one or more of the HCDRs or LCDRs.

In certain embodiments, the three to twelve identical binding domains of the multimeric binding molecule that specifically bind to a human coronavirus, e.g., SARS-CoV and SARS-CoV-2, comprise an antibody VH and a VL, where the VH and VL comprise amino acid sequences at least 80%, at least 85%, at least 90%, at least 95% or 100% identical to SEQ ID NO: 646 and SEQ ID NO: 647, respectively.

In certain embodiments, the three to twelve identical binding domains of the multimeric binding molecule that specifically bind to a human coronavirus, e.g., SARS-CoV-2, comprise a heavy chain variable region (VH) and a light chain variable region (VL), where the VH and VL comprise six immunoglobulin complementarity determining regions HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3, where the HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 comprise the CDRs of an antibody comprising the VH and VL of SEQ ID NO: 654 and SEQ ID NO: 655, respectively, with zero, one, or two single amino acid substitutions in one or more of the HCDRs or LCDRs.

In certain embodiments, the three to twelve identical binding domains of the multimeric binding molecule that specifically bind to a human coronavirus, e.g., MERS-CoV, comprise an antibody VH and a VL, where the VH and VL comprise amino acid sequences at least 80%, at least 85%, at least 90%, at least 95% or 100% identical to SEQ ID NO: 522 and SEQ ID NO: 523, SEQ ID NO: 576 and SEQ ID NO: 577, SEQ ID NO: 610 and SEQ ID NO: 611, SEQ ID NO: 612 and SEQ ID NO: 613, SEQ ID NO: 614 and SEQ ID NO: 615, or SEQ ID NO: 630 and SEQ ID NO: 631, respectively.

IgM Antibodies, IgM-Like Antibodies, Other IgM-Derived Binding Molecules

IgM is the first immunoglobulin produced by B cells in response to stimulation by antigen. Naturally occurring IgM is naturally present at around 1.5 mg/ml in serum with a half-life of about 5 days. IgM is a pentameric or hexameric molecule and thus includes five or six binding units. An IgM binding unit typically includes two light and two heavy chains. While an IgG heavy chain constant region contains three heavy chain constant domains (CH1, CH2 and CH3), the heavy (μ) constant region of IgM additionally contains a fourth constant domain (CH4) and includes a C-terminal “tailpiece.” The human IgM constant region typically comprises the amino acid sequence SEQ ID NO: 1 (identical to, e.g., GenBank Accession Nos. pir∥S37768, CAA47708.1, and CAA47714.1, allele IGHM*03) or SEQ ID NO: 2 (identical to, e.g., GenBank Accession No. sp|P01871.4, allele IGHM*04). The human Cμ1 region ranges from about amino acid 5 to about amino acid 102 of SEQ ID NO: 1 or SEQ ID NO: 2; the human Cμ2 region ranges from about amino acid 114 to about amino acid 205 of SEQ ID NO: 1 or SEQ ID NO: 2, the human Cμ3 region ranges from about amino acid 224 to about amino acid 319 of SEQ ID NO: 1 or SEQ ID NO: 2, the Cμ4 region ranges from about amino acid 329 to about amino acid 430 of SEQ ID NO: 1 or SEQ ID NO: 2, and the tailpiece ranges from about amino acid 431 to about amino acid 453 of SEQ ID NO: 1 or SEQ ID NO: 2.

Other forms and alleles of the human IgM constant region with minor sequence variations exist, including, without limitation, GenBank Accession Nos. CAB37838.1, and pir∥HHU. The amino acid substitutions, insertions, and/or deletions at positions corresponding to SEQ ID NO: 1 or SEQ ID NO: 2 described and claimed elsewhere in this disclosure can likewise be incorporated into alternate human IgM sequences, as well as into IgM constant region amino acid sequences of other species.

Each IgM heavy chain constant region can be associated with a binding domain, e.g., an antigen-binding domain, e.g., a scFv or VHH, or a subunit of an antigen-binding domain, e.g., a VH region. Exemplary antigen-binding domains, e.g., binding domains that bind SARS-CoV-2 are described elsewhere herein. In certain embodiments the binding domain can be a non-antibody binding domain, e.g., an ACE-2 ectodomain.

Five IgM binding units can form a complex with an additional small polypeptide chain (the J-chain), or a functional fragment, variant, or derivative thereof, to form a pentameric IgM antibody or IgM-like antibody, as discussed elsewhere herein. The precursor form of the human J-chain is presented as SEQ ID NO: 6. The signal peptide extends from amino acid 1 to about amino acid 22 of SEQ ID NO: 6, and the mature human J-chain extends from about amino acid 23 to amino acid 159 of SEQ ID NO: 6. The mature human J-chain includes the amino acid sequence SEQ ID NO: 7.

Exemplary variant and modified J-chains are provided elsewhere herein. Without the J-chain, an IgM antibody or IgM-like antibody typically assembles into a hexamer, comprising up to twelve antigen-binding domains. With a J-chain, an IgM antibody or IgM-like antibody typically assembles into a pentamer, comprising up to ten antigen-binding domains, or more, if the J-chain is a modified J-chain comprising one or more heterologous polypeptides comprising additional antigen-binding domain(s). The assembly of five or six IgM binding units into a pentameric or hexameric IgM antibody or IgM-like antibody is thought to involve the Cμ4 and tailpiece domains. See, e.g., Braathen, R., et al., J. Biol. Chem. 277:42755-42762 (2002). Accordingly, a pentameric or hexameric IgM antibody provided in this disclosure typically includes at least the Cμ4 and tailpiece domains (also referred to herein collectively as Cμ4-tp). A “multimerizing fragment” of an IgM heavy chain constant region thus includes at least the Cμ4-tp domains. An IgM heavy chain constant region can additionally include a Cμ3 domain or a fragment thereof, a Cμ2 domain or a fragment thereof, a Cμ1 domain or a fragment thereof, and/or other IgM heavy chain domains. In certain embodiments, an IgM-derived binding molecule, e.g., an IgM antibody, IgM-like antibody, or other IgM-derived binding molecule as provided herein can include a complete IgM heavy (μ) chain constant domain, e.g., SEQ ID NO: 1 or SEQ ID NO: 2, or a variant, derivative, or analog thereof, e.g., as provided herein.

In certain embodiments, the disclosure provides a multimeric binding molecule, e.g., a pentameric or hexameric binding molecule, where the binding molecule includes ten or twelve IgM-derived heavy chains, and where the IgM-derived heavy chains comprise IgM heavy chain constant regions each associated with a binding domain that specifically binds to a target. In certain embodiments, the disclosure provides an IgM antibody, IgM-like antibody, or IgM-derived binding molecule that includes five or six bivalent binding units, where each binding unit includes two IgM or IgM-like heavy chain constant regions or multimerizing fragments or variants thereof, each associated with an antigen-binding domain or subunit thereof. In certain embodiments, the two IgM heavy chain constant regions included in each binding unit are human heavy chain constant regions. In some embodiments, the heavy chains are glycosylated. In some embodiments, the heavy chains can be mutated to affect glycosylation.

Where the IgM antibody, IgM-like antibody, or other IgM-derived binding molecule provided in this disclosure is pentameric, the IgM antibody, IgM-like antibody, or other IgM-derived binding molecule typically further includes a J-chain, or functional fragment or variant thereof. In certain embodiments, the J-chain is a modified J-chain or variant thereof that further comprises one or more heterologous moieties attached to the J-chain, as described elsewhere herein. In certain embodiments, the J-chain can be mutated to affect, e.g., enhance, the serum half-life of the IgM antibody, IgM-like antibody, or other IgM-derived binding molecule provided herein, as discussed elsewhere in this disclosure. In certain embodiments the J-chain can be mutated to affect glycosylation and/or serum half-life of the binding molecule, as discussed elsewhere in this disclosure.

An IgM heavy chain constant region can include one or more of a Cμ11 domain or fragment or variant thereof, a Cμ2 domain or fragment or variant thereof, a Cμ3 domain or fragment or variant thereof, a Cμ4 domain or fragment or variant thereof, and/or an IgM tailpiece, provided that the constant region can serve a desired function in the IgM antibody, IgM-like antibody, or other IgM-derived binding molecule, e.g., associate with second IgM constant region to form a binding unit with one, two, or more antigen-binding domain(s), and/or associate with other binding units (and in the case of a pentamer, a J-chain) to form a hexamer or a pentamer. In certain embodiments the two IgM heavy chain constant regions or fragments or variants thereof within an individual binding unit each comprise a Cμ4 domain or fragment or variant thereof, a tailpiece (tp) or fragment or variant thereof, or a combination of a Cμ4 domain and a tp or fragment or variant thereof. In certain embodiments the two IgM heavy chain constant regions or fragments or variants thereof within an individual binding unit each further comprise a Cμ3 domain or fragment or variant thereof, a Cμ2 domain or fragment or variant thereof, a Cμ1 domain or fragment or variant thereof, or any combination thereof.

In some embodiments, the binding units of the IgM antibody, IgM-like antibody, or other IgM-derived binding molecule each comprise two light chains. In some embodiments, the binding units of the IgM antibody, IgM-like antibody, or other IgM-derived binding molecule each comprise two fragments of light chains. In some embodiments, the light chains are kappa light chains. In some embodiments, the light chains are lambda light chains. In some embodiments, the light chains are hybrid kappa-lambda light chains. In some embodiments, each binding unit comprises two immunoglobulin light chains each comprising a VL situated amino terminal to an immunoglobulin light chain constant region.

IgA Antibodies, IgA-Like Antibodies, Other IgA-Derived Binding Molecules

IgA plays a critical role in mucosal immunity and comprises about 15% of total immunoglobulin produced. IgA can be monomeric or multimeric, forming primarily dimeric molecules, but can also assemble as trimers, tetramers, and/or pentamers. See, e.g., de Sousa-Pereira, P., and J. M. Woof, Antibodies 8:57 (2019). An IgA binding unit typically includes two light and two heavy chains. IgA contains three heavy chain constant region domains (Cα1, Cα2 and Cα3), a hinge region between Cα1 and Cα2, and includes a C-terminal “tailpiece.” Human IgA has two subtypes, IgA1 and IgA2. The human IgA1 constant region typically includes the amino acid sequence SEQ ID NO: 3. The human Cα1 domain extends from about amino acid 6 to about amino acid 98 of SEQ ID NO: 3; the human IgA1 hinge region extends from about amino acid 102 to about amino acid 124 of SEQ ID NO: 3, the human Cα3 domain extends from about amino acid 228 to about amino acid 330 of SEQ ID NO: 3, and the tailpiece extends from about amino acid 331 to about amino acid 352 of SEQ ID NO: 3. The human IgA2 constant region typically includes the amino acid sequence SEQ ID NO: 4. The human Cal domain extends from about amino acid 6 to about amino acid 98 of SEQ ID NO: 4; the human IgA2 hinge region extends from about amino acid 102 to about amino acid 111 of SEQ ID NO: 4, the human Cα2 domain extends from about amino acid 113 to about amino acid 206 of SEQ ID NO: 4, the human Cα3 domain extends from about amino acid 215 to about amino acid 317 of SEQ ID NO: 4, and the tailpiece extends from about amino acid 318 to about amino acid 340 of SEQ ID NO: 4.

Two IgA binding units can form a complex with two additional polypeptide chains, the J-chain (e.g., the mature human J-chain of SEQ ID NO: 7) and the secretory component (precursor, SEQ ID NO: 5, mature: amino acids 19 to 603 of SEQ ID NO: 5) to form a secretory IgA (sIgA) antibody. The assembly of IgA binding units into a dimeric sIgA antibody is thought to involve the Cα3 and tailpiece domains (also referred to herein collectively as the Cα3-tp domain). Accordingly, a dimeric sIgA antibody provided in this disclosure typically includes IgA constant regions that include at least the Cα3 and tailpiece domains. Four IgA binding units can likewise form a tetramer complex with a J-chain. A sIgA antibody can also form as a higher order multimer, e.g., a tetramer or pentamer.

An IgA heavy chain constant region can additionally include a Cα2 domain or a fragment thereof, an IgA hinge region, a Cα1 domain or a fragment thereof, and/or other IgA heavy chain domains. In certain aspects, an IgA antibody or IgA-like binding molecule as provided herein can include a complete IgA heavy (u) chain constant domain (e.g., SEQ ID NO: 3 or SEQ ID NO: 4), or a variant, derivative, or analog thereof. In some embodiments, the IgA heavy chain constant regions or multimerizing fragments thereof are human IgA constant regions.

In some embodiments, each binding unit of an IgA antibody, IgA-like antibody, or other IgA-derived binding molecule comprises two light chains. In some embodiments, each binding unit of an IgA antibody, IgA-like antibody, or other IgA-derived binding molecule comprises two fragments of light chains. In some embodiments, the light chains are kappa light chains. In some embodiments, the light chains are lambda light chains. In some embodiments the light chains are hybrid kappa-lambda light chains. In some embodiments, each binding unit comprises two immunoglobulin light chains each comprising a VL situated amino terminal to an immunoglobulin light chain constant region.

J-Chains and Functional Fragments or Variants Thereof

In certain embodiments, the multimeric binding molecule provided herein comprises a J-chain or functional fragment or variant thereof. In certain embodiments, the multimeric binding molecule provided herein is pentameric and comprises a J-chain or functional fragment or variant thereof. In certain embodiments, the multimeric binding molecule provided herein is a dimeric IgA molecule or a pentameric IgM molecule and comprises a J-chain or functional fragment or variant thereof. In some embodiments, the multimeric binding molecule can comprise a naturally occurring J-chain sequence, such as a mature human J-chain sequence (e.g., SEQ ID NO: 7). Alternatively, in some embodiments, the multimeric binding molecule can comprise a variant J-chain sequence, such as a variant sequence described herein with reduced glycosylation or reduced binding to one or more polymeric Ig receptors (e.g., pIgR, Fc alpha-mu receptor (FcαμR), or Fc mu receptor (FcμR)). See, e.g., U.S. Pat. No. 10,899,835, which is incorporated herein by reference in its entirety. In some embodiments, the multimeric binding molecule can comprise a functional fragment of a naturally occurring or variant J-chain. As persons of ordinary skill in the art will recognize, “a functional fragment” or a “functional variant” in this context includes those fragments and variants that can associate with binding units, e.g., IgM or IgA heavy chain constant regions, to form a pentameric IgM antibody, IgM-like antibody, or IgM-derived binding molecule or a dimeric IgA antibody, IgA-like antibody, or IgA-derived binding molecule, and/or can associate with certain immunoglobulin receptors, e.g., the polymeric immunoglobulin receptor (pIgR).

In certain embodiments, the J-chain can be modified, e.g., by introduction of a heterologous moiety, or two or more heterologous moieties, e.g., polypeptides, without interfering with the ability of binding molecule to assemble and bind to its binding target(s). See U.S. Pat. Nos. 9,951,134, 10,400,038, 10,618,978, and in U.S. Patent Application Publication No. US-2019-0185570, each of which is incorporated herein by reference in its entirety.

Accordingly, a binding molecule provided by this disclosure, including multispecific IgA, IgA-like, IgM, or IgM-like antibodies as described elsewhere herein, can comprise a modified J-chain or functional fragment or variant thereof comprising a heterologous moiety, e.g., a heterologous polypeptide, introduced, e.g., fused or chemically conjugated, into the J-chain or fragment or variant thereof. In certain embodiments, the heterologous polypeptide can be fused to the N-terminus of the J-chain or functional fragment or variant thereof, the C-terminus of the J-chain or functional fragment or variant thereof, or to both the N-terminus and C-terminus of the J-chain or functional fragment or variant thereof. In certain embodiments the heterologous polypeptide can be fused internally within the J-chain or functional fragment or variant thereof. In some embodiments, the heterologous polypeptide can be introduced into the J-chain at or near a glycosylation site. In some embodiments, the heterologous polypeptide can be introduced into the J-chain within about 10 amino acid residues from the C-terminus, or within about 10 amino acids from the N-terminus. In certain embodiments, the heterologous polypeptide can be introduced into the mature human J-chain of SEQ ID NO: 7 between cysteine residues 92 and 101 of SEQ ID NO: 7, or an equivalent location in a J-chain sequence, e.g., a J-chain variant or functional fragment of a J-chain. In a further embodiment, the heterologous polypeptide can be introduced into the mature human J-chain of SEQ ID NO: 7 at or near a glycosylation site. In a further embodiment, the heterologous polypeptide can be introduced into the mature human J-chain of SEQ ID NO: 7 within about 10 amino acid residues from the C-terminus, or within about 10 amino acids from the N-terminus.

In certain embodiments the heterologous moiety can be a peptide or polypeptide sequence fused in frame to the J-chain or chemically conjugated to the J-chain or fragment or variant thereof. In certain embodiments, the heterologous polypeptide is fused to the J-chain or functional fragment thereof via a peptide linker. Any suitable linker can be used, for example the peptide linker can include at least 5 amino acids, at least ten amino acids, and least 20 amino acids, at least 30 amino acids or more, and so on. In certain embodiments, the peptide linker includes least 5 amino acids, but no more than 25 amino acids. In certain embodiments the peptide linker can consist of 5 amino acids, 10 amino acids, 15 amino acids, 20 amino acids, or 25 amino acids. In certain embodiments, the peptide linker consists of GGGGS (SEQ ID NO: 9), GGGGSGGGGS (SEQ ID NO: 10), GGGGSGGGGSGGGGS (SEQ ID NO: 11), GGGGSGGGGSGGGGSGGGGS (SEQ ID NO: 12), or GGGGSGGGGSGGGGSGGGGSGGGGS (SEQ ID NO: 13).

Heterologous moieties to be attached to a J-chain can include, without limitation, a binding moiety, e.g., an antibody or antigen-binding fragment thereof, e.g., a single chain Fv (scFv) molecule, e.g., an scFv that binds pIgR or mucin, a cytokine, e.g., IL-2 or IL-15 (see, e.g., PCT Application No. PCT US2019/057702, which is incorporated herein by reference in its entirety), a stabilizing peptide that can increase the half-life of the binding molecule, e.g., human serum albumin (HSA) or an HSA binding molecule, a pIgR or mucin binding molecule, or a heterologous chemical moiety such as a polymer.

In some embodiments, a modified J-chain can comprise an antigen-binding domain that can include without limitation a polypeptide capable of specifically binding to a target antigen. In certain embodiments, an antigen-binding domain associated with a modified J-chain can be an antibody or an antigen-binding fragment thereof. In certain embodiments the antigen-binding domain can be a scFv antigen-binding domain or a single-chain antigen-binding domain derived, e.g., from a camelid or condricthoid antibody. In certain embodiments, the target is a target epitope, a target antigen, a target cell, or a target organ. In some embodiments, the antigen binding domain binds Interleukin 6 (IL6), mucin, or pIgR.

In certain embodiments, the binding domain, e.g., scFv fragment can specifically bind to human coronavirus. In certain embodiments, binding domain binds to a different epitope of the human coronavirus than the three to twelve identical binding domains of the multimeric binding molecule that specifically bind to the human coronavirus. In certain embodiments, the binding domain, e.g., scFv fragment can specifically bind to SARS-CoV-2.

In some embodiments, the SARS-CoV-2-specific binding domain, e.g., scFv fragment comprises a heavy chain variable region (VH) and a light chain variable region (VL), where the VH and VL comprise six immunoglobulin complementarity determining regions HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3, where the HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 comprise the CDRs of an antibody comprising the VH and VL of SEQ ID NO: SEQ ID NO: 84 and SEQ ID NO: 85, SEQ ID NO: 86 and SEQ ID NO: 87, SEQ ID NO: 88 and SEQ ID NO: 89, SEQ ID NO: 90 and SEQ ID NO: 91, SEQ ID NO: 92 and SEQ ID NO: 93, SEQ ID NO: 94 and SEQ ID NO: 95, SEQ ID NO: 96 and SEQ ID NO: 97, SEQ ID NO: 98 and SEQ ID NO: 99, SEQ ID NO: 100 and SEQ ID NO: 101, SEQ ID NO: 102 and SEQ ID NO: 103, SEQ ID NO: 104 and SEQ ID NO: 105, SEQ ID NO: 106 and SEQ ID NO: 107, SEQ ID NO: 108 and SEQ ID NO: 109, SEQ ID NO: 110 and SEQ ID NO: 111, SEQ ID NO: 112 and SEQ ID NO: 113, SEQ ID NO: 114 and SEQ ID NO: 115, SEQ ID NO: 116 and SEQ ID NO: 117, SEQ ID NO: 118 and SEQ ID NO: 119, SEQ ID NO: 120 and SEQ ID NO: 121, SEQ ID NO: 122 and SEQ ID NO: 123, SEQ ID NO: 124 and SEQ ID NO: 125, SEQ ID NO: 126 and SEQ ID NO: 127, SEQ ID NO: 128 and SEQ ID NO: 129, SEQ ID NO: 130 and SEQ ID NO: 131, SEQ ID NO: 132 and SEQ ID NO: 133, SEQ ID NO: 134 and SEQ ID NO: 135, SEQ ID NO: 136 and SEQ ID NO: 137, SEQ ID NO: 138 and SEQ ID NO: 139, SEQ ID NO: 140 and SEQ ID NO: 141, SEQ ID NO: 142 and SEQ ID NO: 143, SEQ ID NO: 144 and SEQ ID NO: 145, SEQ ID NO: 146 and SEQ ID NO: 147, SEQ ID NO: 148 and SEQ ID NO: 149, SEQ ID NO: 150 and SEQ ID NO: 151, SEQ ID NO: 152 and SEQ ID NO: 153, SEQ ID NO: 154 and SEQ ID NO: 155, SEQ ID NO: 156 and SEQ ID NO: 157, SEQ ID NO: 158 and SEQ ID NO: 159, SEQ ID NO: 160 and SEQ ID NO: 161, SEQ ID NO: 162 and SEQ ID NO: 163, SEQ ID NO: 164 and SEQ ID NO: 165, SEQ ID NO: 166 and SEQ ID NO: 167, SEQ ID NO: 168 and SEQ ID NO: 169, SEQ ID NO: 170 and SEQ ID NO: 171, SEQ ID NO: 172 and SEQ ID NO: 173, SEQ ID NO: 174 and SEQ ID NO: 175, SEQ ID NO: 176 and SEQ ID NO: 177, SEQ ID NO: 178 and SEQ ID NO: 179, SEQ ID NO: 180 and SEQ ID NO: 181, SEQ ID NO: 182 and SEQ ID NO: 183, SEQ ID NO: 184 and SEQ ID NO: 185, SEQ ID NO: 186 and SEQ ID NO: 187, SEQ ID NO: 188 and SEQ ID NO: 189, SEQ ID NO: 190 and SEQ ID NO: 191, SEQ ID NO: 192 and SEQ ID NO: 193, SEQ ID NO: 194 and SEQ ID NO: 195, SEQ ID NO: 196 and SEQ ID NO: 197, SEQ ID NO: 198 and SEQ ID NO: 199, SEQ ID NO: 200 and SEQ ID NO: 201, SEQ ID NO: 202 and SEQ ID NO: 203, SEQ ID NO: 204 and SEQ ID NO: 205, SEQ ID NO: 206 and SEQ ID NO: 207, SEQ ID NO: 208 and SEQ ID NO: 209, SEQ ID NO: 210 and SEQ ID NO: 211, SEQ ID NO: 212 and SEQ ID NO: 213, SEQ ID NO: 214 and SEQ ID NO: 215, SEQ ID NO: 216 and SEQ ID NO: 217, SEQ ID NO: 218 and SEQ ID NO: 219, SEQ ID NO: 220 and SEQ ID NO: 221, SEQ ID NO: 222 and SEQ ID NO: 223, SEQ ID NO: 224 and SEQ ID NO: 225, SEQ ID NO: 226 and SEQ ID NO: 227, SEQ ID NO: 228 and SEQ ID NO: 229, SEQ ID NO: 230 and SEQ ID NO: 231, SEQ ID NO: 232 and SEQ ID NO: 233, SEQ ID NO: 234 and SEQ ID NO: 235, SEQ ID NO: 236 and SEQ ID NO: 237, SEQ ID NO: 238 and SEQ ID NO: 239, SEQ ID NO: 240 and SEQ ID NO: 241, SEQ ID NO: 242 and SEQ ID NO: 243, SEQ ID NO: 244 and SEQ ID NO: 245, SEQ ID NO: 246 and SEQ ID NO: 247, SEQ ID NO: 248 and SEQ ID NO: 249, SEQ ID NO: 250 and SEQ ID NO: 251, SEQ ID NO: 252 and SEQ ID NO: 253, SEQ ID NO: 254 and SEQ ID NO: 255, SEQ ID NO: 256 and SEQ ID NO: 257, SEQ ID NO: 258 and SEQ ID NO: 259, SEQ ID NO: 260 and SEQ ID NO: 261, SEQ ID NO: 264 and SEQ ID NO: 265, SEQ ID NO: 266 and SEQ ID NO: 267, SEQ ID NO: 268 and SEQ ID NO: 269, SEQ ID NO: 270 and SEQ ID NO: 271, SEQ ID NO: 272 and SEQ ID NO: 273, SEQ ID NO: 274 and SEQ ID NO: 275, SEQ ID NO: 276 and SEQ ID NO: 277, SEQ ID NO: 278 and SEQ ID NO: 279, SEQ ID NO: 280 and SEQ ID NO: 281, SEQ ID NO: 282 and SEQ ID NO: 283, SEQ ID NO: 284 and SEQ ID NO: 285, SEQ ID NO: 286 and SEQ ID NO: 287, SEQ ID NO: 288 and SEQ ID NO: 289, SEQ ID NO: 290 and SEQ ID NO: 291, SEQ ID NO: 292 and SEQ ID NO: 293, SEQ ID NO: 294 and SEQ ID NO: 295, SEQ ID NO: 296 and SEQ ID NO: 297, SEQ ID NO: 298 and SEQ ID NO: 299, SEQ ID NO: 300 and SEQ ID NO: 301, SEQ ID NO: 302 and SEQ ID NO: 303, SEQ ID NO: 304 and SEQ ID NO: 305, SEQ ID NO: 306 and SEQ ID NO: 307, SEQ ID NO: 308 and SEQ ID NO: 309, SEQ ID NO: 310 and SEQ ID NO: 311, SEQ ID NO: 312 and SEQ ID NO: 313, SEQ ID NO: 314 and SEQ ID NO: 315, SEQ ID NO: 316 and SEQ ID NO: 317, SEQ ID NO: 318 and SEQ ID NO: 319, SEQ ID NO: 320 and SEQ ID NO: 321, SEQ ID NO: 322 and SEQ ID NO: 323, SEQ ID NO: 324 and SEQ ID NO: 325, SEQ ID NO: 326 and SEQ ID NO: 327, SEQ ID NO: 328 and SEQ ID NO: 329, SEQ ID NO: 330 and SEQ ID NO: 331, SEQ ID NO: 332 and SEQ ID NO: 333, SEQ ID NO: 336 and SEQ ID NO: 337, SEQ ID NO: 338 and SEQ ID NO: 339, SEQ ID NO: 340 and SEQ ID NO: 341, SEQ ID NO: 342 and SEQ ID NO: 343, SEQ ID NO: 344 and SEQ ID NO: 345, SEQ ID NO: 348 and SEQ ID NO: 349, SEQ ID NO: 350 and SEQ ID NO: 351, SEQ ID NO: 352 and SEQ ID NO: 353, SEQ ID NO: 354 and SEQ ID NO: 355, SEQ ID NO: 356 and SEQ ID NO: 357, SEQ ID NO: 358 and SEQ ID NO: 359, SEQ ID NO: 362 and SEQ ID NO: 363, SEQ ID NO: 364 and SEQ ID NO: 365, SEQ ID NO: 366 and SEQ ID NO: 367, SEQ ID NO: 368 and SEQ ID NO: 369, SEQ ID NO: 370 and SEQ ID NO: 371, SEQ ID NO: 372 and SEQ ID NO: 373, SEQ ID NO: 374 and SEQ ID NO: 375, SEQ ID NO: 376 and SEQ ID NO: 377, SEQ ID NO: 378 and SEQ ID NO: 379, SEQ ID NO: 380 and SEQ ID NO: 381, SEQ ID NO: 382 and SEQ ID NO: 383, SEQ ID NO: 384 and SEQ ID NO: 385, SEQ ID NO: 386 and SEQ ID NO: 387, SEQ ID NO: 388 and SEQ ID NO: 389, SEQ ID NO: 390 and SEQ ID NO: 391, SEQ ID NO: 392 and SEQ ID NO: 393, SEQ ID NO: 394 and SEQ ID NO: 395, SEQ ID NO: 396 and SEQ ID NO: 397, SEQ ID NO: 398 and SEQ ID NO: 399, SEQ ID NO: 400 and SEQ ID NO: 401, SEQ ID NO: 402 and SEQ ID NO: 403, SEQ ID NO: 404 and SEQ ID NO: 405, SEQ ID NO: 406 and SEQ ID NO: 407, SEQ ID NO: 408 and SEQ ID NO: 409, SEQ ID NO: 410 and SEQ ID NO: 411, SEQ ID NO: 412 and SEQ ID NO: 413, SEQ ID NO: 414 and SEQ ID NO: 415, SEQ ID NO: 416 and SEQ ID NO: 417, SEQ ID NO: 418 and SEQ ID NO: 419, SEQ ID NO: 420 and SEQ ID NO: 421, SEQ ID NO: 422 and SEQ ID NO: 423, SEQ ID NO: 424 and SEQ ID NO: 425, SEQ ID NO: 426 and SEQ ID NO: 427, SEQ ID NO: 428 and SEQ ID NO: 429, SEQ ID NO: 430 and SEQ ID NO: 431, SEQ ID NO: 432 and SEQ ID NO: 433, SEQ ID NO: 434 and SEQ ID NO: 435, SEQ ID NO: 436 and SEQ ID NO: 437, SEQ ID NO: 438 and SEQ ID NO: 439, SEQ ID NO: 440 and SEQ ID NO: 441, SEQ ID NO: 442 and SEQ ID NO: 443, SEQ ID NO: 444 and SEQ ID NO: 445, SEQ ID NO: 446 and SEQ ID NO: 447, SEQ ID NO: 448 and SEQ ID NO: 449, SEQ ID NO: 450 and SEQ ID NO: 451, SEQ ID NO: 452 and SEQ ID NO: 453, SEQ ID NO: 454 and SEQ ID NO: 455, SEQ ID NO: 456 and SEQ ID NO: 457, SEQ ID NO: 458 and SEQ ID NO: 459, SEQ ID NO: 460 and SEQ ID NO: 461, SEQ ID NO: 462 and SEQ ID NO: 463, SEQ ID NO: 464 and SEQ ID NO: 465, SEQ ID NO: 466 and SEQ ID NO: 467, SEQ ID NO: 468 and SEQ ID NO: 469, SEQ ID NO: 470 and SEQ ID NO: 471, SEQ ID NO: 472 and SEQ ID NO: 473, SEQ ID NO: 474 and SEQ ID NO: 475, SEQ ID NO: 476 and SEQ ID NO: 477, SEQ ID NO: 478 and SEQ ID NO: 479, SEQ ID NO: 480 and SEQ ID NO: 481, SEQ ID NO: 482 and SEQ ID NO: 483, SEQ ID NO: 484 and SEQ ID NO: 485, SEQ ID NO: 486 and SEQ ID NO: 487, SEQ ID NO: 488 and SEQ ID NO: 489, SEQ ID NO: 490 and SEQ ID NO: 491, SEQ ID NO: 492 and SEQ ID NO: 493, SEQ ID NO: 494 and SEQ ID NO: 495, SEQ ID NO: 496 and SEQ ID NO: 497, SEQ ID NO: 498 and SEQ ID NO: 499, SEQ ID NO: 500 and SEQ ID NO: 501, SEQ ID NO: 502 and SEQ ID NO: 503, SEQ ID NO: 504 and SEQ ID NO: 505, SEQ ID NO: 506 and SEQ ID NO: 507, SEQ ID NO: 508 and SEQ ID NO: 509, SEQ ID NO: 628 and SEQ ID NO: 629, SEQ ID NO: 630 and SEQ ID NO: 631, SEQ ID NO: 632 and SEQ ID NO: 633, SEQ ID NO: 634 and SEQ ID NO: 635, SEQ ID NO: 636 and SEQ ID NO: 637, SEQ ID NO: 638 and SEQ ID NO: 639, SEQ ID NO: 640 and SEQ ID NO: 641, SEQ ID NO: 642 and SEQ ID NO: 643, SEQ ID NO: 644 and SEQ ID NO: 645, SEQ ID NO: 646 and SEQ ID NO: 647, SEQ ID NO: 648 and SEQ ID NO: 649, SEQ ID NO: 650 and SEQ ID NO: 651, or SEQ ID NO: 652 and SEQ ID NO: 653, respectively with zero, one, or two single amino acid substitutions in one or more of the HCDRs or LCDRs.

In some embodiments, the SARS-CoV-2-specific binding domain, e.g., scFv fragment comprises an antibody VH and a VL, where the VH and VL comprise amino acid sequences at least 80%, at least 85%, at least 90%, at least 95% or 100% identical to SEQ ID NO: 84 and SEQ ID NO: 85, SEQ ID NO: 86 and SEQ ID NO: 87, SEQ ID NO: 88 and SEQ ID NO: 89, SEQ ID NO: 90 and SEQ ID NO: 91, SEQ ID NO: 92 and SEQ ID NO: 93, SEQ ID NO: 94 and SEQ ID NO: 95, SEQ ID NO: 96 and SEQ ID NO: 97, SEQ ID NO: 98 and SEQ ID NO: 99, SEQ ID NO: 100 and SEQ ID NO: 101, SEQ ID NO: 102 and SEQ ID NO: 103, SEQ ID NO: 104 and SEQ ID NO: 105, SEQ ID NO: 106 and SEQ ID NO: 107, SEQ ID NO: 108 and SEQ ID NO: 109, SEQ ID NO: 110 and SEQ ID NO: 111, SEQ ID NO: 112 and SEQ ID NO: 113, SEQ ID NO: 114 and SEQ ID NO: 115, SEQ ID NO: 116 and SEQ ID NO: 117, SEQ ID NO: 118 and SEQ ID NO: 119, SEQ ID NO: 120 and SEQ ID NO: 121, SEQ ID NO: 122 and SEQ ID NO: 123, SEQ ID NO: 124 and SEQ ID NO: 125, SEQ ID NO: 126 and SEQ ID NO: 127, SEQ ID NO: 128 and SEQ ID NO: 129, SEQ ID NO: 130 and SEQ ID NO: 131, SEQ ID NO: 132 and SEQ ID NO: 133, SEQ ID NO: 134 and SEQ ID NO: 135, SEQ ID NO: 136 and SEQ ID NO: 137, SEQ ID NO: 138 and SEQ ID NO: 139, SEQ ID NO: 140 and SEQ ID NO: 141, SEQ ID NO: 142 and SEQ ID NO: 143, SEQ ID NO: 144 and SEQ ID NO: 145, SEQ ID NO: 146 and SEQ ID NO: 147, SEQ ID NO: 148 and SEQ ID NO: 149, SEQ ID NO: 150 and SEQ ID NO: 151, SEQ ID NO: 152 and SEQ ID NO: 153, SEQ ID NO: 154 and SEQ ID NO: 155, SEQ ID NO: 156 and SEQ ID NO: 157, SEQ ID NO: 158 and SEQ ID NO: 159, SEQ ID NO: 160 and SEQ ID NO: 161, SEQ ID NO: 162 and SEQ ID NO: 163, SEQ ID NO: 164 and SEQ ID NO: 165, SEQ ID NO: 166 and SEQ ID NO: 167, SEQ ID NO: 168 and SEQ ID NO: 169, SEQ ID NO: 170 and SEQ ID NO: 171, SEQ ID NO: 172 and SEQ ID NO: 173, SEQ ID NO: 174 and SEQ ID NO: 175, SEQ ID NO: 176 and SEQ ID NO: 177, SEQ ID NO: 178 and SEQ ID NO: 179, SEQ ID NO: 180 and SEQ ID NO: 181, SEQ ID NO: 182 and SEQ ID NO: 183, SEQ ID NO: 184 and SEQ ID NO: 185, SEQ ID NO: 186 and SEQ ID NO: 187, SEQ ID NO: 188 and SEQ ID NO: 189, SEQ ID NO: 190 and SEQ ID NO: 191, SEQ ID NO: 192 and SEQ ID NO: 193, SEQ ID NO: 194 and SEQ ID NO: 195, SEQ ID NO: 196 and SEQ ID NO: 197, SEQ ID NO: 198 and SEQ ID NO: 199, SEQ ID NO: 200 and SEQ ID NO: 201, SEQ ID NO: 202 and SEQ ID NO: 203, SEQ ID NO: 204 and SEQ ID NO: 205, SEQ ID NO: 206 and SEQ ID NO: 207, SEQ ID NO: 208 and SEQ ID NO: 209, SEQ ID NO: 210 and SEQ ID NO: 211, SEQ ID NO: 212 and SEQ ID NO: 213, SEQ ID NO: 214 and SEQ ID NO: 215, SEQ ID NO: 216 and SEQ ID NO: 217, SEQ ID NO: 218 and SEQ ID NO: 219, SEQ ID NO: 220 and SEQ ID NO: 221, SEQ ID NO: 222 and SEQ ID NO: 223, SEQ ID NO: 224 and SEQ ID NO: 225, SEQ ID NO: 226 and SEQ ID NO: 227, SEQ ID NO: 228 and SEQ ID NO: 229, SEQ ID NO: 230 and SEQ ID NO: 231, SEQ ID NO: 232 and SEQ ID NO: 233, SEQ ID NO: 234 and SEQ ID NO: 235, SEQ ID NO: 236 and SEQ ID NO: 237, SEQ ID NO: 238 and SEQ ID NO: 239, SEQ ID NO: 240 and SEQ ID NO: 241, SEQ ID NO: 242 and SEQ ID NO: 243, SEQ ID NO: 244 and SEQ ID NO: 245, SEQ ID NO: 246 and SEQ ID NO: 247, SEQ ID NO: 248 and SEQ ID NO: 249, SEQ ID NO: 250 and SEQ ID NO: 251, SEQ ID NO: 252 and SEQ ID NO: 253, SEQ ID NO: 254 and SEQ ID NO: 255, SEQ ID NO: 256 and SEQ ID NO: 257, SEQ ID NO: 258 and SEQ ID NO: 259, SEQ ID NO: 260 and SEQ ID NO: 261, SEQ ID NO: 264 and SEQ ID NO: 265, SEQ ID NO: 266 and SEQ ID NO: 267, SEQ ID NO: 268 and SEQ ID NO: 269, SEQ ID NO: 270 and SEQ ID NO: 271, SEQ ID NO: 272 and SEQ ID NO: 273, SEQ ID NO: 274 and SEQ ID NO: 275, SEQ ID NO: 276 and SEQ ID NO: 277, SEQ ID NO: 278 and SEQ ID NO: 279, SEQ ID NO: 280 and SEQ ID NO: 281, SEQ ID NO: 282 and SEQ ID NO: 283, SEQ ID NO: 284 and SEQ ID NO: 285, SEQ ID NO: 286 and SEQ ID NO: 287, SEQ ID NO: 288 and SEQ ID NO: 289, SEQ ID NO: 290 and SEQ ID NO: 291, SEQ ID NO: 292 and SEQ ID NO: 293, SEQ ID NO: 294 and SEQ ID NO: 295, SEQ ID NO: 296 and SEQ ID NO: 297, SEQ ID NO: 298 and SEQ ID NO: 299, SEQ ID NO: 300 and SEQ ID NO: 301, SEQ ID NO: 302 and SEQ ID NO: 303, SEQ ID NO: 304 and SEQ ID NO: 305, SEQ ID NO: 306 and SEQ ID NO: 307, SEQ ID NO: 308 and SEQ ID NO: 309, SEQ ID NO: 310 and SEQ ID NO: 311, SEQ ID NO: 312 and SEQ ID NO: 313, SEQ ID NO: 314 and SEQ ID NO: 315, SEQ ID NO: 316 and SEQ ID NO: 317, SEQ ID NO: 318 and SEQ ID NO: 319, SEQ ID NO: 320 and SEQ ID NO: 321, SEQ ID NO: 322 and SEQ ID NO: 323, SEQ ID NO: 324 and SEQ ID NO: 325, SEQ ID NO: 326 and SEQ ID NO: 327, SEQ ID NO: 328 and SEQ ID NO: 329, SEQ ID NO: 330 and SEQ ID NO: 331, SEQ ID NO: 332 and SEQ ID NO: 333, SEQ ID NO: 336 and SEQ ID NO: 337, SEQ ID NO: 338 and SEQ ID NO: 339, SEQ ID NO: 340 and SEQ ID NO: 341, SEQ ID NO: 342 and SEQ ID NO: 343, SEQ ID NO: 344 and SEQ ID NO: 345, SEQ ID NO: 348 and SEQ ID NO: 349, SEQ ID NO: 350 and SEQ ID NO: 351, SEQ ID NO: 352 and SEQ ID NO: 353, SEQ ID NO: 354 and SEQ ID NO: 355, SEQ ID NO: 356 and SEQ ID NO: 357, SEQ ID NO: 358 and SEQ ID NO: 359, SEQ ID NO: 362 and SEQ ID NO: 363, SEQ ID NO: 364 and SEQ ID NO: 365, SEQ ID NO: 366 and SEQ ID NO: 367, SEQ ID NO: 368 and SEQ ID NO: 369, SEQ ID NO: 370 and SEQ ID NO: 371, SEQ ID NO: 372 and SEQ ID NO: 373, SEQ ID NO: 374 and SEQ ID NO: 375, SEQ ID NO: 376 and SEQ ID NO: 377, SEQ ID NO: 378 and SEQ ID NO: 379, SEQ ID NO: 380 and SEQ ID NO: 381, SEQ ID NO: 382 and SEQ ID NO: 383, SEQ ID NO: 384 and SEQ ID NO: 385, SEQ ID NO: 386 and SEQ ID NO: 387, SEQ ID NO: 388 and SEQ ID NO: 389, SEQ ID NO: 390 and SEQ ID NO: 391, SEQ ID NO: 392 and SEQ ID NO: 393, SEQ ID NO: 394 and SEQ ID NO: 395, SEQ ID NO: 396 and SEQ ID NO: 397, SEQ ID NO: 398 and SEQ ID NO: 399, SEQ ID NO: 400 and SEQ ID NO: 401, SEQ ID NO: 402 and SEQ ID NO: 403, SEQ ID NO: 404 and SEQ ID NO: 405, SEQ ID NO: 406 and SEQ ID NO: 407, SEQ ID NO: 408 and SEQ ID NO: 409, SEQ ID NO: 410 and SEQ ID NO: 411, SEQ ID NO: 412 and SEQ ID NO: 413, SEQ ID NO: 414 and SEQ ID NO: 415, SEQ ID NO: 416 and SEQ ID NO: 417, SEQ ID NO: 418 and SEQ ID NO: 419, SEQ ID NO: 420 and SEQ ID NO: 421, SEQ ID NO: 422 and SEQ ID NO: 423, SEQ ID NO: 424 and SEQ ID NO: 425, SEQ ID NO: 426 and SEQ ID NO: 427, SEQ ID NO: 428 and SEQ ID NO: 429, SEQ ID NO: 430 and SEQ ID NO: 431, SEQ ID NO: 432 and SEQ ID NO: 433, SEQ ID NO: 434 and SEQ ID NO: 435, SEQ ID NO: 436 and SEQ ID NO: 437, SEQ ID NO: 438 and SEQ ID NO: 439, SEQ ID NO: 440 and SEQ ID NO: 441, SEQ ID NO: 442 and SEQ ID NO: 443, SEQ ID NO: 444 and SEQ ID NO: 445, SEQ ID NO: 446 and SEQ ID NO: 447, SEQ ID NO: 448 and SEQ ID NO: 449, SEQ ID NO: 450 and SEQ ID NO: 451, SEQ ID NO: 452 and SEQ ID NO: 453, SEQ ID NO: 454 and SEQ ID NO: 455, SEQ ID NO: 456 and SEQ ID NO: 457, SEQ ID NO: 458 and SEQ ID NO: 459, SEQ ID NO: 460 and SEQ ID NO: 461, SEQ ID NO: 462 and SEQ ID NO: 463, SEQ ID NO: 464 and SEQ ID NO: 465, SEQ ID NO: 466 and SEQ ID NO: 467, SEQ ID NO: 468 and SEQ ID NO: 469, SEQ ID NO: 470 and SEQ ID NO: 471, SEQ ID NO: 472 and SEQ ID NO: 473, SEQ ID NO: 474 and SEQ ID NO: 475, SEQ ID NO: 476 and SEQ ID NO: 477, SEQ ID NO: 478 and SEQ ID NO: 479, SEQ ID NO: 480 and SEQ ID NO: 481, SEQ ID NO: 482 and SEQ ID NO: 483, SEQ ID NO: 484 and SEQ ID NO: 485, SEQ ID NO: 486 and SEQ ID NO: 487, SEQ ID NO: 488 and SEQ ID NO: 489, SEQ ID NO: 490 and SEQ ID NO: 491, SEQ ID NO: 492 and SEQ ID NO: 493, SEQ ID NO: 494 and SEQ ID NO: 495, SEQ ID NO: 496 and SEQ ID NO: 497, SEQ ID NO: 498 and SEQ ID NO: 499, SEQ ID NO: 500 and SEQ ID NO: 501, SEQ ID NO: 502 and SEQ ID NO: 503, SEQ ID NO: 504 and SEQ ID NO: 505, SEQ ID NO: 506 and SEQ ID NO: 507, SEQ ID NO: 508 and SEQ ID NO: 509, SEQ ID NO: 628 and SEQ ID NO: 629, SEQ ID NO: 630 and SEQ ID NO: 631, SEQ ID NO: 632 and SEQ ID NO: 633, SEQ ID NO: 634 and SEQ ID NO: 635, SEQ ID NO: 636 and SEQ ID NO: 637, SEQ ID NO: 638 and SEQ ID NO: 639, SEQ ID NO: 640 and SEQ ID NO: 641, SEQ ID NO: 642 and SEQ ID NO: 643, SEQ ID NO: 644 and SEQ ID NO: 645, SEQ ID NO: 646 and SEQ ID NO: 647, SEQ ID NO: 648 and SEQ ID NO: 649, SEQ ID NO: 650 and SEQ ID NO: 651, or SEQ ID NO: 652 and SEQ ID NO: 653, respectively.

In some embodiments, the SARS-CoV-specific binding domain, e.g., scFv fragment comprises a heavy chain variable region (VH) and a light chain variable region (VL), where the VH and VL comprise six immunoglobulin complementarity determining regions HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3, where the HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 comprise the CDRs of an antibody comprising the VH and VL of SEQ ID NO: 84 and SEQ ID NO: 85, SEQ ID NO: 118 and SEQ ID NO: 119, SEQ ID NO: 120 and SEQ ID NO: 121, SEQ ID NO: 138 and SEQ ID NO: 139, SEQ ID NO: 162 and SEQ ID NO: 163, SEQ ID NO: 222 and SEQ ID NO: 223, SEQ ID NO: 236 and SEQ ID NO: 237, SEQ ID NO: 252 and SEQ ID NO: 253, SEQ ID NO: 260 and SEQ ID NO: 261, SEQ ID NO: 262 and SEQ ID NO: 263, SEQ ID NO: 296 and SEQ ID NO: 297, SEQ ID NO: 384 and SEQ ID NO: 385, SEQ ID NO: 628 and SEQ ID NO: 629, SEQ ID NO: 632 and SEQ ID NO: 633, SEQ ID NO: 634 and SEQ ID NO: 635, SEQ ID NO: 636 and SEQ ID NO: 637, SEQ ID NO: 638 and SEQ ID NO: 639, SEQ ID NO: 640 and SEQ ID NO: 641, SEQ ID NO: 642 and SEQ ID NO: 643, SEQ ID NO: 644 and SEQ ID NO: 645, or SEQ ID NO: 646 and SEQ ID NO: 647, respectively with zero, one, or two single amino acid substitutions in one or more of the HCDRs or LCDRs.

In some embodiments, the SARS-CoV-specific binding domain, e.g., scFv fragment comprises an antibody VH and a VL, where the VH and VL comprise amino acid sequences at least 80%, at least 85%, at least 90%, at least 95% or 100% identical to SEQ ID NO: 84 and SEQ ID NO: 85, SEQ ID NO: 118 and SEQ ID NO: 119, SEQ ID NO: 120 and SEQ ID NO: 121, SEQ ID NO: 138 and SEQ ID NO: 139, SEQ ID NO: 162 and SEQ ID NO: 163, SEQ ID NO: 222 and SEQ ID NO: 223, SEQ ID NO: 236 and SEQ ID NO: 237, SEQ ID NO: 252 and SEQ ID NO: 253, SEQ ID NO: 260 and SEQ ID NO: 261, SEQ ID NO: 262 and SEQ ID NO: 263, SEQ ID NO: 296 and SEQ ID NO: 297, SEQ ID NO: 384 and SEQ ID NO: 385, SEQ ID NO: 628 and SEQ ID NO: 629, SEQ ID NO: 632 and SEQ ID NO: 633, SEQ ID NO: 634 and SEQ ID NO: 635, SEQ ID NO: 636 and SEQ ID NO: 637, SEQ ID NO: 638 and SEQ ID NO: 639, SEQ ID NO: 640 and SEQ ID NO: 641, SEQ ID NO: 642 and SEQ ID NO: 643, SEQ ID NO: 644 and SEQ ID NO: 645, or SEQ ID NO: 646 and SEQ ID NO: 647, respectively.

In some embodiments, the MERS-CoV-specific binding domain, e.g., scFv fragment comprises a heavy chain variable region (VH) and a light chain variable region (VL), where the VH and VL comprise six immunoglobulin complementarity determining regions HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3, where the HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 comprise the CDRs of an antibody comprising the VH and VL of SEQ ID NO: 510 and SEQ ID NO: 511, SEQ ID NO: 512 and SEQ ID NO: 513, SEQ ID NO: 514 and SEQ ID NO: 515, SEQ ID NO: 516 and SEQ ID NO: 517, SEQ ID NO: 518 and SEQ ID NO: 519, SEQ ID NO: 520 and SEQ ID NO: 521, SEQ ID NO: 522 and SEQ ID NO: 523, SEQ ID NO: 524 and SEQ ID NO: 525, SEQ ID NO: 526 and SEQ ID NO: 527, SEQ ID NO: 528 and SEQ ID NO: 529, SEQ ID NO: 530 and SEQ ID NO: 531, SEQ ID NO: 532 and SEQ ID NO: 533, SEQ ID NO: 534 and SEQ ID NO: 535, SEQ ID NO: 536 and SEQ ID NO: 537, SEQ ID NO: 538 and SEQ ID NO: 539, SEQ ID NO: 540 and SEQ ID NO: 541, SEQ ID NO: 542 and SEQ ID NO: 543, SEQ ID NO: 544 and SEQ ID NO: 545, SEQ ID NO: 546 and SEQ ID NO: 547, SEQ ID NO: 548 and SEQ ID NO: 549, SEQ ID NO: 550 and SEQ ID NO: 551, SEQ ID NO: 552 and SEQ ID NO: 553, SEQ ID NO: 554 and SEQ ID NO: 555, SEQ ID NO: 556 and SEQ ID NO: 557, SEQ ID NO: 558 and SEQ ID NO: 559, SEQ ID NO: 560 and SEQ ID NO: 561, SEQ ID NO: 562 and SEQ ID NO: 563, SEQ ID NO: 564 and SEQ ID NO: 565, SEQ ID NO: 566 and SEQ ID NO: 567, SEQ ID NO: 568 and SEQ ID NO: 569, SEQ ID NO: 570 and SEQ ID NO: 571, SEQ ID NO: 572 and SEQ ID NO: 573, SEQ ID NO: 574 and SEQ ID NO: 575, SEQ ID NO: 576 and SEQ ID NO: 577, SEQ ID NO: 578 and SEQ ID NO: 579, SEQ ID NO: 580 and SEQ ID NO: 581, SEQ ID NO: 582 and SEQ ID NO: 583, SEQ ID NO: 584 and SEQ ID NO: 585, SEQ ID NO: 586 and SEQ ID NO: 587, SEQ ID NO: 588 and SEQ ID NO: 589, SEQ ID NO: 590 and SEQ ID NO: 591, SEQ ID NO: 592 and SEQ ID NO: 593, SEQ ID NO: 594 and SEQ ID NO: 595, SEQ ID NO: 596 and SEQ ID NO: 597, SEQ ID NO: 598 and SEQ ID NO: 599, SEQ ID NO: 600 and SEQ ID NO: 601, SEQ ID NO: 602 and SEQ ID NO: 603, SEQ ID NO: 604 and SEQ ID NO: 605, SEQ ID NO: 606 and SEQ ID NO: 607, SEQ ID NO: 608 and SEQ ID NO: 609, SEQ ID NO: 610 and SEQ ID NO: 611, SEQ ID NO: 612 and SEQ ID NO: 613, SEQ ID NO: 614 and SEQ ID NO: 615, SEQ ID NO: 616 and SEQ ID NO: 617, SEQ ID NO: 618 and SEQ ID NO: 619, SEQ ID NO: 620 and SEQ ID NO: 621, SEQ ID NO: 622 and SEQ ID NO: 623, SEQ ID NO: 624 and SEQ ID NO: 625, SEQ ID NO: 626 and SEQ ID NO: 627, or SEQ ID NO: 630 and SEQ ID NO: 631, respectively with zero, one, or two single amino acid substitutions in one or more of the HCDRs or LCDRs.

In some embodiments, the MERS-CoV-specific binding domain, e.g., scFv fragment comprises an antibody VH and a VL, where the VH and VL comprise amino acid sequences at least 80%, at least 85%, at least 90%, at least 95% or 100% identical to SEQ ID NO: 510 and SEQ ID NO: 511, SEQ ID NO: 512 and SEQ ID NO: 513, SEQ ID NO: 514 and SEQ ID NO: 515, SEQ ID NO: 516 and SEQ ID NO: 517, SEQ ID NO: 518 and SEQ ID NO: 519, SEQ ID NO: 520 and SEQ ID NO: 521, SEQ ID NO: 522 and SEQ ID NO: 523, SEQ ID NO: 524 and SEQ ID NO: 525, SEQ ID NO: 526 and SEQ ID NO: 527, SEQ ID NO: 528 and SEQ ID NO: 529, SEQ ID NO: 530 and SEQ ID NO: 531, SEQ ID NO: 532 and SEQ ID NO: 533, SEQ ID NO: 534 and SEQ ID NO: 535, SEQ ID NO: 536 and SEQ ID NO: 537, SEQ ID NO: 538 and SEQ ID NO: 539, SEQ ID NO: 540 and SEQ ID NO: 541, SEQ ID NO: 542 and SEQ ID NO: 543, SEQ ID NO: 544 and SEQ ID NO: 545, SEQ ID NO: 546 and SEQ ID NO: 547, SEQ ID NO: 548 and SEQ ID NO: 549, SEQ ID NO: 550 and SEQ ID NO: 551, SEQ ID NO: 552 and SEQ ID NO: 553, SEQ ID NO: 554 and SEQ ID NO: 555, SEQ ID NO: 556 and SEQ ID NO: 557, SEQ ID NO: 558 and SEQ ID NO: 559, SEQ ID NO: 560 and SEQ ID NO: 561, SEQ ID NO: 562 and SEQ ID NO: 563, SEQ ID NO: 564 and SEQ ID NO: 565, SEQ ID NO: 566 and SEQ ID NO: 567, SEQ ID NO: 568 and SEQ ID NO: 569, SEQ ID NO: 570 and SEQ ID NO: 571, SEQ ID NO: 572 and SEQ ID NO: 573, SEQ ID NO: 574 and SEQ ID NO: 575, SEQ ID NO: 576 and SEQ ID NO: 577, SEQ ID NO: 578 and SEQ ID NO: 579, SEQ ID NO: 580 and SEQ ID NO: 581, SEQ ID NO: 582 and SEQ ID NO: 583, SEQ ID NO: 584 and SEQ ID NO: 585, SEQ ID NO: 586 and SEQ ID NO: 587, SEQ ID NO: 588 and SEQ ID NO: 589, SEQ ID NO: 590 and SEQ ID NO: 591, SEQ ID NO: 592 and SEQ ID NO: 593, SEQ ID NO: 594 and SEQ ID NO: 595, SEQ ID NO: 596 and SEQ ID NO: 597, SEQ ID NO: 598 and SEQ ID NO: 599, SEQ ID NO: 600 and SEQ ID NO: 601, SEQ ID NO: 602 and SEQ ID NO: 603, SEQ ID NO: 604 and SEQ ID NO: 605, SEQ ID NO: 606 and SEQ ID NO: 607, SEQ ID NO: 608 and SEQ ID NO: 609, SEQ ID NO: 610 and SEQ ID NO: 611, SEQ ID NO: 612 and SEQ ID NO: 613, SEQ ID NO: 614 and SEQ ID NO: 615, SEQ ID NO: 616 and SEQ ID NO: 617, SEQ ID NO: 618 and SEQ ID NO: 619, SEQ ID NO: 620 and SEQ ID NO: 621, SEQ ID NO: 622 and SEQ ID NO: 623, SEQ ID NO: 624 and SEQ ID NO: 625, SEQ ID NO: 626 and SEQ ID NO: 627, or SEQ ID NO: 630 and SEQ ID NO: 631, respectively.

In some embodiments, the binding domain comprises a single domain variable region (VHH), where the VHH comprises three immunoglobulin complementarity determining regions HCDR1, HCDR2, and HCDR3, where the HCDR1, HCDR2, and HCDR3 the CDRs of an antibody comprising the VHH of SEQ ID NO: 19, SEQ ID NO: 20, SEQ ID NO: 21, SEQ ID NO: 22, SEQ ID NO: 23, SEQ ID NO: 24, SEQ ID NO: 25, SEQ ID NO: 26, SEQ ID NO: 27, SEQ ID NO: 28, SEQ ID NO: 29, SEQ ID NO: 30, SEQ ID NO: 31, SEQ ID NO: 32, SEQ ID NO: 33, SEQ ID NO: 34, SEQ ID NO: 35, SEQ ID NO: 36, SEQ ID NO: 37, SEQ ID NO: 38, SEQ ID NO: 39, SEQ ID NO: 40, SEQ ID NO: 41, SEQ ID NO: 42, SEQ ID NO: 43, SEQ ID NO: 44, SEQ ID NO: 45, SEQ ID NO: 46, SEQ ID NO: 47, SEQ ID NO: 48, SEQ ID NO: 49, SEQ ID NO: 50, SEQ ID NO: 51, SEQ ID NO: 52, SEQ ID NO: 53, SEQ ID NO: 54, SEQ ID NO: 55, SEQ ID NO: 56, SEQ ID NO: 57, SEQ ID NO: 58, SEQ ID NO: 59, SEQ ID NO: 60, SEQ ID NO: 61, SEQ ID NO: 62, SEQ ID NO: 63, SEQ ID NO: 64, SEQ ID NO: 65, SEQ ID NO: 66, SEQ ID NO: 67, SEQ ID NO: 68, SEQ ID NO: 69, SEQ ID NO: 70, SEQ ID NO: 71, SEQ ID NO: 72, SEQ ID NO: 73, SEQ ID NO: 74, SEQ ID NO: 75, SEQ ID NO: 76, SEQ ID NO: 77, SEQ ID NO: 78, SEQ ID NO: 79, SEQ ID NO: 80, SEQ ID NO: 81, SEQ ID NO: 82, or SEQ ID NO: 83, with zero, one, or two single amino acid substitutions in one or more of the HCDRs.

In some embodiments, the binding domain comprises a VHH amino acid sequence at least 80%, at least 85%, at least 90%, at least 95% or 100% identical to SEQ ID NO: 19, SEQ ID NO: 20, SEQ ID NO: 21, SEQ ID NO: 22, SEQ ID NO: 23, SEQ ID NO: 24, SEQ ID NO: 25, SEQ ID NO: 26, SEQ ID NO: 27, SEQ ID NO: 28, SEQ ID NO: 29, SEQ ID NO: 30, SEQ ID NO: 31, SEQ ID NO: 32, SEQ ID NO: 33, SEQ ID NO: 34, SEQ ID NO: 35, SEQ ID NO: 36, SEQ ID NO: 37, SEQ ID NO: 38, SEQ ID NO: 39, SEQ ID NO: 40, SEQ ID NO: 41, SEQ ID NO: 42, SEQ ID NO: 43, SEQ ID NO: 44, SEQ ID NO: 45, SEQ ID NO: 46, SEQ ID NO: 47, SEQ ID NO: 48, SEQ ID NO: 49, SEQ ID NO: 50, SEQ ID NO: 51, SEQ ID NO: 52, SEQ ID NO: 53, SEQ ID NO: 54, SEQ ID NO: 55, SEQ ID NO: 56, SEQ ID NO: 57, SEQ ID NO: 58, SEQ ID NO: 59, SEQ ID NO: 60, SEQ ID NO: 61, SEQ ID NO: 62, SEQ ID NO: 63, SEQ ID NO: 64, SEQ ID NO: 65, SEQ ID NO: 66, SEQ ID NO: 67, SEQ ID NO: 68, SEQ ID NO: 69, SEQ ID NO: 70, SEQ ID NO: 71, SEQ ID NO: 72, SEQ ID NO: 73, SEQ ID NO: 74, SEQ ID NO: 75, SEQ ID NO: 76, SEQ ID NO: 77, SEQ ID NO: 78, SEQ ID NO: 79, SEQ ID NO: 80, SEQ ID NO: 81, SEQ ID NO: 82, or SEQ ID NO: 83.

In some embodiments, the binding domain is an extracellular SARS-CoV-2 RBD-binding fragment of angiotensin-converting enzyme 2 (ACE2). In some embodiments, the binding domain is an extracellular SARS-CoV-2 RBD-binding fragment comprising amino acids 18 to 740 of SEQ ID NO: 14. In some embodiments, the binding domain comprises an amino acid sequence at least 80%, at least 85%, at least 90%, at least 95% or 100% identical to amino acids 18 to 740 of SEQ ID NO: 14.

The antigen-binding domain can be introduced into the J-chain at any location that allows the binding of the antigen-binding domain to its binding target without interfering with J-chain function or the function of an associated multimeric binding molecule, e.g., a pentameric IgM or a dimeric or tetrameric IgA antibody. Insertion locations include but are not limited to at or near the C-terminus, at or near the N-terminus or at an internal location that, based on the three-dimensional structure of the J-chain, is accessible.

Variant J-Chains that Confer Increased Serum Half-Life

In certain embodiments, the J-chain is a functional variant J-chain that includes one or more single amino acid substitutions, deletions, or insertions relative to a reference J-chain identical to the variant J-chain except for the one or more single amino acid substitutions, deletions, or insertions. For example, certain amino acid substitutions, deletions, or insertions can result in the IgM-derived binding molecule exhibiting an increased serum half-life upon administration to a subject animal relative to a reference IgM-derived binding molecule that is identical except for the one or more single amino acid substitutions, deletions, or insertions in the variant J-chain, and is administered using the same method to the same animal species. In certain embodiments the variant J-chain can include one, two, three, or four single amino acid substitutions, deletions, or insertions relative to the reference J-chain. Exemplary J-chains that confer increased serum half-life can be found, e.g., in U.S. Pat. No. 10,899,935, which is incorporated herein by reference in its entirety.

In certain embodiments, the J-chain, such as a modified J-chain, comprises an amino acid substitution at the amino acid position corresponding to amino acid Y102 of the mature wild-type human J-chain (SEQ ID NO: 7). By “an amino acid corresponding to amino acid Y102 of the mature wild-type human J-chain” is meant the amino acid in the sequence of the J-chain, which is homologous to Y102 in the human J-chain. For example, see U.S. Pat. No. 10,899,835, which is incorporated herein by reference in its entirety. The position corresponding to Y102 in SEQ ID NO: 7 is conserved in the J-chain amino acid sequences of at least 43 other species. See FIG. 4 of U.S. Pat. No. 9,951,134, which is incorporated by reference herein. Certain mutations at the position corresponding to Y102 of SEQ ID NO: 7 can inhibit the binding of IgM pentamers comprising the variant J-chain to certain immunoglobulin receptors, e.g., the human or murine Fcαμ receptor, the murine Fcμ receptor, and/or the human or murine polymeric Ig receptor (pIgR).

A multimeric binding molecule comprising a mutation at the amino acid corresponding to Y102 of SEQ ID NO: 7 has an improved serum half-life when administered to an animal than a corresponding multimeric binding molecule that is identical except for the substitution, and which is administered to the same species in the same manner. In certain embodiments, the amino acid corresponding to Y102 of SEQ ID NO: 7 can be substituted with any amino acid. In certain embodiments, the amino acid corresponding to Y102 of SEQ ID NO: 7 can be substituted with alanine (A), serine (S) or arginine (R). In a particular embodiment, the amino acid corresponding to Y102 of SEQ ID NO: 7 can be substituted with alanine. In a particular embodiment the J-chain or functional fragment or variant thereof is a variant human J-chain referred to herein as “J*,” and comprises the amino acid sequence SEQ ID NO: 8.

Wild-type J-chains typically include one N-linked glycosylation site. In certain embodiments, a variant J-chain or functional fragment thereof of a multimeric binding molecule as provided herein includes a mutation within the asparagine(N)-linked glycosylation motif N-X₁-S/T, e.g., starting at the amino acid position corresponding to amino acid 49 (motif N6) of the mature human J-chain (SEQ ID NO: 7) or J* (SEQ ID NO: 8), where N is asparagine, X₁is any amino acid except proline, and S/T is serine or threonine, and where the mutation prevents glycosylation at that motif. As demonstrated in U.S. Pat. No. 10,899,835, mutations preventing glycosylation at this site can result in the multimeric binding molecule as provided herein, exhibiting an increased serum half-life upon administration to a subject animal relative to a reference multimeric binding molecule that is identical except for the mutation or mutations preventing glycosylation in the variant J-chain, and is administered in the same way to the same animal species.

For example, in certain embodiments the variant J-chain or functional fragment thereof of a pentameric IgM-derived or dimeric IgA-derived binding molecule as provided herein can include an amino acid substitution at the amino acid position corresponding to amino acid N49 or amino acid S51 of SEQ ID NO: 7 or SEQ ID NO: 8, provided that the amino acid corresponding to S51 is not substituted with threonine (T), or where the variant J-chain comprises amino acid substitutions at the amino acid positions corresponding to both amino acids N49 and S51 of SEQ ID NO: 7 or SEQ ID NO: 8. In certain embodiments, the position corresponding to N49 of SEQ ID NO: 7 or SEQ ID NO: 8 is substituted with any amino acid, e.g., alanine (A), glycine (G), threonine (T), serine (S) or aspartic acid (D). In a particular embodiment, the position corresponding to N49 of SEQ ID NO: 7 or SEQ ID NO: 8 can be substituted with alanine (A). In another particular embodiment, the position corresponding to N49 of SEQ ID NO: 7 or SEQ ID NO: 8 can be substituted with aspartic acid (D). In some embodiments, the position corresponding to S51 of SEQ ID NO: 7 or SEQ ID NO: 8 is substituted with alanine (A) or glycine (G). In some embodiments, the position corresponding to S51 of SEQ ID NO: 7 or SEQ ID NO: 8 is substituted with alanine (A).

Variant IgM Constant Regions

IgM heavy chain constant regions of a multimeric binding molecule as provided herein can be engineered to confer certain desirable properties to the multimeric binding molecules provided herein. For example, in certain embodiments, IgM heavy chain constant regions can be engineered to confer enhanced serum half-life to multimeric binding molecules as provided herein. Exemplary IgM heavy chain constant region mutations that can enhance serum half-life of an IgM-derived binding molecule are disclosed in U.S. Pat. No. 10,899,835, which is incorporated by reference herein in its entirety. For example, a variant IgM heavy chain constant region of the IgM antibody, IgM-like antibody, or IgM-derived binding molecule as provided herein can include an amino acid substitution at a position corresponding to amino acid S401, E402, E403, R344, and/or E345 of a wild-type human IgM constant region (e.g., SEQ ID NO: 1 or SEQ ID NO: 2). By “an amino acid corresponding to amino acid S401, E402, E403, R344, and/or E345 of a wild-type human IgM constant region” is meant the amino acid in the sequence of the IgM constant region of any species which is homologous to 5401, E402, E403, R344, and/or E345 in the human IgM constant region. In certain embodiments, the amino acid corresponding to 5401, E402, E403, R344, and/or E345 of SEQ ID NO: 1 or SEQ ID NO: 2 can be substituted with any amino acid, e.g., alanine.

In certain embodiments, an IgM antibody, IgM-like antibody, or other IgM-derived binding molecule as provided herein, can be engineered to exhibit reduced complement-dependent cytotoxicity (CDC) activity to cells in the presence of complement, relative to a reference IgM antibody, IgM-like antibody, or other IgM-derived binding molecule with corresponding reference human IgM constant regions identical, except for the mutations conferring reduced CDC activity. These CDC mutations can be combined with any of the mutations to confer increased serum half-life as provided herein. By “corresponding reference human IgM constant region” is meant a human IgM constant region that is identical to the variant IgM constant region except for the modification or modifications in the constant region affecting CDC activity. In certain embodiments, the variant human IgM constant region includes one or more amino acid substitutions, e.g., in the Cμ3 domain, relative to a wild-type human IgM constant region as described, e.g., in U.S. Patent Application Publication No. US 2021-0147567, which is incorporated herein by reference in its entirety. Assays for measuring CDC are well known to those of ordinary skill in the art, and exemplary assays are described e.g., in U.S. Patent Application Publication No. US 2021-0147567.

In certain embodiments, a variant human IgM constant region conferring reduced CDC activity includes an amino acid substitution corresponding to the wild-type human IgM constant region at position L310, P311, P313, and/or K315 of SEQ ID NO: 1 (human IgM constant region allele IGHM*03) or SEQ ID NO: 2 (human IgM constant region allele IGHM*04). In certain embodiments, a variant human IgM constant region conferring reduced CDC activity includes an amino acid substitution corresponding to the wild-type human IgM constant region at position P311 of SEQ ID NO: 1 or SEQ ID NO: 2. In other embodiments the variant IgM constant region as provided herein contains an amino acid substitution corresponding to the wild-type human IgM constant region at position P313 of SEQ ID NO: 1 or SEQ ID NO: 2. In other embodiments the variant IgM constant region as provided herein contains a combination of substitutions corresponding to the wild-type human IgM constant region at positions P311 of SEQ ID NO: 1 or SEQ ID NO: 2 and P313 of SEQ ID NO: 1 or SEQ ID NO: 2. These proline residues can be independently substituted with any amino acid, e.g., with alanine, serine, or glycine. In certain embodiments, a variant human IgM constant region conferring reduced CDC activity includes an amino acid substitution corresponding to the wild-type human IgM constant region at position K315 of SEQ ID NO: 1 or SEQ ID NO: 2. The lysine residue can be independently substituted with any amino acid, e.g., with alanine, serine, glycine, or aspartic acid. In certain embodiments, a variant human IgM constant region conferring reduced CDC activity includes an amino acid substitution corresponding to the wild-type human IgM constant region at position K315 of SEQ ID NO: 1 or SEQ ID NO: 2 with aspartic acid.

Human and certain non-human primate IgM constant regions typically include five (5) naturally occurring asparagine (N)-linked glycosylation motifs or sites. As used herein “an N-linked glycosylation motif” comprises or consists of the amino acid sequence N-X₁-S/T, where N is asparagine, X₁is any amino acid except proline (P), and S/T is serine (S) or threonine (T). The glycan is attached to the nitrogen atom of the asparagine residue. See, e.g., Drickamer K, Taylor M E (2006), Introduction to Glycobiology (2nd ed.). Oxford University Press, USA. N-linked glycosylation motifs occur in the human IgM heavy chain constant regions of SEQ ID NO: 1 or SEQ ID NO: 2 starting at positions 46 (“N1”), 209 (“N2”), 272 (“N3”), 279 (“N4”), and 440 (“N5”). These five motifs are conserved in non-human primate IgM heavy chain constant regions, and four of the five are conserved in the mouse IgM heavy chain constant region. Accordingly, in some embodiments, IgM heavy chain constant regions of a multimeric binding molecule as provided herein comprise 5 N-linked glycosylation motifs: N1, N2, N3, N4, and N5. In some embodiments, at least three of the N-linked glycosylation motifs (e.g., N1, N2, and N3) on each IgM heavy chain constant region are occupied by a complex glycan.

In certain embodiments, at least one, at least two, at least three, or at least four of the N-X₁-S/T motifs can include an amino acid insertion, deletion, or substitution that prevents glycosylation at that motif. In certain embodiments, the IgM-derived multimeric binding molecule can include an amino acid insertion, deletion, or substitution at motif N1, motif N2, motif N3, motif N5, or any combination of two or more, three or more, or all four of motifs N1, N2, N3, or N5, where the amino acid insertion, deletion, or substitution prevents glycosylation at that motif. In some embodiment, the IgM constant region comprises one or more substitutions relative to a wild-type human IgM constant region at positions 46, 209, 272, or 440 of SEQ ID NO: 1 (human IgM constant region allele IGHM*03) or SEQ ID NO: 2 (human IgM constant region allele IGHM*04). See, e.g., PCT Application No. PCT/US2020/047495, which is incorporated herein by reference in its entirety.

Polynucleotides and Vectors

In certain embodiments, this disclosure provides a polynucleotide comprising a nucleic acid sequence that encodes a polypeptide subunit of a multimeric binding molecule described herein. In some embodiments, the polynucleotide encodes a polypeptide subunit comprising a heavy chain constant region and at least an antibody VH or VHH portion of the SARS-CoV-2-binding domain of the multimeric binding molecule. In some embodiments, the polynucleotide encodes a polypeptide subunit comprising the heavy chain of the multimeric binding molecule. In some embodiments, the polynucleotide encodes a polypeptide subunit comprising a human IgM constant region or fragment thereof fused to the C-terminal end of a VH or VHH comprising HCDR1, HCDR2, and HCDR3 regions comprising the CDRs contained in the VH or VHH amino acid sequences SEQ ID NO: 19, SEQ ID NO: 20, SEQ ID NO: 21, SEQ ID NO: 22, SEQ ID NO: 23, SEQ ID NO: 24, SEQ ID NO: 25, SEQ ID NO: 26, SEQ ID NO: 27, SEQ ID NO: 28, SEQ ID NO: 29, SEQ ID NO: 30, SEQ ID NO: 31, SEQ ID NO: 32, SEQ ID NO: 33, SEQ ID NO: 34, SEQ ID NO: 35, SEQ ID NO: 36, SEQ ID NO: 37, SEQ ID NO: 38, SEQ ID NO: 39, SEQ ID NO: 40, SEQ ID NO: 41, SEQ ID NO: 42, SEQ ID NO: 43, SEQ ID NO: 44, SEQ ID NO: 45, SEQ ID NO: 46, SEQ ID NO: 47, SEQ ID NO: 48, SEQ ID NO: 49, SEQ ID NO: 50, SEQ ID NO: 51, SEQ ID NO: 52, SEQ ID NO: 53, SEQ ID NO: 54, SEQ ID NO: 55, SEQ ID NO: 56, SEQ ID NO: 57, SEQ ID NO: 58, SEQ ID NO: 59, SEQ ID NO: 60, SEQ ID NO: 61, SEQ ID NO: 62, SEQ ID NO: 63, SEQ ID NO: 64, SEQ ID NO: 65, SEQ ID NO: 66, SEQ ID NO: 67, SEQ ID NO: 68, SEQ ID NO: 69, SEQ ID NO: 70, SEQ ID NO: 71, SEQ ID NO: 72, SEQ ID NO: 73, SEQ ID NO: 74, SEQ ID NO: 75, SEQ ID NO: 76, SEQ ID NO: 77, SEQ ID NO: 78, SEQ ID NO: 79, SEQ ID NO: 80, SEQ ID NO: 81, SEQ ID NO: 82, SEQ ID NO: 83, SEQ ID NO: 84, SEQ ID NO: 86, SEQ ID NO: 88, SEQ ID NO: 90, SEQ ID NO: 92, SEQ ID NO: 94, SEQ ID NO: 96, SEQ ID NO: 98, SEQ ID NO: 100, SEQ ID NO: 102, SEQ ID NO: 104, SEQ ID NO: 106, SEQ ID NO: 108, SEQ ID NO: 110, SEQ ID NO: 112, SEQ ID NO: 114, SEQ ID NO: 116, SEQ ID NO: 118, SEQ ID NO: 120, SEQ ID NO: 122, SEQ ID NO: 124, SEQ ID NO: 126, SEQ ID NO: 128, SEQ ID NO: 130, SEQ ID NO: 132, SEQ ID NO: 134, SEQ ID NO: 136, SEQ ID NO: 138, SEQ ID NO: 140, SEQ ID NO: 142, SEQ ID NO: 144, SEQ ID NO: 146, SEQ ID NO: 148, SEQ ID NO: 150, SEQ ID NO: 152, SEQ ID NO: 154, SEQ ID NO: 156, SEQ ID NO: 158, SEQ ID NO: 160, SEQ ID NO: 162, SEQ ID NO: 164, SEQ ID NO: 166, SEQ ID NO: 168, SEQ ID NO: 170, SEQ ID NO: 172, SEQ ID NO: 174, SEQ ID NO: 176, SEQ ID NO: 178, SEQ ID NO: 180, SEQ ID NO: 182, SEQ ID NO: 184, SEQ ID NO: 186, SEQ ID NO: 188, SEQ ID NO: 190, SEQ ID NO: 192, SEQ ID NO: 194, SEQ ID NO: 196, SEQ ID NO: 198, SEQ ID NO: 200, SEQ ID NO: 202, SEQ ID NO: 204, SEQ ID NO: 206, SEQ ID NO: 208, SEQ ID NO: 210, SEQ ID NO: 212, SEQ ID NO: 214, SEQ ID NO: 216, SEQ ID NO: 218, SEQ ID NO: 220, SEQ ID NO: 222, SEQ ID NO: 224, SEQ ID NO: 226, SEQ ID NO: 228, SEQ ID NO: 230, SEQ ID NO: 232, SEQ ID NO: 234, SEQ ID NO: 236, SEQ ID NO: 238, SEQ ID NO: 240, SEQ ID NO: 242, SEQ ID NO: 244, SEQ ID NO: 246, SEQ ID NO: 248, SEQ ID NO: 250, SEQ ID NO: 252, SEQ ID NO: 254, SEQ ID NO: 256, SEQ ID NO: 258, SEQ ID NO: 260, SEQ ID NO: 264, SEQ ID NO: 266, SEQ ID NO: 268, SEQ ID NO: 270, SEQ ID NO: 272, SEQ ID NO: 274, SEQ ID NO: 276, SEQ ID NO: 278, SEQ ID NO: 280, SEQ ID NO: 282, SEQ ID NO: 284, SEQ ID NO: 286, SEQ ID NO: 288, SEQ ID NO: 290, SEQ ID NO: 292, SEQ ID NO: 294, SEQ ID NO: 296, SEQ ID NO: 298, SEQ ID NO: 300, SEQ ID NO: 302, SEQ ID NO: 304, SEQ ID NO: 306, SEQ ID NO: 308, SEQ ID NO: 310, SEQ ID NO: 312, SEQ ID NO: 314, SEQ ID NO: 316, SEQ ID NO: 318, SEQ ID NO: 320, SEQ ID NO: 322, SEQ ID NO: 324, SEQ ID NO: 326, SEQ ID NO: 328, SEQ ID NO: 330, SEQ ID NO: 332, SEQ ID NO: 336, SEQ ID NO: 338, SEQ ID NO: 340, SEQ ID NO: 342, SEQ ID NO: 344, SEQ ID NO: 348, SEQ ID NO: 350, SEQ ID NO: 352, SEQ ID NO: 354, SEQ ID NO: 356, SEQ ID NO: 358, SEQ ID NO: 362, SEQ ID NO: 364, SEQ ID NO: 366, SEQ ID NO: 368, SEQ ID NO: 370, SEQ ID NO: 372, SEQ ID NO: 374, SEQ ID NO: 376, SEQ ID NO: 378, SEQ ID NO: 380, SEQ ID NO: 382, SEQ ID NO: 384, SEQ ID NO: 386, SEQ ID NO: 388, SEQ ID NO: 390, SEQ ID NO: 392, SEQ ID NO: 394, SEQ ID NO: 396, SEQ ID NO: 398, SEQ ID NO: 400, SEQ ID NO: 402, SEQ ID NO: 404, SEQ ID NO: 406, SEQ ID NO: 408, SEQ ID NO: 410, SEQ ID NO: 412, SEQ ID NO: 414, SEQ ID NO: 416, SEQ ID NO: 418, SEQ ID NO: 420, SEQ ID NO: 422, SEQ ID NO: 424, SEQ ID NO: 426, SEQ ID NO: 428, SEQ ID NO: 430, SEQ ID NO: 432, SEQ ID NO: 434, SEQ ID NO: 436, SEQ ID NO: 438, SEQ ID NO: 440, SEQ ID NO: 442, SEQ ID NO: 444, SEQ ID NO: 446, SEQ ID NO: 448, SEQ ID NO: 450, SEQ ID NO: 452, SEQ ID NO: 454, SEQ ID NO: 456, SEQ ID NO: 458, SEQ ID NO: 460, SEQ ID NO: 462, SEQ ID NO: 464, SEQ ID NO: 466, SEQ ID NO: 468, SEQ ID NO: 470, SEQ ID NO: 472, SEQ ID NO: 474, SEQ ID NO: 476, SEQ ID NO: 478, SEQ ID NO: 480, SEQ ID NO: 482, SEQ ID NO: 484, SEQ ID NO: 486, SEQ ID NO: 488, SEQ ID NO: 490, SEQ ID NO: 492, SEQ ID NO: 494, SEQ ID NO: 496, SEQ ID NO: 498, SEQ ID NO: 500, SEQ ID NO: 502, SEQ ID NO: 504, SEQ ID NO: 506, SEQ ID NO: 508, SEQ ID NO: 628, SEQ ID NO: 630, SEQ ID NO: 632, SEQ ID NO: 634, SEQ ID NO: 636, SEQ ID NO: 638, SEQ ID NO: 640, SEQ ID NO: 642, SEQ ID NO: 644, SEQ ID NO: 646, SEQ ID NO: 648, SEQ ID NO: 650, or SEQ ID NO: 652, with zero, one, or two single amino acid substitutions in one or more of the HCDRs. In some embodiments, the polynucleotide encodes a polypeptide subunit comprising a human IgM constant region or fragment thereof fused to the C-terminal end of a VH or VHH comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 95% or 100% identical to SEQ ID NO: 19, SEQ ID NO: 20, SEQ ID NO: 21, SEQ ID NO: 22, SEQ ID NO: 23, SEQ ID NO: 24, SEQ ID NO: 25, SEQ ID NO: 26, SEQ ID NO: 27, SEQ ID NO: 28, SEQ ID NO: 29, SEQ ID NO: 30, SEQ ID NO: 31, SEQ ID NO: 32, SEQ ID NO: 33, SEQ ID NO: 34, SEQ ID NO: 35, SEQ ID NO: 36, SEQ ID NO: 37, SEQ ID NO: 38, SEQ ID NO: 39, SEQ ID NO: 40, SEQ ID NO: 41, SEQ ID NO: 42, SEQ ID NO: 43, SEQ ID NO: 44, SEQ ID NO: 45, SEQ ID NO: 46, SEQ ID NO: 47, SEQ ID NO: 48, SEQ ID NO: 49, SEQ ID NO: 50, SEQ ID NO: 51, SEQ ID NO: 52, SEQ ID NO: 53, SEQ ID NO: 54, SEQ ID NO: 55, SEQ ID NO: 56, SEQ ID NO: 57, SEQ ID NO: 58, SEQ ID NO: 59, SEQ ID NO: 60, SEQ ID NO: 61, SEQ ID NO: 62, SEQ ID NO: 63, SEQ ID NO: 64, SEQ ID NO: 65, SEQ ID NO: 66, SEQ ID NO: 67, SEQ ID NO: 68, SEQ ID NO: 69, SEQ ID NO: 70, SEQ ID NO: 71, SEQ ID NO: 72, SEQ ID NO: 73, SEQ ID NO: 74, SEQ ID NO: 75, SEQ ID NO: 76, SEQ ID NO: 77, SEQ ID NO: 78, SEQ ID NO: 79, SEQ ID NO: 80, SEQ ID NO: 81, SEQ ID NO: 82, SEQ ID NO: 83, SEQ ID NO: 84, SEQ ID NO: 86, SEQ ID NO: 88, SEQ ID NO: 90, SEQ ID NO: 92, SEQ ID NO: 94, SEQ ID NO: 96, SEQ ID NO: 98, SEQ ID NO: 100, SEQ ID NO: 102, SEQ ID NO: 104, SEQ ID NO: 106, SEQ ID NO: 108, SEQ ID NO: 110, SEQ ID NO: 112, SEQ ID NO: 114, SEQ ID NO: 116, SEQ ID NO: 118, SEQ ID NO: 120, SEQ ID NO: 122, SEQ ID NO: 124, SEQ ID NO: 126, SEQ ID NO: 128, SEQ ID NO: 130, SEQ ID NO: 132, SEQ ID NO: 134, SEQ ID NO: 136, SEQ ID NO: 138, SEQ ID NO: 140, SEQ ID NO: 142, SEQ ID NO: 144, SEQ ID NO: 146, SEQ ID NO: 148, SEQ ID NO: 150, SEQ ID NO: 152, SEQ ID NO: 154, SEQ ID NO: 156, SEQ ID NO: 158, SEQ ID NO: 160, SEQ ID NO: 162, SEQ ID NO: 164, SEQ ID NO: 166, SEQ ID NO: 168, SEQ ID NO: 170, SEQ ID NO: 172, SEQ ID NO: 174, SEQ ID NO: 176, SEQ ID NO: 178, SEQ ID NO: 180, SEQ ID NO: 182, SEQ ID NO: 184, SEQ ID NO: 186, SEQ ID NO: 188, SEQ ID NO: 190, SEQ ID NO: 192, SEQ ID NO: 194, SEQ ID NO: 196, SEQ ID NO: 198, SEQ ID NO: 200, SEQ ID NO: 202, SEQ ID NO: 204, SEQ ID NO: 206, SEQ ID NO: 208, SEQ ID NO: 210, SEQ ID NO: 212, SEQ ID NO: 214, SEQ ID NO: 216, SEQ ID NO: 218, SEQ ID NO: 220, SEQ ID NO: 222, SEQ ID NO: 224, SEQ ID NO: 226, SEQ ID NO: 228, SEQ ID NO: 230, SEQ ID NO: 232, SEQ ID NO: 234, SEQ ID NO: 236, SEQ ID NO: 238, SEQ ID NO: 240, SEQ ID NO: 242, SEQ ID NO: 244, SEQ ID NO: 246, SEQ ID NO: 248, SEQ ID NO: 250, SEQ ID NO: 252, SEQ ID NO: 254, SEQ ID NO: 256, SEQ ID NO: 258, SEQ ID NO: 260, SEQ ID NO: 264, SEQ ID NO: 266, SEQ ID NO: 268, SEQ ID NO: 270, SEQ ID NO: 272, SEQ ID NO: 274, SEQ ID NO: 276, SEQ ID NO: 278, SEQ ID NO: 280, SEQ ID NO: 282, SEQ ID NO: 284, SEQ ID NO: 286, SEQ ID NO: 288, SEQ ID NO: 290, SEQ ID NO: 292, SEQ ID NO: 294, SEQ ID NO: 296, SEQ ID NO: 298, SEQ ID NO: 300, SEQ ID NO: 302, SEQ ID NO: 304, SEQ ID NO: 306, SEQ ID NO: 308, SEQ ID NO: 310, SEQ ID NO: 312, SEQ ID NO: 314, SEQ ID NO: 316, SEQ ID NO: 318, SEQ ID NO: 320, SEQ ID NO: 322, SEQ ID NO: 324, SEQ ID NO: 326, SEQ ID NO: 328, SEQ ID NO: 330, SEQ ID NO: 332, SEQ ID NO: 336, SEQ ID NO: 338, SEQ ID NO: 340, SEQ ID NO: 342, SEQ ID NO: 344, SEQ ID NO: 348, SEQ ID NO: 350, SEQ ID NO: 352, SEQ ID NO: 354, SEQ ID NO: 356, SEQ ID NO: 358, SEQ ID NO: 362, SEQ ID NO: 364, SEQ ID NO: 366, SEQ ID NO: 368, SEQ ID NO: 370, SEQ ID NO: 372, SEQ ID NO: 374, SEQ ID NO: 376, SEQ ID NO: 378, SEQ ID NO: 380, SEQ ID NO: 382, SEQ ID NO: 384, SEQ ID NO: 386, SEQ ID NO: 388, SEQ ID NO: 390, SEQ ID NO: 392, SEQ ID NO: 394, SEQ ID NO: 396, SEQ ID NO: 398, SEQ ID NO: 400, SEQ ID NO: 402, SEQ ID NO: 404, SEQ ID NO: 406, SEQ ID NO: 408, SEQ ID NO: 410, SEQ ID NO: 412, SEQ ID NO: 414, SEQ ID NO: 416, SEQ ID NO: 418, SEQ ID NO: 420, SEQ ID NO: 422, SEQ ID NO: 424, SEQ ID NO: 426, SEQ ID NO: 428, SEQ ID NO: 430, SEQ ID NO: 432, SEQ ID NO: 434, SEQ ID NO: 436, SEQ ID NO: 438, SEQ ID NO: 440, SEQ ID NO: 442, SEQ ID NO: 444, SEQ ID NO: 446, SEQ ID NO: 448, SEQ ID NO: 450, SEQ ID NO: 452, SEQ ID NO: 454, SEQ ID NO: 456, SEQ ID NO: 458, SEQ ID NO: 460, SEQ ID NO: 462, SEQ ID NO: 464, SEQ ID NO: 466, SEQ ID NO: 468, SEQ ID NO: 470, SEQ ID NO: 472, SEQ ID NO: 474, SEQ ID NO: 476, SEQ ID NO: 478, SEQ ID NO: 480, SEQ ID NO: 482, SEQ ID NO: 484, SEQ ID NO: 486, SEQ ID NO: 488, SEQ ID NO: 490, SEQ ID NO: 492, SEQ ID NO: 494, SEQ ID NO: 496, SEQ ID NO: 498, SEQ ID NO: 500, SEQ ID NO: 502, SEQ ID NO: 504, SEQ ID NO: 506, SEQ ID NO: 508, SEQ ID NO: 628, SEQ ID NO: 630, SEQ ID NO: 632, SEQ ID NO: 634, SEQ ID NO: 636, SEQ ID NO: 638, SEQ ID NO: 640, SEQ ID NO: 642, SEQ ID NO: 644, SEQ ID NO: 646, SEQ ID NO: 648, SEQ ID NO: 650, or SEQ ID NO: 652.

In some embodiments, the polynucleotide encodes a polypeptide subunit comprising a light chain constant region and an antibody VL portion of the SARS-CoV-2-binding domain of the multimeric binding molecule. In some embodiments, the polynucleotide encodes a polypeptide subunit comprising the light chain of the multimeric binding molecule. In some embodiments, the polynucleotide encodes a polypeptide subunit comprises a human kappa or lambda light chain constant region or fragment thereof fused to the C-terminal end of a VL comprising LCDR1, LCDR2, and LCDR3 regions comprising the CDRs contained in the VL amino acid sequences SEQ ID NO: 85, SEQ ID NO: 87, SEQ ID NO: 89, SEQ ID NO: 91, SEQ ID NO: 93, SEQ ID NO: 95, SEQ ID NO: 97, SEQ ID NO: 99, SEQ ID NO: 101, SEQ ID NO: 103, SEQ ID NO: 105, SEQ ID NO: 107, SEQ ID NO: 109, SEQ ID NO: 111, SEQ ID NO: 113, SEQ ID NO: 115, SEQ ID NO: 117, SEQ ID NO: 119, SEQ ID NO: 121, SEQ ID NO: 123, SEQ ID NO: 125, SEQ ID NO: 127, SEQ ID NO: 129, SEQ ID NO: 131, SEQ ID NO: 133, SEQ ID NO: 135, SEQ ID NO: 137, SEQ ID NO: 139, SEQ ID NO: 141, SEQ ID NO: 143, SEQ ID NO: 145, SEQ ID NO: 147, SEQ ID NO: 149, SEQ ID NO: 151, SEQ ID NO: 153, SEQ ID NO: 155, SEQ ID NO: 157, SEQ ID NO: 159, SEQ ID NO: 161, SEQ ID NO: 163, SEQ ID NO: 165, SEQ ID NO: 167, SEQ ID NO: 169, SEQ ID NO: 171, SEQ ID NO: 173, SEQ ID NO: 175, SEQ ID NO: 177, SEQ ID NO: 179, SEQ ID NO: 181, SEQ ID NO: 183, SEQ ID NO: 185, SEQ ID NO: 187, SEQ ID NO: 189, SEQ ID NO: 191, SEQ ID NO: 193, SEQ ID NO: 195, SEQ ID NO: 197, SEQ ID NO: 199, SEQ ID NO: 201, SEQ ID NO: 203, SEQ ID NO: 205, SEQ ID NO: 207, SEQ ID NO: 209, SEQ ID NO: 211, SEQ ID NO: 213, SEQ ID NO: 215, SEQ ID NO: 217, SEQ ID NO: 219, SEQ ID NO: 221, SEQ ID NO: 223, SEQ ID NO: 225, SEQ ID NO: 227, SEQ ID NO: 229, SEQ ID NO: 231, SEQ ID NO: 233, SEQ ID NO: 235, SEQ ID NO: 237, SEQ ID NO: 239, SEQ ID NO: 241, SEQ ID NO: 243, SEQ ID NO: 245, SEQ ID NO: 247, SEQ ID NO: 249, SEQ ID NO: 251, SEQ ID NO: 253, SEQ ID NO: 255, SEQ ID NO: 257, SEQ ID NO: 259, SEQ ID NO: 261, SEQ ID NO: 265, SEQ ID NO: 267, SEQ ID NO: 269, SEQ ID NO: 271, SEQ ID NO: 273, SEQ ID NO: 275, SEQ ID NO: 277, SEQ ID NO: 279, SEQ ID NO: 281, SEQ ID NO: 283, SEQ ID NO: 285, SEQ ID NO: 287, SEQ ID NO: 289, SEQ ID NO: 291, SEQ ID NO: 293, SEQ ID NO: 295, SEQ ID NO: 297, SEQ ID NO: 299, SEQ ID NO: 301, SEQ ID NO: 303, SEQ ID NO: 305, SEQ ID NO: 307, SEQ ID NO: 309, SEQ ID NO: 311, SEQ ID NO: 313, SEQ ID NO: 315, SEQ ID NO: 317, SEQ ID NO: 319, SEQ ID NO: 321, SEQ ID NO: 323, SEQ ID NO: 325, SEQ ID NO: 327, SEQ ID NO: 329, SEQ ID NO: 331, SEQ ID NO: 333, SEQ ID NO: 337, SEQ ID NO: 339, SEQ ID NO: 341, SEQ ID NO: 343, SEQ ID NO: 345, SEQ ID NO: 349, SEQ ID NO: 351, SEQ ID NO: 353, SEQ ID NO: 355, SEQ ID NO: 357, SEQ ID NO: 359, SEQ ID NO: 363, SEQ ID NO: 365, SEQ ID NO: 367, SEQ ID NO: 369, SEQ ID NO: 371, SEQ ID NO: 373, SEQ ID NO: 375, SEQ ID NO: 377, SEQ ID NO: 379, SEQ ID NO: 381, SEQ ID NO: 383, SEQ ID NO: 385, SEQ ID NO: 387, SEQ ID NO: 389, SEQ ID NO: 391, SEQ ID NO: 393, SEQ ID NO: 395, SEQ ID NO: 397, SEQ ID NO: 399, SEQ ID NO: 401, SEQ ID NO: 403, SEQ ID NO: 405, SEQ ID NO: 407, SEQ ID NO: 409, SEQ ID NO: 411, SEQ ID NO: 413, SEQ ID NO: 415, SEQ ID NO: 417, SEQ ID NO: 419, SEQ ID NO: 421, SEQ ID NO: 423, SEQ ID NO: 425, SEQ ID NO: 427, SEQ ID NO: 429, SEQ ID NO: 431, SEQ ID NO: 433, SEQ ID NO: 435, SEQ ID NO: 437, SEQ ID NO: 439, SEQ ID NO: 441, SEQ ID NO: 443, SEQ ID NO: 445, SEQ ID NO: 447, SEQ ID NO: 449, SEQ ID NO: 451, SEQ ID NO: 453, SEQ ID NO: 455, SEQ ID NO: 457, SEQ ID NO: 459, SEQ ID NO: 461, SEQ ID NO: 463, SEQ ID NO: 465, SEQ ID NO: 467, SEQ ID NO: 469, SEQ ID NO: 471, SEQ ID NO: 473, SEQ ID NO: 475, SEQ ID NO: 477, SEQ ID NO: 479, SEQ ID NO: 481, SEQ ID NO: 483, SEQ ID NO: 485, SEQ ID NO: 487, SEQ ID NO: 489, SEQ ID NO: 491, SEQ ID NO: 493, SEQ ID NO: 495, SEQ ID NO: 497, SEQ ID NO: 499, SEQ ID NO: 501, SEQ ID NO: 503, SEQ ID NO: 505, SEQ ID NO: 507, SEQ ID NO: 509, SEQ ID NO: 629, SEQ ID NO: 631, SEQ ID NO: 633, SEQ ID NO: 635, SEQ ID NO: 637, SEQ ID NO: 639, SEQ ID NO: 641, SEQ ID NO: 643, SEQ ID NO: 645, SEQ ID NO: 647, SEQ ID NO: 649, SEQ ID NO: 651, or SEQ ID NO: 653, with zero, one, or two single amino acid substitutions in one or more of the LCDRs. In some embodiments, the polynucleotide encodes a polypeptide subunit comprises a human kappa or lambda light chain constant region or fragment thereof fused to the C-terminal end of a VL comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 95% or 100% identical to SEQ ID NO: 85, SEQ ID NO: 87, SEQ ID NO: 89, SEQ ID NO: 91, SEQ ID NO: 93, SEQ ID NO: 95, SEQ ID NO: 97, SEQ ID NO: 99, SEQ ID NO: 101, SEQ ID NO: 103, SEQ ID NO: 105, SEQ ID NO: 107, SEQ ID NO: 109, SEQ ID NO: 111, SEQ ID NO: 113, SEQ ID NO: 115, SEQ ID NO: 117, SEQ ID NO: 119, SEQ ID NO: 121, SEQ ID NO: 123, SEQ ID NO: 125, SEQ ID NO: 127, SEQ ID NO: 129, SEQ ID NO: 131, SEQ ID NO: 133, SEQ ID NO: 135, SEQ ID NO: 137, SEQ ID NO: 139, SEQ ID NO: 141, SEQ ID NO: 143, SEQ ID NO: 145, SEQ ID NO: 147, SEQ ID NO: 149, SEQ ID NO: 151, SEQ ID NO: 153, SEQ ID NO: 155, SEQ ID NO: 157, SEQ ID NO: 159, SEQ ID NO: 161, SEQ ID NO: 163, SEQ ID NO: 165, SEQ ID NO: 167, SEQ ID NO: 169, SEQ ID NO: 171, SEQ ID NO: 173, SEQ ID NO: 175, SEQ ID NO: 177, SEQ ID NO: 179, SEQ ID NO: 181, SEQ ID NO: 183, SEQ ID NO: 185, SEQ ID NO: 187, SEQ ID NO: 189, SEQ ID NO: 191, SEQ ID NO: 193, SEQ ID NO: 195, SEQ ID NO: 197, SEQ ID NO: 199, SEQ ID NO: 201, SEQ ID NO: 203, SEQ ID NO: 205, SEQ ID NO: 207, SEQ ID NO: 209, SEQ ID NO: 211, SEQ ID NO: 213, SEQ ID NO: 215, SEQ ID NO: 217, SEQ ID NO: 219, SEQ ID NO: 221, SEQ ID NO: 223, SEQ ID NO: 225, SEQ ID NO: 227, SEQ ID NO: 229, SEQ ID NO: 231, SEQ ID NO: 233, SEQ ID NO: 235, SEQ ID NO: 237, SEQ ID NO: 239, SEQ ID NO: 241, SEQ ID NO: 243, SEQ ID NO: 245, SEQ ID NO: 247, SEQ ID NO: 249, SEQ ID NO: 251, SEQ ID NO: 253, SEQ ID NO: 255, SEQ ID NO: 257, SEQ ID NO: 259, SEQ ID NO: 261, SEQ ID NO: 265, SEQ ID NO: 267, SEQ ID NO: 269, SEQ ID NO: 271, SEQ ID NO: 273, SEQ ID NO: 275, SEQ ID NO: 277, SEQ ID NO: 279, SEQ ID NO: 281, SEQ ID NO: 283, SEQ ID NO: 285, SEQ ID NO: 287, SEQ ID NO: 289, SEQ ID NO: 291, SEQ ID NO: 293, SEQ ID NO: 295, SEQ ID NO: 297, SEQ ID NO: 299, SEQ ID NO: 301, SEQ ID NO: 303, SEQ ID NO: 305, SEQ ID NO: 307, SEQ ID NO: 309, SEQ ID NO: 311, SEQ ID NO: 313, SEQ ID NO: 315, SEQ ID NO: 317, SEQ ID NO: 319, SEQ ID NO: 321, SEQ ID NO: 323, SEQ ID NO: 325, SEQ ID NO: 327, SEQ ID NO: 329, SEQ ID NO: 331, SEQ ID NO: 333, SEQ ID NO: 337, SEQ ID NO: 339, SEQ ID NO: 341, SEQ ID NO: 343, SEQ ID NO: 345, SEQ ID NO: 349, SEQ ID NO: 351, SEQ ID NO: 353, SEQ ID NO: 355, SEQ ID NO: 357, SEQ ID NO: 359, SEQ ID NO: 363, SEQ ID NO: 365, SEQ ID NO: 367, SEQ ID NO: 369, SEQ ID NO: 371, SEQ ID NO: 373, SEQ ID NO: 375, SEQ ID NO: 377, SEQ ID NO: 379, SEQ ID NO: 381, SEQ ID NO: 383, SEQ ID NO: 385, SEQ ID NO: 387, SEQ ID NO: 389, SEQ ID NO: 391, SEQ ID NO: 393, SEQ ID NO: 395, SEQ ID NO: 397, SEQ ID NO: 399, SEQ ID NO: 401, SEQ ID NO: 403, SEQ ID NO: 405, SEQ ID NO: 407, SEQ ID NO: 409, SEQ ID NO: 411, SEQ ID NO: 413, SEQ ID NO: 415, SEQ ID NO: 417, SEQ ID NO: 419, SEQ ID NO: 421, SEQ ID NO: 423, SEQ ID NO: 425, SEQ ID NO: 427, SEQ ID NO: 429, SEQ ID NO: 431, SEQ ID NO: 433, SEQ ID NO: 435, SEQ ID NO: 437, SEQ ID NO: 439, SEQ ID NO: 441, SEQ ID NO: 443, SEQ ID NO: 445, SEQ ID NO: 447, SEQ ID NO: 449, SEQ ID NO: 451, SEQ ID NO: 453, SEQ ID NO: 455, SEQ ID NO: 457, SEQ ID NO: 459, SEQ ID NO: 461, SEQ ID NO: 463, SEQ ID NO: 465, SEQ ID NO: 467, SEQ ID NO: 469, SEQ ID NO: 471, SEQ ID NO: 473, SEQ ID NO: 475, SEQ ID NO: 477, SEQ ID NO: 479, SEQ ID NO: 481, SEQ ID NO: 483, SEQ ID NO: 485, SEQ ID NO: 487, SEQ ID NO: 489, SEQ ID NO: 491, SEQ ID NO: 493, SEQ ID NO: 495, SEQ ID NO: 497, SEQ ID NO: 499, SEQ ID NO: 501, SEQ ID NO: 503, SEQ ID NO: 505, SEQ ID NO: 507, SEQ ID NO: 509, SEQ ID NO: 629, SEQ ID NO: 631, SEQ ID NO: 633, SEQ ID NO: 635, SEQ ID NO: 637, SEQ ID NO: 639, SEQ ID NO: 641, SEQ ID NO: 643, SEQ ID NO: 645, SEQ ID NO: 647, SEQ ID NO: 649, SEQ ID NO: 651, or SEQ ID NO: 653.

In some embodiments, the polynucleotide encodes a polypeptide subunit comprising a light chain constant region and an antibody VL portion of the SARS-CoV-binding domain of the multimeric binding molecule. In some embodiments, the polynucleotide encodes a polypeptide subunit comprising the light chain of the multimeric binding molecule. In some embodiments, the polynucleotide encodes a polypeptide subunit comprises a human kappa or lambda light chain constant region or fragment thereof fused to the C-terminal end of a VL comprising LCDR1, LCDR2, and LCDR3 regions comprising the CDRs contained in the VL amino acid sequences SEQ ID NO: 85, SEQ ID NO: 119, SEQ ID NO: 121, SEQ ID NO: 139, SEQ ID NO: 163, SEQ ID NO: 223, SEQ ID NO: 237, SEQ ID NO: 253, SEQ ID NO: 261, SEQ ID NO: 263, SEQ ID NO: 297, SEQ ID NO: 345, SEQ ID NO: 629, SEQ ID NO: 633, SEQ ID NO: 635, SEQ ID NO: 637, SEQ ID NO: 639, SEQ ID NO: 641, SEQ ID NO: 643, SEQ ID NO: 645, or SEQ ID NO: 647, with zero, one, or two single amino acid substitutions in one or more of the LCDRs. In some embodiments, the polynucleotide encodes a polypeptide subunit comprises a human kappa or lambda light chain constant region or fragment thereof fused to the C-terminal end of a VL comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 95% or 100% identical to SEQ ID NO: 85, SEQ ID NO: 119, SEQ ID NO: 121, SEQ ID NO: 139, SEQ ID NO: 163, SEQ ID NO: 223, SEQ ID NO: 237, SEQ ID NO: 253, SEQ ID NO: 261, SEQ ID NO: 263, SEQ ID NO: 297, SEQ ID NO: 345, SEQ ID NO: 629, SEQ ID NO: 633, SEQ ID NO: 635, SEQ ID NO: 637, SEQ ID NO: 639, SEQ ID NO: 641, SEQ ID NO: 643, SEQ ID NO: 645, or SEQ ID NO: 647.

In some embodiments, the polynucleotide encodes a polypeptide subunit comprising a light chain constant region and an antibody VL portion of the MERS-CoV-binding domain of the multimeric binding molecule. In some embodiments, the polynucleotide encodes a polypeptide subunit comprising the light chain of the multimeric binding molecule. In some embodiments, the polynucleotide encodes a polypeptide subunit comprises a human kappa or lambda light chain constant region or fragment thereof fused to the C-terminal end of a VL comprising LCDR1, LCDR2, and LCDR3 regions comprising the CDRs contained in the VL amino acid sequences SEQ ID NO: 511, SEQ ID NO: 513, SEQ ID NO: 515, SEQ ID NO: 517, SEQ ID NO: 519, SEQ ID NO: 521, SEQ ID NO: 523, SEQ ID NO: 525, SEQ ID NO: 527, SEQ ID NO: 529, SEQ ID NO: 531, SEQ ID NO: 533, SEQ ID NO: 535, SEQ ID NO: 537, SEQ ID NO: 539, SEQ ID NO: 541, SEQ ID NO: 543, SEQ ID NO: 545, SEQ ID NO: 547, SEQ ID NO: 549, SEQ ID NO: 551, SEQ ID NO: 553, SEQ ID NO: 555, SEQ ID NO: 557, SEQ ID NO: 559, SEQ ID NO: 561, SEQ ID NO: 563, SEQ ID NO: 565, SEQ ID NO: 567, SEQ ID NO: 569, SEQ ID NO: 571, SEQ ID NO: 573, SEQ ID NO: 575, SEQ ID NO: 577, SEQ ID NO: 579, SEQ ID NO: 581, SEQ ID NO: 583, SEQ ID NO: 585, SEQ ID NO: 587, SEQ ID NO: 589, SEQ ID NO: 591, SEQ ID NO: 593, SEQ ID NO: 595, SEQ ID NO: 597, SEQ ID NO: 599, SEQ ID NO: 601, SEQ ID NO: 603, SEQ ID NO: 605, SEQ ID NO: 607, SEQ ID NO: 609, SEQ ID NO: 611, SEQ ID NO: 613, SEQ ID NO: 615, SEQ ID NO: 617, SEQ ID NO: 619, SEQ ID NO: 621, SEQ ID NO: 623, SEQ ID NO: 625, SEQ ID NO: 627, or SEQ ID NO: 631, with zero, one, or two single amino acid substitutions in one or more of the LCDRs. In some embodiments, the polynucleotide encodes a polypeptide subunit comprises a human kappa or lambda light chain constant region or fragment thereof fused to the C-terminal end of a VL comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 95% or 100% identical to SEQ ID NO: 511, SEQ ID NO: 513, SEQ ID NO: 515, SEQ ID NO: 517, SEQ ID NO: 519, SEQ ID NO: 521, SEQ ID NO: 523, SEQ ID NO: 525, SEQ ID NO: 527, SEQ ID NO: 529, SEQ ID NO: 531, SEQ ID NO: 533, SEQ ID NO: 535, SEQ ID NO: 537, SEQ ID NO: 539, SEQ ID NO: 541, SEQ ID NO: 543, SEQ ID NO: 545, SEQ ID NO: 547, SEQ ID NO: 549, SEQ ID NO: 551, SEQ ID NO: 553, SEQ ID NO: 555, SEQ ID NO: 557, SEQ ID NO: 559, SEQ ID NO: 561, SEQ ID NO: 563, SEQ ID NO: 565, SEQ ID NO: 567, SEQ ID NO: 569, SEQ ID NO: 571, SEQ ID NO: 573, SEQ ID NO: 575, SEQ ID NO: 577, SEQ ID NO: 579, SEQ ID NO: 581, SEQ ID NO: 583, SEQ ID NO: 585, SEQ ID NO: 587, SEQ ID NO: 589, SEQ ID NO: 591, SEQ ID NO: 593, SEQ ID NO: 595, SEQ ID NO: 597, SEQ ID NO: 599, SEQ ID NO: 601, SEQ ID NO: 603, SEQ ID NO: 605, SEQ ID NO: 607, SEQ ID NO: 609, SEQ ID NO: 611, SEQ ID NO: 613, SEQ ID NO: 615, SEQ ID NO: 617, SEQ ID NO: 619, SEQ ID NO: 621, SEQ ID NO: 623, SEQ ID NO: 625, SEQ ID NO: 627, or SEQ ID NO: 631.

In certain embodiments, this disclosure provides a vector comprising one or more polynucleotides described herein. In some embodiments, the vector further comprises a polynucleotide comprising a nucleic acid sequence that encodes a J-chain or a functional fragment or variant thereof, such as a J-chain, functional fragment or variant thereof described herein.

In some embodiments, the vector is a viral vector, such as an adenoviral or adeno-associated viral (AAV) vector. In some embodiments, this disclosure provides a viral particle comprising a viral vector disclosed herein. In some embodiments, the viral particle is an adenoviral particle or an AAV particle.

In certain embodiments, this disclosure provides a composition comprising a first vector and a second vector, where: a) the first vector comprises a polynucleotide comprising a nucleic acid sequence that encodes the heavy chain of the multimeric binding molecule and the second vector comprises a polynucleotide comprising a nucleic acid sequence that encodes the light chain of the multimeric binding molecule, b) the first vector comprises a polynucleotide comprising a nucleic acid sequence that encodes the heavy chain of the multimeric binding molecule and a polynucleotide comprising a nucleic acid sequence that encodes the light chain of the multimeric binding molecule and the second vector comprises a polynucleotide comprising a nucleic acid sequence that encodes a J-chain or a functional fragment or variant thereof, c) the first vector comprises a polynucleotide comprising a nucleic acid sequence that encodes the heavy chain of the multimeric binding molecule and a polynucleotide comprising a nucleic acid sequence that encodes a J-chain or a functional fragment or variant thereof and the second vector comprises a polynucleotide comprising a nucleic acid sequence that encodes the light chain of the multimeric binding molecule, or d) the first vector comprises a polynucleotide comprising a nucleic acid sequence that encodes the light chain of the multimeric binding molecule and a polynucleotide comprising a nucleic acid sequence that encodes a J-chain or a functional fragment or variant thereof and the second vector comprises a polynucleotide comprising a nucleic acid sequence that encodes the heavy chain of the multimeric binding molecule. In certain embodiments, this disclosure provides a composition comprising a first vector, a second vector, and a third vector, where the first vector comprises a polynucleotide comprising a nucleic acid sequence that encodes the heavy chain of the multimeric binding molecule, the second vector comprises a polynucleotide comprising a nucleic acid sequence that encodes the light chain of the multimeric binding molecule, and the third vector comprises a polynucleotide comprising a nucleic acid sequence that encodes a J-chain or a functional fragment or variant thereof.

Host Cells

In certain embodiments, this disclosure provides a host cell that is capable of producing the multimeric binding molecule as provided herein. In certain embodiments, the host cell comprises one or more vectors, a composition comprising multiple vectors, or polynucleotides disclosed herein. The disclosure also provides a method of producing the multimeric binding molecule as provided herein, where the method comprises culturing the provided host cell, and recovering the multimeric binding molecule.

Methods of Use

The disclosure further provides a method of treating a disease or disorder in a subject in need of treatment, where the method includes administering to the subject a therapeutically effective amount of a multimeric binding molecule as provided herein. By “therapeutically effective dose or amount” or “effective amount” is intended an amount of a multimeric binding molecule that when administered brings about a positive therapeutic response with respect to treatment of subject. Examples of positive therapeutic responses include, without limitation, prevention of respiratory tract colonization or infection by a human coronavirus, e.g., SARS-CoV, SARS-CoV-2, or MERS-CoV, prevention of human coronavirus, e.g., SARS-CoV, SARS-CoV-2, or MERS-CoV attachment, penetration, and/or replication upon exposure to the virus, prevention of human coronavirus, e.g., SARS-CoV, SARS-CoV-2, or MERS-CoV symptoms, alleviation of human coronavirus, e.g., SARS-CoV, SARS-CoV-2, or MERS-CoV symptoms, reduction of the number of human coronavirus, e.g., SARS-CoV, SARS-CoV-2, or MERS-CoV symptoms, or reduction in the severity of human coronavirus, e.g., SARS-CoV, SARS-CoV-2, or MERS-CoV symptoms. “Symptoms” include, without limitation, one or more of fever, chills, muscle or body aches, fatigue, headache, sore throat, coughing, shortness of breath, difficulty breathing, loss of taste and/or the ability to smell, pneumonia, congestion, nausea, or diarrhea.

Effective doses of compositions for treatment of a disease or disorder vary depending upon many different factors, including means of administration, target site, physiological state of the subject, whether the subject is human or an animal, other medications administered, and whether treatment is prophylactic or therapeutic. Usually, the subject is a human, but non-human mammals including transgenic mammals can also be treated. Treatment dosages can be titrated using routine methods known to those of skill in the art to optimize safety and efficacy.

In certain embodiments, the disclosure provides a method for treating a human coronavirus disease, e.g., Corona Virus Disease 2019 (COVID-19) in a subject in need of treatment, where the method includes administering to the subject an effective amount of a multimeric binding molecule as provided herein. In certain embodiments, administration of a multimeric binding molecule as provided herein to a subject results in greater potency, e.g., greater efficacy at an equivalent dose or the ability to administer a lower dose and achieve equivalent efficacy, than administration of an equivalent amount of a monomeric binding molecule, such as an IgG, binding to the same binding partner. By “efficacy” is meant the ability of the treatment to, for example, reduce symptoms in an infected subject, reduce the severity of symptoms in an infected subject, prevent symptoms in an infected but asymptomatic subject, reduce the need for auxiliary oxygen in an infected subject or reduce time on a ventilator, reduce the need or the dosage of concomitant medications, reduce the time in intensive care, spare hospital resources, or prevent or reduce transmission from an infected subject to non-infected persons. In certain embodiments the multimeric binding molecule as provided herein can also treat the subject more safely, e.g., by preventing antibody-dependent enhancement of infection, and by effectively neutralizing “escape mutant” viruses. In certain embodiments the monomeric binding molecule includes identical binding polypeptides to the multimeric binding molecule as provided herein. By “an equivalent amount” is meant, e.g., an amount measured by molecular weight, e.g., in total milligrams, or alternatively, a molar equivalent, e.g., where equivalent numbers of molecules are administered.

In other embodiments, the disclosure provides a method for preventing a human coronavirus disease, e.g., Corona Virus Disease 2019 (COVID-19) in a subject in need thereof, e.g., a subject susceptible to human coronavirus, e.g., SARS-CoV-2 infection or a subject susceptible to more severe human coronavirus infection-associated disease or disorder, e.g., COVID-19 symptoms due to proximity to human coronavirus infection-associated disease or disorder, e.g., COVID-19 patients, e.g., healthcare providers and/or family members, or due to secondary conditions such as advanced age, diabetes, heart disease, or obesity, where the method includes administering to the subject an effective amount of a multimeric binding molecule as provided herein. In certain embodiments, administration of a multimeric binding molecule as provided herein to a subject results in greater potency, e.g., as noted above, than administration of an equivalent amount of a monomeric binding polypeptide, such as an IgG, binding to the same binding partner. In certain embodiments the monomeric binding molecule includes identical antigen binding domains to the multimeric binding molecule as provided herein. By “an equivalent amount” is meant, e.g., an amount measured by molecular weight, e.g., in total milligrams, or alternative, a molar equivalent, e.g., where equivalent numbers of molecules are administered.

The subject can be any animal, e.g., a mammal, in need of treatment or prevention, in certain embodiments, the subject is a human subject.

In its simplest form, a preparation to be administered to a subject is multimeric binding molecule as provided herein administered in a conventional dosage form, which can be combined with a pharmaceutical excipient, carrier or diluent as described elsewhere herein.

A multimeric binding molecule of the disclosure can be administered by any suitable method, e.g., parenterally, intraventricularly, orally, by inhalation spray, topically, rectally, intranasally, buccally, vaginally, via an implanted reservoir, or a combination thereof. The term “parenteral” as used herein includes subcutaneous, intravenous, intramuscular, intra-articular, intra-synovial, intrasternal, intrathecal, intrahepatic, intralesional and intracranial injection or infusion techniques.

In certain embodiments the multimeric binding molecule is delivered intranasally, e.g., in an atomized form produced by a suitable spray delivery device, e.g., a MAD NASAL™ Intranasal Mucosal Atomization Device, produced by Teleflex. In certain embodiments, the multimeric binding molecule is delivered orally, e.g., in an atomized form produced by a suitable spray delivery device, e.g., a MAD NASAL™ Intranasal Mucosal Atomization Device, produced by Teleflex. In certain embodiments, the multimeric binding molecule is delivered intranasally and orally, e.g., in an atomized form produced by a suitable spray delivery device, e.g., a MAD NASAL™ Intranasal Mucosal Atomization Device, produced by Teleflex.

In certain embodiments the multimeric binding molecule is delivered via inhalation, e.g., in a nebulized form.

In certain embodiments the multimeric binding molecule is delivered intravenously. In certain embodiments the multimeric binding molecule is delivered intranasally, e.g., in an atomized form produced by a suitable spray delivery device, e.g., a MAD NASAL™ Intranasal Mucosal Atomization Device, produced by Teleflex and is delivered intravenously. In certain embodiments, the multimeric binding molecule is delivered orally, e.g., in an atomized form produced by a suitable spray delivery device, e.g., a MAD NASAL™ Intranasal Mucosal Atomization Device, produced by Teleflex and is delivered intravenously. In certain embodiments, the multimeric binding molecule is delivered intranasally and orally, e.g., in an atomized form produced by a suitable spray delivery device, e.g., a MAD NASAL™ Intranasal Mucosal Atomization Device, produced by Teleflex and is delivered intravenously.

Pharmaceutical Compositions and Administration Methods

The disclosure further provides a composition, e.g., a pharmaceutical composition, comprising a multimeric binding molecule, or two or more multimeric binding molecules, as provided herein. In certain embodiments the composition includes a cocktail of two or more different multimeric binding molecules as described here, that bind to different epitopes on a single human coronavirus, e.g., SARS-CoV-2 or MERS-CoV. In certain aspects the different epitopes can be on the same coronavirus protein, e.g., structural protein, for example the spike (S) protein. A composition as provided herein can further include a pharmaceutically acceptable carrier and/or excipient and can be formulated so as to be suitable for a desired mode of administration.

Methods of preparing and administering a multimeric binding molecule as provided herein to a subject in need thereof can be determined by a skilled person in view of this disclosure. The route of administration of can be, for example, oral, parenteral, intranasally, by inhalation, by aerosol, or topical. The term parenteral as used herein includes, e.g., intravenous, intraarterial, intraperitoneal, intramuscular, subcutaneous, rectal, or vaginal administration. While these forms of administration are contemplated as suitable forms, another example of a form for administration would be a solution for injection, in particular for intravenous, or intraarterial injection or drip. A suitable pharmaceutical composition can include a buffer (e.g., acetate, phosphate, or citrate buffer), a surfactant (e.g., polysorbate), optionally a stabilizer agent (e.g., human albumin), etc.

As discussed herein, a multimeric binding molecule as provided herein can be administered in a pharmaceutically effective amount for the treatment of a subject in need thereof. In this regard, it will be appreciated that the disclosed multimeric binding molecule can be formulated so as to facilitate administration and promote stability of the active agent. Pharmaceutical compositions accordingly can include a pharmaceutically acceptable, non-toxic, sterile carrier such as physiological saline, non-toxic buffers, preservatives, and the like. A pharmaceutically effective amount of a multimeric binding molecule as provided herein means an amount sufficient to achieve effective binding to a target and to achieve a therapeutic benefit. Suitable formulations are described in Remington's Pharmaceutical Sciences (Mack Publishing Co.) 16th ed. (1980).

Certain pharmaceutical compositions provided herein can be orally administered in an acceptable dosage form including, e.g., capsules, tablets, aqueous suspensions, or solutions.

Certain pharmaceutical compositions also can be administered by nasal aerosol or inhalation. Such compositions can be prepared as solutions in saline, employing benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, and/or other conventional solubilizing or dispersing agents. In some embodiments, the pharmaceutical composition is administered by nasal aerosol. In some embodiments, the pharmaceutical composition is for administration by nasal aerosol. In some embodiments, the pharmaceutical composition, such as a pharmaceutical composition for administration by nasal aerosol, comprises a pH adjuster, such as HCl; a buffer; an emulsifier, such as polysorbate or carbomer; sugar or mono- or polyol, such as a monosaccharide (e.g., glucose, dextrose, or fructose), disaccharide (e.g., sucrose, lactose, or maltose), ribose, glycerin, sorbitol, xylitol, inositol, propylene glycol, galactose, mannose, xylose, rhamnose, glutaraldehyde, ethanol, mannitol, polyethylene glycol, glycerol, chitosal, phenylethyl alcohol; a preservative; cellulose, such as microcrystalline cellulose or carboxymethylcellulose; or mixtures thereof.

In some embodiments, the pharmaceutical composition is administered by inhalation. In some embodiments, the pharmaceutical composition is for administration by inhalation. In some embodiments, the pharmaceutical composition, such as a pharmaceutical composition for administration by inhalation, is a dry powder, such as for a dry powder inhaler, or a liquid, such as for a nebulizer, such as an airjet-compressor nebulizer or a mesh-based nebulizer. In some embodiments, the pharmaceutical composition, such as a pharmaceutical composition for administration by inhalation, comprises sugar or mono- or polyol, such as lactose, trelose, mannitol, sorbitol; buffer, such as histidine, proline, or arginine buffer; saline; polysorbate; or mixtures thereof.

The amount of a multimeric binding molecule that can be combined with carrier materials to produce a single dosage form will vary depending, e.g., upon the subject treated and the particular mode of administration. The composition can be administered as a single dose, multiple doses or over an established period of time in an infusion. Dosage regimens also can be adjusted to provide the optimum desired response (e.g., a therapeutic or prophylactic response).

In keeping with the scope of the present disclosure, a multimeric binding molecule as provided herein can be administered to a subject in need of therapy in an amount sufficient to produce a therapeutic effect or a prophylactic effect. A multimeric binding molecule as provided herein can be administered to the subject in a conventional dosage form prepared by combining the multimeric binding molecule of the disclosure with a conventional pharmaceutically acceptable carrier or diluent according to known techniques. The form and character of the pharmaceutically acceptable carrier or diluent can be dictated by the amount of active ingredient with which it is to be combined, the route of administration and other well-known variables.

This disclosure also provides for the use of a multimeric binding molecule as provided herein in the manufacture of a medicament for treating, preventing, or managing a human coronavirus infection, e.g., COVID-19.

In some embodiments, the compositions and methods provided herein can be used for the treatment of infections that have not been effectively treated using existing or established treatments.

This disclosure employs, unless otherwise indicated, conventional techniques of cell biology, cell culture, molecular biology, transgenic biology, microbiology, recombinant DNA, and immunology, which are within the skill of the art. Such techniques are explained fully in the literature. See, for example, Green and Sambrook, ed. (2012) Molecular Cloning A Laboratory Manual (4th ed.; Cold Spring Harbor Laboratory Press); Sambrook et al., ed. (1992) Molecular Cloning: A Laboratory Manual, (Cold Springs Harbor Laboratory, NY); D. N. Glover and B. D. Hames, eds., (1995) DNA Cloning 2d Edition (IRL Press), Volumes 1-4; Gait, ed. (1990) Oligonucleotide Synthesis (IRL Press); Mullis et al. U.S. Pat. No. 4,683,195; Hames and Higgins, eds. (1985) Nucleic Acid Hybridization (IRL Press); Hames and Higgins, eds. (1984) Transcription And Translation (IRL Press); Freshney (2016) Culture Of Animal Cells, 7th Edition (Wiley-Blackwell); Woodward, J., Immobilized Cells And Enzymes (IRL Press) (1985); Perbal (1988) A Practical Guide To Molecular Cloning; 2d Edition (Wiley-Interscience); Miller and Calos eds. (1987) Gene Transfer Vectors For Mammalian Cells, (Cold Spring Harbor Laboratory); S. C. Makrides (2003) Gene Transfer and Expression in Mammalian Cells (Elsevier Science); Methods in Enzymology, Vols. 151-155 (Academic Press, Inc., N.Y.); Mayer and Walker, eds. (1987) Immunochemical Methods in Cell and Molecular Biology (Academic Press, London); Weir and Blackwell, eds.; and in Ausubel et al. (1995) Current Protocols in Molecular Biology (John Wiley and Sons).

General principles of antibody engineering are set forth, e.g., in Strohl, W. R., and L. M. Strohl (2012), Therapeutic Antibody Engineering (Woodhead Publishing). General principles of protein engineering are set forth, e.g., in Park and Cochran, eds. (2009), Protein Engineering and Design (CDC Press). General principles of immunology are set forth, e.g., in: Abbas and Lichtman (2017) Cellular and Molecular Immunology 9th Edition (Elsevier). Additionally, standard methods in immunology known in the art can be followed, e.g., in Current Protocols in Immunology (Wiley Online Library); Wild, D. (2013), The Immunoassay Handbook 4th Edition (Elsevier Science); Greenfield, ed. (2013), Antibodies, a Laboratory Manual, 2d Edition (Cold Spring Harbor Press); and Ossipow and Fischer, eds., (2014), Monoclonal Antibodies: Methods and Protocols (Humana Press).

All of the references cited above, as well as all references cited herein, are incorporated herein by reference in their entireties.

The following examples are offered by way of illustration and not by way of limitation.

EXEMPLARY EMBODIMENTS

Among the provided embodiments are:

Embodiment 1. A multimeric binding molecule comprising two to six bivalent binding units or variants or fragments thereof, wherein each binding unit comprises two IgM or IgA heavy chain constant regions or multimerizing fragments or variants thereof, each associated with a binding domain, wherein three to twelve of the binding domains are identical and specifically bind to a human coronavirus, and wherein the binding molecule is more potent than a bivalent reference IgG antibody comprising two of the binding domains that specifically bind to the human coronavirus.

Embodiment 2. The multimeric binding molecule of embodiment 1, wherein the human coronavirus is SARS-CoV, MERS-CoV, SARS-CoV-2, variants thereof, derivatives thereof, or any combination thereof.

Embodiment 3. The multimeric binding molecule of embodiment 1 or embodiment 2, wherein the binding molecule can neutralize infectivity of the human coronavirus at a greater potency than the bivalent reference IgG antibody comprising two of the binding domains that specifically bind to the human coronavirus.

Embodiment 4. The multimeric binding molecule of embodiment 3, wherein the binding molecule can neutralize infectivity of the human coronavirus at a lower 50% effective concentration (EC50) than the bivalent reference IgG antibody.

Embodiment 5. The multimeric binding molecule of embodiment 4, wherein the EC50 is at least two-fold, at least five-fold, at least ten-fold, at least fifty-fold, at least 100-fold, at least 500-fold, or at least 1000-fold lower than the EC50 of the bivalent reference IgG antibody.

Embodiment 6. The multimeric binding molecule of embodiment 1 or embodiment 2, wherein the binding molecule can inhibit binding of the human coronavirus to its receptor at a lower 50% inhibitory concentration (IC50) than the bivalent reference IgG antibody.

Embodiment 7. The multimeric binding molecule of embodiment 6, wherein the human coronavirus is SARS-CoV or SARS-CoV-2 and the receptor is human angiotensin-converting enzyme 2 (ACE2), or wherein the human coronavirus is MERS-CoV and the receptor is human dipeptidyl-peptidase 4 (DPP4).

Embodiment 8. The multimeric binding molecule of any one of embodiments 1 to 7, wherein the three to twelve binding domains that specifically bind to a human coronavirus bind a human coronavirus structural protein or fragment thereof.

Embodiment 9. The multimeric binding molecule of embodiment 8, wherein the human coronavirus structural protein comprises a nucleocapsid (N) protein, a membrane (M) protein, an envelope (E) protein, a spike (S) protein, any fragment thereof, any subunit thereof, or any combination thereof.

Embodiment 10. The multimeric binding molecule of embodiment 9, wherein the human coronavirus structural protein comprises the S protein, a fragment thereof, or a subunit thereof.

Embodiment 11. The multimeric binding molecule of embodiment 10, wherein the three to twelve binding domains that specifically bind to the human coronavirus S protein bind the S protein subunit 1 (S1), the S protein receptor binding domain (RBD), the S protein subunit 2 (S2), the S protein furin cleavage site, or any combination thereof.

Embodiment 12. The multimeric binding molecule of embodiment 11, wherein the three to twelve binding domains that specifically bind to the human coronavirus S protein bind the S protein RBD.

Embodiment 13. The multimeric binding molecule of any one of embodiments 1 to 12, wherein the three to twelve identical binding domains are immunoglobulin antigen binding domains comprising a heavy chain variable region (VH) and a light chain variable region (VL).

Embodiment 14. The multimeric binding molecule of embodiment 13, wherein each binding unit comprises two heavy chains each comprising a VH and two light chains each comprising a VL.

Embodiment 15. The multimeric binding molecule of embodiment 13 or embodiment 14, wherein the immunoglobulin antigen-binding domains are human or humanized antigen binding domains.

Embodiment 16. The multimeric binding molecule of any one of embodiments 1 to 12, wherein the three to twelve identical binding domains are single-domain variable regions (VHH), and wherein each binding unit comprises two heavy chains each comprising the VHH.

Embodiment 17. The multimeric binding molecule of any one of embodiments 1 to 16, wherein the human coronavirus is SARS-CoV-2.

Embodiment 18. The multimeric binding molecule of embodiment 17, wherein the three to twelve identical binding domains each specifically bind to SARS-CoV-2 and comprise a heavy chain variable region (VH) and a light chain variable region (VL), wherein the VH and VL comprise six immunoglobulin complementarity determining regions HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3, and wherein the HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 comprise the CDRs of an antibody comprising the VH and VL of SEQ ID NO: 84 and SEQ ID NO: 85, SEQ ID NO: 86 and SEQ ID NO: 87, SEQ ID NO: 88 and SEQ ID NO: 89, SEQ ID NO: 90 and SEQ ID NO: 91, SEQ ID NO: 92 and SEQ ID NO: 93, SEQ ID NO: 94 and SEQ ID NO: 95, SEQ ID NO: 96 and SEQ ID NO: 97, SEQ ID NO: 98 and SEQ ID NO: 99, SEQ ID NO: 100 and SEQ ID NO: 101, SEQ ID NO: 102 and SEQ ID NO: 103, SEQ ID NO: 104 and SEQ ID NO: 105, SEQ ID NO: 106 and SEQ ID NO: 107, SEQ ID NO: 108 and SEQ ID NO: 109, SEQ ID NO: 110 and SEQ ID NO: 111, SEQ ID NO: 112 and SEQ ID NO: 113, SEQ ID NO: 114 and SEQ ID NO: 115, SEQ ID NO: 116 and SEQ ID NO: 117, SEQ ID NO: 118 and SEQ ID NO: 119, SEQ ID NO: 120 and SEQ ID NO: 121, SEQ ID NO: 122 and SEQ ID NO: 123, SEQ ID NO: 124 and SEQ ID NO: 125, SEQ ID NO: 126 and SEQ ID NO: 127, SEQ ID NO: 128 and SEQ ID NO: 129, SEQ ID NO: 130 and SEQ ID NO: 131, SEQ ID NO: 132 and SEQ ID NO: 133, SEQ ID NO: 134 and SEQ ID NO: 135, SEQ ID NO: 136 and SEQ ID NO: 137, SEQ ID NO: 138 and SEQ ID NO: 139, SEQ ID NO: 140 and SEQ ID NO: 141, SEQ ID NO: 142 and SEQ ID NO: 143, SEQ ID NO: 144 and SEQ ID NO: 145, SEQ ID NO: 146 and SEQ ID NO: 147, SEQ ID NO: 148 and SEQ ID NO: 149, SEQ ID NO: 150 and SEQ ID NO: 151, SEQ ID NO: 152 and SEQ ID NO: 153, SEQ ID NO: 154 and SEQ ID NO: 155, SEQ ID NO: 156 and SEQ ID NO: 157, SEQ ID NO: 158 and SEQ ID NO: 159, SEQ ID NO: 160 and SEQ ID NO: 161, SEQ ID NO: 162 and SEQ ID NO: 163, SEQ ID NO: 164 and SEQ ID NO: 165, SEQ ID NO: 166 and SEQ ID NO: 167, SEQ ID NO: 168 and SEQ ID NO: 169, SEQ ID NO: 170 and SEQ ID NO: 171, SEQ ID NO: 172 and SEQ ID NO: 173, SEQ ID NO: 174 and SEQ ID NO: 175, SEQ ID NO: 176 and SEQ ID NO: 177, SEQ ID NO: 178 and SEQ ID NO: 179, SEQ ID NO: 180 and SEQ ID NO: 181, SEQ ID NO: 182 and SEQ ID NO: 183, SEQ ID NO: 184 and SEQ ID NO: 185, SEQ ID NO: 186 and SEQ ID NO: 187, SEQ ID NO: 188 and SEQ ID NO: 189, SEQ ID NO: 190 and SEQ ID NO: 191, SEQ ID NO: 192 and SEQ ID NO: 193, SEQ ID NO: 194 and SEQ ID NO: 195, SEQ ID NO: 196 and SEQ ID NO: 197, SEQ ID NO: 198 and SEQ ID NO: 199, SEQ ID NO: 200 and SEQ ID NO: 201, SEQ ID NO: 202 and SEQ ID NO: 203, SEQ ID NO: 204 and SEQ ID NO: 205, SEQ ID NO: 206 and SEQ ID NO: 207, SEQ ID NO: 208 and SEQ ID NO: 209, SEQ ID NO: 210 and SEQ ID NO: 211, SEQ ID NO: 212 and SEQ ID NO: 213, SEQ ID NO: 214 and SEQ ID NO: 215, SEQ ID NO: 216 and SEQ ID NO: 217, SEQ ID NO: 218 and SEQ ID NO: 219, SEQ ID NO: 220 and SEQ ID NO: 221, SEQ ID NO: 222 and SEQ ID NO: 223, SEQ ID NO: 224 and SEQ ID NO: 225, SEQ ID NO: 226 and SEQ ID NO: 227, SEQ ID NO: 228 and SEQ ID NO: 229, SEQ ID NO: 230 and SEQ ID NO: 231, SEQ ID NO: 232 and SEQ ID NO: 233, SEQ ID NO: 234 and SEQ ID NO: 235, SEQ ID NO: 236 and SEQ ID NO: 237, SEQ ID NO: 238 and SEQ ID NO: 239, SEQ ID NO: 240 and SEQ ID NO: 241, SEQ ID NO: 242 and SEQ ID NO: 243, SEQ ID NO: 244 and SEQ ID NO: 245, SEQ ID NO: 246 and SEQ ID NO: 247, SEQ ID NO: 248 and SEQ ID NO: 249, SEQ ID NO: 250 and SEQ ID NO: 251, SEQ ID NO: 252 and SEQ ID NO: 253, SEQ ID NO: 254 and SEQ ID NO: 255, SEQ ID NO: 256 and SEQ ID NO: 257, SEQ ID NO: 258 and SEQ ID NO: 259, SEQ ID NO: 260 and SEQ ID NO: 261, SEQ ID NO: 264 and SEQ ID NO: 265, SEQ ID NO: 266 and SEQ ID NO: 267, SEQ ID NO: 268 and SEQ ID NO: 269, SEQ ID NO: 270 and SEQ ID NO: 271, SEQ ID NO: 272 and SEQ ID NO: 273, SEQ ID NO: 274 and SEQ ID NO: 275, SEQ ID NO: 276 and SEQ ID NO: 277, SEQ ID NO: 278 and SEQ ID NO: 279, SEQ ID NO: 280 and SEQ ID NO: 281, SEQ ID NO: 282 and SEQ ID NO: 283, SEQ ID NO: 292 and SEQ ID NO: 293, SEQ ID NO: 294 and SEQ ID NO: 295, SEQ ID NO: 296 and SEQ ID NO: 297, SEQ ID NO: 298 and SEQ ID NO: 299, SEQ ID NO: 300 and SEQ ID NO: 301, SEQ ID NO: 302 and SEQ ID NO: 303, SEQ ID NO: 304 and SEQ ID NO: 305, SEQ ID NO: 306 and SEQ ID NO: 307, SEQ ID NO: 308 and SEQ ID NO: 309, SEQ ID NO: 310 and SEQ ID NO: 311, SEQ ID NO: 312 and SEQ ID NO: 313, SEQ ID NO: 314 and SEQ ID NO: 315, SEQ ID NO: 316 and SEQ ID NO: 317, SEQ ID NO: 318 and SEQ ID NO: 319, SEQ ID NO: 320 and SEQ ID NO: 321, SEQ ID NO: 322 and SEQ ID NO: 323, SEQ ID NO: 324 and SEQ ID NO: 325, SEQ ID NO: 326 and SEQ ID NO: 327, SEQ ID NO: 328 and SEQ ID NO: 329, SEQ ID NO: 330 and SEQ ID NO: 331, SEQ ID NO: 332 and SEQ ID NO: 333, SEQ ID NO: 336 and SEQ ID NO: 337, SEQ ID NO: 338 and SEQ ID NO: 339, SEQ ID NO: 340 and SEQ ID NO: 341, SEQ ID NO: 342 and SEQ ID NO: 343, SEQ ID NO: 344 and SEQ ID NO: 345, SEQ ID NO: 348 and SEQ ID NO: 349, SEQ ID NO: 350 and SEQ ID NO: 351, SEQ ID NO: 352 and SEQ ID NO: 353, SEQ ID NO: 354 and SEQ ID NO: 355, SEQ ID NO: 356 and SEQ ID NO: 357, SEQ ID NO: 358 and SEQ ID NO: 359, SEQ ID NO: 362 and SEQ ID NO: 363, SEQ ID NO: 364 and SEQ ID NO: 365, SEQ ID NO: 366 and SEQ ID NO: 367, SEQ ID NO: 368 and SEQ ID NO: 369, SEQ ID NO: 370 and SEQ ID NO: 371, SEQ ID NO: 372 and SEQ ID NO: 373, SEQ ID NO: 374 and SEQ ID NO: 375, SEQ ID NO: 376 and SEQ ID NO: 377, SEQ ID NO: 378 and SEQ ID NO: 379, SEQ ID NO: 380 and SEQ ID NO: 381, SEQ ID NO: 382 and SEQ ID NO: 383, SEQ ID NO: 384 and SEQ ID NO: 385, SEQ ID NO: 386 and SEQ ID NO: 387, SEQ ID NO: 388 and SEQ ID NO: 389, SEQ ID NO: 390 and SEQ ID NO: 391, SEQ ID NO: 392 and SEQ ID NO: 393, SEQ ID NO: 394 and SEQ ID NO: 395, SEQ ID NO: 396 and SEQ ID NO: 397, SEQ ID NO: 398 and SEQ ID NO: 399, SEQ ID NO: 400 and SEQ ID NO: 401, SEQ ID NO: 402 and SEQ ID NO: 403, SEQ ID NO: 404 and SEQ ID NO: 405, SEQ ID NO: 406 and SEQ ID NO: 407, SEQ ID NO: 408 and SEQ ID NO: 409, SEQ ID NO: 410 and SEQ ID NO: 411, SEQ ID NO: 412 and SEQ ID NO: 413, SEQ ID NO: 414 and SEQ ID NO: 415, SEQ ID NO: 416 and SEQ ID NO: 417, SEQ ID NO: 418 and SEQ ID NO: 419, SEQ ID NO: 420 and SEQ ID NO: 421, SEQ ID NO: 422 and SEQ ID NO: 423, SEQ ID NO: 424 and SEQ ID NO: 425, SEQ ID NO: 426 and SEQ ID NO: 427, SEQ ID NO: 428 and SEQ ID NO: 429, SEQ ID NO: 430 and SEQ ID NO: 431, SEQ ID NO: 432 and SEQ ID NO: 433, SEQ ID NO: 434 and SEQ ID NO: 435, SEQ ID NO: 436 and SEQ ID NO: 437, SEQ ID NO: 438 and SEQ ID NO: 439, SEQ ID NO: 440 and SEQ ID NO: 441, SEQ ID NO: 442 and SEQ ID NO: 443, SEQ ID NO: 444 and SEQ ID NO: 445, SEQ ID NO: 446 and SEQ ID NO: 447, SEQ ID NO: 448 and SEQ ID NO: 449, SEQ ID NO: 450 and SEQ ID NO: 451, SEQ ID NO: 452 and SEQ ID NO: 453, SEQ ID NO: 454 and SEQ ID NO: 455, SEQ ID NO: 456 and SEQ ID NO: 457, SEQ ID NO: 458 and SEQ ID NO: 459, SEQ ID NO: 460 and SEQ ID NO: 461, SEQ ID NO: 462 and SEQ ID NO: 463, SEQ ID NO: 464 and SEQ ID NO: 465, SEQ ID NO: 466 and SEQ ID NO: 467, SEQ ID NO: 468 and SEQ ID NO: 469, SEQ ID NO: 470 and SEQ ID NO: 471, SEQ ID NO: 472 and SEQ ID NO: 473, SEQ ID NO: 474 and SEQ ID NO: 475, SEQ ID NO: 476 and SEQ ID NO: 477, SEQ ID NO: 478 and SEQ ID NO: 479, SEQ ID NO: 480 and SEQ ID NO: 481, SEQ ID NO: 482 and SEQ ID NO: 483, SEQ ID NO: 484 and SEQ ID NO: 485, SEQ ID NO: 486 and SEQ ID NO: 487, SEQ ID NO: 488 and SEQ ID NO: 489, SEQ ID NO: 490 and SEQ ID NO: 491, SEQ ID NO: 492 and SEQ ID NO: 493, SEQ ID NO: 494 and SEQ ID NO: 495, SEQ ID NO: 496 and SEQ ID NO: 497, SEQ ID NO: 498 and SEQ ID NO: 499, SEQ ID NO: 500 and SEQ ID NO: 501, SEQ ID NO: 502 and SEQ ID NO: 503, SEQ ID NO: 504 and SEQ ID NO: 505, SEQ ID NO: 506 and SEQ ID NO: 507, SEQ ID NO: 508 and SEQ ID NO: 509, SEQ ID NO: 628 and SEQ ID NO: 629, SEQ ID NO: 630 and SEQ ID NO: 631, SEQ ID NO: 632 and SEQ ID NO: 633, SEQ ID NO: 634 and SEQ ID NO: 635, SEQ ID NO: 636 and SEQ ID NO: 637, SEQ ID NO: 638 and SEQ ID NO: 639, SEQ ID NO: 640 and SEQ ID NO: 641, SEQ ID NO: 642 and SEQ ID NO: 643, SEQ ID NO: 644 and SEQ ID NO: 645, SEQ ID NO: 646 and SEQ ID NO: 647, SEQ ID NO: 648 and SEQ ID NO: 649, SEQ ID NO: 650 and SEQ ID NO: 651, or SEQ ID NO: 652 and SEQ ID NO: 653, respectively with zero, one, or two single amino acid substitutions in one or more of the HCDRs or LCDRs.

Embodiment 19. The multimeric binding molecule of embodiment 18, wherein the VH and VL comprise amino acid sequences at least 80%, at least 85%, at least 90%, at least 95% or 100% identical to the recited VH and VL amino acid sequences, respectively.

Embodiment 20. The multimeric binding molecule of embodiment 18, wherein the VH and VL comprise six immunoglobulin complementarity determining regions HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3, and wherein the HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 comprise the CDRs of an antibody comprising the VH and VL of SEQ ID NO: 86 and SEQ ID NO: 87, SEQ ID NO: 88 and SEQ ID NO: 89, SEQ ID NO: 90 and SEQ ID NO: 91, SEQ ID NO: 92 and SEQ ID NO: 93, SEQ ID NO: 94 and SEQ ID NO: 95, SEQ ID NO: 96 and SEQ ID NO: 97, SEQ ID NO: 98 and SEQ ID NO: 99, SEQ ID NO: 100 and SEQ ID NO: 101, SEQ ID NO: 102 and SEQ ID NO: 103, SEQ ID NO: 106 and SEQ ID NO: 107, SEQ ID NO: 110 and SEQ ID NO: 111, SEQ ID NO: 118 and SEQ ID NO: 119, SEQ ID NO: 128 and SEQ ID NO: 129, SEQ ID NO: 130 and SEQ ID NO: 131, SEQ ID NO: 132 and SEQ ID NO: 133, SEQ ID NO: 134 and SEQ ID NO: 135, SEQ ID NO: 136 and SEQ ID NO: 137, SEQ ID NO: 142 and SEQ ID NO: 143, SEQ ID NO: 146 and SEQ ID NO: 147, SEQ ID NO: 150 and SEQ ID NO: 151, SEQ ID NO: 156 and SEQ ID NO: 157, SEQ ID NO: 160 and SEQ ID NO: 161, SEQ ID NO: 162 and SEQ ID NO: 163, SEQ ID NO: 164 and SEQ ID NO: 165, SEQ ID NO: 166 and SEQ ID NO: 167, SEQ ID NO: 168 and SEQ ID NO: 169, SEQ ID NO: 170 and SEQ ID NO: 171, SEQ ID NO: 172 and SEQ ID NO: 173, SEQ ID NO: 174 and SEQ ID NO: 175, SEQ ID NO: 176 and SEQ ID NO: 177, SEQ ID NO: 180 and SEQ ID NO: 181, SEQ ID NO: 182 and SEQ ID NO: 183, SEQ ID NO: 186 and SEQ ID NO: 187, SEQ ID NO: 188 and SEQ ID NO: 189, SEQ ID NO: 194 and SEQ ID NO: 195, SEQ ID NO: 200 and SEQ ID NO: 201, SEQ ID NO: 206 and SEQ ID NO: 207, SEQ ID NO: 208 and SEQ ID NO: 209, SEQ ID NO: 218 and SEQ ID NO: 219, SEQ ID NO: 220 and SEQ ID NO: 221, SEQ ID NO: 222 and SEQ ID NO: 223, SEQ ID NO: 224 and SEQ ID NO: 225, SEQ ID NO: 228 and SEQ ID NO: 229, SEQ ID NO: 230 and SEQ ID NO: 231, SEQ ID NO: 240 and SEQ ID NO: 241, SEQ ID NO: 244 and SEQ ID NO: 245, SEQ ID NO: 246 and SEQ ID NO: 247, SEQ ID NO: 256 and SEQ ID NO: 257, SEQ ID NO: 258 and SEQ ID NO: 259, SEQ ID NO: 260 and SEQ ID NO: 261, SEQ ID NO: 264 and SEQ ID NO: 265, SEQ ID NO: 266 and SEQ ID NO: 267, SEQ ID NO: 268 and SEQ ID NO: 269, SEQ ID NO: 270 and SEQ ID NO: 271, SEQ ID NO: 272 and SEQ ID NO: 273, SEQ ID NO: 274 and SEQ ID NO: 275, SEQ ID NO: 276 and SEQ ID NO: 277, SEQ ID NO: 278 and SEQ ID NO: 279, SEQ ID NO: 280 and SEQ ID NO: 281, SEQ ID NO: 282 and SEQ ID NO: 283, SEQ ID NO: 292 and SEQ ID NO: 293, SEQ ID NO: 294 and SEQ ID NO: 295, SEQ ID NO: 296 and SEQ ID NO: 297, SEQ ID NO: 298 and SEQ ID NO: 299, SEQ ID NO: 300 and SEQ ID NO: 301, SEQ ID NO: 302 and SEQ ID NO: 303, SEQ ID NO: 304 and SEQ ID NO: 305, SEQ ID NO: 306 and SEQ ID NO: 307, SEQ ID NO: 308 and SEQ ID NO: 309, SEQ ID NO: 310 and SEQ ID NO: 311, SEQ ID NO: 312 and SEQ ID NO: 313, SEQ ID NO: 314 and SEQ ID NO: 315, SEQ ID NO: 316 and SEQ ID NO: 317, SEQ ID NO: 318 and SEQ ID NO: 319, SEQ ID NO: 320 and SEQ ID NO: 321, SEQ ID NO: 322 and SEQ ID NO: 323, SEQ ID NO: 324 and SEQ ID NO: 325, SEQ ID NO: 326 and SEQ ID NO: 327, SEQ ID NO: 328 and SEQ ID NO: 329, SEQ ID NO: 330 and SEQ ID NO: 331, SEQ ID NO: 332 and SEQ ID NO: 333, SEQ ID NO: 336 and SEQ ID NO: 337, SEQ ID NO: 338 and SEQ ID NO: 339, SEQ ID NO: 340 and SEQ ID NO: 341, SEQ ID NO: 342 and SEQ ID NO: 343, SEQ ID NO: 344 and SEQ ID NO: 345, SEQ ID NO: 348 and SEQ ID NO: 349, SEQ ID NO: 350 and SEQ ID NO: 351, SEQ ID NO: 352 and SEQ ID NO: 353, SEQ ID NO: 354 and SEQ ID NO: 355, SEQ ID NO: 356 and SEQ ID NO: 357, SEQ ID NO: 358 and SEQ ID NO: 359, SEQ ID NO: 360 and SEQ ID NO: 361, SEQ ID NO: 362 and SEQ ID NO: 363, SEQ ID NO: 364 and SEQ ID NO: 365, SEQ ID NO: 366 and SEQ ID NO: 367, SEQ ID NO: 368 and SEQ ID NO: 369, SEQ ID NO: 370 and SEQ ID NO: 371, SEQ ID NO: 372 and SEQ ID NO: 373, SEQ ID NO: 374 and SEQ ID NO: 375, SEQ ID NO: 376 and SEQ ID NO: 377, SEQ ID NO: 378 and SEQ ID NO: 379, SEQ ID NO: 380 and SEQ ID NO: 381, SEQ ID NO: 382 and SEQ ID NO: 383, SEQ ID NO: 384 and SEQ ID NO: 385, SEQ ID NO: 386 and SEQ ID NO: 387, SEQ ID NO: 388 and SEQ ID NO: 389, SEQ ID NO: 390 and SEQ ID NO: 391, SEQ ID NO: 392 and SEQ ID NO: 393, SEQ ID NO: 394 and SEQ ID NO: 395, SEQ ID NO: 396 and SEQ ID NO: 397, SEQ ID NO: 398 and SEQ ID NO: 399, SEQ ID NO: 400 and SEQ ID NO: 401, SEQ ID NO: 402 and SEQ ID NO: 403, SEQ ID NO: 404 and SEQ ID NO: 405, SEQ ID NO: 406 and SEQ ID NO: 407, SEQ ID NO: 408 and SEQ ID NO: 409, SEQ ID NO: 410 and SEQ ID NO: 411, SEQ ID NO: 412 and SEQ ID NO: 413, SEQ ID NO: 414 and SEQ ID NO: 415, SEQ ID NO: 416 and SEQ ID NO: 417, SEQ ID NO: 418 and SEQ ID NO: 419, SEQ ID NO: 420 and SEQ ID NO: 421, SEQ ID NO: 422 and SEQ ID NO: 423, SEQ ID NO: 424 and SEQ ID NO: 425, SEQ ID NO: 426 and SEQ ID NO: 427, SEQ ID NO: 428 and SEQ ID NO: 429, SEQ ID NO: 430 and SEQ ID NO: 431, SEQ ID NO: 432 and SEQ ID NO: 433, SEQ ID NO: 434 and SEQ ID NO: 435, SEQ ID NO: 436 and SEQ ID NO: 437, SEQ ID NO: 438 and SEQ ID NO: 439, SEQ ID NO: 440 and SEQ ID NO: 441, SEQ ID NO: 442 and SEQ ID NO: 443, SEQ ID NO: 444 and SEQ ID NO: 445, SEQ ID NO: 446 and SEQ ID NO: 447, SEQ ID NO: 448 and SEQ ID NO: 449, SEQ ID NO: 450 and SEQ ID NO: 451, SEQ ID NO: 452 and SEQ ID NO: 453, SEQ ID NO: 454 and SEQ ID NO: 455, SEQ ID NO: 456 and SEQ ID NO: 457, SEQ ID NO: 458 and SEQ ID NO: 459, SEQ ID NO: 460 and SEQ ID NO: 461, SEQ ID NO: 462 and SEQ ID NO: 463, SEQ ID NO: 464 and SEQ ID NO: 465, SEQ ID NO: 466 and SEQ ID NO: 467, SEQ ID NO: 468 and SEQ ID NO: 469, SEQ ID NO: 470 and SEQ ID NO: 471, SEQ ID NO: 472 and SEQ ID NO: 473, SEQ ID NO: 474 and SEQ ID NO: 475, SEQ ID NO: 476 and SEQ ID NO: 477, SEQ ID NO: 478 and SEQ ID NO: 479, SEQ ID NO: 480 and SEQ ID NO: 481, SEQ ID NO: 482 and SEQ ID NO: 483, SEQ ID NO: 484 and SEQ ID NO: 485, SEQ ID NO: 486 and SEQ ID NO: 487, SEQ ID NO: 488 and SEQ ID NO: 489, SEQ ID NO: 490 and SEQ ID NO: 491, SEQ ID NO: 492 and SEQ ID NO: 493, SEQ ID NO: 494 and SEQ ID NO: 495, SEQ ID NO: 496 and SEQ ID NO: 497, SEQ ID NO: 498 and SEQ ID NO: 499, SEQ ID NO: 500 and SEQ ID NO: 501, SEQ ID NO: 502 and SEQ ID NO: 503, SEQ ID NO: 504 and SEQ ID NO: 505, SEQ ID NO: 506 and SEQ ID NO: 507, SEQ ID NO: 508 and SEQ ID NO: 509, SEQ ID NO: 628 and SEQ ID NO: 629, SEQ ID NO: 632 and SEQ ID NO: 633, SEQ ID NO: 634 and SEQ ID NO: 635, SEQ ID NO: 636 and SEQ ID NO: 637, SEQ ID NO: 638 and SEQ ID NO: 639, SEQ ID NO: 640 and SEQ ID NO: 641, SEQ ID NO: 642 and SEQ ID NO: 643, SEQ ID NO: 644 and SEQ ID NO: 645, SEQ ID NO: 646 and SEQ ID NO: 647, SEQ ID NO: 648 and SEQ ID NO: 649, SEQ ID NO: 650 and SEQ ID NO: 651, or SEQ ID NO: 652 and SEQ ID NO: 653, respectively, with zero, one, or two single amino acid substitutions in one or more HCDRs or LCDRs.

Embodiment 21. The multimeric binding molecule of embodiment 20, wherein the HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 comprise the CDRs of an antibody comprising the VH and VL of SEQ ID NO: 88 and SEQ ID NO: 89.

Embodiment 22. The multimeric binding molecule of embodiment 20, wherein the HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 comprise the CDRs of an antibody comprising the VH and VL of SEQ ID NO: 260 and SEQ ID NO: 261.

Embodiment 23. The multimeric binding molecule of embodiment 20, wherein the HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 comprise the CDRs of an antibody comprising the VH and VL of SEQ ID NO: 264 and SEQ ID NO: 265.

Embodiment 24. The multimeric binding molecule of embodiment 20, wherein the HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 comprise the CDRs of an antibody comprising the VH and VL of SEQ ID NO: 266 and SEQ ID NO: 267.

Embodiment 25. The multimeric binding molecule of embodiment 20, wherein the HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 comprise the CDRs of an antibody comprising the VH and VL of SEQ ID NO: 274 and SEQ ID NO: 275, SEQ ID NO: 278, and SEQ ID NO: 279, SEQ ID NO: 280 and SEQ ID NO: 281, or SEQ ID NO: 282 and SEQ ID NO: 283.

Embodiment 26. The multimeric binding molecule of embodiment 20, wherein the HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 comprise the CDRs of an antibody comprising the VH and VL of SEQ ID NO: 292 and SEQ ID NO: 293.

Embodiment 27. The multimeric binding molecule of any one of embodiments 20 to 26, wherein the VH and VL comprise amino acid sequences at least 80%, at least 85%, at least 90%, at least 95% or 100% identical to the recited VH and VL amino acid sequences, respectively.

Embodiment 28. The multimeric binding molecule of any one of embodiments 20 to 27, wherein the bivalent reference IgG antibody comprising two of the binding domains can neutralize SARS-CoV-2.

Embodiment 29. The multimeric binding molecule of embodiment 20, wherein the VH and VL comprise six immunoglobulin complementarity determining regions HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3, and wherein the HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 comprise the CDRs of an antibody comprising the VH and VL of SEQ ID NO: 118 and SEQ ID NO: 119, SEQ ID NO: 162 and SEQ ID NO: 163, SEQ ID NO: 222 and SEQ ID NO: 223, SEQ ID NO: 260 and SEQ ID NO: 261, SEQ ID NO: 296 and SEQ ID NO: 297, SEQ ID NO: 384 and SEQ ID NO: 385, SEQ ID NO: 628 and SEQ ID NO: 629, SEQ ID NO: 632 and SEQ ID NO: 633, SEQ ID NO: 634 and SEQ ID NO: 635, SEQ ID NO: 636 and SEQ ID NO: 637, SEQ ID NO: 638 and SEQ ID NO: 639, SEQ ID NO: 640 and SEQ ID NO: 641, SEQ ID NO: 642 and SEQ ID NO: 643, SEQ ID NO: 644 and SEQ ID NO: 645, or SEQ ID NO: 646 and SEQ ID NO: 647, respectively.

Embodiment 30. The multimeric binding molecule of embodiment 29, wherein the VH and VL comprise amino acid sequences at least 80%, at least 85%, at least 90%, at least 95% or 100% identical to the recited VH and VL amino acid sequences, respectively.

Embodiment 31. The multimeric binding molecule of embodiment 29 or embodiment 30, wherein the bivalent reference IgG antibody comprising two of the binding domains can neutralize SARS-CoV-2 and specifically binds to SARS-CoV.

Embodiment 32. The multimeric binding molecule of embodiment 29, wherein the VH and VL comprise six immunoglobulin complementarity determining regions HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3, and wherein the HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 comprise the CDRs of an antibody comprising the VH and VL of SEQ ID NO: 260 and SEQ ID NO: 261, SEQ ID NO: 296 and SEQ ID NO: 297, SEQ ID NO: 384 and SEQ ID NO: 385, SEQ ID NO: 628 and SEQ ID NO: 629, SEQ ID NO: 632 and SEQ ID NO: 633, SEQ ID NO: 634 and SEQ ID NO: 635, SEQ ID NO: 636 and SEQ ID NO: 637, SEQ ID NO: 638 and SEQ ID NO: 639, SEQ ID NO: 640 and SEQ ID NO: 641, SEQ ID NO: 642 and SEQ ID NO: 643, SEQ ID NO: 644 and SEQ ID NO: 645, or SEQ ID NO: 646 and SEQ ID NO: 647, respectively.

Embodiment 33. The multimeric binding protein of embodiment 32, wherein the VH and VL comprise the CDRs of an antibody comprising the VH and VL of SEQ ID NO:384 and SEQ ID NO: 385.

Embodiment 34. The multimeric binding protein of embodiment 32, wherein the VH and VL comprise the CDRs of an antibody comprising the VH and VL of SEQ ID NO: 646 and SEQ ID NO: 647.

Embodiment 35. The multimeric binding molecule of any one of embodiments 32 to 34, wherein the VH and VL comprise amino acid sequences at least 80%, at least 85%, at least 90%, at least 95% or 100% identical to the recited VH and VL amino acid sequences, respectively.

Embodiment 36. The multimeric binding molecule of any one of embodiments 32 to 35, wherein the bivalent reference IgG antibody comprising two of the binding domains can neutralize SARS-CoV and SARS-CoV-2.

Embodiment 37. The multimeric binding molecule of embodiment 17, wherein the three to twelve identical binding domains each specifically bind to SARS-CoV-2 and comprise a single domain variable region (VHH), wherein the VHH comprises three immunoglobulin complementarity determining regions HCDR1, HCDR2, and HCDR3, wherein the HCDR1, HCDR2, and HCDR3 comprise the CDRs of an antibody comprising the VHH of SEQ ID NO: SEQ ID NO: 19, SEQ ID NO: 20, SEQ ID NO: 21, SEQ ID NO: 22, SEQ ID NO: 23, SEQ ID NO: 24, SEQ ID NO: 25, SEQ ID NO: 26, SEQ ID NO: 27, SEQ ID NO: 28, SEQ ID NO: 29, SEQ ID NO: 30, SEQ ID NO: 31, SEQ ID NO: 32, SEQ ID NO: 33, SEQ ID NO: 34, SEQ ID NO: 35, SEQ ID NO: 36, SEQ ID NO: 37, SEQ ID NO: 38, SEQ ID NO: 39, SEQ ID NO: 40, SEQ ID NO: 41, SEQ ID NO: 42, SEQ ID NO: 43, SEQ ID NO: 44, SEQ ID NO: 45, SEQ ID NO: 46, SEQ ID NO: 47, SEQ ID NO: 48, SEQ ID NO: 49, SEQ ID NO: 50, SEQ ID NO: 51, SEQ ID NO: 52, SEQ ID NO: 53, SEQ ID NO: 54, SEQ ID NO: 55, SEQ ID NO: 56, SEQ ID NO: 57, SEQ ID NO: 58, SEQ ID NO: 59, SEQ ID NO: 60, SEQ ID NO: 61, SEQ ID NO: 62, SEQ ID NO: 63, SEQ ID NO: 64, SEQ ID NO: 65, SEQ ID NO: 66, SEQ ID NO: 67, SEQ ID NO: 68, SEQ ID NO: 69, SEQ ID NO: 70, SEQ ID NO: 71, SEQ ID NO: 72, SEQ ID NO: 73, SEQ ID NO: 74, SEQ ID NO: 75, SEQ ID NO: 76, SEQ ID NO: 77, SEQ ID NO: 78, SEQ ID NO: 79, SEQ ID NO: 80, SEQ ID NO: 81, SEQ ID NO: 82, or SEQ ID NO:83, with zero, one, or two single amino acid substitutions in one or more of the HCDRs.

Embodiment 38. The multimeric binding molecule of embodiment 37, wherein the VHH comprises an amino acid sequence at least 80%, at least 85%, at least 90%, at least 95% or 100% identical to the recited VHH amino acid sequence.

Embodiment 39. The multimeric binding molecule of any one of embodiments 1 to 11, wherein the three to twelve identical binding domains of the multimeric binding molecule that specifically bind to a human coronavirus comprise an extracellular SARS-CoV-2 RBD-binding fragment of angiotensin-converting enzyme 2 (ACE2).

Embodiment 40. The multimeric binding molecule of any one of embodiments 1 to 16, wherein the human coronavirus is SARS-CoV.

Embodiment 41. The multimeric binding molecule of embodiment 40, wherein the three to twelve identical binding domains each specifically bind to SARS-CoV and comprise a heavy chain variable region (VH) and a light chain variable region (VL), wherein the VH and VL comprise six immunoglobulin complementarity determining regions HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3, and wherein the HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 comprise the CDRs of an antibody comprising the VH and VL SEQ ID NO: 84 and SEQ ID NO: 85, SEQ ID NO: 118 and SEQ ID NO: 119, SEQ ID NO: 120 and SEQ ID NO: 121, SEQ ID NO: 138 and SEQ ID NO: 139, SEQ ID NO: 162 and SEQ ID NO: 163, SEQ ID NO: 222 and SEQ ID NO: 223, SEQ ID NO: 236 and SEQ ID NO: 237, SEQ ID NO: 252 and SEQ ID NO: 253, SEQ ID NO: 260 and SEQ ID NO: 261, SEQ ID NO: 262 and SEQ ID NO: 263, SEQ ID NO: 296 and SEQ ID NO: 297, SEQ ID NO: 628 and SEQ ID NO: 629, SEQ ID NO: 632 and SEQ ID NO: 633, SEQ ID NO: 634 and SEQ ID NO: 635, SEQ ID NO: 636 and SEQ ID NO: 637, SEQ ID NO: 638 and SEQ ID NO: 639, SEQ ID NO: 640 and SEQ ID NO: 641, SEQ ID NO: 642 and SEQ ID NO: 643, or SEQ ID NO: 644 and SEQ ID NO: 645.

Embodiment 42. The multimeric binding molecule of embodiment 41, wherein the VH and VL comprise amino acid sequences at least 80%, at least 85%, at least 90%, at least 95% or 100% identical to the recited VH and VL amino acid sequences, respectively.

Embodiment 43. The multimeric binding molecule of embodiment 41, wherein the VH and VL comprise six immunoglobulin complementarity determining regions HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3, wherein the HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 comprise the CDRs of an antibody comprising the VH and VL of SEQ ID NO: 84 and SEQ ID NO: 85, SEQ ID NO: 260 and SEQ ID NO: 261, SEQ ID NO: 262 and SEQ ID NO: 263, SEQ ID NO: 296 and SEQ ID NO: 297, SEQ ID NO: 628 and SEQ ID NO: 629, SEQ ID NO: 632 and SEQ ID NO: 633, SEQ ID NO: 634 and SEQ ID NO: 635, SEQ ID NO: 636 and SEQ ID NO: 637, SEQ ID NO: 638 and SEQ ID NO: 639, SEQ ID NO: 640 and SEQ ID NO: 641, SEQ ID NO: 642 and SEQ ID NO: 643, or SEQ ID NO: 644 and SEQ ID NO: 645.

Embodiment 44. The multimeric binding molecule of embodiment 43, wherein the VH and VL comprise amino acid sequences at least 80%, at least 85%, at least 90%, at least 95% or 100% identical to the recited VH and VL amino acid sequences, respectively.

Embodiment 45. The multimeric binding molecule of embodiment 43 or embodiment 44, wherein the bivalent reference IgG antibody comprising two of the binding domains can neutralize SARS-CoV.

Embodiment 46. The multimeric binding molecule of any one of embodiments 1 to 16, wherein the human coronavirus is MERS-CoV.

Embodiment 47. The multimeric binding molecule of embodiment 46, wherein the three to twelve identical binding domains each specifically bind to MERS-CoV and comprise a heavy chain variable region (VH) and a light chain variable region (VL), wherein the VH and VL comprise six immunoglobulin complementarity determining regions HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3, and wherein the HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 comprise the CDRs of an antibody comprising the VH and VL SEQ ID NO:510 and SEQ ID NO:511, SEQ ID NO:512 and SEQ ID NO:513, SEQ ID NO:514 and SEQ ID NO:515, SEQ ID NO:516 and SEQ ID NO:517, SEQ ID NO:518 and SEQ ID NO:519, SEQ ID NO:520 and SEQ ID NO:521, SEQ ID NO:522 and SEQ ID NO:523, SEQ ID NO:524 and SEQ ID NO:525, SEQ ID NO:526 and SEQ ID NO:527, SEQ ID NO:528 and SEQ ID NO:529, SEQ ID NO:530 and SEQ ID NO:531, SEQ ID NO:532 and SEQ ID NO:533, SEQ ID NO:534 and SEQ ID NO:535, SEQ ID NO:536 and SEQ ID NO:537, SEQ ID NO:538 and SEQ ID NO:539, SEQ ID NO:540 and SEQ ID NO:541, SEQ ID NO:542 and SEQ ID NO:543, SEQ ID NO:544 and SEQ ID NO:545, SEQ ID NO:546 and SEQ ID NO:547, SEQ ID NO:548 and SEQ ID NO:549, SEQ ID NO:550 and SEQ ID NO:551, SEQ ID NO:552 and SEQ ID NO:553, SEQ ID NO:554 and SEQ ID NO:555, SEQ ID NO:556 and SEQ ID NO:557, SEQ ID NO:558 and SEQ ID NO:559, SEQ ID NO:560 and SEQ ID NO:561, SEQ ID NO:562 and SEQ ID NO:563, SEQ ID NO:564 and SEQ ID NO:565, SEQ ID NO:566 and SEQ ID NO:567, SEQ ID NO:568 and SEQ ID NO:569, SEQ ID NO:570 and SEQ ID NO:571, SEQ ID NO:572 and SEQ ID NO:573, SEQ ID NO:574 and SEQ ID NO:575, SEQ ID NO:576 and SEQ ID NO:577, SEQ ID NO:578 and SEQ ID NO:579, SEQ ID NO:580 and SEQ ID NO:581, SEQ ID NO:582 and SEQ ID NO:583, SEQ ID NO:584 and SEQ ID NO:585, SEQ ID NO:586 and SEQ ID NO:587, SEQ ID NO:588 and SEQ ID NO:589, SEQ ID NO:590 and SEQ ID NO:591, SEQ ID NO:592 and SEQ ID NO:593, SEQ ID NO:594 and SEQ ID NO:595, SEQ ID NO:596 and SEQ ID NO:597, SEQ ID NO:598 and SEQ ID NO:599, SEQ ID NO:600 and SEQ ID NO:601, SEQ ID NO:602 and SEQ ID NO:603, SEQ ID NO:604 and SEQ ID NO:605, SEQ ID NO:606 and SEQ ID NO:607, SEQ ID NO:608 and SEQ ID NO:609, SEQ ID NO:610 and SEQ ID NO:611, SEQ ID NO:612 and SEQ ID NO:613, SEQ ID NO:614 and SEQ ID NO:615, SEQ ID NO:616 and SEQ ID NO:617, SEQ ID NO:618 and SEQ ID NO:619, SEQ ID NO:620 and SEQ ID NO:621, SEQ ID NO:622 and SEQ ID NO:623, SEQ ID NO:624 and SEQ ID NO:625, SEQ ID NO:626 and SEQ ID NO:627, or SEQ ID NO:630 and SQ ID NO:631, respectively, with zero, one, or two single amino acid substitutions in one or more of the HCDRs or LCDRs.

Embodiment 48. The multimeric binding molecule of embodiment 47, wherein the VH and VL comprise amino acid sequences at least 80%, at least 85%, at least 90%, at least 95% or 100% identical to the recited VH and VL amino acid sequences, respectively.

Embodiment 49. The multimeric binding molecule of any of embodiment 47, wherein the HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 comprise the CDRs of an antibody comprising the VH and VL of SEQ ID NO: 510 and SEQ ID NO: 511, SEQ ID NO: 512 and SEQ ID NO: 513, SEQ ID NO: 514 and SEQ ID NO: 515, SEQ ID NO: 516 and SEQ ID NO: 517, SEQ ID NO: 518 and SEQ ID NO: 519, SEQ ID NO: 520 and SEQ ID NO: 521, SEQ ID NO: 522 and SEQ ID NO: 523, SEQ ID NO: 524 and SEQ ID NO: 525, SEQ ID NO: 526 and SEQ ID NO: 527, SEQ ID NO: 528 and SEQ ID NO: 529, SEQ ID NO: 530 and SEQ ID NO: 531, SEQ ID NO: 532 and SEQ ID NO: 533, SEQ ID NO: 534 and SEQ ID NO: 535, SEQ ID NO: 536 and SEQ ID NO: 537, SEQ ID NO: 538 and SEQ ID NO: 539, SEQ ID NO: 540 and SEQ ID NO: 541, SEQ ID NO: 542 and SEQ ID NO: 543, SEQ ID NO: 544 and SEQ ID NO: 545, SEQ ID NO: 546 and SEQ ID NO: 547, SEQ ID NO: 548 and SEQ ID NO: 549, SEQ ID NO: 550 and SEQ ID NO: 551, SEQ ID NO: 552 and SEQ ID NO: 553, SEQ ID NO: 554 and SEQ ID NO: 555, SEQ ID NO: 556 and SEQ ID NO: 557, SEQ ID NO: 558 and SEQ ID NO: 559, SEQ ID NO: 560 and SEQ ID NO: 561, SEQ ID NO: 562 and SEQ ID NO: 563, SEQ ID NO: 564 and SEQ ID NO: 565, SEQ ID NO: 566 and SEQ ID NO: 567, SEQ ID NO: 568 and SEQ ID NO: 569, SEQ ID NO: 574 and SEQ ID NO: 575, SEQ ID NO: 576 and SEQ ID NO: 577, SEQ ID NO: 578 and SEQ ID NO: 579, SEQ ID NO: 580 and SEQ ID NO: 581, SEQ ID NO: 582 and SEQ ID NO: 583, SEQ ID NO: 584 and SEQ ID NO: 585, SEQ ID NO: 586 and SEQ ID NO: 587, SEQ ID NO: 588 and SEQ ID NO: 589, SEQ ID NO: 590 and SEQ ID NO: 591, SEQ ID NO: 592 and SEQ ID NO: 593, SEQ ID NO: 594 and SEQ ID NO: 595, SEQ ID NO: 596 and SEQ ID NO: 597, SEQ ID NO: 598 and SEQ ID NO: 599, SEQ ID NO: 600 and SEQ ID NO: 601, SEQ ID NO: 602 and SEQ ID NO: 603, SEQ ID NO: 604 and SEQ ID NO: 605, SEQ ID NO: 606 and SEQ ID NO: 607, SEQ ID NO: 608 and SEQ ID NO: 609, SEQ ID NO: 610 and SEQ ID NO: 611, SEQ ID NO: 612 and SEQ ID NO: 613, SEQ ID NO: 614 and SEQ ID NO: 615, SEQ ID NO: 616 and SEQ ID NO: 617, SEQ ID NO: 618 and SEQ ID NO: 619, SEQ ID NO: 620 and SEQ ID NO: 621, SEQ ID NO: 622 and SEQ ID NO: 623, SEQ ID NO: 624 and SEQ ID NO: 625, SEQ ID NO: 626 and SEQ ID NO: 627, or SEQ ID NO: 630 and SEQ ID NO: 631, respectively.

Embodiment 50. The multimeric binding molecule of any of embodiment 49, wherein the HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 comprise the CDRs of an antibody comprising the VH and VL of SEQ ID NO: 522 and SEQ ID NO: 523, SEQ ID NO: 576 and SEQ ID NO: 577, SEQ ID NO: 610 and SEQ ID NO: 611, SEQ ID NO: 612 and SEQ ID NO: 613, SEQ ID NO: 614 and SEQ ID NO: 615, or SEQ ID NO: 630 and SEQ ID NO: 631, respectively.

Embodiment 51. The multimeric binding molecule of embodiment 49 or embodiment 50, wherein the VH and VL comprise amino acid sequences at least 80%, at least 85%, at least 90%, at least 95% or 100% identical to the recited VH and VL amino acid sequences, respectively.

Embodiment 52. The multimeric binding molecule of any one of embodiments 49 to 51, wherein the bivalent reference IgG antibody comprising two of the binding domains can neutralize MERS-CoV.

Embodiment 53. The multimeric binding molecule of embodiment 46, wherein the three to twelve identical binding domains of the multimeric binding molecule comprise an extracellular MERS-CoV RBD-binding fragment of dipeptidyl peptidase 4 (DPP4).

Embodiment 54. The multimeric binding molecule of any one of embodiments 1 to 53, which can neutralize escape mutants of the bivalent reference IgG antibody comprising two of the binding domains.

Embodiment 55. The multimeric binding molecule of any one of embodiments 1 to 54, comprising two or four bivalent IgA or IgA-like binding units and a J chain or functional fragment or variant thereof, wherein each binding unit comprises two IgA heavy chain constant regions or multimerizing fragments or variants thereof, each comprising an IgA Cα3 domain and an IgA tailpiece domain.

Embodiment 56. The multimeric binding molecule of embodiment 55, which is a dimeric binding molecule comprising two bivalent IgA or IgA-like binding units.

Embodiment 57. The multimeric binding molecule of embodiment 55 or embodiment 56, wherein each IgA heavy chain constant region or multimerizing fragment or variant thereof further comprises a Cα1 domain, a Cα2 domain, an IgA hinge region, or any combination thereof.

Embodiment 58. The multimeric binding molecule of any one of embodiments 55 to 57, wherein the IgA heavy chain constant regions or multimerizing fragments or variants thereof are human IgA constant regions.

Embodiment 59. The multimeric binding molecule of any one of embodiments 55 to 58, wherein each binding unit comprises two IgA heavy chains each comprising a VH situated amino terminal to the IgA constant region or multimerizing fragment thereof, and two immunoglobulin light chains each comprising a VL situated amino terminal to an immunoglobulin light chain constant region.

Embodiment 60. The multimeric binding molecule of any one of embodiments 1 to 54, comprising five or six bivalent IgM or IgM-like binding units, wherein each binding unit comprises two IgM heavy chain constant regions or multimerizing fragments or variants thereof, each comprising an IgM Cμ4 and IgM tailpiece domain.

Embodiment 61. The multimeric binding molecule of embodiment 60, wherein each IgM heavy chain constant region or multimerizing fragment or variant thereof further comprises a Cμ1 domain, a Cμ2 domain, a Cμ3 domain, or any combination thereof.

Embodiment 62. The multimeric binding molecule of embodiment 60 or embodiment 61, wherein the IgM heavy chain constant regions or multimerizing fragments or variants thereof are human IgM constant regions.

Embodiment 63. The multimeric binding molecule of embodiment 62, wherein the IgM heavy chain constant regions each comprise the amino acid sequence SEQ ID NO: 1, SEQ ID NO: 2, or a multimerizing fragment or variant thereof.

Embodiment 64. The multimeric binding molecule of any one of embodiments 60 to 63, wherein each binding unit comprises two IgM heavy chains each comprising a VH situated amino terminal to the IgM constant region or fragment thereof, and two immunoglobulin light chains each comprising a VL situated amino terminal to an immunoglobulin light chain constant region.

Embodiment 65. The multimeric binding molecule of any one of embodiments 60 to 63, wherein the IgM constant regions each comprise one or more amino acid substitutions corresponding to a wild-type human IgM constant region at position 310, 311, 313, and/or 315 of SEQ ID NO: 1 or SEQ ID NO: 2, and wherein the multimeric binding molecule exhibits reduced complement-dependent cytotoxicity (CDC) activity to cells in the presence of complement, relative to a reference binding molecule that is identical except for the one or more amino acid substitutions.

Embodiment 66. The multimeric binding molecule of any one of embodiments 60 to 64, wherein the IgM constant regions each comprise one or more substitutions corresponding to a wild-type human IgM constant region at positions 46, 209, 272, or 440 of SEQ ID NO: 1 or SEQ ID NO: 2, wherein the one or more amino acid substitutions prevent asparagine (N)-linked glycosylation.

Embodiment 67. The multimeric binding molecule of any one of embodiments 60 to 66 which is pentameric, and further comprises a J-chain or functional fragment or variant thereof.

Embodiment 68. The multimeric binding molecule of any one of embodiments 55 to 59 or 67, which can transport across vascular endothelial cells via J-chain binding to the polymeric Ig receptor (PIgR).

Embodiment 69. The multimeric binding molecule of any one of embodiments 55 to 59 or 67, further comprising a secretory component, or fragment or variant thereof.

Embodiment 70. The multimeric binding molecule of any one of embodiments 55 to 59 or 67 to 69, wherein the J-chain or functional fragment or variant thereof further comprises a heterologous polypeptide, wherein the heterologous polypeptide is directly or indirectly fused to the J-chain or functional fragment or variant thereof.

Embodiment 71. The multimeric binding molecule of embodiment 70, wherein the heterologous polypeptide is fused to the J-chain or fragment thereof via a peptide linker.

Embodiment 72. The multimeric binding molecule of embodiment 71, wherein the peptide linker comprises at least 5 amino acids, but no more than 25 amino acids.

Embodiment 73. The multimeric binding molecule of embodiment 71 or 72, wherein the peptide linker consists of GGGGS (SEQ ID NO: 9), GGGGSGGGGS (SEQ ID NO: 10), GGGGSGGGGSGGGGS (SEQ ID NO: 11), GGGGSGGGGSGGGGSGGGGS (SEQ ID NO: 12), or GGGGSGGGGSGGGGSGGGGSGGGGS (SEQ ID NO: 13).

Embodiment 74. The multimeric binding molecule of any one of embodiments 70 to 73, wherein the heterologous polypeptide is fused to the N-terminus of the J-chain or fragment or variant thereof, the C-terminus of the J-chain or fragment or variant thereof, or to both the N-terminus and C-terminus of the J-chain or fragment or variant thereof.

Embodiment 75. The multimeric binding molecule of any one of embodiments 70 to 74, wherein the heterologous polypeptide can influence the absorption, distribution, metabolism and/or excretion (ADME) of the multimeric binding molecule.

Embodiment 76. The multimeric binding molecule of any one of embodiments 70 to 75, wherein the heterologous polypeptide comprises an albumin or an albumin binding domain.

Embodiment 77. The multimeric binding molecule of any one of embodiments 70 to 76, wherein the heterologous polypeptide comprises human serum albumin.

Embodiment 78. The multimeric binding molecule of any one of embodiments 70 to 77, wherein the heterologous polypeptide comprises an antigen binding domain.

Embodiment 79. The multimeric binding molecule of embodiment 78, wherein the antigen binding domain binds to the human coronavirus.

Embodiment 80. The multimeric binding molecule of embodiment 79, wherein the antigen binding domain binds to a different epitope of the human coronavirus than the three to twelve identical binding domains of the multimeric binding molecule that specifically bind to the human coronavirus.

Embodiment 81. The multimeric binding molecule of any one of embodiments 78 to 80, wherein the antigen binding domain of the heterologous polypeptide is an antibody or antigen-binding fragment thereof.

Embodiment 82. The multimeric binding molecule of embodiment 81, wherein the antigen-binding fragment comprises a Fab fragment, a Fab′ fragment, a F(ab′)2 fragment, a Fd fragment, a Fv fragment, a single-chain Fv (scFv) fragment, a disulfide-linked Fv (sdFv) fragment, or any combination thereof.

Embodiment 83. The multimeric binding molecule of embodiment 81 or embodiment 82, wherein the antigen-binding fragment is a scFv fragment.

Embodiment 84. The multimeric binding molecule of any one of embodiments 70 to 74, wherein the heterologous polypeptide comprises an extracellular SARS-CoV-2 RBD-binding fragment of angiotensin-converting enzyme 2 (ACE2).

Embodiment 85. The multimeric binding molecule of any one of embodiments 70 to 74, wherein the heterologous polypeptide comprises an extracellular MERS-COV RBD-binding fragment of dipeptidyl peptidase 4 (DPP4).

Embodiment 86. The multimeric binding molecule of any one of embodiments 74 to 85, wherein the J-chain or functional fragment or variant thereof further comprises an additional heterologous polypeptide, wherein the additional heterologous polypeptide is directly or indirectly fused to the J-chain or functional fragment or variant thereof.

Embodiment 87. The multimeric binding molecule of embodiment 86, wherein the additional heterologous polypeptide can influence the absorption, distribution, metabolism and/or excretion (ADME) of the multimeric binding molecule.

Embodiment 88. The multimeric binding molecule of embodiment 86 or embodiment 87, wherein the additional heterologous polypeptide comprises an albumin or an albumin binding protein.

Embodiment 89. The multimeric binding molecule of embodiment 88, wherein the additional heterologous polypeptide comprises human serum albumin.

Embodiment 90. A composition comprising the multimeric binding molecule of any one of embodiments 1 to 89.

Embodiment 91. A composition comprising two or more nonidentical multimeric binding molecules according to any one of embodiments 1 to 89, wherein the two or more multimeric binding molecules bind to different epitopes of a single human coronavirus.

Embodiment 92. A polynucleotide comprising a nucleic acid sequence that encodes a polypeptide subunit of the binding molecule of any one of embodiments 1 to 89.

Embodiment 93. A vector comprising the polynucleotide of embodiment 92.

Embodiment 94. A host cell comprising the polynucleotide of embodiment 92, or the vector of embodiment 93, wherein the host cell can express the multimeric binding molecule of any one of embodiments 1 to 89, or a subunit thereof.

Embodiment 95. A method of producing the multimeric binding molecule of any one of embodiments 1 to 89, comprising culturing the host cell of embodiment 94, and recovering the multimeric binding molecule.

Embodiment 96. The method of embodiment 95, further comprising contacting the multimeric binding molecule with a secretory component, or fragment or variant thereof.

Embodiment 97. A method for treating a human coronavirus disease in a subject in need of treatment comprising administering to the subject an effective amount of the multimeric binding molecule of any one of embodiments 1 to 89, wherein the multimeric binding molecule exhibits greater potency than an equivalent amount of a bivalent reference IgG antibody comprising two of the binding domains that specifically bind to the human coronavirus.

Embodiment 98. A method for preventing a human coronavirus disease in a subject, comprising administering to the subject an effective amount of the multimeric binding molecule of any one of embodiments 1 to 89, wherein the multimeric binding molecule exhibits greater potency than an equivalent amount of a bivalent reference IgG antibody comprising two of the binding domains that specifically bind to the human coronavirus.

Embodiment 99. The method of embodiment 97 or embodiment 98, wherein the human coronavirus disease is severe acute respiratory syndrome (SARS).

Embodiment 100. The method of embodiment 97 or embodiment 98, wherein the human coronavirus disease is coronavirus disease 2019 (COVID-19).

Embodiment 101. The method of embodiment 97 or embodiment 98, wherein the human coronavirus disease is Middle East Respiratory Syndrome (MERS).

Embodiment 102. The method of any one of embodiments 97 to 101, wherein the subject is human.

Embodiment 103. The method of any one of embodiments 97 to 102, wherein the administering comprises intravenous, subcutaneous, intramuscular, intranasal, and/or inhalation administration.

EXAMPLES
Example 1: Generation of Antibodies to SARS-CoV-1 and SARS-CoV-2

The VH and VL regions of two anti-SARS-CoV-1 antibodies, CR3022 and CR3014 (US20060121580), were incorporated into IgM, IgA1, and IgA2m2 formats (each with an exemplary J-chain, SEQ ID NO: 7) and IgG format according to standard cloning protocols. CR3022 IgG is known to bind SARS-CoV-2 and CR3014 IgG does not. CR3022 constructs included the VH and VL amino acid sequences SEQ ID NO: 84 and SEQ ID NO: 85, respectively, and CR3014 constructs included the VH and VL amino acid sequences SEQ ID NO: 262 and SEQ ID NO: 263, respectively.

The IgM and IgG antibody constructs were expressed and purified according to methods described in WO2017196867. The IgA antibody constructs were expressed using the same methods described in WO2017196867 as the IgM antibody constructs, except that the appropriate IgA heavy chain was used. The IgM antibodies assembled as pentamers with a J-chain, and the IgA antibodies assembled as dimers and/or tetramers with a J-chain (data not shown).

Example 2: Antibody Binding Measured by ELISA

CR3022 was originally developed as an anti-SARS-CoV-1 IgG antibody (US20060121580) and CR3022 IgG has recently been demonstrated to also bind SARS-CoV-2 (Tian et al. Emerging Microbes & Infections, 2020, doi: 10.1080/22221751.2020.1729069). ELISA was used to determine how the IgM, IgA1, IgA2m2, and IgG1 formats affect binding to SARS-CoV-1 and SARS-CoV-2.

Binding of CR3022 IgM, IgA1, IgA2m2, and IgG (described in Example 1) to SARS-CoV-1 and SARS-CoV-2 was measured in ELISA assays as follows. 96-well white polystyrene ELISA plates (Pierce 15042) were coated with 100 μL per well of 0.5 μg/mL recombinant SARS-CoV-1 Receptor Binding Domain (RBD) with a his tag, recombinant SARS-CoV-2 RBD with a his tag, recombinant SARS-CoV-2 RBD with a Fc tag, or recombinant SARS-CoV-2 spike (S) protein trimer, overnight at 4° C. Plates were then washed 5 times with 0.05% PBS-Tween and blocked with 2% BSA-PBS. After blocking, 100 μL of serial dilutions of CR3022 IgM, IgA1, IgA2m2, or IgG; standards; or controls were added to the wells and incubated at room temperature for 2 hours. The plates were then washed 10 times and incubated with HRP conjugated mouse anti-human kappa (Southern Biotech, 9230-05; 1:6000 diluted in 2% BSA-PBS) for 30 min. After 10 final washes using 0.05% PBS-Tween, the plates were read out using SuperSignal chemiluminescent substrate (ThermoFisher, 37070). Luminescent data were collected on an EnVision plate reader (Perkin-Elmer) and analyzed with GraphPad Prism using a 4-parameter logistic model. Binding to SARS-CoV-1 RBD is shown in FIG. 1A, and binding to SARS-CoV-2 RBD is shown in FIG. 1B. Similar binding profiles were seen with SARS-CoV-2 RBD his tag, SARS-CoV-2 Fc, and SARS-CoV-2 S trimer.

Example 3: Pseudovirus Neutralization Assay

CR3022 IgG and CR3014 IgG have both been reported to neutralize SARS-CoV-1 (US20060121580). CR3014 IgG does not bind SARS-CoV-2 RBD whereas CR3022 IgG does bind SARS-CoV-2 RBD (Tian et al., Emerging Microbes & Infections, doi: 10.1080/22221751.2020.1729069, 2020). However, there has been disagreement whether CR3022 IgG is capable of neutralizing SARS-CoV-2 (Yuan et al., Science 10.1126/science.abb7269; 2020), Huo et al., Cell Host Microbe, doi: 10.1016/j.chom.2020.06.010, 2020). A pseudovirus neutralization assay was used to determine how the IgM, IgA1, IgA2m2, and IgG1 formats affect neutralization of pseudoviruses comprising the SARS-CoV-1 or SARS-CoV-2 spike protein.

A SARS-CoV pseudovirus neutralization assay was performed generally as described in Richman et al. (PNAS, 2003, 100(7): 4144-4149), wherein host cells that have been infected with an HIV-based pseudovirus express luciferase. In the SARS-CoV-1 or SARS-CoV-2 pseudovirus neutralization assay, the pseudovirus was engineered to express SARS-CoV-1 or SARS-CoV-2 spike proteins in place of HIV gp160. Various concentrations of CR3022 IgG1, IgA1, IgA2m2, or IgM or CR3014 IgG1 and IgM were incubated with the SARS-CoV-1 or SARS-CoV-2 pseudovirus for 1 hr. at 37° C. HEK-293 cells expressing human ACE-2 were then inoculated with the antibody/pseudovirus solution. The amount of luciferase activity in the infected cells was measured 72 h post-inoculation to determine the neutralizing activity. A decrease in luciferase activity indicated neutralizing activity by the antibody assayed. Neutralizing activity was calculated as the percent inhibition of viral replication (luciferase activity) at each antibody dilution compared with an antibody-negative control. The percent inhibitions of the SARS-CoV-1 pseudovirus for CR3022 IgG1, CR3022 IgA1, CR3022 IgA2m2, CR3022 IgM, CR3014 IgG1, and CR3014 IgM are shown in FIGS. 2A-2F, respectively. Neither CR3022 nor CR3014, in any format, neutralized SARS-CoV-2 pseudovirus infectivity. In contrast, all forms of CR3022 and CR3014 neutralized SARS-CoV-1, with the IgM and IgA forms being the most potent. The IC₅₀and fold improvement over IgG1 for each IgA and IgM antibody are shown in Table 2. CR3022 is ˜6-fold more potent as an IgM than as an IgG1 in neutralizing SARS-CoV-1 pseudovirus on a weight basis, and CR3014 is at least 13-fold more potent as an IgM than as an IgG.

TABLE 2

Pseudovirus Neutralization Results

IC₅₀(μg/mL)
Fold Over IgG1 (CoV-1)

SARS-
SARS-
By
By

Antibody
CoV-1
CoV-2
Weight
Molar

CR3022-IgG1
2.9
>100,000
1.0
1.0

CR3022-IgA1 + J
1.9
>100,000
1.5
3.4

CR3022-IgA2m2 + J
2.3
>100,000
1.3
2.8

CR3022-IgM + J
0.47
>100,000
6.2
37

CR3014-IgG1
0.068
>100,000
1.0
1.0

CR3014-IgM + J
<0.0051
>100,000
>13
>80

Example 4: Antibody Transcytosis

To determine if CR3022 IgA1, IgA2, and IgM antibodies are capable of functionally interacting with the polymeric immunoglobulin receptor (pIgR) and being transcytosed across a cell barrier, an in vitro transcytosis assay was developed, modified from the transcytosis assay describe by Chung et al. (2019, mAbs, 11(5): 942-955).

MDCK.2 (Sigma) cells were transfected to express human pIgR. The hpIgR-expressing MDCK.2 cells were seeded at a density of 1×10⁵cells/well in growth medium (DMEM High Glucose supplemented with 10% FBS) in a 96-well trans-well plate and were incubated for 48 hours at 37° C. The transwell insert and corresponding monolayer of cells were transferred to a receiver plate in which the basolateral chamber contained 11.1, 33.3, or 100 μg/mL of CR3022 IgA1, IgA2, or IgM antibodies in growth medium. A human IgG antibody was also included as a control. The cells were incubated at 37° C. for another 24 hours. The media from the apical chamber were then collected and the amount of transcytosed molecules was determined by ELISA. The resulting concentrations for each antibody format are shown in FIG. 3. CR3022 IgA1, IgA2 and IgM antibodies were efficiently transcytosed across the cell monolayer, whereas the IgG antibody was not.

Example 5: Additional SARS-CoV-2 Antibody Generation

The VH and VL regions of eight anti-SARS-CoV-2 antibodies were incorporated into IgM with an exemplary J-chain, SEQ ID NO: 7 and IgG format according to standard cloning protocols. The VH and VL amino acid sequences used for each antibodies construct are shown in Table 3.

TABLE 3

Antibody Constructs Generated

SEQ ID NO

VH
VL

Ab1
88
89

Ab2
260
261

Ab3
264
265

Ab4
266
267

Ab5
284
285

Ab6
286
287

Ab7
288
289

Ab8
290
291

Ab9
292
293

Ab10
274
275

Ab11
278
279

Ab12
280
281

Ab13
282
283

The IgM antibodies were purified according to methods described in Keyt, B., et al. Antibodies: 9:53, doi: 10.3390/antib9040053 (2020), or, e.g., as described in WO2017196867. The IgA and IgG antibodies were purified by affinity chromatography. The IgM antibodies assembled as pentamers with a J-chain and the IgG antibodies properly assembled as monomers (data not shown).

Example 6: Antibody Binding to SARS-CoV-2 Measured by ELISA

ELISA was used to determine how the IgM and IgG1 formats affect binding to SARS-CoV-2. Binding of Ab1-Ab4 IgM and IgG (described in Example 5) to SARS-CoV-2 was measured in ELISA assays as follows. 96-well white polystyrene ELISA plates (Pierce 15042) were coated with 100 μL per well of 0.5 μg/mL recombinant SARS-CoV-2 RBD with a HIS tag (for Ab1-Ab4) or S protein trimer (for Ab10-Ab13) overnight at 4° C. Plates were then washed 5 times with 0.05% PBS-Tween and blocked with 2% BSA-PBS. After blocking, 100 μL of serial dilutions of IgM or IgG antibodies, standards, or controls were added to the wells and incubated at room temperature for 2 hours. The plates were then washed 10 times and incubated with HRP conjugated mouse anti-human kappa (Southern Biotech, 9230-05; 1:6000 diluted in 2% BSA-PBS) or mouse anti-human lambda (clone JDC-12, Southern Biotech, 9180-05; 1:6000 diluted in 2% BSA-PBS) for 30 min. After 10 final washes using 0.05% PBS-Tween, the plates were read out using SuperSignal chemiluminescent substrate (ThermoFisher, 37070). Luminescent data were collected on an EnVision plate reader (PerkinElmer) and analyzed with GraphPad Prism using a 4-parameter logistic model. Binding of Ab1-Ab4 to SARS-CoV-2 RBD is shown in FIGS. 4A-4D, respectively. Binding of Ab10, Ab11, and Ab13 to SARS-CoV-2 S protein trimer is shown in FIGS. 4E-4G, respectively.

For Ab1-Ab4, Ab10, Ab11, and Ab13, both the IgG and IgM versions bound well to the SARS-CoV-2 RBD or S trimer but, in each case, the IgM bound much better than the IgG. Ab12 poorly bound the S trimer in both the IgG and IgM formats (data not shown).

Example 7: SARS-CoV-2 Neutralization Assay

A SARS-CoV-2 live virus microneutralization assay was performed generally as described in Graham et al. (Clin Transl Immunology, 2020, 9(10):e1189, doi: 10.1002/cti2.1189.) using a focus reduction microneutralization test (FRNT) with various concentrations of antibodies. Specifically, the neutralizing activity of IgG1 and IgM versions of Ab1-Ab9 were assessed in vitro. Antibodies were combined with focus forming units of SARS-CoV-2 and incubated for 60 minutes at 37° C. and then assayed undiluted and in serial dilutions until reaching an endpoint of 1:3200. Samples were applied to confluent cell monolayers in 96 well plates and were incubated for 60 minutes at 37° C., followed by overlaying the wells with 1.2% methylcellulose in cDMEM and incubation at 37° C., 5% CO₂for 24 hours. Infected cells were fixed in 25% formaldehyde in 3×PBS, then permeabilized with 0.1% Triton in 1×PBS for 15 minutes and then incubated with a primary anti-SARS-CoV monoclonal antibody, and then a secondary detectable antibody. Cell levels were counted using established methods. IC₅₀determinations were made using a non-linear regression curve fit (log [inhibitor] vs. normalized response−variable slope) in GraphPad Prism. The IC₅₀and fold improvement over IgG1 for each antibody are shown in Table 4.

TABLE 4

Neutralization Results

IgM IC₅₀
IgG IC₅₀
IgM Fold Improvement

(ng/mL)
(ng/mL)
Over IgG1

Ab1
13
130
10

Ab2
50
92
1.8

Ab3
3.8
11
2.9

Ab4
3.1
180
59

Ab5
11
70
6.2

Ab6
41
2800
68

Ab7
1.6
30
19

Ab8
28
93
3.3

Ab9
1.0
3.2
3.2

All antibodies tested neutralized SARS-CoV-2 and all IgM formatted antibodies were more potent at neutralizing SARS-CoV-2 relative to the IgGs.

Example 8: In Vivo Assays

A variety of animal models are contemplated for testing of the disclosed binding molecule, e.g., antibodies to the spike protein of SARS-CoV-2. Such animal models included models described in Munoz-Fontela et al., Nature, 2020, 586: 509-515, which is herein incorporated by reference in its entirety. The most common animal models involve studies in mice, hamsters, and ferrets, as well as non-human primates such as rhesus macaques, cynomolgus macaques, and African green monkeys. Inoculation of virus in all animal models is done via intranasal administration—primate studies may also include intratracheal inoculation. For these studies, authentic SARS-CoV-2 virus, variant strains of SARS-CoV-2, or pseudovirus (e.g., VSV, HIV, Lentivirus, etc.) expressing the SARS-CoV-2 spike protein are used for infection, and dosing of experimental agents is done prophylactically (dosed before infection) or therapeutically (dosed after infection).

Since mice are not normally susceptible to infection by SARS-CoV-2 due to differences in their ACE2 protein, several methods have been developed to allow reproducible virus replication in this species. These include (i) the use of mice transgenic for human ACE2, (ii) the transduction of human ACE2 into mice via adenovirus or adeno-associated viral vectors, and (iii) the use of mouse-adapted SARS-CoV-2 virus that has been adapted to bind mouse ACE2 via repeated passage in mice. Some examples of mouse-adapted SARS-CoV-2 strains have been described by Li et al., Proc. Natl. Acad. Sci. USA, 2020, 117(47):29832-29838. and Gu et al., Science, 2020, 369 (6511): 1603-1607.

Similarly, multiple routes of administration for the test antibodies are contemplated for use herein in animal studies of SARS-CoV-2 infection. These include intravenous (IV), intraperitoneal (IP), intranasal (IN), intramuscular (IM), subcutaneous (SC) and inhalation (INH). Antibodies to be tested can be administered before (prophylaxis) or after (treatment) viral infection at doses ranging from for example 0.01 to 50 mg/kg. For mouse studies, typical times for prophylaxis or treatment range from 4 to 48 hrs. before or after infection. Control groups receive isotype control antibodies. Two days after infection, lung samples are harvested from all mice and homogenized in 1 mL PBS and analyzed for infectious virus by plaque assay or by RT-qPCR. In some studies, lung tissues are also collected and examined for changes in morphology, cytokines, and other markers of inflammation. Exemplary protocols are discussed below for studying antibodies to SARS-CoV-2 in vivo.

Studies with Mouse-Adapted SARS-CoV-2

BALB/c mice (10 to 12 weeks old, 5 to 10 per group) are anesthetized with isoflurane and infected intranasally (IN) with 10⁴pfu of a mouse-adapted SARS-CoV-2 strain in 50 μL of phosphate-buffered saline (PBS). Antibodies to be tested are administered IP or IN before (prophylaxis) or after (treatment) viral infection, and viral loads in the lung are assessed 48 hrs. post infection.

Studies with Transgenic Mice (e.g., Zhang et al., bioRxiv, 2020, doi: 10.1101/2020.12.08.416677)

hACE2 transgenic mice (e.g., K18-hACE2, 6- to 9-wk-old, 5 to 6 per group) are treated IP with 0.3 mg (15 mg/kg) of antibody or negative controls 15 h prior to IN infection with 10⁵pfu of wild-type SARS-CoV-2. Lung tissue is homogenized in phosphate-buffered saline (PBS) and virus replication assessed by plaque assay.

Alternatively, antibodies of various concentrations are administered IN (20 μL per nostril). Ten hours later, mice are infected IN with SARS-CoV-2 spike protein-expressing pseudotype lentivirus (20 μL per nostril). Seven days after intranasal administration of virus, bioluminescent imaging is performed for each mouse.

Studies with Transduced Mice (e.g., Zost et al., Nature, 2020, 584: 443-449)

BalbC mice (10-11 weeks old) are given a single intraperitoneal injection of 2 mg of anti-IFNAR1 monoclonal antibody (MAR1-5A355, Leinco) one day before intranasal administration of 2.5×10⁸PFU of AdV-hACE2. Five days after AdV transduction, mice are inoculated with 4×10⁵PFU of SARS-CoV-2 via the IN route. Anti-SARS-CoV-2 human monoclonal antibodies or isotype control monoclonal antibodies are administered 24 h before (prophylaxis) or 12 h after (treatment) SARS-CoV-2 inoculation. Weights are monitored on a daily basis, and mice are euthanized at 2 or 7 dpi and tissues are collected for analysis of PFU.

Studies in Syrian Hamsters (e.g., Tortorici et al., Science, 2020, 370: 950-957)

Female hamsters of 6-10 weeks old are anesthetized with ketamine/xylazine/atropine and inoculated intranasally with 50 μL containing 2×10⁶TCID₅₀SARS-CoV-2. Antibodies to be tested are administered IP up to 48 hours before infection. Hamsters are monitored for appearance, behavior, and weight. At day 4 post infection (pi), hamsters are euthanized by intraperitoneal injection of 500 μL Dolethal (200 mg/mL sodium pentobarbital, Vetoquinol SA). Lungs are collected, and viral RNA and infectious virus were quantified by RT-qPCR and plaque assays, respectively.

Studies in Rhesus Macaques (e.g., Baum et al., Science, 2020, 370: 1110-1115)

Antibodies or saline are administered through intravenous infusion. Animals (4 per group) are challenged with 1.1×10⁵PFU SARS-CoV-2 (USA-WA1/2020 (NR-52281; BEI Resources) total dose divided between IN and intratracheal routes. Virus is administered using a 3 mL syringe to drop-wise instill 1 mL by the intranasal (IN) route (0.5 mL in each nare) and using a French rubber tube, is administered 1 mL via the intratracheal (IT) route. Viral titers are collected by nasal swabs (2× Copan flocked per animal, placed into one vial each with 1 mL PBS) and bronchioalveolar lavage (BAL) using 10 mL saline via a rubber feeding tube. Collected swabs and BAL aliquots are stored at −80° C. until viral load analysis.

Example 9: Neutralization Assay

A SARS-CoV-2 live virus microneutralization assay was performed generally as described in Graham et al. (Clin Transl Immunology, 2020, 9(10):e1189, doi: 10.1002/cti2.1189.) as described in Example 7, using various concentrations of IgG1 and IgM versions of Ab10-Ab13. Data were analyzed with using a non-linear regression curve fit (log [inhibitor] vs. normalized response−variable slope) in GraphPad Prism. The resulting % Neutralization of Ab10-Ab13 are shown in FIGS. 5A-5D, respectively. The IC₅₀and fold improvement over IgG1 for each antibody are shown in Table 5.

TABLE 5

Neutralization Results

IgM IC₅₀
IgG IC₅₀
IgM Fold Improvement

(ng/mL)
(ng/mL)
Over IgG1

Ab10
1.2
470
390

Ab11
57
>50,000
>870

Ab12
8.1
2700
330

Ab13
5.8
>50,000
>8,600

All antibodies tested neutralized SARS-CoV-2 and all IgM formatted antibodies were more potent at neutralizing SARS-CoV-2 relative to the IgGs.

Example 10: Pseudovirus Neutralization Assay

A lentivirus-based SARS-CoV-2 pseudovirus particle was generated expressing spike protein on the surface (Accession number: MN908947.3). The pseudovirus neutralization assay is based on previously described methodologies using luciferase-expressing HIV-1 pseudovirions (Richman et al. (Proc. Natl. Acad. Sci. USA, 2003, 100(7): 4144-4149), Folegatti et al., Lancet, 2020, 396: 467-478). Briefly, neutralizing antibody (Nab) titers were determined by creating 9 serial four-fold dilutions of Ab1-Ab13 IgM or IgG antibodies, which were mixed with ˜10⁵relative light units (RLU) of SARS-CoV-2 pseudotyped virus and incubated at 37° C. for one hour. Separately, irrelevant pseudotyped control virus was also mixed with test samples. Following the 1-hour incubation, HEK 293 ACE2-transfected cells were added to the well. The plates were incubated for 60-80 hours at 37° C. and then assayed for luciferase expression. Neutralization titers are reported as the reciprocal of the serum dilution conferring 50% inhibition (ID₅₀) of pseudovirus infection. % Inhibition=100%−(((RLU_{(vector+sample+Diluent)}−RLU_(Background))/(RLU_{(Vector+Diluent)}−RLU_(Background)))×100%). SARS CoV-2 nAb Assay Positive and Negative Control Sera were included on each 96-well assay plate. The data for Ab9 did not meet quality control standards, and therefore are not included in the analysis. Data were analyzed using a non-linear regression curve fit (log [inhibitor] vs. normalized response−variable slope) in GraphPad Prism. The resulting % Neutralization of Ab1-Ab8, and Ab10-Ab13 are shown in FIGS. 6A-6L, respectively. The IC₅₀and fold improvement over IgG1 for each antibody are shown in Table 6.

TABLE 6

Pseudovirus Neutralization Results

IgM IC₅₀
IgG IC₅₀
IgM Fold Improvement

(ng/mL)
(ng/mL)
Over IgG1

Ab1
0.15
10
67

Ab2
36
530
15

Ab3
0.11
0.57
5.2

Ab4
0.058
1.8
31

Ab5
0.38
1.7
4.5

Ab6
0.055
16
290

Ab7
0.042
0.37
8.8

Ab8
2.7
1.9
—

Ab10
0.092
5.9
64

Ab11
3.7
320
86

Ab12
0.42
77
180

Ab13
4.6
36
7.8

Example 11: Biolayer Interferometry Affinity Measurement Assay

The binding affinities & avidity of Ab7, Ab8, or Ab10 IgG or IgM antibodies with SARS-CoV-2 RBD (MW 26.5 KDa) or variant RBDs were determined by biolayer interferometry (BLI) on an Octet-384 (Sartorius/ForteBio, NY, USA) using Anti-Penta-His biosensors(Sartorius/Fortebio Cat #18-5120). PBST (1×PBS+1% BSA+0.05% Tween-20) buffer was used as Antibody/RBD/ACE-2 dilution and sensor hydration buffer. The experiment followed a six-step sequential assay at 24° C. First, biosensors were hydrated for 10 minutes. Samples and buffer were applied in 384-well plate. After initial baseline of 30 s, sensors were loaded with various RBDs for 240 s, then moved into buffer for a baseline for 30 s. Next, various concentrations of antibody were associated for 240 s and dissociated for 500 s in PBST. Results were analyzed by ForteBio Data Analysis software 9.0 using global fit model. The K_Dvalues are shown in Tables 7-9. Underline indicates significant difference between IgM and IgG formats. WB indicates weak binding.

Example 12: ACE2 Blocking Assay

Analysis of the ability of IgG1 and IgM versions of Ab7, Ab8, or Ab10 to block ACE2-Fc (Acrobiosystems, Cat #AC2-H5257) binding of SARS-CoV-2 WT and various variant RBDs was performed by BLI on an Octet-384 (Sartorius/Fortebio, NY, USA) using anti-Penta His biosensors (Sartorius/Fortebio Cat #18-5120). PBST (1×PBS+1% BSA+0.05% Tween-20) buffer was used as Antibody/RBD/ACE-2 dilution and sensor hydration buffer. The experiment followed a six-step sequential assay at 24° C. First, biosensors were hydrated for 10 minutes. Samples and buffer were applied in 384-well plate. After initial baseline of 30 s, sensors were loaded with RBD for 400 s, then moved into buffer for a baseline for 30 s. Next, various concentrations of antibody were associated for 600 s followed by baseline for 20 s. Then, 100 nM of ACE-2 was associated for 600 s. Results were analyzed by ForteBio Data Analysis software 9.0. as (nm) rise of ACE2 binding. % RBD-ACE2 blocking was plotted & IC₅₀values were calculated using GraphPad Prism 8.0. The IC₅₀values in nM and M are shown in Tables 7-9. Underline indicates significant difference between IgM and IgG formats. WB indicates weak binding.

TABLE 7

Binding Kinetics and ACE2 Blocking Assay Results for Ab7

RBD

Ab7
Ab Format
WT
K417E
G446V
Y453F
E484K
Q493K

Avidity
IgM
<0.001
<0.001
<0.001
<0.001
0.007
<0.001

KD (nM)
IgG
<0.001
<0.001
<0.001
<0.001

WB

<0.001

ACE2 Blocking
IgM
0.11
0.36
0.32
0.42

0.87

0.30

IC₅₀(nM)
IgG
0.88
2.4
2.1
3.2

>69
2.2

ACE2 Blocking
IgM
0.098
0.31
0.28
0.36

0.76

0.26

IC₅₀(μg/mL)
IgG
0.13
0.35
0.30
0.46

>10
0.32

TABLE 8

Binding Kinetics and ACE2 Blocking Assay Results for Ab8

RBD

Ab8
Ab Format
WT
K417E
G446V
Y453F
E484K
Q493K

Avidity
IgM
<0.001
<0.001
<0.001
<0.001
<0.001
<0.001

KD (nM)
IgG
<0.001

2.0

<0.001
<0.001
<0.001
<0.001

ACE2 Blocking
IgM
0.30
1.2
0.90
1.1
1.5
1.3

IC₅₀(nM)
IgG
2.8
7.2
6.1
7.2
19
24

ACE2 Blocking
IgM
0.26
1.0
0.78
0.98
1.3
1.1

IC₅₀(μg/mL)
IgG
0.41
1.0
0.88
1.0
2.8
3.5

TABLE 9

Binding Kinetics and ACE2 Blocking Assay Results for Ab10

RBD

Ab10
Ab Format
WT
K417E
G446V
Y453F
E484K
Q493K

Avidity
IgM
<0.001
<0.001
0.11
<0.001
<0.001
<0.001

KD (nM)
IgG
<0.001
<0.001

120

<0.001
<0.001
0.60

ACE2 Blocking
IgM
0.27
0.32
5.0
0.49
0.47
0.35

IC₅₀(nM)
IgG
3.2
3.8

>69

8.6
10
4.4

ACE2 Blocking
IgM
0.23
0.28
4.3
0.42
0.41
0.30

IC₅₀(μg/mL)
IgG
0.46
0.55

>10

1.2
1.5
0.64

Example 13: Biolayer Interferometry Affinity Measurement Assay

The binding affinities & avidities of Ab3 and Ab4 IgG or IgM antibodies were determined as described in Example 11 with SARS-CoV-2 RBD (MW 26.5 KDa) or a larger number of variant RBDs. The KD values (in nM) are shown in Table 10. Underline indicates significant difference between IgM and IgG formats. NB indicates no binding.

TABLE 10

Binding Kinetics for Ab3 and Ab4

Ab3
Ab4

Ab
Avidity KD (nM)
Avidity KD (nM)

Format
IgM
IgG
IgM
IgG

RBD
WT
<0.001
<0.001
<0.001
<0.001

K417E
<0.001
1.4
<0.001
<0.001

G446V
<0.001
<0.001
<0.001
<0.001

Y453F
0.017

64
<0.001
<0.001

E484K
0.004

0.67

<0.001
<0.001

N501Y
<0.001
<0.001
<0.001
<0.001

S494P
<0.001
0.0098
<0.001
<0.001

G446V
<0.001
<0.001

2.3

NB

F490S
<0.001
<0.001
<0.001
<0.001

N439K
<0.001
<0.001
<0.001
0.48

G476S
<0.001
<0.001
0.0096
0.020

L455F

<0.001

1.1
<0.001
<0.001

Example 14: Generation of Anti-MERS-CoV Antibodies

The VH and VL regions of human anti-MERS antibodies, e.g., those listed in Table 13, e.g., the VH and VL of SEQ ID NO: 522 and SEQ ID NO: 523, SEQ ID NO: 576 and SEQ ID NO: 577, SEQ ID NO: 610 and SEQ ID NO: 611, SEQ ID NO: 612 and SEQ ID NO: 613, SEQ ID NO: 614 and SEQ ID NO: 615, or SEQ ID NO: 630 and SEQ ID NO: 631, respectively, are incorporated into IgM, IgA1, and IgA2m2 formats (which may comprise an exemplary J-chain, e.g., a human J-chain, a modified J-chain, or a functional fragment or variant thereof) and IgG format according to standard cloning protocols.

The IgM, IgA, and IgG antibody constructs are expressed in Expi293 or CHO cells. The IgM antibodies are purified according to methods described in Keyt, B., et al. Antibodies: 9:53, doi: 10.3390/antib9040053 (2020). The IgA and IgG antibodies are purified by affinity chromatography. The IgM antibodies assemble as hexamers or pentamers with a J-chain, and the IgA antibodies assembled as dimers or tetramers with a J-chain.

Example 15: MERS-CoV Antibody Binding Measured by ELISA

Binding of anti-MERS-CoV IgM, IgA1, IgA2m2, and IgG antibodies (produced as described in Example 15) to MERS-CoV is measured in ELISA assays as follows: 96-well white polystyrene ELISA plates (Pierce 15042) are coated with 100 μL per well of 0.5 μg/mL recombinant MERS-CoV Receptor Binding Domain (RBD) with a his tag, recombinant MERS-CoV RBD with a Fc tag, or recombinant MERS-CoV spike (S) protein trimer, overnight at 4° C. Plates are then washed 5 times with 0.05% PBS-Tween and blocked with 2% BSA-PBS. After blocking, 100 μL of serial dilutions of anti-MERS-CoV IgM, IgA1, IgA2m2, or IgG antibodies; standards; or controls are added to the wells and are incubated at room temperature for 2 hours. The plates are then washed 10 times and are incubated with HRP conjugated mouse anti-human kappa (Southern Biotech, 9230-05; 1:6000 diluted in 2% BSA-PBS) for 30 min. After 10 final washes using 0.05% PBS-Tween, the plates are read using SuperSignal chemiluminescent substrate (ThermoFisher, 37070). Luminescent data is collected on an EnVision plate reader (Perkin-Elmer) and is analyzed with GraphPad Prism using a 4-parameter logistic model.

Example 16: MERS-CoV Pseudovirus Neutralization Assay

A MERS-CoV pseudovirus neutralization assay is performed generally as described in Example 10 using recombinant pseudoviruses expressing the MERS-CoV spike protein, and various concentrations of anti-MERS-CoV antibodies are produced as described in Example 15.

Briefly, lentivirus-based MERS-CoV pseudovirus particles are generated expressing the MERS-CoV spike protein (e.g., SEQ ID NO: 18) on the surface. The pseudovirus neutralization assay is based on previously described methodologies using luciferase-expressing HIV-1 pseudovirions (Richman et al. (Proc. Natl. Acad. Sci. USA, 2003, 100(7): 4144-4149), Folegatti et al., Lancet, 2020, 396: 467-478). Briefly, neutralizing antibody (Nab) titers are determined by creating 9 serial four-fold dilutions of anti-MERS-CoV IgM, IgG, or IgA antibodies that are produced as described in Example 15, which are mixed with ˜10⁵relative light units (RLU) of MERS-CoV pseudotyped virus and are incubated at 37° C. for one hour. Separately, irrelevant pseudotyped control virus is also mixed with test samples. Following a 1-hour incubation, human DPP4-expressing cells, e.g., HEK 293 human DPP4-transfected cells are added to the well. The plates are incubated for 60-80 hours at 37° C. and then are assayed for luciferase expression. Neutralization titers are reported as the reciprocal of the serum dilution conferring 50% inhibition (ID₅₀) of pseudovirus infection. % Inhibition=100%−(((RLU_{(Vector+Sample+Diluent)}−RLU_(Background))/(RLU_{(Vector+Dluent)}−RLU_(Background)))×100%). MERS-CoV nAb Assay Positive and Negative Control Sera are included on each 96-well assay plate. Data are analyzed using a non-linear regression curve fit (log [inhibitor] vs. normalized response−variable slope) in GraphPad Prism.

TABLE 11

Sequences of the Disclosure

SEQ

ID
Nickname (source)
Sequence

1
Human IgM Constant
GSASAPTLFPLVSCENSPSDTSSVAVGCLAQDFLPDSITFSWKYKNNSDISSTRGFPSVLRGGKYAATSQVL

region IMGT allele
LPSKDVMQGTDEHVVCKVQHPNGNKEKNVPLPVIAELPPKVSVFVPPRDGFFGNPRKSKLICQATGFSPRQI

IGHM*03 (GenBank:
QVSWLREGKQVGSGVTTDQVQAEAKESGPTTYKVTSTLTIKESDWLSQSMFTCRVDHRGLTFQQNASSMCVP

pir|S37768|)
DQDTAIRVFAIPPSFASIFLTKSTKLTCLVTDLTTYDSVTISWTRQNGEAVKTHTNISESHPNATFSAVGEA

SICEDDWNSGERFTCTVTHTDLPSPLKQTISRPKGVALHRPDVYLLPPAREQLNLRESATITCLVTGFSPAD

VFVQWMQRGQPLSPEKYVTSAPMPEPQAPGRYFAHSILTVSEEEWNTGETYTCVVAHEALPNRVTERTVDKS

TGKPTLYNVSLVMSDTAGTCY

2
Human IgM Constant
GSASAPTLFPLVSCENSPSDTSSVAVGCLAQDFLPDSITFSWKYKNNSDISSTRGFPSVLRGGKYAATSQVL

region IMGT allele
LPSKDVMQGTDEHVVCKVQHPNGNKEKNVPLPVIAELPPKVSVFVPPRDGFFGNPRKSKLICQATGFSPRQI

IGHM*04 (GenBank:
QVSWLREGKQVGSGVTTDQVQAEAKESGPTTYKVTSTLTIKESDWLGQSMFTCRVDHRGLTFQQNASSMCVP

sp|P01871.4|)
DQDTAIRVFAIPPSFASIFLTKSTKLTCLVTDLTTYDSVTISWTRQNGEAVKTHTNISESHPNATFSAVGEA

SICEDDWNSGERFTCTVTHTDLPSPLKQTISRPKGVALHRPDVYLLPPAREQLNLRESATITCLVTGFSPAD

VFVQWMQRGQPLSPEKYVTSAPMPEPQAPGRYFAHSILTVSEEEWNTGETYTCVVAHEALPNRVTERTVDKS

TGKPTLYNVSLVMSDTAGTCY

3
Human IgA1 heavy chain
ASPTSPKVFPLSLCSTQPDGNVVIACLVQGFFPQEPLSVTWSESGQGVTARNFPPSQDASGDLYTTSSQLTL

constant region, e.g.,
PATQCLAGKSVTCHVKHYTNPSQDVTVPCPVPSTPPTPSPSTPPTPSPSCCHPRLSLHRPALEDLLLGSEAN

amino acids 144 to 496
LTCTLTGLRDASGVTFTWTPSSGKSAVQGPPERDLCGCYSVSSVLPGCAEPWNHGKTFTCTAAYPESKTPLT

of GenBank AIC59035.1
ATLSKSGNTFRPEVHLLPPPSEELALNELVTLTCLARGFSPKDVLVRWLQGSQELPREKYLTWASRQEPSQG

TTTFAVTSILRVAAEDWKKGDTFSCMVGHEALPLAFTQKTIDRLAGKPTHVNVSVVMAEVDGTCY

4
Human IgA2 heavy chain
ASPTSPKVFPLSLDSTPQDGNVVVACLVQGFFPQEPLSVTWSESGQNVTARNFPPSQDASGDLYTTSSQLTL

constant region, e.g.,
PATQCPDGKSVTCHVKHYTNSSQDVTVPCRVPPPPPCCHPRLSLHRPALEDLLLGSEANLTCTLTGLRDASG

amino acids 1 to 340
ATFTWTPSSGKSAVQGPPERDLCGCYSVSSVLPGCAQPWNHGETFTCTAAHPELKTPLTANITKSGNTFRPE

of GenBank P01877.4
VHLLPPPSEELALNELVTLTCLARGFSPKDVLVRWLQGSQELPREKYLTWASRQEPSQGTTTYAVTSILRVA

AEDWKKGETFSCMVGHEALPLAFTQKTIDRMAGKPTHINVSVVMAEADGTCY

5
Precursor Human
MLLFVLTCLLAVFPAISTKSPIFGPEEVNSVEGNSVSITCYYPPTSVNRHTRKYWCRQGARGGCITLISSEG

Secretory Component
YVSSKYAGRANLTNFPENGTFVVNIAQLSQDDSGRYKCGLGINSRGLSFDVSLEVSQGPGLLNDTKVYTVDL

GRTVTINCPFKTENAQKRKSLYKQIGLYPVLVIDSSGYVNPNYTGRIRLDIQGTGQLLFSVVINQLRLSDAG

QYLCQAGDDSNSNKKNADLQVLKPEPELVYEDLRGSVTFHCALGPEVANVAKFLCRQSSGENCDVVVNTLGK

RAPAFEGRILLNPQDKDGSFSVVITGLRKEDAGRYLCGAHSDGQLQEGSPIQAWQLFVNEESTIPRSPTVVK

GVAGGSVAVLCPYNRKESKSIKYWCLWEGAQNGRCPLLVDSEGWVKAQYEGRLSLLEEPGNGTFTVILNQLT

SRDAGFYWCLTNGDTLWRTTVEIKIIEGEPNLKVPGNVTAVLGETLKVPCHFPCKFSSYEKYWCKWNNTGCQ

ALPSQDEGPSKAFVNCDENSRLVSLTLNLVTRADEGWYWCGVKQGHFYGETAAVYVAVEERKAAGSRDVSLA

KADAAPDEKVLDSGFREIENKAIQDPRLFAEEKAVADTRDQADGSRASVDSGSSEEQGGSSRALVSTLVPLG

LVLAVGAVAVGVARARHRKNVDRVSIRSYRTDISMSDFENSREFGANDNMGASSITQETSLGGKEEFVATTE

STTETKEPKKAKRSSKEEAEMAYKDFLLQSSTVAAEAQDGPQEA

6
Precursor Human J
MKNHLLFWGVLAVFIKAVHVKAQEDERIVLVDNKCKCARITSRIIRSSEDPNEDIVERNIRIIVPLNNRENI

Chain
SDPTSPLRTRFVYHLSDLCKKCDPTEVELDNQIVTATQSNICDEDSATETCYTYDRNKCYTAVVPLVYGGET

KMVETALTPDACYPD

7
Mature Human J Chain
QEDERIVLVDNKCKCARITSRIIRSSEDPNEDIVERNIRIIVPLNNRENISDPTSPLRTRFVYHLSDLCKKC

DPTEVELDNQIVTATQSNICDEDSATETCYTYDRNKCYTAVVPLVYGGETKMVETALTPDACYPD

8
J Chain Y102A mutation
QEDERIVLVDNKCKCARITSRIIRSSEDPNEDIVERNIRIIVPLNNRENISDPTSPLRTRFVYHLSDLCKKC

DPTEVELDNQIVTATQSNICDEDSATETCATYDRNKCYTAVVPLVYGGETKMVETALTPDACYPD

9
“5” Peptide linker
GGGGS

10
“10” Peptide linker
GGGGSGGGGS

11
“15” Peptide linker
GGGGSGGGGSGGGGS

12
“20” Peptide linker
GGGGSGGGGSGGGGSGGGGS

13
“25” Peptide linker
GGGGSGGGGSGGGGSGGGGSGGGGS

14
human ACE2 UniprotKB
>sp|Q9BYF1|ACE2_HUMAN Angiotensin-converting enzyme 2

Q9BYF1
OS = Homo sapiens OX = 9606 GN = ACE2 PE = 1 SV = 2

MSSSSWLLLSLVAVTAAQSTIEEQAKTFLDKFNHEAEDLFYQSSLASWNYNTNITEENVQ

NMNNAGDKWSAFLKEQSTLAQMYPLQEIQNLTVKLQLQALQQNGSSVLSEDKSKRLNTIL

NTMSTIYSTGKVCNPDNPQECLLLEPGLNEIMANSLDYNERLWAWESWRSEVGKQLRPLY

EEYVVLKNEMARANHYEDYGDYWRGDYEVNGVDGYDYSRGQLIEDVEHTFEEIKPLYEHL

HAYVRAKLMNAYPSYISPIGCLPAHLLGDMWGRFWINLYSLTVPFGQKPNIDVTDAMVDQ

AWDAQRIFKEAEKFFVSVGLPNMTQGFWENSMLTDPGNVQKAVCHPTAWDLGKGDFRILM

CTKVTMDDFLTAHHEMGHIQYDMAYAAQPFLLRNGANEGFHEAVGEIMSLSAATPKHLKS

IGLLSPDFQEDNETEINFLLKQALTIVGILPFTYMLEKWRWMVFKGEIPKDQWMKKWWEM

KREIVGVVEPVPHDETYCDPASLFHVSNDYSFIRYYTRTLYQFQFQEALCQAAKHEGPLH

KCDISNSTEAGQKLFNMLRLGKSEPWILALENVVGAKNMNVRPLLNYFEPLFTWLKDQNK

NSFVGWSTDWSPYADQSIKVRISLKSALGDKAYEWNDNEMYLFRSSVAYAMRQYFLKVKN

QMILFGEEDVRVANLKPRISFNFFVTAPKNVSDIIPRTEVEKAIRMSRSRINDAFRLNDN

SLEFLGIQPTLGPPNQPPVSIWLIVFGVVMGVIVVGIVILIFTGIRDRKKKNKARSGENP

YASIDISKGENNPGFQNTDDVQTSF

15
human ACE2
QSTIEEQAKTFLDKFNHEAEDLFYQSSLASWNYNTNITEENVQNMNNAGDKWSAFLKEQS

Extracellular
TLAQMYPLQEIQNLTVKLQLQALQQNGSSVLSEDKSKRLNTILNTMSTIYSTGKVCNPDN

domain-variant human
PQECLLLEPGLNEIMANSLDYNERLWAWESWRSEVGKQLRPLYEEYVVLKNEMARANHYE

IgG1 hinge region-
DYGDYWRGDYEVNGVDGYDYSRGQLIEDVEHTFEEIKPLYEHLHAYVRAKLMNAYPSYIS

Cmu3, 4tp human P311A,
PIGCLPAHLLGDMWGRFWTNLYSLTVPFGQKPNIDVTDAMVDQAWDAQRIFKEAEKFFVS

P313S
VGLPNMTQGFWENSMLTDPGNVQKAVCHPTAWDLGKGDFRILMCTKVTMDDFLTAHHEMG

HIQYDMAYAAQPFLLRNGANEGFHEAVGEIMSLSAATPKHLKSIGLLSPDFQEDNETEIN

FLLKQALTIVGTLPFTYMLEKWRWMVFKGEIPKDQWMKKWWEMKREIVGVVEPVPHDETY

CDPASLFHVSNDYSFIRYYTRTLYQFQFQEALCQAAKHEGPLHKCDISNSTEAGQKLFNM

LRLGKSEPWTLALENVVGAKNMNVRPLLNYFEPLFTWLKDQNKNSFVGWSTDWSPYADQS

IKVRISLKSALGDKAYEWNDNEMYLFRSSVAYAMRQYFLKVKNQMILFGEEDVRVANLKP

RISFNFFVTAPKNVSDIIPRTEVEKAIRMSRSRINDAFRLNDNSLEFLGIQPILGPPNQP

PVSVEPKSSDKTHTCPPCPAPDQDTAIRVFAIPPSFASIFLTKSTKLTCLVTDLTTYDSV

TISWTRQNGEAVKTHTNISESHPNATFSAVGEASICEDDWNSGERFTCTVTHTDLASSLK

QTISRPKGVALHRPDVYLLPPAREQLNLRESATITCLVTGFSPADVFVQWMQRGQPLSPE

KYVTSAPMPEPQAPGRYFAHSILTVSEEEWNTGETYTCVVAHEALPNRVTERTVDKSTGK

PTLYNVSLVMSDTAGTCY

16
SARS CoV Spike
>sp|P59594|SPIKE_SARS Spike glycoprotein OS = Severe acute

Protein
respiratory syndrome coronavirus OX=694009 GN = S PE = 1 SV = 1

MFIFLLFLTLTSGSDLDRCTTFDDVQAPNYTQHTSSMRGVYYPDEIFRSDTLYLTQDLFL

PFYSNVTGFHTINHTFGNPVIPFKDGIYFAATEKSNVVRGWVFGSTMNNKSQSVIIINNS

TNVVIRACNFELCDNPFFAVSKPMGTQTHTMIFDNAFNCTFEYISDAFSLDVSEKSGNFK

HLREFVFKNKDGFLYVYKGYQPIDVVRDLPSGFNTLKPIFKLPLGINITNFRAILTAFSP

AQDIWGTSAAAYFVGYLKPTTFMLKYDENGTITDAVDCSQNPLAELKCSVKSFEIDKGIY

QTSNFRVVPSGDVVRFPNITNLCPFGEVFNATKFPSVYAWERKKISNCVADYSVLYNSTF

FSTFKCYGVSATKLNDLCFSNVYADSFVVKGDDVRQIAPGQTGVIADYNYKLPDDFMGCV

LAWNTRNIDATSTGNYNYKYRYLRHGKLRPFERDISNVPFSPDGKPCTPPALNCYWPLND

YGFYTTTGIGYQPYRVVVLSFELLNAPATVCGPKLSTDLIKNQCVNFNFNGLTGTGVLTP

SSKRFQPFQQFGRDVSDFTDSVRDPKTSEILDISPCSFGGVSVITPGTNASSEVAVLYQD

VNCTDVSTAIHADQLTPAWRIYSTGNNVFQTQAGCLIGAEHVDTSYECDIPIGAGICASY

HTVSLLRSTSQKSIVAYTMSLGADSSIAYSNNTIAIPTNFSISITTEVMPVSMAKTSVDC

NMYICGDSTECANLLLQYGSFCTQLNRALSGIAAEQDRNTREVFAQVKQMYKTPTLKYFG

GFNFSQILPDPLKPTKRSFIEDLLFNKVTLADAGFMKQYGECLGDINARDLICAQKFNGL

TVLPPLLTDDMIAAYTAALVSGTATAGWTFGAGAALQIPFAMQMAYRFNGIGVTQNVLYE

NQKQIANQFNKAISQIQESLTTTSTALGKLQDVVNQNAQALNTLVKQLSSNFGAISSVLN

DILSRLDKVEAEVQIDRLITGRLQSLQTYVTQQLIRAAEIRASANLAATKMSECVLGQSK

RVDFCGKGYHLMSFPQAAPHGVVFLHVTYVPSQERNFTTAPAICHEGKAYFPREGVFVFN

GTSWFITQRNFFSPQIITTDNTFVSGNCDVVIGIINNTVYDPLQPELDSFKEELDKYFKN

HTSPDVDLGDISGINASVVNIQKEIDRLNEVAKNLNESLIDLQELGKYEQYIKWPWYVWL

GFIAGLIAIVMVTILLCCMTSCCSCLKGACSCGSCCKFDEDDSEPVLKGVKLHYT

17
SARS-CoV-2 Spike (S)
MFVFLVLLPLVSSQCVNLTTRTQLPPAYTNSFTRGVYYPDKVFRSSVLHSTQDLFLPFFS

Protein, UniProt
NVTWFHAIHVSGTNGTKRFDNPVLPFNDGVYFASTEKSNIIRGWIFGTTLDSKTQSLLIV

P0DTC2
NNATNVVIKVCEFQFCNDPFLGVYYHKNNKSWMESEFRVYSSANNCTFEYVSQPFLMDLE

GKQGNFKNLREFVFKNIDGYFKIYSKHTPINLVRDLPQGFSALEPLVDLPIGINITRFQT

LLALHRSYLTPGDSSSGWTAGAAAYYVGYLQPRTFLLKYNENGTITDAVDCALDPLSETK

CTLKSFTVEKGIYQTSNFRVQPTESIVRFPNITNLCPFGEVFNATRFASVYAWNRKRISN

CVADYSVLYNSASFSTFKCYGVSPTKLNDLCFTNVYADSFVIRGDEVRQIAPGQTGKIAD

YNYKLPDDFTGCVIAWNSNNLDSKVGGNYNYLYRLFRKSNLKPFERDISTEIYQAGSTPC

NGVEGFNCYFPLQSYGFQPTNGVGYQPYRVVVLSFELLHAPATVCGPKKSTNLVKNKCVN

FNFNGLTGTGVLTESNKKFLPFQQFGRDIADTTDAVRDPQTLEILDITPCSFGGVSVITP

GTNTSNQVAVLYQDVNCTEVPVAIHADQLTPTWRVYSIGSNVFQTRAGCLIGAEHVNNSY

ECDIPIGAGICASYQTQTNSPRRARSVASQSIIAYTMSLGAENSVAYSNNSIAIPTNFTI

SVTTEILPVSMTKTSVDCTMYICGDSTECSNLLLQYGSFCTQLNRALTGIAVEQDKNTQE

VFAQVKQIYKTPPIKDFGGFNFSQILPDPSKPSKRSFIEDLLFNKVTLADAGFIKQYGDC

LGDIAARDLICAQKFNGLTVLPPLLTDEMIAQYTSALLAGTITSGWTFGAGAALQIPFAM

QMAYRFNGIGVTQNVLYENQKLIANQFNSAIGKIQDSLSSTASALGKLQDVVNQNAQALN

TLVKQLSSNFGAISSVLNDILSRLDKVEAEVQIDRLITGRLQSLQTYVTQQLIRAAEIRA

SANLAATKMSECVLGQSKRVDFCGKGYHLMSFPQSAPHGVVFLHVTYVPAQEKNFTTAPA

ICHDGKAHFPREGVFVSNGTHWFVTQRNFYEPQIITTDNTFVSGNCDVVIGIVNNTVYDP

LQPELDSFKEELDKYFKNHTSPDVDLGDISGINASVVNIQKEIDRLNEVAKNLNESLIDL

QELGKYEQYIKWPWYIWLGFIAGLIAIVMVTIMLCCMTSCCSCLKGCCSCGSCCKFDEDD

SEPVLKGVKLHYT

18
MERS Spike (S)
>sp|K9N5Q8|SPIKE_MERS1 Spike glycoprotein OS = Middle East

Protein,
respiratory syndrome-related coronavirus (isolate United

UniProtKB-K9N5Q8
Kingdom/H123990006/2012) OX=1263720 GN = S PE = 1 SV = 1

(SPIKE_MERS1)
MIHSVFLLMFLLTPTESYVDVGPDSVKSACIEVDIQQTFFDKTWPRPIDVSKADGIIYPQ

GRTYSNITITYQGLFPYQGDHGDMYVYSAGHATGTTPQKLFVANYSQDVKQFANGFVVRI

GAAANSTGTVIISPSTSATIRKIYPAFMLGSSVGNFSDGKMGRFFNHTLVLLPDGCGTLL

RAFYCILEPRSGNHCPAGNSYTSFATYHTPATDCSDGNYNRNASLNSFKEYFNLRNCTFM

YTYNITEDEILEWFGITQTAQGVHLFSSRYVDLYGGNMFQFATLPVYDTIKYYSIIPHSI

RSIQSDRKAWAAFYVYKLQPLTFLLDFSVDGYIRRAIDCGFNDLSQLHCSYESFDVESGV

YSVSSFEAKPSGSVVEQAEGVECDFSPLLSGTPPQVYNFKRLVFTNCNYNLTKLLSLFSV

NDFTCSQISPAAIASNCYSSLILDYFSYPLSMKSDLSVSSAGPISQFNYKQSFSNPTCLI

LATVPHNLTTITKPLKYSYINKCSRFLSDDRTEVPQLVNANQYSPCVSIVPSTVWEDGDY

YRKQLSPLEGGGWLVASGSTVAMTEQLQMGFGITVQYGTDTNSVCPKLEFANDTKIASQL

GNCVEYSLYGVSGRGVFQNCTAVGVRQQRFVYDAYQNLVGYYSDDGNYYCLRACVSVPVS

VIYDKETKTHATLFGSVACEHISSTMSQYSRSTRSMLKRRDSTYGPLQTPVGCVLGLVNS

SLFVEDCKLPLGQSLCALPDTPSTLTPRSVRSVPGEMRLASIAFNHPIQVDQLNSSYFKL

SIPTNFSFGVTQEYIQTTIQKVTVDCKQYVCNGFQKCEQLLREYGQFCSKINQALHGANL

RQDDSVRNLFASVKSSQSSPIIPGFGGDFNLTLLEPVSISTGSRSARSAIEDLLFDKVTI

ADPGYMQGYDDCMQQGPASARDLICAQYVAGYKVLPPLMDVNMEAAYTSSLLGSIAGVGW

TAGLSSFAAIPFAQSIFYRLNGVGITQQVLSENQKLIANKFNQALGAMQTGFTTTNEAFH

KVQDAVNNNAQALSKLASELSNTFGAISASIGDIIQRLDVLEQDAQIDRLINGRLTTLNA

FVAQQLVRSESAALSAQLAKDKVNECVKAQSKRSGFCGQGTHIVSFVVNAPNGLYFMHVG

YYPSNHIEVVSAYGLCDAANPTNCIAPVNGYFIKTNNTRIVDEWSYTGSSFYAPEPITSL

NTKYVAPQVTYQNISTNLPPPLLGNSTGIDFQDELDEFFKNVSTSIPNFGSLTQINTTLL

DLTYEMLSLQQVVKALNESYIDLKELGNYTYYNKWPWYIWLGFIAGLVALALCVFFILCC

TGCGTNCMGKLKCNRCCDRYEEYDLEPHKVHVH

TABLE 12

Antibody VHH Sequences*

SEQ

Neutral-

ID
VH
Source
Binds to
izes

19
QVQLVESGGGLVQAGGSLRLSCAASGFPVRKANMHWYRQAPGK
Walter, J., et al., (2020), 18
SARS-CoV2

EREWVAAIMSKGEQTVYADSVEGRFTISRDNAKNTVYLQMNSL
pages, bioRxiv preprint doi:

KPEDTAVYYCRVFVGWHYFGQGTQVTVS
10.1101/2020.04.16.045419

20
QVQLVESGGGLVQAGGSLRLSCATSGFPVYQANMHWYRQAPGK
Walter, J., et al., (2020), 18
SARS-CoV2

EREWVAAIQSYGDGTHYADSVKGRFTISRDNAKNTVYLQMNSL
pages, bioRxiv preprint doi:

KPEDTAVYYCRAVYVGMHYFGQGTQVTVS
10.1101/2020.04.16.045419

21
QVQLVESGGGLVQAGGSLRLSCAASGFPVNYKTMWWYRQAPGK
Walter, J., et al., (2020), 18
SARS-CoV2

EREWVAAIWSYGHTTHYADSVKGRFTISRDNAKNTVYLQMNSL
pages, bioRxiv preprint doi:

KPEDTAVYYCVVWVGHNYEGQGTQVTVS
10.1101/2020.04.16.045419

22
QVQLVESGGGLVQAGGSLRLSCAASGFPVYAQNMHWYRQAPGK
Walter, J., et al., (2020), 18
SARS-CoV2

EREWVAAIYSHGYWTLYADSVKGRFTISRDNAKNTVYLQMNSL
pages, bioRxiv preprint doi:

KPEDTAVYYCEVQVGAWYTGQGTQVTVS
10.1101/2020.04.16.045419

23
QVQLVESGGGLVQAGGSLRLSCAASGFPVFSGHMHWYRQAPGK
Walter, J., et al., (2020), 18
SARS-CoV2

EREWVAAILSNGDSTHYADSVKGRFTISRDNAKNTVYLQMNSL
pages, bioRxiv preprint doi:

KPEDTAVYYCRVHVGAHYFGQGTQVTVS
10.1101/2020.04.16.045419

24
QVQLVESGGGLVQAGGSLRLSCAASGFPVEQGRMYWYRQAPGK
Walter, J., et al., (2020), 18
SARS-CoV2

EREWVAAIISHGTVTVYADSVKGRFTISRDNAKNTVYLQMNSL
pages, bioRxiv preprint doi:

KPEDTAVYYCYVYVGAQYWGQGTQVTVS
10.1101/2020.04.16.045419

25
QVQLVESGGGLVQAGGSLRLSCAASGFPVLFTYMHWYRQAPGK
Walter, J., et al., (2020), 18
SARS-CoV2
SARS-CoV2

EREWVAAIWSSGNSTWYADSVKGRFTISRDNAKNTVYLQMNSL
pages, bioRxiv preprint doi:

KPEDTAVYYCFVKVGNWYAGQGTQVTVS
10.1101/2020.04.16.045419

26
QVQLVESGGGLVQAGGSLRLSCAASGFPVNAGNMHWYRQAPGK
Walter, J., et al., (2020), 18
SARS-CoV2

EREWVAAIQSYGRTTYYADSVKGRFTISRDNAKNTVYLQMNSL
pages, bioRxiv preprint doi:

KPEDTAVYYCRVFVGMHYFGQGTQVTVS
10.1101/2020.04.16.045419

27
QVQLVESGGGLVQAGGSLRLSCAASGFPVSSSTMTWYRQAPGK
Walter, J., et al., (2020), 18
SARS-CoV2

EREWVAAINSYGWETHYADSVKGRFTISRDNAKNTVYLQMNSL
pages, bioRxiv preprint doi:

KPEDTAVYYCYVYVGGSYIGQGTQVTVS
10.1101/2020.04.16.045419

28
QVQLVESGGGLVQAGGSLRLSCAASGFPVQSHYMRWYRQAPGK
Walter, J., et al., (2020), 18
SARS-CoV2

EREWVAAIESTGHHTAYADSVKGRFTISRDNAKNTVYLQMNSL
pages, bioRxiv preprint doi:

KPEDTAVYYCTVYVGYEYHGQGTQVTVS
10.1101/2020.04.16.045419

29
QVQLVESGGGLVQAGGSLRLSCAASGFPVETENMHWYRQAPGK
Walter, J., et al., (2020), 18
SARS-CoV2

EREWVAAIYSHGMWTAYADSVKGRFTISRDNTKNTVYLQMNSL
pages, bioRxiv preprint doi:

KPEDTAVYYCEVEVGKWYFGQGTQVTVS
10.1101/2020.04.16.045419

30
QVQLVESGGGLVQAGGSLRLSCAASGFPVKASRMYWYRQAPGK
Walter, J., et al., (2020), 18
SARS-CoV2
SARS-CoV2

EREWVAAIQSFGEVTWYADSVKGRFTISRDNAKNTVYLQMNSL
pages, bioRxiv preprint doi:

KPEDTAVYYCYVWVGQEYWGQGTQVTVS
10.1101/2020.04.16.045419

31
QVQLVESGGGLVQAGGSLRLSCAASGFPVYASNMHWYRQAPGK
Walter, J., et al., (2020), 18
SARS-CoV2

EREWVAAIESQGYMTAYADSVKGRFTISRDNAKNTVYLQMNSL
pages, bioRxiv preprint doi:

KPEDTAVYYCWVIVGEYYVGQGTQVTVS
10.1101/2020.04.16.045419

32
QVQLVESGGGLVQAGGSLRLSCAASGFPVQAREMEWYRQAPGK
Walter, J., et al., (2020), 18
SARS-CoV2
SARS-CoV2

EREWVAAIKSTGTYTAYAYSVKGRFTISRDNAKNTVYLQMNSL
pages, bioRxiv preprint doi:

KPEDTAVYYCYVYVGSSYIGQGTQVTVS
10.1101/2020.04.16.045419

33
QVQLVESGGGLVQAGGSLRLSCAASGFPVKNFEMEWYRKAPGK
Walter, J., et al., (2020), 18
SARS-CoV2
SARS-CoV2

EREWVAAIQSGGVETYYADSVKGRFTISRDNAKNTVYLQMNSL
pages, bioRxiv preprint doi:

KPEDTAVYYCEVYVGRSYIGQGTQVTVS
10.1101/2020.04.16.045419

34
QVQLVESGGGLVQAGGSLRLSCAASGFPVAYKTMWWYRQAPGK
Walter, J., et al., (2020), 18
SARS-CoV2
SARS-CoV2

EREWVAAIESYGIKWTRYADSVKGRFTISRDNAKNTVYLQMNS
pages, bioRxiv preprint doi:

LKPEDTAVYYCIVWVGAQYHGQGTQVTVS
10.1101/2020.04.16.045419

35
QVQLVESGGGLVQAGGSLRLSCAASGFPVAGRNMWWYRQAPGK
Walter, J., et al., (2020), 18
SARS-CoV2
SARS-CoV2

EREWVAAIYSSGTYTEYADSVKGRFTISRDNAKNTVYLQMNSL
pages, bioRxiv preprint doi:

KPEDTAVYYCHVWVGSLYKGQGTQVTVS
10.1101/2020.04.16.045419

36
QVQLVESGGGLVQAGGSLRLSCAASGFPVKHARMWWYRQAPGK
Walter, J., et al., (2020), 18
SARS-CoV2

EREWVAAIDSHGDTTWYADSVKGRFTISRDNAKNTVYLQMNSL
pages, bioRxiv preprint doi:

KPEDTAVYYCYVYVGASYWGQGTQVTVS
10.1101/2020.04.16.045419

37
QVQLVESGGGLVQAGGSLRLSCAASGFPVNSHEMTWYRQAPGK
Walter, J., et al., (2020), 18
SARS-CoV2

EREWVAAIQSTGTVTEYADSVKGRFTISRDNAKNTVYLQMNSL
pages, bioRxiv preprint doi:

KPEDTAVYYCYVYVGSSYLGQGTQVTVS
10.1101/2020.04.16.045419

38
QVQLVESGGGLVQAGGSLRLSCAASGFPVEQREMEWYRQAPGK
Walter, J., et al., (2020), 18
SARS-CoV2

EREWVAAIDSNGNYTFYADSVKGRFTISRDNAKNTVYLQMNSL
pages, bioRxiv preprint doi:

KPEDTAVYYCYVYVGKSYIGQGTQVTVS
10.1101/2020.04.16.045419

39
QVQLVESGGGLVQAGGSLRLSCAASGFPVKHHWMFWYRQAPGK
Walter, J., et al., (2020), 18
SARS-CoV2

EREWVAAIKSYGYGTEYADSVKGRFTISRDNAKNTVYLQMNSL
pages, bioRxiv preprint doi:

KPEDTAVYYCFVGVGTHYAGQGTQVTVS
10.1101/2020.04.16.045419

40
QVQLVESGGGLVQAGGSLRLSCAASGFPVYAAEMEWYRQAPGK
Walter, J., et al., (2020), 18
SARS-CoV2
SARS-CoV2

EREWVAAISSQGTITYYADSVKGRFTISRDNAKNTVYLQMNSL
pages, bioRxiv preprint doi:

KPEDTAVYYCEVYVGKSYIGQGTQVSVS
10.1101/2020.04.16.045419

41
QVQLVESGGGLVQAGGSLRLSCAASGFPVYAAEMEWYRQAPGK
Walter, J., et al., (2020), 18
SARS-CoV2
SARS-CoV2

EREWVAAISSQGTITYYADSVKGRFTISRDNAKNTVYLQMNSL
pages, bioRxiv preprint doi:

KPEDTAVYYCEVYVGKSYIGQGTQVSVS
10.1101/2020.04.16.045419

42
QVQLVESGGGLVQAGGSLRLSCAASGFPVHAWEMAWYRQAPGK
Walter, J., et al., (2020), 18
SARS-CoV2

EREWVAAIRSFGSSTHYADSVKGRFTISRDNAKNTVYLQMNSL
pages, bioRxiv preprint doi:

KPEDTAVYYCNVKDFGTHHYAYDYWGQGTQVTVS
10.1101/2020.04.16.045419

43
QVQLVESGGGLVQAGGSLRLSCAASGFPVNTWWMHWYRQAPGK
Walter, J., et al., (2020), 18
SARS-CoV2

EREWVAAITSWGFRTYYADSVKGRFTISRDNAKNTVYLQMNSL
pages, bioRxiv preprint doi:

KPEDTAVYYCNVKDKGMAVQWYDYWGQGTQVTVS
10.1101/2020.04.16.045419

44
QVQLVESGGGLVQAGGSLRLSCAASGFPVYNTWMEWYRQAPGK
Walter, J., et al., (2020), 18
SARS-CoV2

EREWVAAITSHGYKTYYADSVKGRFTISRDNAKNTVYLQMNSL
pages, bioRxiv preprint doi:

KPEDTAVYYCNVKDEGDMFTAYDYWGQGTQVTVS
10.1101/2020.04.16.045419

45
QVQLVESGGGLVQAGGSLRLSCAASGFPVYHSTMFWYRQAPGK
Walter, J., et al., (2020), 18
SARS-CoV2

EREWVAAIYSSGQHTYYADSVKGRFTISRDNAKNTVYLQMNSL
pages, bioRxiv preprint doi:

KPEDTAVYYCNVKDSGQWRQEYDYWGQGTQVTVS
10.1101/2020.04.16.045419

46
QVQLVESGGGLVQAGGSLRLSCAASGFPVEHEMAWYRQAPGKE
Walter, J., et al., (2020), 18
SARS-CoV2

REWVAAIRSMGRKTLYADSVKGRFTISRDNAKNTVYLQMNSLK
pages, bioRxiv preprint doi:

PEDTAVYYCNVKDFGYTWHEYDYWGQGTQVTVS
10.1101/2020.04.16.045419

47
QVQLVESGGGLVQAGGSLRLSCAASGFPVTMAWMWWYRQAPGK
Walter, J., et al., (2020), 18
SARS-CoV2

EREWVAAIRSEGVRTYYADSVKGRFTISRDNAKNTVYLQMNSL
pages, bioRxiv preprint doi:

KPEDTAVYYCNVKDYGQAHAYYDYWGQGTQVTVS
10.1101/2020.04.16.045419

48
QVQLVESGGGLVQAGGSLRLSCAASGFPVNSHFMEWYRQAPGK
Walter, J., et al., (2020), 18
SARS-CoV2

EREWVAAIQHSSGFHTYYADSVKGRFTISRDNAKNTVYLQMNS
pages, bioRxiv preprint doi:

LKPEDTAVYYCNVKDTGTTEDYDYWGQGTQVTVS
10.1101/2020.04.16.045419

49
QVQLDESGGGLVQAGGSLRLSCAASGFPVYHAWMEWYRQAPGK
Walter, J., et al., (2020), 18
SARS-CoV2

EREWVAAITSSGRHTYYADSVKGRFTISRDNAKNTVYLQMNSL
pages, bioRxiv preprint doi:

KPEDTAVYYCNVKDAGRVYNSYDYWGQGTQVTVS
10.1101/2020.04.16.045419

50
QVQLVESGGGLVQAGGSLRLSCAASGFPVAHAWMEWYRQAPGK
Walter, J., et al., (2020), 18
SARS-CoV2

EREWVAAITSYGYKTYYADSVKGRFTISRDNAKNTVYLQMNSL
pages, bioRxiv preprint doi:

KPEDTAVYYCNVKDTGTYRFYYDYWGQGTQVTVS
10.1101/2020.04.16.045419

51
QVQLVESGGGLVQAGGSLRLSCAASGFPVWNQTMVWYRQAPGK
Walter, J., et al., (2020), 18
SARS-CoV2

EREWVAAIWSMGHTYYADSVKGRFTISRDNAKNTVYLQMNSLK
pages, bioRxiv preprint doi:

PEDTAVYYCNVKDAGVYNRYYDYWGQGTQVTVS
10.1101/2020.04.16.045419

52
QVQLVESGGGLVQAGGSLRLSCAASGFPVEHYWMEWYRQAPGK
Walter, J., et al., (2020), 18
SARS-CoV2

EREWVAAITSFGYRTYYADSVKGRFTISRDNAKNTVYLQMNSL
pages, bioRxiv preprint doi:

KPEDTAVYYCNVKDWGFASHAYDYWGQGIQVTVS
10.1101/2020.04.16.045419

53
QVQLVESGGGLVQAGGSLRLSCAASGFPEIAWEMAWYRQAPGK
Walter, J., et al., (2020), 18
SARS-CoV2

EREWVAAIRSFGERTLYADSVKGRFTISRDNAKNTVYLQMNSL
pages, bioRxiv preprint doi:

KPEDTAVYYCNVKDFGWQHQEYDYWGQGTQVTVS
10.1101/2020.04.16.045419

54
QVQLVESGGGLVQAGGSLRLSCAASGFPVYHAYMEWYRQAPGK
Walter, J., et al., (2020), 18
SARS-CoV2

EREWVAAIYSNGEHTYYADSVKGRFTISRDNAKNTVYLQMNSL
pages, bioRxiv preprint doi:

KPEDTAVYYCNVKDSGSFNQAYDYWGQGTQVTVS
10.1101/2020.04.16.045419

55
QVQLVESGGGLVQAGGSLRLSCAASGFPVEWSHMHWYRQAPGK
Walter, J., et al., (2020), 18
SARS-CoV2

EREWVAAIVSKGGYTLYADSVKGRFTISRDNAKNTVYLQMNSL
pages, bioRxiv preprint doi:

KPEDTAVYYCNVKDYGVHFKRYDYWGQGTQVTVI
10.1101/2020.04.16.045419

56
QVQLVESGGGLVQAGGSLRLSCAASGFPVFHVWMEWYRQAPGK
Walter, J., et al., (2020), 18
SARS-CoV2

EREWVAAIDSAGWHTYYADSVKGRFTISRDNAKNTVYLQMNSL
pages, bioRxiv preprint doi:

KPEDTAVYYCNVKDAGNTTSAYDYWGQGTQVTVS
10.1101/2020.04.16.045419

57
QVQLVESGGGLVQAGGSLRLSCAASGFPVYYNWMEWYRQAPGK
Walter, J., et al., (2020), 18
SARS-CoV2

EREWVAAIHSNGDETFYADSVKGRFTISRDNAKNTVYLQMNSL
pages, bioRxiv preprint doi:

KPEDTAVYYCNVKDIDAEAYAYDYWGQGTQVTVS
10.1101/2020.04.16.045419

58
QVQLVESGGGLVQAGGSLRLSCAASGFPVYHVWMEWYRQAPGK
Walter, J., et al., (2020), 18
SARS-CoV2

EREWVAAITSSGSHTYYADSVKGRFTISRDNAKNTVYLQMNSL
pages, bioRxiv preprint doi:

KPEDTAVYYCNVKDSGQWRVQYDYWGQGTQVTVS
10.1101/2020.04.16.045419

59
QVQLVESGGGLVQAGGSLRLSCAASGFPVYWHHMHWYRQAPGK
Walter, J., et al., (2020), 18
SARS-CoV2
SARS-CoV2

EREWVAAIISWGWYTTYADSVKGRFTISRDNAKNTVYLQMNSL
pages, bioRxiv preprint doi:

KPEDTAVYYCNVKDHGAQNQMYDYWGQGTQVTVS
10.1101/2020.04.16.045419

60
QVQLVESGGGLVQAGGSLRLSCAASGFPVYRDRMAWYRQAPGK
Walter, J., et al., (2020), 18
SARS-CoV2
SARS-CoV2

EREWVAAIYSAGQQTRYADSVKGRFTISRDNAKNTVYLQMNSL
pages, bioRxiv preprint doi:

KPEDTAVYYCNVKDVGHHYEYYDYWGQGTQVTVS
10.1101/2020.04.16.045419

61
QVQLVESGGGLVQAGGSLRLSCAASGFPVDNGYMHWYRQAPGK
Walter, J., et al., (2020), 18
SARS-CoV2
SARS-CoV2

EREWVAAIDSYGWHTIYADSVKGRFTISRDNAKNTVYLQMNSL
pages, bioRxiv preprint doi:

KPEDTAVYYCNVKDKGQMRAAYDYWGQGTQVTVS
10.1101/2020.04.16.045419

62
QVQLVESGGGLVQAGGSLRLSCAASGFPVSWHSMYWYRQAPGK
Walter, J., et al., (2020), 18
SARS-CoV2

EREWVAAIFSEGDWTYYADSVKGRFTISRDNAKNTVYLQMNSL
pages, bioRxiv preprint doi:

KPEDTAVYYCNVKDYGSSYYKYDYWGQGTQVTVS
10.1101/2020.04.16.045419

63
QVQLVESGGGLVQAGGSLRLSCAASGFPVSQSVMAWYRQAPGK
Walter, J., et al., (2020), 18
SARS-CoV2

EREWVAAIYSKGQYTHYADSVKGRFTISRDNAKNTVYLQMNSL
pages, bioRxiv preprint doi:

KPEDTAVYYCNVKDAGSSYWDYDYWGQGTQVTVS
10.1101/2020.04.16.045419

64
QVQLVESGGGSVQAGGSLRLSCAASGSIGQIEYLGWFRQAPGK
Walter, J., et al., (2020), 18
SARS-CoV2

EREGVAALNTWTGRTYYADSVKGRFTVSLDNAKNTVYLQMNSL
pages, bioRxiv preprint doi:

KPEDTALYYCAAARWGRTKPLNTYYYSYWGQGTPVTVS
10.1101/2020.04.16.045419

65
QVQLVESGGGSVQAGGSLRLSCAASGYIDKIVYLGWFRQAPGK
Walter, J., et al., (2020), 18
SARS-CoV2

EREGVAALYTLSGHTYYADSVKGRFTVSLDNAKNTVYLQMNSL
pages, bioRxiv preprint doi:

KPEDTALYYCAAATEGHAHALYRLHYYWGQGTQVTVS
10.1101/2020.04.16.045419

66
QVQLVESGGGLVQAGGSLRLSCAASGFPVYQGEMHWYRQAPGK
Walter, J., et al., (2020), 18
SARS-CoV2

EREWVAAIRSTGVQTWYADSVKGRFTISRDNAKNTVYLQMNSL
pages, bioRxiv preprint doi:

KPEDTAVYYCRVWVGTHYFGQGTQVTVS
10.1101/2020.04.16.045419

67
QVQLVESGGGSVQAGGSLRLSCAASGNIQRIYYLGWFRQAPGK
Walter, J., et al., (2020), 18
SARS-CoV2

EREGVAALMTYTGHTYYADSVKGRFTVSLDNAKNTVYLQMNSL
pages, bioRxiv preprint doi:

KPEDTALYYCAAAYVGAENPLPYSMYGYWGQGTQVTVS
10.1101/2020.04.16.045419

68
QVQLVESGGGSVQAGGSLRLSCAASGQISHIKYLGWFRQAPGK
Walter, J., et al., (2020), 18
SARS-CoV2

EREGVAALITRWGQTYYADSVKGRFTVSLDNAKNTVYLQMNSL
pages, bioRxiv preprint doi:

KPEDTALYYCAAADYGASDPLWFIHYLYWGQGTQVTVS
10.1101/2020.04.16.045419

69
QVQLVESGGGSVQAGGSLRLSCAASGKIWTIKYLGWFRQAPGK
Walter, J., et al., (2020), 18
SARS-CoV2

EREGVAALMTRWGYTYYADSVKGRFTVSLDNAKNTVYLQMNSL
pages, bioRxiv preprint doi:

KPEDTALYYCAAANYGSNFPLAEEDYWYWGQGTQVTVS
10.1101/2020.04.16.045419

70
QVQLVESGGGSVQAGGSLRLSCAASGNISQIHYLGWFRQAPGK
Walter, J., et al., (2020), 18
SARS-CoV2

EREGVAALNTDYGYTYYADSVKGRFTVSLDNAKNTVYLQMNSL
pages, bioRxiv preprint doi:

KPEDTALYYCAAAYYFGDDIPLWWEAYSYWGQGTQVTVS
10.1101/2020.04.16.045419

71
QVQLVESGGGSVQAGGSLRLSCAASGNISTIEYLGWFRQAPGK
Walter, J., et al., (2020), 18
SARS-CoV2

EREGVAALYTWHGQTYYADSVKGRFTVSLDNAKNTVYLQMNSL
pages, bioRxiv preprint doi:

KPEDTALYYCAAARWGRHMPLSATEYSYWGQGTQVTVS
10.1101/2020.04.16.045419

72
QVQLVESGGGSVQAGGSLRLSCAASGNIESIYYLGWFRQAPGK
Walter, J., et al., (2020), 18
SARS-CoV2

EREGVAALWTGDGETYYADSVKGRFTVSLDNAKNTVYLQMNSL
pages, bioRxiv preprint doi:

KPEDTALYYCAAAAWGNSAPLTTYRYYYWGQGTQVTVS
10.1101/2020.04.16.045419

73
QVQLVESGGGSVQAGGSLRLSCAASGFIYGITYLGWFRQAPGK
Walter, J., et al., (2020), 18
SARS-CoV2

EREGVAALVTWNGQTYYADSVKGRFTVSLDNAKNTVYLQMNSL
pages, bioRxiv preprint doi:

KPEDTALYYCAAADWGYDWPLWDEWYWYWGQGTQVTVS
10.1101/2020.04.16.045419

74
QVQLVESGGGSVQAGGSLRLSCAASGTIADIKYLGWFRQAPGK
Walter, J., et al., (2020), 18
SARS-CoV2
SARS-CoV2

EREGVAALMTRWGSTYYADSVKGRFTVSLDNAKNTVYLQMNSL
pages, bioRxiv preprint doi:

KPEDTALYYCAAANYGANYPLYSQQYSYWGQGTQVTVS
10.1101/2020.04.16.045419

75
QVQLVESGGGSVQAGGSLRLSCAASGSISSIKYLGWFRQAPGK
Walter, J., et al., (2020), 18
SARS-CoV2

EREGVAALMTRWGMTYYADSVKGRFTVSLDNAKNTVYLQMNSL
pages, bioRxiv preprint doi:

KPEDTALYYCAAANYGANEPLQYTHYNYWGQGTQVTVS
10.1101/2020.04.16.045419

76
QVQLVESGGGSVQAGGSLRLSCAASGEIESIFYLGWFRQAPGK
Walter, J., et al., (2020), 18
SARS-CoV2

EREGVAALYTYVGQTYYADSVKGRFTVSLDNAKNTVYLQMNSL
pages, bioRxiv preprint doi:

KPEDTALYYCAAASYGAAHPLSIMRYYYWGQGTQVTVS
10.1101/2020.04.16.045419

77
QVQLVESGGGSVQAGGSLRLSCAASGTIAHIKYLGWFRQAPGK
Walter, J., et al., (2020), 18
SARS-CoV2

EREGVAALMTKWGQTYYADSVKGRFTVSLDNAKNTVYLQMNSL
pages, bioRxiv preprint doi:

KPEDTALYYCAAASYGANFPLKASDYSYWGQGTQVTVS
10.1101/2020.04.16.045419

78
QVQLVESGGGSVQAGGSLRLSCAASGSIQAITYLGWFRQAPGK
Walter, J., et al., (2020), 18
SARS-CoV2

EREGVAALVTWNGQTYYADSVKGRFTVSLDNAKNTVYLQMNSL
pages, bioRxiv preprint doi:

KPEDTALYYCAAADWGYDWPLWDEWYWYWGQGTQVTVS
10.1101/2020.04.16.045419

79
QVQLVESGGGSVQAGGSLRLSCAASGSISSITYLGWFRQAPGK
Walter, J., et al., (2020), 18
SARS-CoV2

EREGVAALVTYSGNTYYADSVKGRFTVSLDNAKNTVYLQMNSL
pages, bioRxiv preprint doi:

KPEDTALYYCAAATWGHSWPLYNDEYWYWGQGSQVTVS
10.1101/2020.04.16.045419

80
QVQLVESGGGSVQAGGSLRLSCAASGSISSITYLGWFRQAPGK
Walter, J., et al., (2020), 18
SARS-CoV2
SARS-CoV2

EREGVAALITVNGHTYYADSVKGRFTVSLDNAKNTVYLQMNSL
pages, bioRxiv preprint doi:

KPEDTALYYCAAAAWGYAWPLHQDDYWYWGQGTQVTVS
10.1101/2020.04.16.045419

81
QVQLVESGGGSVQAGGSLRLSCAASGSISSITYLGWFRQAPGK
Walter, J., et al., (2020), 18
SARS-CoV2

EREGVAALNTFNGTTYYADSVKGRFTVSLDNAKNTVYLQMNSL
pages, bioRxiv preprint doi:

KPEDTALYYCAAATWGYSWPLIAEYNWYWGQGTQVTVS
10.1101/2020.04.16.045419

82
QVQLVESGGGSVQAGGSLRLSCAASGSISSITYLGWFRQAPGK
Walter, J., et al., (2020), 18
SARS-CoV2

EREGVAALKTQAGFTYYADSVKGRFTVSLDNAKNTVYLQMNSL
pages, bioRxiv preprint doi:

KPEDTALYYCAAANWGYSWPLYEADDWYWGQGTQVTVS
10.1101/2020.04.16.045419

83
QVQLQESGGGLVQAGGSLRLSCAASGRTFSEYAMGWFRQAPGK
Daniel Wrapp et al., 2020
SARS-
SARS-CoV2

EREFVATISWSGGSTYYTDSVKGRFTISRDNAKNTVYLQMNSL
(www.sciencedirect.com/
CoV1,
and SARS-

KPDDTAVYYCAAAGLGTVVSEWDYDYDYWGQGTQVTVSS
science/article/pii/
SARS-CoV2
CoV1

S0092867420304943)

*Sequence, binding, and neutralization data derived from the CoV-AbDab database: opig.stats.ox.ac.uk/webapps/covabdab/(last visited July 5, 2021) (Raybould, MIJ, et al., Bioinformatics doi = 10.1093/bioinformatics/btaa739 (2020)).

TABLE 13

Antibody VH and VL Sequences*

SEQ

SEQ

Neutral-

ID
VH
ID
VL
Binds to
izes
Source

84
QMQLVQSGTEVKKPGESLKISCKG
85
DIQLTQSPDSLAVSLGERATIN
SARS-
SARS-
Meulen, J., et al.,

SGYGFITYWIGWVRQMPGKGLEW

CKSSQSVLYSSINKNYLAWYQ
CoV1,
CoV1
(2006), PLoS

MGIIYPGDSETRYSPSFQGQVTISA

QKPGQPPKLLIYWASTRESGV
SARS-

Medicine, Vol. 3(7):

DKSINTAYLQWSSLKASDTAIYYC

PDRFSGSGSGTDFTLTISSLQAE
CoV2

e237, 1071-1079

AGGSGISTPMDVWGQGTTVTVSS

DVAVYYCQQYYSTPYTFGQG

TKVEIK

86
EVQLVQSGAEVKKPGASVKVSCK
87
DIVMTQTPATLSLSPGERATLS
SARS-
SARS-
Shi, R., et al., Nature

ASGYTFTSYGISWVRQAPGQGLE

CRASQSVSSYLAWYQQKPGQ
CoV2
CoV2
584: 120-124 (2020)

WMGWISAYNGNTNYAQKLQGRV

APRLLIYDASNRATGIPARFSG

TMTTDTSTSTAYMELRSLRSDDTA

SGSGTDFTLTISSLEPEDFAVY

VYYCAREGYCSGGSCYSGYYYYY

YCQQRRNWGTFGPGTKVDIK

GMDVWGQGTTVTVSS

88
EVQLVESGGGLVQPGGSLRLSCAA
89
DIVMTQSPSSLSASVGDRVTIT
SARS-
SARS-
Shi, R., et al., Nature

SGFTVSSNYMSWVRQAPGKGLEW

CRASQSISRYLNWYQQKPGKA
CoV2
CoV2
584: 120-124 (2020)

VSVIYSGGSTFYADSVKGRFTISRD

PKLLIYAASSLQSGVPSRFSGS

NSMNTLFLQMNSLRAEDTAVYYC

GSGTDFTLTISSLQPEDFATYY

ARVLPMYGDYLDYWGQGTLVTV

CQQSYSTPPEYTFGQGTKLEIK

SS

90
EVQLVESGGGVVQPGRSLRLSCAA
91
DIQLTQSPSSLSASVGDRVTITC
SARS-
SARS-
Robbiani, D., et al.,

SGFTFSIYGMHWVRQAPGKGLEW

RASQSISSYLNWYQQKPGKAP
CoV2
CoV2
Nature 584: 437-442

VAVISYDGSNKYYADSVKGRFTIS

KLLIYAASSLQSGVPSRFSGSG

(2020)

RDNSKNTLYLQMNSLRAEDTAVY

SGTDFTLTISSLQPEDFATYYC

YCAKEGRPSDIVVVVAFDYWGQG

QQSYSTPRTFGQGTKVEIK

TLVTVSS

92
EVQLVESGGGLIQPGGSLRLSCAA
93
EIVLTQSPGTLSLSPGERATLSC
SARS-
SARS-
Robbiani, D., et al.,

SGFTVSSNYMSWVRQAPGKGLEW

RASQSVSSTYLAWYQQKPGQ
CoV2
CoV2
Nature 584: 437-442

VSVIYSGGSTYYADSVKGRFTISRD

APRLLIYGASSRATGIPDRFSGS

(weak)
(2020)

NSKNTLYLQMNSLRAGDTAVYYC

GSGTDFTLTISRLEPEDFAVYY

ARDYGDFYFDYWGQGTLVTVSS

CQQYGSSPRTFGQGTKLEIK

94
QVQLVQSGAEVKKPGASVKVSCK
95
AIRMTQSPSSLSASVGDRVTIT
SARS-
SARS-
Robbiani, D., et al.,

ASGYTFTGYYMHWVRQAPGQGLE

CQASQDISNYLNWYQQKPGK
CoV2
CoV2
Nature 584: 437-442

WMGWINPISGGTNYAQKFQGRVT

APKLLIYDASNLETGVPSRFSG

(2020)

MTRDTSISTAYMELSRLRSDDTAV

SGSGTDFTFTISSLQPEDIATYY

YYCASPASRGYSGYDHGYYYYMD

CQQYDNLPITFGQGTRLEIK

VWGKGTTVTVSS

96
QVQLVQSGPEVKKPGTSVKVSCK
97
EIVLTQSPGTLSLSPGERATLSC
SARS-
SARS-
Robbiani, D., et al.,

ASGFTFTSSAVQWVRQARGQRLE

RASQSVRSSYLAWYQQKPGQ
CoV2
CoV2
Nature 584: 437-442

WIGWIVVGSGNTNYAQKFQERVTI

APRLLIYGASSRATGIPDRFSGS

(2020)

TRDMSTSTAYMELSSLRSEDTAVY

GSGTDFTLTISRLEPEDFAVYY

YCAAPHCSGGSCLDAFDIWGQGT

CQQYGSSPWTFGQGTKVEIK

MVTVSS

98
QVQLVESGGGLVKPGGSLRLSCAA
99
QSVLTQPPSASGTPGQRVTVSC
SARS-
SARS-
Robbiani, D., et al.,

SGFIFSDYCMSWIRRAPGKGLEWL

SGSSSNIGSNTVNWYQQLPGT
CoV2
CoV2
Nature 584: 437-442

SYISNSGTTRYYADSVKGRFTISRD

APKLLIYSNNQRPSGVPDRFSG

(weak)
(2020)

NGRNSLYLQMDSLSAEDTAVYYC

SKSGTSASLAISGLQSEDEADY

ARRGDGSSSIYYYNYMDVWGKGT

FCAAWDDSLNGPVFGGGTKL

TVTVSS

TVL

100
EVQLVESGGGVVQPGRSLRLSCAA
101
DIQMTQSPSTLSASVGDRVTIT
SARS-
SARS-
Robbiani, D., et al.,

SGFTFSSYGMHWVRQAPGKGLEW

CRANQSISSWLAWYQQKPGK
CoV2
CoV2
Nature 584: 437-442

VTVISYDGRNKYYADSVKGRFTIS

APKLLIYKASSLESGVPSRFSG

(weak)
(2020)

RDNSKNTLYLQMNSLRAEDTAVY

SGSGTEFTLTISSLQPDDFATY

YCAREFGDPEWYFDYWGQGTLVT

YCQQYNSYWTFGQGTKVEIK

VSS

102
QVQLVQSGAEVKKPGASVKVSCM
103
QSALTQPPSASGSPGQSVTISC
SARS-
SARS-
Robbiani, D., et al.,

ASGYTFTGYYMHWVRQAPGQGLE

TGTSSDVGGYNYVSWYQQHP
CoV2
CoV2
Nature 584: 437-442

WMGWINPNSGGTNYAQKFQGRV

GKAPKLMIYEVSKRPSGVPDR

(2020)

TMTRDTSISTAYMELSRLRSDDTA

FSGSKSGNTASLTVSGLQAED

VYYCARDSPFSALGASNDYWGQG

EAEYYCSSDAGSNNVVFGGGT

TLVTVSS

KLTVL

104
EVQLVESGGGVVQPGRSLRLSCAA
105
DIQLTQSPSSLSASVGDRVTITC
SARS-

Robbiani, D., et al.,

SGFTFSSYAMHWVRQAPAKGLEW

RASQSISTYLNWYQQKPGKAP
CoV2

Nature 584: 437-442

VAVILYDGSGKYYADSVKGRFTIS

KLLIYAASSLQSGVPSRFSGSG

(2020)

RDNSKNTLYLQMNSLRAEDTAVY

SGTDFTLTISSLQPEDFATYYC

YCARDGIVDTALVTWFDYWGQGT

QQSYSTPPWTFGQGTKVEIK

LVTVSS

106
QVQLVQSGAEVKKPGSSVKVSCK
107
EIVLTQSPATLSLSPGERATLSC
SARS-
SARS-
Robbiani, D., et al.,

ASGGTFSSYAISWVRQAPGQGLEW

RASQSVSSYLAWYQQKPGQA
CoV2
CoV2
Nature 584: 437-442

MGGIIPIFGTANYAQKFQGRVTITA

PRLLIYDASNRATGIPARFSGS

(weak)
(2020)

DESTSTAYMELSSLRSEDTAVYYC

GSGTDFTLTISSLEPEDFAVYY

ARGNRLLYCSSTSCYLDAVRQGY

CQQRSNWPLTFGGGTKVEIK

YYYYYMDVWGKGTTVTVSS

108
EVQLVESGGGVVQPGRSLRLSCAA
109
AIRMTQSPSSLSASVGDRVTIT
SARS-

Robbiani, D., et al.,

SGFTFSRYGMHWVRQAPGKGLEW

CQASQDISNYLNWYQQKPGK
CoV2

Nature 584: 437-442

VAVISYDGSNKYYADSVKGRFTIS

APKLLIYDASNLETGVPSRFSG

(2020)

RDNSKNTLYLQMNSLRAEDTAVY

SGSGTDFTFTINSLQPEDIATYY

YCAKVTAPYCSGGSCYGGNFDYW

CQQYDNLPPTFGGGTKVEIK

GQGTLVTVSS

110
EVQLVESGGGLVQPGRSLRLSCAA
111
EIVLTQSPATLSLSPGERATLSC
SARS-
SARS-
Robbiani, D., et al.,

SGFTFDDYAMHWVRQAPGKGLE

RASQSVSSYLAWYQQKPGQA
CoV2
CoV2
Nature 584: 437-442

WVSGISWNSGTIGYADSVKGRFTI

PRLLIYDASNRATGIPARFSGS

(2020)

SRDNAKNSLYLQMNSLRAEDTAF

GSGTDFTLTISSLEPEDFAVYY

YYCAKAGVRGIAAAGPDLNFDHW

CQQRITFGQGTRLEIK

GQGTLVTVSS

112
EVQLVESGGGVVQPGRSLRLSCAA
113
DIQLTQSPSSLSASVGDRVTITC
SARS-

Robbiani, D., et al.,

SGFTFSNYAIHWVRQAPGKGLEW

RASQSIRSYLNWYQQKPGKAP
CoV2

Nature 584: 437-442

VAVISYDGSNKYYADSVKGRFTIS

KLLIYAASSLQSGVPSRFSGSG

(2020)

RDNSKNTLYLQMNSLRAEDTAVY

SGTDFTLTISSLQPDDFATYYC

YCARDFDDSSFWAFDYWGQGTLV

QQSYSTPPATFGQGTKLEIK

TVSS

114
QVQLVQSGAEVKKPGASVKVSCK
115
SYELTQPPSVSVAPGKTARITC
SARS-

Robbiani, D., et al.,

ASGYTFTSYYMHWVRQAPGQGLE

GENNIGSKSVHWYQQKPGQA
CoV2

Nature 584: 437-442

WMGIINPSGGSTSYAQKFQGRVTM

PVLVIYYDSDRPSGIPERFSGSN

(2020)

TRDTSTSTVYMELSSLRSEDTAVY

SGNTATLTINRVEAGDEADYY

YCARVPREGTPGFDPWGQGTLVT

CQVWDSSSDHVVFGGGTKLT

VSS

VL

116
QVQLQESGPGLVKPSQTLSLTCTV
117
DIVMTQSPLSLPVTPGEPASISC
SARS-

Robbiani, D., et al.,

SGGSISSGGYYWSWIRQHPGKGLE

RSSQSLLHSNGYNYLDWYLQ
CoV2

Nature 584: 437-442

WIGYIYYSGSTYYNPSLKSRVTISV

KPGQSPQLLIYLGSNRASGVPD

(2020)

DTSKNQFSLKLSSVTAADTAVYYC

RFSGSGSGTDFTLKISRVEAED

ARVWQYYDSSGSFDYWGQGTLVT

VGVYYCMQALQTPFTFGPGTK

VSS

VDIK

118
QVQLQESGPGLVKPSETLSVTCTV
119
DIQMTQSPSTLSASVGDSVTIT
SARS-
SARS-
Robbiani, D., et al.,

SGGSISSSRYYWGWIRQPPGKGLE

CRASQSISSWLAWYQQKPGKA
CoV1,
CoV2
Nature 584: 437-442

WIGSIYYSGSTYYNPSLKSRVTISV

PKLLIYKASSLESGVPSRFSGS
SARS-

(2020)

DTSKNQFSLKLSSVTAADTAVYYC

GSGTEFTLTISSLQPDDFATYY
CoV2

ARHAAAYYDRSGYYFIEYFQHWG

CQQYNNYRYTFGQGTKLEIK

QGTLVTVSS

120
EVQLVESGGGVVQPGRSLRLSCAA
121
DIQMTQSPSTLSASVGDRVTIT
SARS-

Robbiani, D., et al.,

SGFTFSSYGMHWVRQAPGKGLEW

CRASQSISSWLAWYQQKPGKA
CoV1

Nature 584: 437-442

VAVISYDGSNKYYADSVKGRFTIS

PKLLIYKASSLESGVPSRFSGS
(weak),

(2020)

RDNSKNTLYLQMNSLRAEDTAVY

GSGTEFTLTISSLQPDDFATYY
SARS-

YCAKASGIYCSGGDCYSYYFDYW

CQQYNSYSTFGQGTKVEIK
CoV2

GQGTLVTVSS

122
QVQLQESGPGLVKPSQTLSLTCTV
123
DIVMTQSPLSLPVTPGEPASISC
SARS-

Robbiani, D., et al.,

SGGSISSGGYYWSWIRQHPGKGLE

RSSQSLLHSNGYNYLDWYLQ
CoV2

Nature 584: 437-442

WIGYIYYSGSTYYNPSLKSRVTISV

KPGQSPQLLIYLGSNRASGVPD

(2020)

DTSKNQFSLKLSSVTAADTAVYYC

RFSGSGSGTDFTLKISRVEAED

ARTMYYYDSSGSFDYWGQGTLVT

VGVYYCMQALQTPHTFGGGT

VSS

KVEIK

124
EVQLVESGGGVVQPGRSLRLSCAA
125
DIQMTQSPSTLSASVGDRVTIT
SARS-

Robbiani, D., et al.,

SGFTFSSYGMHWVRQAPGKGLEW

CRASQSISSWLAWYQQKPGKA
CoV2

Nature 584: 437-442

VAVISYDGSNKYYADSVKGRFTIS

PKLLIYKASSLESGVPSRFSGS

(2020)

RDNSKNTLYLQMNSLRAEDTAVY

GSGTEFTLTISSLQPDDFATYY

YCAKASGIYCSGGNCYSYYFDYW

CQQYNSYSTFGQGTKVEIK

GQGTLVTVSS

126
EVQLVESGGGLVQPGGSLRLSCAA
127
DIQMTQSPSSLSASVGDRVTIT
SARS-

Robbiani, D., et al.,

SGFTFSSYDMHWVRQATGKGLEW

CRASQSISSYLNWYQQKPGKA
CoV2

Nature 584: 437-442

VSAIGTAGDTYYPGSVKGRFTISRE

PKVLIYAASSLQSGVPSRFSGS

(2020)

NAKNSLYLQMNSLRAGDTAVYYC

GSGTDFTLTISSLQPEDFATYY

ARVGYDSSGYSGWYFDLWGRGTL

CQQSYSTPPLTFGGGTKVEIK

VTVSS

128
QVQLVESGGGLIQPGGSLRLSCAA
129
EIVLTQSPGTLSLSPGERATLSC
SARS-
SARS-
Robbiani, D., et al.,

SGFIVSSNYMSWVRQAPGKGLEW

RASQSVSSSYLAWYQQKPGQ
CoV2
CoV2
Nature 584: 437-442

VSVIYSGGSTFYTDSVKGRFTISRD

APRLLIYGASSRATGIPDRFSG

(2020)

NSKNTLYLQMNSLRAEDTAVYYC

GGSETDFTLTISRLEPEDCAVY

VRDYGDFYFDYWGQGTLVTVSS

YCQQYGSSPRTFGQGTKVEIK

130
QVQLVESGGGLIQPGGSLRLSCAA
131
EIVLTQSPGTLSLSPGERATLSC
SARS-
SARS-
Robbiani, D., et al.,

SGFIVSSNYMSWVRQAPGKGLEW

RASQSVSSSYLAWYQQKPGQ
CoV2
CoV2
Nature 584: 437-442

VSVIYSGGSTFYADSVKGRFTISRD

APRLLIYGASSRATGIPDRFSGS

(2020)

NSKNTLYLQMNSLRAEDTAVYYC

GSGTDFTLTISRLEPEDFAVYY

ARDYGDYYFDYWGQGTLVTVSS

CQQYGSSPRTFGQGTKVEIK

132
QVQLQQWGAGLLKPSETLSLTCA
133
EIVLTQSPGTLSLSPGERATLSC
SARS-
SARS-
Robbiani, D., et al.,

VSGGSLSGFYWTWIRQPPGKGLE

RASQTVTANYLAWYQQKPGQ
CoV2
CoV2
Nature 584: 437-442

WIGETNHFGSTGYKPSLKSRVTISV

APRLLIYGASKRATGIPDRFSG

(2020)

DMSRNQFSLKVTSVTAADTAVYY

SGSGTDFTLSISRLEPEDFAVY

CARKPLLYSDFSPGAFDIWGQGTM

YCQQYTTTPRTFGGGTKVEIK

VTVSS

134
QVQLQQWGAGLLKPSETLSLSCA
135
EIVLTQSPGTVSLSPGERATLS
SARS-
SARS-
Robbiani, D., et al.,

VYGGSLSGYYWSWIRQPPGKGLE

CWASQSVSASYLAWYQQKPG
CoV2
CoV2
Nature 584: 437-442

WIGEINHFGSTGYNPSLKSRVTISV

QAPRLLIYGASSRATGIPDRFS

(2020)

DTSKSQFSVKLSSVTAADTAVYYC

GSGSGTDFTLTISRLEPEDFAV

ARKPLLYSNLSPGAFDIWGQGTMV

YYCQQYGTTPRTFGGGTKVEI

TVSS

K

136
QVQLVESGGGLIQPGGSLRLSCAA
137
QSALTQPPSASGSPGQSVTISC
SARS-
SARS-
Robbiani, D., et al.,

SGFTVSSNYMSWVRQAPGKGLEW

TGTSSDVGGYKYVSWYQQHP
CoV2
CoV2
Nature 584: 437-442

VSVIYSGGSTYYADSVKGRFTISRD

GKAPKLMIYEVSKRPSGVPDR

(2020)

NSKNTLYLQMNSLRAEDTAVYYC

FSGSKSGNTASLTVSGLQAED

ARGEGWELPYDYWGQGTLVTVSS

EADYYCSSYEGSNNFVVFGGG

TKLTVL

138
QLQLQESGPGLVKPSETLSLTCTVS
139
SYELTQPPSVSVAPGKTARITC
SARS-

Robbiani, D., et al.,

GASVSSGSYYWSWIRQPPGKGLE

GGNNIGSKSVHWYQQKPGQA
CoV1,

Nature 584: 437-442

WIGYIYYSGSTNYNPSLKSRVTISV

PVLVIYFDSDRPSGIPERFSGSN
SARS-

(2020)

DTSKNQFSLKLSSVTAADTAVYYC

SGNTATLTISRVEAGDEADYY
CoV2

ARERPGGTYSNTWYTPTDTNWFD

CQVWDSSRDHVVFGGGTKLT

TWGQGTLVTVSS

VL

140
QVQLVQSGAEVKKPGASVRVSCK
141
QSVLTQPPSASGTPGQRVTISC
SARS-

Robbiani, D., et al.,

ASGYTFTSYGFSWVRQAPGQGLE

SGSSSNIGSNYVYWYQQLPGT
CoV2

Nature 584: 437-442

WMGWISAYNGNTNFAQKLQGRV

APKLLIYRNNQRPSGVPDRFSG

(2020)

TMTTDTSTSTAYMELRSLRSDDTA

SKSGTSASLAISGLRSEDEADY

VYYCARGEAVAGTTGFFDYWGQ

YCAAWDDSLSGFVVFGGGTK

GTLVTVSS

LTVL

142
QVQLQESGPGLVKPSGTLSLTCAV
143
QSALTQPASVSGSPGQSITISCT
SARS-
SARS-
Robbiani, D., et al.,

SGGSISSTNWWSWVRQPPGKGLE

GTSSDVGGYNYVSWYQQHPG
CoV2
CoV2
Nature 584: 437-442

WIGEIYHTGSTNYNPSLKSRVTISV

KAPKLMIYDVSNRPSGVSNRF

(weak)
(2020)

DKSKNQFSLKLSSVTAADTAVYYC

SGSKSGNTASLTISGLQAEDEA

VRDGGRPGDAFDIWGQGTMVTVS

DYYCNSYTSSSTRVFGTGTKV

S

TVL

144
EVQLVESGGGLVQPGGSLRLSCAA
145
QSALTQPPSASGSPGQSVTISC
SARS-

Robbiani, D., et al.,

SGFTFSSYWMSWVRQAPGKGLEW

TGTSSDVGGYNYVSWYQQHP
CoV2

Nature 584: 437-442

VANIKQDGSEKYYVDSVKGRFTIS

GKAPKLMIYEVTKRPSGVPDR

(2020)

GDNAKNSLYLHMNSLRAEDTAVY

FSGSKSGNTASLTVSGLQAED

YCAIQLWLRGGYDYWGQGTLVTV

EADYYCSSYAGSNNYVVFGG

SS

GTKLTVL

146
QVQLQQSGAEVKKPGESLKISCKG
147
DIQMTQSPSTLSASVGDRVTIT
SARS-
SARS-
Robbiani, D., et al.,

SGYSFTSYWIGWVRQMPGKGLEW

CRASQSISYWLAWYQQKPGK
CoV2
CoV2
Nature 584: 437-442

MGIIYPGDSDTRYSPSFQGQVTISA

APKLLIYQASSLESGVPSRFSG

(2020)

DKSISTAYMQWSSLKASDTAMYY

SESGTEFTLTISSLQPDDFATYY

CARSFRDDPRIAVAGPADAFDIWG

CQQYNSYPYTFGQGTKLEIK

QGTMVTVSS

148
QLQLQESGPGLVKPSETLSLTCTVS
149
QSVLTQPPSVSEAPRQRVTISC
SARS-

Robbiani, D., et al.,

GGSISSYYWSWIRQPPGKGLEWIG

SGSSSNIGNNAVNWYQQVPGK
CoV2

Nature 584: 437-442

YIYYSGSTNYNPSLKSRVTISVDTS

APKLLIYYDDLLPSGVSDRFSG

(2020)

KNQFSLKLSSVTAADTAVYYCAR

SKSGTSASLAISGLQSEDEADY

VEDWGYCSSTNCYSGAFDIWGQG

YCAAWDDSLNGAWVFGGGT

TMVTVSS

KLTVL

150
QVQLVESGGGVVQPGRSLRLSCA
151
QSALTQPASVSGSPGQSITISCT
SARS-
SARS-
Robbiani, D., et al.,

ASGFTFSSHAMHWVRQAPGKGLE

GTSSDVGGYNYVSWYQQHPG
CoV2
CoV2
Nature 584: 437-442

WVAVISYDGSNKYYADSVKGRFTI

KAPKLMIYDVSNRPSGVSNRF

(weak)
(2020)

SRDNSKNTLYLQMNSLRAEDTAV

SGSKSGNTASLTISGLQAEDEA

YYCAREDYYDSSGSFDYWGQGTL

DYYCSSYTSSSTWVFGGGTKL

VTVSS

TVL

152
QVQLVESGGGVVQPGRSLRLSCA
153
DIQMTQSPSTLSASVGDRVTIT
SARS-

Robbiani, D., et al.,

ASGFTFSNFGMHWVRQAPGKGLE

CRASQSMSSWLAWYQQKPGN
CoV2

Nature 584: 437-442

WVAVIWYDGSNKYYADSVKGRFT

APKLLIYKASSLESGVPSRFSG

(2020)

ISRDNSKNTLYLQMNSLRAEDTAV

SGSGTEFTLTISSLQPDDFATY

YYCARGVNPDDILTGVDAFDIWG

YCQQHNSSPLTFGGGTKVEIK

QGTMVTVSS

154
QVQLVESGGGLIQPGGSLKLSCVV
155
QSVLTQPPSVSGAPGQRVTISC
SARS-

Robbiani, D., et al.,

SGFTVSKNYISWVRQAPGKGLEW

TGTSSNIGAGYDVHWYQQLPG
CoV2

Nature 584: 437-442

VSVIFAGGSTFYADSVKGRFAISRD

RAPKVLISGNNIRPSEVPDRFS

(2020)

NSNNTLFLQMNSLRVEDTAIYYCA

GSRSGTSASLAITSLQPEDEAQ

RGDGELFFDQWGQGTLVTVSS

YYCQSYDSSLYAVFGGGTKLT

VL

156
QVQLVESGGGLIKPGRSLRLSCTAS
157
DIVMTQSPLSLSVTPGEPASISC
SARS-
SARS-
Robbiani, D., et al.,

GFTFGDYAMTWFRQAPGKGLEW

RSSQSLLHSNGNNYFDWYLQK
CoV2
CoV2
Nature 584: 437-442

VGFIRSKAYGGTTGYAASVKYRFT

PGQSPQLLIYLGSNRASGVPDR

(weak)
(2020)

ISRDDSKSIAYLQMDSLKTEDTAV

FSGSGSGTDFTLKISRVEAEDV

YYCTRWDGWSQHDYWGQGTLVT

GVYYCMQVLQIPYTFGQGTKL

VSS

EIK

158
QVQLVESGGGVVQPGRSLRLSCA
159
NFMLTQPHSVSESPGKTVTISC
SARS-

Robbiani, D., et al.,

ASGFTYSTYAMHWVRQAPGKGLE

TGSSGSIASNYVQWYQQRPGS
CoV2

Nature 584: 437-442

WVAFISYDGSNKYYADSVKGRFTI

APTTVIYEDNQRPSGVPDRFSG

(2020)

SRDNSKNTLYLQMNSLRAEDTAV

SIDRSSNSASLTISGLKTEDEAD

YYCARDFYHNWFDPWGQGTLVT

YYCQSYDSGNHWVVFGGGTR

VSS

LTVL

160
QVQLVESGGGVVQPGRSLRLSCA
161
QSVLTQPPSVSAAPGQKVTISC
SARS-
SARS-
Robbiani, D., et al.,

ASGFTFSTYAMHWVRQAPGEGLE

SGSSSNIGNNLVSWYQQLPGT
CoV2
CoV2
Nature 584: 437-442

WVAVISYDGSNTYYADSVKGRFTI

APKLLIYENNKRPSGIPDRFSG

(weak)
(2020)

SRDNSKNTLYLQMNSLRAEDTAV

SKSGTSATLGITGLQTGDEAD

YYCARDPIWFGELLSPPFVHFDYW

YYCGAWDSSLSAGGVYVFGT

GQGTLVTVSS

GTKVTVL

162
QVQLVESGGGVVQPGRSLRLSCA
163
QPVLTQSPSASASLGASVKLTC
SARS-
SARS-
Robbiani, D., et al.,

ASGFTFSNYAMHWVRQAPGKGLE

TLSSGHSSYAIAWHQQQPEKG
CoV1,
CoV2
Nature 584: 437-442

WVAVISYDGSNKYYADSVKGRFTI

PRYLMKLNTDGSHSKGDGIPD
SARS-
(weak)
(2020)

SRDNSKNTLYLQMNSLRAEDTAIY

RFSGSSSGAERYLTISSLQSEDE
CoV2

YCASGYTGYDYFVRGDYYGLDV

ADYYCQTWGTGILVFGGGTK

WGQGTTVTVSS

LTVL

164
QVQLVQSGAEVKKPGASVKVSCK
165
QSALTQPASVSGSPGQSITISCT
SARS-
SARS-
Robbiani, D., et al.,

ASGYTFTSYYMHWVRQAPGQGLE

GTSSDVGGYKYVSWYQRHPG
CoV2
CoV2
Nature 584: 437-442

WMGIINPSGGSTSYAQKLQGRVT

KAPKLMIYDVSNRPSGVSNRF

(2020)

MTRDTSTSTVYMELSSLRSEDTAV

SGSKSGNTASLTISGLQAEDEA

YYCARANHETTMDTYYYYYYMD

DYYCSSYTSSSTSVVFGGGTQ

VWGKGTTVTVSS

LTVL

166
EVQLVESGGGLIQPGGSLRLSCAA
167
AIRMTQSPSSLSASVGDTVTIT
SARS-
SARS-
Robbiani, D., et al.,

SGFTVSSNYMTWVRQAPGKGLEW

CQASQDISKYLNWYQQKPGK
CoV2
CoV2
Nature 584: 437-442

VSLIYPGGSTYYADSVKGRFTISRD

APKLLIYDASNLETGVPSRFSG

(2020)

NSKNTLYLQMNSLRAEDTAVYYC

SGSGTDFTFTISSLQPEDIATYY

AREGMGMAAAGTWGQGTLVTVSS

CQQYDNLPQTFGGGTKVEIK

168
QVQLVQSGAEVKKPGASVKVSCK
169
QSALTQPASVSGSPGQSITISCT
SARS-
SARS-
Robbiani, D., et al.,

ASGYTFTGYYMHWVRQAPGQGLE

GTSSDVGSYNLVSWYQQHPG
CoV2
CoV2
Nature 584: 437-442

WMGWISPVSGGTNYAQKFQGRVT

KAPKLMIYEGSKRPSGVSNRFS

(2020)

MTRDTSISTAYMELSRLRSDDTAV

GSKSGNTASLTISGLQAEDEAD

YYCARAPLFPTGVLAGDYYYYGM

YYCCSYAGSSTLVFGGGTKLT

DVWGQGTTVTVSS

VL

170
EVQLVESGGGLIQPGGSLRLSCAA
171
DIQLTQSPSFLSASVGDRVTITC
SARS-
SARS-
Robbiani, D., et al.,

SGLTVSSNYMSWVRQAPGKGLEW

RASQGISSYLAWYQQKPGKAP
CoV2
CoV2
Nature 584: 437-442

VSVLYSGGSSFYADSVKGRFTISRD

KLLIYAASTLQSGVPSRFSGSG

(2020)

NSKNTLYLQMNSLRAEDTAVYYC

SGTEFTLTISSLQPEDFATYYC

ARESGDTTMAFDYWGQGTLVTVSS

QQLNSDSYTFGQGTKLEIK

172
EVQLVESGGGLIQPGGSLRLSCAA
173
DIQLTQSPSFLSASVGDRVTITC
SARS-
SARS-
Robbiani, D., et al.,

SGVTVSRNYMSWVRQAPGKGLE

RASQGISSYLAWYQQKPGKAP
CoV2
CoV2
Nature 584: 437-442

WVSVIYSGGSTYYADSVKGRFTIS

KLLIYAASTLQSGVPSRFSGSG

(2020)

RDNSKNTLYLQMNSLRAEDTAVY

SGTEFTLTISSLQPEDFATYYC

YCARDLSAAFDIWGQGTMVTVSS

QQLNSYPPAFGQGTRLEIK

174
EVQLVESGGGLVQPGGSLRLSCAA
175
EIVLTQSPATLSLSPGERATLSC
SARS-
SARS-
Robbiani, D., et al.,

SGFTFSGYSMNWVRQAPGKGPEW

RASQSFSSYLAWYQQKPGQAP
CoV2
CoV2
Nature 584: 437-442

VSYISRSSSTIYYADSVKGRFTISRD

RLLIYDASNRATGIPARFSGSG

(weak)
(2020)

NAKNSLYLQMNSLRDEDTAVYYC

SGTDFTLTISSLEPEDFAVYYC

AREGARVGATYDTYYFDYWGQG

QQRNNWPPEWTFGQGTKVEI

TLVTVSS

K

176
QVQLVQSGPEVKKPGTSVKVSCK
177
EIVLTQSPGTLSLSPGERATLSC
SARS-
SARS-
Robbiani, D., et al.,

ASGFTFTSSAVQWVRQARGQRLE

RASQSVSSSYLAWYQQKPGQ
CoV2
CoV2
Nature 584: 437-442

WIGWIVVGSGNTNYAQKFQERVTI

APRLLIYGASSRATGIPDRFSGS

(2020)

TRDMSTSTAYMELSSLRSEDTAVY

GSGTDFTLTISRLEPEDFAVYY

YCAAPYCSGGSCSDAFDIWGQGT

CQQYGSSPWTFGQGTKVEIK

MVTVSS

178
QVQLQESGPGLVKPSETLSLSCAV
179
NFMLTQPHSVSESPGKTVTISC
SARS-

Robbiani, D., et al.,

SGGSIGSYFWSWIRQPPGKGLEWI

TGSSGSIASNYVQWYQQRPGS
CoV2

Nature 584: 437-442

GYLHYSGSTNYNPSLKSRVTISVD

APTTVINEDNQRPSGVPDRFSG

(2020)

TSKNQFSLKLSSVTAADTAVYYCA

SIDSSSNSASLTISGLKTEDEAD

RLQWLRGAFDIWGQGTMVTVSS

YYCQSYDSSNLVFGGGTKLTV

L

180
QVQLVQSGAEVKKPGASVKVSCK
181
QSVLTQPPSASGTPGQRVTISC
SARS-
SARS-
Robbiani, D., et al.,

ASGYTFTGYYMHWVRQAPGQGLE

SGSSSNIGSNTVNWYQQLPGT
CoV2
CoV2
Nature 584: 437-442

WMGWINPNSGGTNYAQKFQGRV

APKLLIYSNNQRPSGVPDRFSG

(2020)

TMTRDTSISTAYMELSRLRSDDTA

SKSGTSASLAISGLQSEDEADY

VYYCATAHPRRIQGVFFLGPGVW

YCAAWDDSLNGVVFGGGTKL

GQGTTVTVSS

TVL

182
EVQLLESGGGLVQPGGSLRLSCAA
183
EIVLTQSPGTLSLSPGERATLSC
SARS-
SARS-
Robbiani, D., et al.,

SGFTFSTYAMSWVRQAPGKGLEW

RASQSVNSRQLAWYQQKPGQ
CoV2
CoV2
Nature 584: 437-442

VSTITGSGRDTYYADSVKGRFTISR

APRLLIYGASSRATGIPERFSGS

(2020)

DNSKNTLFLQLNSLRAEDAAVYSC

GSGTDFTLTISRLESEDFAVYH

ANHPLASGDDYYHYYMDVWGKG

CQQYGSSRALTFGGGTKVEIK

TTVTVSS

184
QVQLVQSGAEVKKPGASVKVSCK
185
SYELTQPPSVSVAPGKTARITC
SARS-

Robbiani, D., et al.,

ASGYTFTNYYMHWVRQAPGQGLE

GGNNIGSKSVHWYQQKPGQA
CoV2

Nature 584: 437-442

WMGIINPSGGSTGYAQKFQGRVT

PVLVIYYDSDRPSGIPERFSGSN

(2020)

MTRDTSTSTVYMELSSLRSEDTAV

SGNTATLTISRVEAGDEADYY

YYCARSRPTPDWYFDLWGRGTLV

CQVWDSSSDHPGVVFGGGTK

TVSS

LTVL

186
QVQLVQSGSEVKKPGSSVKVSCK
187
EIVMTQSPATLSVSPGERATLS
SARS-
SARS-
Robbiani, D., et al.,

ASGGTFSSYAFSWVRQAPGQGLE

CRASQSVSSNLAWYQQKPGQ
CoV2
CoV2
Nature 584: 437-442

WMGRIIPILALANYAQKFQGRVTIT

APRLLIYGASTRATGIPARFSG

(2020)

ADKSTSTAYMELSSLRSEDTAVYY

SGSGTEFTLTISSLQSEDFAVY

CARVNQAVTTPFSMDVWGQGTTV

YCQQYNNWPITFGQGTRLEIK

TVSS

188
QVQLQESGPGLVKPSGTLSLTCAV
189
QSALTQPASVSGSPGQSITISCT
SARS-
SARS-
Robbiani, D., et al.,

SGGSISSNNWWSCVRQPPGKGLE

GTSSDVGGYNYVSWYQQHPG
CoV2
CoV2
Nature 584: 437-442

WIGEIYHSGSTNYNPSLKSRVTISV

KAPKLMIYDVSNRPSGVSNRF

(weak)
(2020)

DKSKNQFSLKLSSVTAADTAVYYC

SGSKSGNTASLTISGLQAEDEA

ARGGDTAMGPEYFDYWGQGTLV

DYYCSSYTSSSTLLFGGGTKLT

TVSS

VL

190
QVQLVESGGGVVQPGRSLRLSCA
191
DIQMTQSPSSLSASVGDRVTIT
SARS-

Robbiani, D., et al.,

ASGFTFSSYAMHWVRQAPGKGLE

CRASQSISSYLNWYQQKPGKA
CoV2

Nature 584: 437-442

WVAVILYDGSNKYYADSVKGRFTI

PKLLIYAASSLQSGVPSRFSGS

(2020)

SRDNSKNTLYLQMNSLRAEDTAV

GSGTDFTLTISSLQPEDFATYY

YYCARDSDVDTSMVTWFDYWGQ

CQQSYSTPPWTFGQGTKVEIK

GTLVTVSS

192
EVQLLESGGGLVQPGGSLRLSCAA
193
SYELTQPPSVSVAPGKTARITC
SARS-

Robbiani, D., et al.,

SGFTFSNYAMSWVRQAPGKGLEW

GGNNIGSKSVHWYQQKPGQA
CoV2

Nature 584: 437-442

VSAISGSDGSTYYAGSVKGRFTISR

PVLVIYYDSDRPSGIPERFSGSN

(2020)

DNSKNTLYLQMNSLRAEDTAVYY

SGNTATLTISRVEAGDEAEYH

CAKDPLITGPTYQYFHYWGQGTL

CQVWDSSSDRPGVVFGGGTK

VTVSS

LTVL

194
QVQLVESGGGVVQPGRSLRLSCA
195
DIQMTQSPSTLSASVGDRVTIT
SARS-
SARS-
Robbiani, D., et al.,

ASGFTFSSYAMHWVRQAPGKGLE

CRASQSISNWLAWFQQKPGKA
CoV2
CoV2
Nature 584: 437-442

WVAVIPFDGRNKYYADSVTGRFTI

PKLLIYEASSLESGVPSRFSGSG

(2020)

SRDNSKNTLYLQMNSLRAEDTAV

SGTEFTLTISSLQPDDFATYYC

YYCASSSGYLFHSDYWGQGTLVT

QQYNSYPWTFGQGTKVEIK

VSS

196
EVQLVESGGGLVQPGGSLRLSCAA
197
NFMLTQPHSVSESPGKTVTISC
SARS-

Robbiani, D., et al.,

SGFTFSTYWMSWVRQPPGKGLEW

TGSSGSIASNYVQWYQQRPGS
CoV2

Nature 584: 437-442

VANIKQDGSEKYYVDSVKGRFTIS

APTTVIYEDNQRPSGVPDRFSG

(2020)

RDNAKNSLYLQMNSLRADDTAVY

SIDSSSNSASLTISGLKTEDEAD

YCAGGTWLRSSFDYWGQGTLVTV

YYCQSYDSSNWVFGGGTKLT

SS

VL

198
EVQLVESGGGVVQPGRSLRLSCAA
199
DIQMTQSPSSLSASVGDRVTIT
SARS-

Robbiani, D., et al.,

SGFTFSSYAMHWVRQAPGKGLEW

CQASQDISNYLNWYQQKPGK
CoV2

Nature 584: 437-442

VAVISYDGSNKYSADSVKGRFTIS

APKLLIYDASNLETGVPSRFSG

(2020)

RDNSKNTLYLQMNSLRAEDTAVY

SGSGTDFTFTISSLQPEDIATYY

YCAKGGAYSYYYYMDVWGKGTT

CQQYDNLPLTFGGGTKVEIK

VTVSS

200
EVQLVESGGGLVQPGGSLRLSCAA
201
DIQLTQSPSFLSASVGDRVTITC
SARS-
SARS-
Robbiani, D., et al.,

SGVTVSSNYMSWVRQAPGKGLEW

RASQGISSYLAWYQQKPGKAP
CoV2
CoV2
Nature 584: 437-442

VSLIYSGGSTFYADSVKGRFTISRD

KLLIYAASTLQSGVPSRFSGSG

(2020)

NSENTLYLQMNTLRAEDTAVYYC

SGTEFTLTISSLQPEDFATYYC

ARDLYYYGMDVWGQGTTVTVSS

QQLNSYSYTFGQGTKLEIK

202
EVQLVESGGGVVQPGRSLRLSCAA
203
NFMLTQPHSVSESPGKTVTISC
SARS-

Robbiani, D., et al.,

SGFTFSSYAMFWVRQAPGKGLEW

TGSSGSIASNYVQWYQQRPGS
CoV2

Nature 584: 437-442

VAVISYDGSNKYYADSVKGRFTIS

APTTVIYEDNQRPSGVPDRFSG

(2020)

RDNSKNTLYLQMNSLRAEDTAVY

SIDSSSNSASLTISGLKTEDEAD

YCARADLGYCTNGVCYVDYWGQ

YYCQSYDSSNWVFGGGTKLT

GTLVTVSS

VL

204
EVQLVESGGGLVQPGGSLRLSCAA
205
QSALTQPASVSGSPGQSITISCT
SARS-

Robbiani, D., et al.,

SGFSVSTKYMTWVRQAPGKGLEW

GTSNDVGSYTLVSWYQQYPG
CoV2

Nature 584: 437-442

VSVLYSGGSDYYADSVKGRFTISR

KAPKLLIFEGTKRSSGISNRFSG

(2020)

DNSKNALYLQMNSLRVEDTGVYY

SKSGNTASLTISGLQGEDEADY

CARDSSEVRDHPGHPGRSVGAFDI

YCCSYAGASTFVFGGGTKLTV

WGQGTMVTVSS

L

206
EVQLVESGGGLIQPGGSLRLSCAA
207
QSALTQPASVSGSPGQSITISCT
SARS-
SARS-
Robbiani, D., et al.,

SGFTVSNNYMSWVRQAPGKGLEW

GTSSDVGGYNYVSWYQQHPG
CoV2
CoV2
Nature 584: 437-442

VSVIYSGGSTYYADSVKGRFTISRD

KAPKLMIYDVSNRPSGVSNRF

(2020)

KSKNTLYLQMNRLRAEDTAVYYC

SGSKSGNTASLTISGLQAEDEA

AREGEVEGYNDFWSGYSRDRYYF

DYYCSSYTSSSTRVFGTGTKV

DYWGQGTLVTVSS

TVL

208
EVQLVESGGGLIQPGGSLRLSCAA
209
QSALTQPASVSGSPGQSITISCT
SARS-
SARS-
Robbiani, D., et al.,

SGFSVSSNYMSWVRQAPGKGLEW

GTSSDVGGYNYVSWYQQHPG
CoV2
CoV2
Nature 584: 437-442

VSVIYSGGSTYYADSVKGRFTISRD

KAPKLMIYDVSNRPSGVSNRF

(2020)

NSKNTLYLQMNSLRAEDTAVYYC

SGSKSGNTASLTISGLQAEDEA

AREGEVEGYYDFWSGYSRDRYYF

DYYCSSYTSSTTRVFGTGTRV

DYWGQGTLVTVSS

TVL

210
EVQLVESGGGLVKPGGSLRLSCAA
211
QSALTQPASVSGSPGQSITISCT
SARS-

Robbiani, D., et al.,

SGLTFTAYRMNWVRQAPGKGLE

GTSSDIGVYNYISWSQQHPGK
CoV2

Nature 584: 437-442

WLSSISNTNGDIYYADSVKGRFTIS

APKVMIYDVTNRPSGVSNRFS

(2020)

RDNAKNSLYLQMNSLRADDTAVY

GSKSGNTASLTISGLQAEDEAD

YCARDVASNYAYFDLWGQGTLVT

YYCSSYRGSSTPYVFGTGTKV

VSS

TVL

212
EVQLVQSGAEVKKPGESLKISCKG
213
QAVVTQEPSLTVSPGGTVTLT
SARS-

Robbiani, D., et al.,

SGYRFTNYWIGWVRQMPGKGLE

CGSSTGAVTSGHYPYWFQQKS
CoV2

Nature 584: 437-442

WMGIIYPGDSDTRYSPSFQGQVTIS

GQAPRTLIYETSIKHSWTPARF

(2020)

ADKSITTAYLQWSSLKASDTAMY

SGSLLGGKAALTLSGAQPEDE

YCARLSDRWYSPFDPWGQGTLVT

ADYYCLLSYSGARPVFGGGTK

VSS

LTVL

214
EVQLVESGGGLVQPGGSQRLSCAA
215
EIVMTQSPATLSVSPGERATLS
SARS-

Robbiani, D., et al.,

SGFTVSSNYMSWIRQAPGKGLEW

CRASQSVSSHLAWYQQKPGQ
CoV2

Nature 584: 437-442

VSVIYSGGSAYYVDSVKGRFTISR

APRLLIYGASTRATGIPTRFSGS

(2020)

DNSKNTLYLQMNSLRPEDTAVYY

GSGTEFTLTISSLQSEDFAVYY

CARIANYMDVWGKGTTVTVSS

CQQYNNWPPLTFGGGTKVEIK

216
EVQLVESGGGLVQPGGSLRLSCVA
217
QSALTQPASVSGSPGQSITISCT
SARS-

Robbiani, D., et al.,

SGFTFSSYWMHWVRQVPGKGPV

GTSSDVGYYNFVSWYQQHPG
CoV2

Nature 584: 437-442

WVSHINSEGSSTNYADSVRGRFTIS

KAPKLMIYEVSNRPSGVSNRFS

(2020)

RDNAKDTLYLQMNNLRAEDTAVY

GSKSGNTASLIISGLQAEDEAD

YCARPTAVAAAGNYFYYYGMDV

YYCSSYRSSSTLVFGGGTKLT

WGQGTTVTVSS

VL

218
EVQLVESGGGLVKPGGSLRLSCAA
219
NFMLTQPHSVSESPGKTVTISC
SARS-
SARS-
Robbiani, D., et al.,

SGFTFSSYNMNWVRQAPGKGLEW

TGSSGSIASNYVQWYQQRPGS
CoV2
CoV2
Nature 584: 437-442

VSCISSSSSYIYYADSVKGRFTISRD

APTTVIYEDNQRPSGVPDRFSG

(weak)
(2020)

NAKNSLYLQMNSLRAEDTAVYYC

SIDSSSNSASLTISGLKTEDEAD

ARERGYDGGKTPPFLGGQGTLVT

YYCQSYDSSNYWVFGGGTKL

VSS

TVL

220
EVQLVESGGGLIQPGGSLRLSCAA
221
QSALTQPASVSGSPGQSITISCT
SARS-
SARS-
Nature 584: 437-442

SGFTVSSNYMSWVRQAPGKGLEW

GTSSDVGSYNLVSWYQQHPG
CoV2
CoV2
(2020)

VSVIYSGYSTYYVDSVKGRFTISRD

KAPKLMIYEGSKRPSGVSNRFS

(weak)

NSKNTLYLQMNSLRAEDTAVYYC

GSKSGNTASLTISGLQAEDEAD

ARVGGAHSGYDGSFDYWGQGTL

YYCCSYAGSSTWVFGGGTKLT

VTVSS

VL

222
QVQLVESGGGVVQPGRSLRLSCA
223
DIQMTQSPSSLSASVGDRVTIT
SARS-
SARS-
Robbiani, D., et al.,

ASGFTFSRYGMHWVRQAPGKGLE

CQASQGISNYLNWYQQKPGK
CoV1,
CoV2
Nature 584: 437-442

WVAVMSYDGSSKYYADSVKGRFT

APKLLIYDASNLETGVPSRFSG
SARS-
(weak)
(2020)

ISRDNSKNTLCLQMNSLRAEDTAV

SGSGTDFTFTISSLQPEDIATYY
CoV2

YYCAKQAGPYCSGGSCYSAPFDY

CQQYDNLPITFGQGTRLEIK

WGQGTLVTVSS

224
EVQLVESGGGLIQPGGSLRLSCAA
225
EIVMTQSPATLSVSPGERATLS
SARS-
SARS-
Robbiani, D., et al.,

SGFIVSSNYMSWVRQAPGKGLEW

CRASQSVSSNLAWYQQKPGQ
CoV2
CoV2
Nature 584: 437-442

VSVIYSGGSTFYADSVKGRFTISRD

APRLLIYGASTRATAIPARFSG

(2020)

NSKNTLYLQMNSLRAEDTAVYYC

SGSGTEFTLTISSLQSEDFAVY

ARDFGEFYFDYWGQGTLVTVSS

YCQQYNNWPRTFGQGTKVEI

K

226
QVQLVESGGGVVQPGRSLRLSCA
227
SYELTQPPSVSVAPGQTARISC
SARS-

Robbiani, D., et al.,

ASGFTFSNYGMHWVRQAPGKGLE

GGNNIGSKNVHWYQQKPGQA
CoV2

Nature 584: 437-442

WVAVISYDGNNKYYADSVKGRFT

PVLVVYDDSDRPSGIPERFSGS

(2020)

ISRDNSKNTLYLQMNSLRAEDTAV

NSGNTATLTISRVEAGDEADY

YYCAKDPFPLAVAGTGYFDYWGQ

YCQVWDSSSDPWVFGGGTKL

GTLVTVSS

TVL

228
EVQLVESGGGLVQPGGSLRLSCAA
229
QSALTQPASVSGSPGQSITISCT
SARS-
SARS-
Robbiani, D., et al.,

SGFSVSTKYMTWVRQAPGKGLEW

GTSNDVGSYTLVSWYQQYPG
CoV2
CoV2
Nature 584: 437-442

VSVLYSGGSDYYADSVKGRFTISR

KAPKLLIFEVTKRSSGISNRFSG

(weak)
(2020)

DNSKNALYLQMNSLRVEDTGVYY

SKSGNTASLTISGLQGEDEADY

CARDSSEVRDHPGHPGRSVGAFDI

YCCSYAGASTFVFGGGTKLTV

WGQGTMVTVSS

L

230
QVQLVQSGAEVKKPGSSVKVSCK
231
EIVLTQSPGTLSLSPGERATLSC
SARS-
SARS-
Robbiani, D., et al.,

ASGGTFSSYAINWVRQAPGQGLE

RASQSVSSTYLAWYQQKPGQ
CoV2
CoV2
Nature 584: 437-442

WMGRIIPIVGIANYAQKFQGRVTIT

APRLLIYGASSRATGIPDRFSGS

(2020)

ADKSSSTAYMELSSLRSEDTAVYY

GSGTDFTLTISRLEPEDFAVYY

CARDLLDPQLDDAFDIWGQGTMV

CQQYGSSPWTFGQGTKVEIK

TVSS

232
EVQLVESGGGLVQPGRSLRLSCAA
233
IRMTQSPSSVSASVGDRVTITC
SARS-

Robbiani, D., et al.,

SGFTFDDYAMHWVRQAPGKGLE

RASQGISSWLAWYQQKPGKA
CoV2

Nature 584: 437-442

WVSGISWNSGSIGYADSVKGRFTIS

PKLLIYVESSLQSGVPSRFSGS

(2020)

RDNAKNSLYLQMNSLRAEDTALY

GSGTDFTLTISSLQPEDFATYY

YCVKGVEYSSSSNFDYWGQGTLV

CQQANSFPLTFGGGTKVEIK

TVSS

234
EVQLVESGGGLVQPGGSLRLSCAA
235
DIQLTQSPSSLSASVGDRVTITC
SARS-

Robbiani, D., et al.,

SGFTVSSNYMSWVRQAPGKGLEW

QASQDISNYLNWYQQKPGKA
CoV2

Nature 584: 437-442

VSLIYSGGSTYYADSVKGRFTISRD

PKLLIYDASNLETGVPSRFSGS

(2020)

NSKNTLYLQMNSLRAEDTAVYYC

GSGTDFTFTISSLQPEDIATYYC

ARDTLGRGGDYWGQGTLVTVSS

QQYDNLPRSFGQGTKLEIK

236
EVQLLESGGGLEQPGGSLRLSCAA
237
DIQLTQSPSSLSASVGDRVTITC
SARS-

Robbiani, D., et al.,

SGFTFSTYAMSWVRQAPGKGLEW

RASQSISSYLNWYQQKPGKAP
CoV1,

Nature 584: 437-442

VSAISGSGAGTFYADSVKGRFTISR

KLLIYAASSLQSGVPSRFSGSG
SARS-

(2020)

DNSKNTLYLQMNSLRAEDTAVYY

SGTDFTLTISSLQPEDFATYYC
CoV2

CARESDCGSTSCYQVGWFDPWGQ

QQSYSTPPWTFGQGTKVEIK

GTLVTVSS

238
QVQLVQSGAEVKKPGASVKVSCK
239
EIVLTQSPGTLSLSPGERATLSC
SARS-

Robbiani, D., et al.,

ASGHTFTSYYMHWVRQAPGQGLE

RASQSVSSSYLAWYQQKPGQ
CoV2

Nature 584: 437-442

WMGIINPSGGSTSYAQKFQGRVTM

APRLLIYGASSRATGIPDRFSGS

(2020)

TRDTSTSTVYMELSSLRSEDTAVY

GSGTDFTLTISRLEPEDFAVYY

YCARGPERGIVGATDYFDYWGQG

CQQYVSSPWTFGQGTKVEIK

TLVTVSS

240
EVQLLESGGGLVQPGGSLRLSCAA
241
EIVLTQSPATLSLSPGERATLSC
SARS-
SARS-
Robbiani, D., et al.,

SGFTFSSYAMSWVRQAPGKGLEW

RASQSVSSYLAWYQQKPGQA
CoV2
CoV2
Nature 584: 437-442

VSAISGSGGSTYYADSVKGRFTISR

PRLLIYDASNRATGIPARFSGS

(weak)
(2020)

DNSKNTLYLQMNSLRAEDTAVYY

GSGTDFTLTISSLEPEDFAVYY

CAKEPIGQPLLWWDYWGQGTLVT

CQQRSNWPRGFGQGTKVEIK

VSS

242
EVQLVQSGAEVKKPGESLKISCKG
243
EIVLTQSPGTLSLSPGERATLSC
SARS-

Robbiani, D., et al.,

SGYSFTSYWIGWVRQMPGKGLEW

RASQSVSGSYLAWYQQRPGQ
CoV2

Nature 584: 437-442

MGIIYPGDSDTRYSPSFQGQVTISA

APRLLIYGASSRATGIPDRFSGS

(2020)

DKSISTAYLKWSSLKASDSAMYYC

GSGTDFTLTISRLEPEDFAVYY

ARGPNLQNWFDPWGQGTLVTVSS

CQQYGSSLTFGGGTKVEIK

244
EVQLVESGGGLIQPGGSLRLSCAA
245
DIQLTQSPSFLSASVGDRVTITC
SARS-
SARS-
Robbiani, D., et al.,

SGFTVSSNYMSWVRQAPGKGLEW

RASQGISSYLAWYQQKPGKAP
CoV2
CoV2
Nature 584: 437-442

VSVIYSGGSTFYADSVKGRFTFSRD

KLLIYAASTLQSGVPSRFSGSG

(2020)

NSKNTLYLQMNSLRAEDTAVYYC

SGTEFTLTISSLQPEDFATYYC

ARDLMAYGMDVWGQGTTVTVSS

QQLNSYPQGTFGGGTKVEIK

246
EVQLVESGGGLVQPGGSLRLSCAA
247
EIVMTQSPATLSVSPGERATLS
SARS-
SARS-
Robbiani, D., et al.,

SEFTVSSNYMSWVRQAPGKGLEW

CRASQSVSSNLAWYQQKPGQ
CoV2
CoV2
Nature 584: 437-442

VSVIYSGGSTFYADSVKGRFTISRD

GPRLLIYGASTRATGIPARFSG

(2020)

NSKNTLYLQMNSLRPEDTAVYYC

SGSGTEFTLTISSLQSEDFAVY

ARDYGDFYFDFWGQGTLVTVSS

YCQQYNNWPRTFGQGTKVEIK

248
QVQLVQSGAEVKKPGASVKVSCK
249
LTQPASVSGSPGQSITISCTGTS
SARS-

Robbiani, D., et al.,

ASGYTVTGYYIHWVRQAPGQGLE

SDVGSYNLVSWYQQHPGKAP
CoV2

Nature 584: 437-442

WMGWISPNSGGTNYAQKFQGWV

KLMIYEDSKRPSGVSNRFSGSK

(2020)

TMTRDMSITTAYMELSRLRSDDTA

SGNTASLTISGLQAEDEADYY

VYYCARERYFDLGGMDVWGQGT

CCSYAGSSTRLFGGGTKLTVL

TVTVSS

250
QVQLVESGGGVVQPGRSLRLSCA
251
DIQLTQSPSSLSASVGDRVTITC
SARS-

Robbiani, D., et al.,

ASGFTFSSYGMHWVRQAPGKGLE

RASQSISSYLTWYQQKPGKAP
CoV2

Nature 584: 437-442

WVAAIWYDGSNKHYADSVKGRFT

KLLIYAASSLQSGVPSRFSGSG

(2020)

ISRDNSKNTLYLQMNSLRAEDTAV

SGTDFTLTISSLQPEDFATYYC

YYCARDVGRVTTWFDPWGQGTL

QQSYSTPPWTFGQGTKVEIK

VTVSS

252
EVQLLESGGGLVQPGGSLRLSCAA
253
DIQLTQSPSSLSASVGDRVTITC
SARS-

Robbiani, D., et al.,

SGFTFSSYAMSWVRQAPGKGLEW

RASQSISSYLNWYQQKPGKAP
CoV1,

Nature 584: 437-442

VSAITDSGDGTFYADSVKGRFTISR

KLLIYAASSLQSGVPSRFSGSG
SARS-

(2020)

DNSKNTLYLQMNSLRAEDTAVYY

SGTDFTLTISSLQPEDFATYYC
CoV2

CASEEDYSNYVGWFDPWGQGTLV

QQSYSTPPWTFGQGTKVEIK

TVSS

254
EVQLVESGGGLVQPGGSLRLSCAA
255
DIQLTQSPSSLSASVGDRVTITC
SARS-

Robbiani, D., et al.,

SGFTFSSYDMHWVRQATGKGLEW

RASQSISSYLNWYQQKPGKAP
CoV2

Nature 584: 437-442

VSAIGTAGDTYYPDSVKGRFTISRE

KLLIYVASSLQSGVPSRFSGSG

(2020)

NAKNSLYLQMNSLRAGDTAVYYC

SGTDFTLTISSLQPEDFATYYC

ARDRGSSGWYGWYFDLWGRGTL

QQSYSTPPITFGQGTRLEIK

VTVSS

256
EVQLVESGGGLVQPGGSLRLSCAA
257
DIVMTQSPSFLSASVGDRVTIT
SARS-
SARS-
Wu, Y., et al.,

SGFIVSSNYMSWVRQAPGKGLEW

CRASQGISSYLAWYQQKPGKA
CoV2
CoV2
Science 368: 1274-

VSVIYSGGSTYYADSVKGRFTISRH

PKLLIYAASTLQSGVPSRFSGS

1278 (2020)

NSKNTLYLQMNSLRAEDTAVYYC

GSGTEFTLTISSLQPEDFATYY

AREAYGMDVWGQGTTVTVSS

CQQLNSYPPYTFGQGTKLEIK

258
QVQLVQSGAEVKKPGASVKVSCK
259
DIQMTQSPLSLPVTPGEPASISC
SARS-
SARS-
Wu, Y., et al.,

ASGYTFTGYYMHWVRQAPGQGLE

RSSQSLLDSDDGNTYLDWYLQ
CoV2
CoV2
Science 368: 1274-

WMGRINPNSGGTNYAQKFQGRVT

KPGQSPQLLIYTLSYRASGVPD

1278 (2020)

MTRDTSISTAYMELSRLRSDDTAV

RFSGSGSGTDFTLKISRVEAED

YYCARVPYCSSTSCHRDWYFDLW

VGVYYCMQRIEFPLTFGGGTK

GRGTLVTVSS

VEIK

260
QVQLVQSGAEVKKPGASVKVSCK
261
EIVLTQSPGTLSLSPGERATLSC
SARS-
SARS-
Pinto, D., et al.,

ASGYPFTSYGISWVRQAPGQGLEW

RASQTVSSTSLAWYQQKPGQA
CoV1,
CoV2
Nature 583: 290-295

MGWISTYNGNTNYAQKFQGRVT

PRLLIYGASSRATGIPDRFSGSG
SARS-
and
(2020)

MTTDTSTTTGYMELRRLRSDDTA

SGTDFTLTISRLEPEDFAVYYC
CoV2
SARS-

VYYCARDYTRGAWFGESLIGGFD

QQHDTSLTFGGGTKVEIK

CoV1

NWGQGTLVTVSS

262
EVQLVESGGGLVQPGGSLRLSCAA
263
DIQMTQSPSSLSASVGDRVTIT
SARS-
SARS-
Meulen, J., et al.,

SGFTFSDHYMDWVRQAPGKGLEW

CRASQSISSYLNWYQQKPGKA
CoV1
CoV1
(2006), PLoS

VGRTRNKANSYTTEYAASVKGRF

PKLLIYAASSLQSGVPSRFSGS

Medicine, Vol. 3(7):

TISRDDSKNSLYLQMNSLKTEDTA

GSGTDFTLTISSLQPEDFATYY

e237, 1071-1079

VYYCARGISPFYFDYWGQGTLVT

CQQSYSTPPTFGQGTKVEIK

VSS

264
QVQLVESGGGLVKPGGSLRLSCAA
265
DIQMTQSPSSLSASVGDRVTIT
SARS-
SARS-
U.S. patent

SGFTFSDYYMSWIRQAPGKGLEW

CQASQDITNYLNWYQQKPGK
CoV2
CoV2
application

VSYITYSGSTIYYADSVKGRFTISR

APKLLIYAASNLETGVPSRFSG

Ser. No.

DNAKSSLYLQMNSLRAEDTAVYY

SGSGTDFTFTISGLQPEDIATYY

10/787,501

CARDRGTTMVPFDYWGQGTLVTV

CQQYDNLPLTFGGGTKVEIK

SS

266
QVQLVESGGGVVQPGRSLRLSCA
267
QSALTQPASVSGSPGQSITISCT
SARS-
SARS-
U.S. patent

ASGFTFSNYAMYWVRQAPGKGLE

GTSSDVGGYNYVSWYQQHPG
CoV2
CoV2
application

WVAVISYDGSNKYYADSVKGRFTI

KAPKLMIYDVSKRPSGVSNRF

Ser. No.

SRDNSKNTLYLQMNSLRTEDTAV

SGSKSGNTASLTISGLQSEDEA

10/787,501

YYCASGSDYGDYLLVYWGQGTLV

DYYCNSLTSISTWVFGGGTKL

TVSS

TVL

268
QVQLVQSGAEVKKPGSSVKVSCK
269
DIQMTQSPSSLSASVGDRVTIT
SARS-
SARS-
INN Proposed List

ASGGTFSNYAISWVRQAPGQGLE

CRASQSISSYLSWYQQKPGKA
CoV2
CoV2
P124

WMGRIIPILGIANYAQKFQGRVTIT

PKLLIYAASSLQSGVPSRFSGS

(who.int/medicines/

ADKSTSTAYMELSSLRSEDTAVYY

GSGTDFTLTITSLQPEDFATYY

publications/

CARGYYEARHYYYYYAMDVWGQ

CQQSYSTPRTFGQGTKVEIK

druginformation/

GTAVTVSS

innlists/PL124-

COVID.pdf)

270
EVQLLESGGGVVQPGGSLRLSCAA
271
DIVMTQSPLSLPVTPGEPASISC
SARS-
SARS-
Shuo Du et al., 2020

SGFAFTTYAMNWVRQAPGRGLEW

RSSQSLLHSNGYNYLDWYLQ
CoV2
CoV2
(biorxiv.org/content/

VSAISDGGGSAYYADSVKGRFTIS

KPGQSPQLLIYLGSNRASGVPD

10.1101/

RDNSKNTLYLQMNSLRAEDTAVY

RFSGSGSGTDFTLKISRVEAED

2020.07.09.195263)

YCAKTRGRGLYDYVWGSKDYWG

VGVYYCMQALQTPGTFGQGT

QGTLVTVSS

RLEIK

272
QVQLVQSGAEVKKPGASVKVSCK
273
QSALTQPPSASGSPGQSVTISC
SARS-
SARS-
Lihong Liu et al.,

ASGYTFTGYYMHWVRQAPGQGLE

TGTSSDVGGYNYVSWYQQHP
CoV2
CoV2
2020

WMGWINPNSGGTNYTQMFQGRV

GKAPKLMIYEVSKRPSGVPDR

(nature.com/articles/

TMTRDTSISTAYMEVSRLRSDDTA

FSGSKSGNTASLTVSGLQAED

s41586-020-2571-7)

VYYCARDRSWAVVYYYMDVWG

EADYYCSSYAGSNNLVFGGGT

KGTTVTVSS

KLTVL

274
QITLKESGPTLVKPTQTLTLTCTFS
275
QSALAQPASVSGSPGQSITISCT
SARS-
SARS-
Lihong Liu et al.,

GFSLSTSGVGVGWIRQPPGKALEW

GTSSDVGAYNYVSWYQQHPG
CoV2
CoV2
2020

LALIYWDDDKRYSPSLKSRLTITK

KAPKLMIYDVSKRPSGVSNRF

(nature.com/articles/

DTSKNQVVLTMTNMDPVDTATYY

SGSKSGNTASLTISGLQAEDEA

s41586-020-2571-7)

CAHHKIERIFDYWGQGTLVTVSS

DYYCSSYTTSSTVFGGGTKLT

VL

276
QVQLVQSGAEVKKPGASVRVSCK
277
QSALTQPASVSGSPGQSITISCT
SARS-
SARS-
Lihong Liu et al.,

ASGYTFTGYYMHWVRQAPGQGLE

GTSSDVGGYNFVSWYQQHPG
CoV2
CoV2
2020

WMGWINPISDGTNYAQKFQGWVT

KAPKLMIYDVSKRPSGVSNRF

(nature.com/articles/

MTRDTSISTVYMELSRLRSDDTAV

SGSKSGNTASLTISGLQAEDEA

s41586-020-2571-7)

YYCARGGSRCSGGNCYGWAYDA

DCYCSSYTSSSTFVFGTGTKVT

FDIWGQGTMITVSS

VL

278
QVQLVQSGAEVKKPGSSVKVSCK
279
EIVMTQSPATLSVSPGERATLS
SARS-
SARS-
Lihong Liu et al.,

ASGGTFSSYAISWVRQAPGQGLEW

CRASQSVSSDLAWYQHKPGQ
CoV2
CoV2
2020

MGGNIPIFGTANYAQKFQGRVTIT

APRLLIYGASTRATGIPVRFSG

(nature.com/articles/

ADESTSTAYMELSSLRSEDTAVYY

SGSGTEFTLTISSLQSEDFAVY

s41586-020-2571-7)

CARGVGYRGVIPLNWFDPWGQGT

YCQQYNNWPPFTFGGGTKVEI

VVTVSS

K

280
QVQLVQSGAEVKKPGASVKVSCK
281
QSALTQPASVSGSPGQSITISCT
SARS-
SARS-
Lihong Liu et al.,

ASGYTFTGYYMHWVRQAPGQGLE

GTSSDVGGYNYVSWYQQHPG
CoV2
CoV2
2020

WMGWINPNSGGTNYAQKFQGRV

KAPKLMIYDVSKRPSGVSNRF

(nature.com/articles/

TMTRDTSITTAYMELRRLRSDDTA

SGSKSGNTASLTISGLQAEDEG

s41586-020-2571-7)

VYYCARGLGVGCSGGNCYLDYYY

DYYCSSYTSSSTWVFGGGTKL

MDVWGKGTTVTVSS

TVL

282
QVQLVQSGAEVKKAGSSVKVSCK
283
SYELTQPPSVSVSPGQTASITCS
SARS-
SARS-
Lihong Liu et al.,

ASGGTFSSHTITWVRQAPGQGLEW

GDKLGDKYACWYQQKPGQSP
CoV2
CoV2
2020

MGRIIPILGIANYAQKFQGRVTITA

VLVIYQDNKRPSGIPERFSGSN

(nature.com/articles/

DKSTSTAYMELSSLRSEDTAVYYC

SGNTATLTISGTQAMDEADYY

s41586-020-2571-7)

ASLQTVDTAIEKYYGMDVWGQGT

CQAWDSSTAVFGGGTKLTVL

TVTVSS

284
EVQLVESGGGLVQPGGSLRLSCAA
285
QSVLTQPPSVSGAPGQRVTISC
SARS-
SARS-
Rodda, L., 2021 (pub.

SEITVSSNYMSWVRQAPGKGLEW

TGSSSNIGAGYDVHWYQQLPG
CoV2
CoV2
2020), Cell, doi:

VSLIYSGGSTFYADSVKGRFIISRD

TAPKLLIYGNSNRPSGVPDRFS

10.1016/

NSKNTLYLQMNSLRAEDTAVYHC

GSKSGTSASLAITGLQAEDEAD

j.ce11.2020.11.029

ARGGEEPLPFDPWGQGTLVTVSS

YYCQSYDSSLSVSVVFGGGTK

LTVL

286
QVQLVQSGAEVKKPGSSVKVSCK
287
QSVLTQPPSVSGAPGQRVIISC
SARS-
SARS-
Rodda, L., 2021 (pub.

ASGGTFSSYPISWVRQAPGQGLEW

TGSNSNIGAGYDVHWYQQLP
CoV2
CoV2
2020), Cell, doi:

MGRIIPILRVANFAQRFEGRVTITA

GTAPKLLIYGNNNRPSGVPDR

10.1016/

DKSTGTAYMELSSLRSEDTAMYY

FSGSKSGTSASLAITGLQAEDG

j.cell.2020.11.029

CARDEAQTTVNTNWFDPWGQGTL

ADYYCQSYDSSLSDVVFGGGT

VTVSS

KLTVL

288
EVQLVESGGGLVQPGGSLRLSCAV
289
DIQMTQSPSSLSASVGDRVTIT
SARS-
SARS-
Rodda, L., 2021 (pub.

SGFTVSSNYMSWVRQAPGKGLEW

CRASQSISNYLNWYHQKPGKA
CoV2
CoV2
2020), Cell, doi:

VSVIYTGGGTYYADSVKGRFTISR

PKLLIYAASSLQSGVPSRFSGS

10.1016/

DNSKNTLYLQMNTLRAEDTTVYY

GSGTDFTLTISSLQPEDFATYY

j.cell.2020.11.029

CARGDGSYYRAFDYWGQGTLVTV

CQQSYSPPPTFGPGTKVEIK

SS

290
EVQLVESGGGLIQPGGSLRLSCAA
291
DIQMTQSPSSLSASVGDRVTIT
SARS-
SARS-
Rodda, L., 2021 (pub.

SGFTVSRNYMNWVRQAPGKGLE

CRASQSISSYLNWYQQKPGKA
CoV2
CoV2
2020), Cell, doi:

WVSVIYSGGSTFYADSVKGRFTISR

PKLLIYASSSLQRGVPSRFSGS

10.1016/

DNSKNTLYLQMNSLRAEDTAVYY

GSGTDFTLTISSLQPEDFATYY

j.cell.2020.11.029

CARDASSYGIDWGQGTLVTVSS

CQQSYSTPPITFGQGTRLEIK

292
QVQLKQSGPGLVAPSQSLSITCTVS
293
QAVVTQESALTTSPGETVTLT
SARS-
SARS-
Alsoussi, W., 2020,

GFSLINYAISWVRQPPGKGLEWLG

CRSSTGAVTTSNYANWVQEKP
CoV2
CoV2
J Immunol, 205: 915-

VIWTGGGTNYNSALKSRLSISKDN

DHLFTGLIGGTNNRAPGVPAR

922

SKSQVFLKMNSLQTDDTARYYCA

FSGSLIGDKAALTITGAQTEDE

RKDYYGRYYGMDYWGQGTSVTV

AIYFCALWYNNHWVFGGGTK

SS

LTVL

294
EVQLVQSGPEVKKPGTSVKVSCKA
295
EIVLTQSPGTLSLSPGERATLSC
SARS-
SARS-
Aaron Schmitz et al.,

SGFTFSSSAVQWVRQARGQRLEWI

RASQSVSSSYLAWYQQKPGQ
CoV2
CoV2
2021

GWIVVGSGNYAQKFQERVTITRD

APRLLICATSSRATGIPDRFSGS

(biorxiv.org/content/

MSTNTAYMELSSLRSEDTAVYYC

GSGTDFTLTIRRLEPEDFALYY

10.1101/

AAAYCSGGSCSDGFDIWGQGTMV

CQQYGSSPWTFGQGTKVEIK

2021.03.24.436864v1)

TVSS

296
EVQLQQSGAELVKPGASVKLSCTT
297
DIVMTQSQKFMSTSVGDRVSV
SARS-
SARS-
PDB

SGFNIIDTYMHWVKQRPEEGLEWI

TCKASQNVGTHVAWYQQKPG
CoV2;SARS-
CoV2;
(rcsb.org/structure/

GGIDPVNGNSEYDPKFQDKATITA

QSPKALIYSASYRYSGVPDRFT
CoV1
SARS-
7EAN)

DTSSNTAYLHLSRLTSEDTAVYYC

GSGVGTDFTLTITNVQSEDLAE

CoV1

ASAHYYGSSSSFPYWGQGTDLVT

YFCQQYNSYFTFGSGTKLEIK

VSA

298
QVQLQQWGAGLLKPSETLSLTCA
299
NFMLTQPHSVSASPGKTVTIPC
SARS-
SARS-
Asarnow et al., 2021,

VYGGSFSGYYWSWIRQPPGKGLE

TGSSGNIASNYVQWYQQRPGS
CoV2
CoV2
Cell 184, 3192-3204

WIGEINHSGSTNYNPSLKSRVTISV

APTTVIYEDNQRPSGVPDRFSG

(weak)

DTSKNQFSLKLSSVTAADTAVYYC

SIDSSSNSASLTISGLKTEDEAD

ARRWWLRGAFDIWGQGTTVTVSS

YYCQSYDNNIQVFGGGTKLTV

L

300
QVQLQESGGGLVQPGGSLRLSCAA
301
DIQLTQSPSSLSASVGHRVTITC
SARS-
SARS-
Asarnow et al., 2021,

SGFTFSSYEMNWVRQAPGKGLEW

RASQSISSYLNWYQQKPGKAP
CoV2
CoV2
Cell 184, 3192-3204

VAVISYDGSNKYYADSVKGRFTIS

KLLIYAASSLQSGVPSRFSGSG

RDNAKNSLYLQMNSLRAEDTAVY

SGTDFTLTISSLQPEDFATYYC

YCARLITMVRGEDYWGQGTLVTV

QQSYNLPRTFGGGTKLEVL

SS

302
EVQLVESGGGLVQPGGSLRLSCAA
303
LTQPASVSGSPGQSITISCTGTS
SARS-
SARS-
Cao, Y., et al., Cell

SGVTVSSNYMSWVRQAPGKGLEW

SDVGSYNLVSWYQQRPGKAP
CoV2
CoV2
Research (2021)

VSAVYSGGSTYYADSVKGRFTISR

KLILYEVTKRPSGVSNRFSGSK

31: 732-741

HNSKNTLYLQMKSLRPEDTAIYYC

SGNTASLAISGLQAEDEADYY

ARLINHYYDSSGDGGAFDIWGQGT

CCSYAGSSTWVFGGGTKLTVL

MVTVSS

304
QVQLVQSGAEVKKPGSSVKVSCK
305
EIVLTQSPGTLSLSPGERATLSC
SARS-
SARS-
Scheid et al., Cell

ASGGTFSSYAISWVRQAPGQGLEW

RASQSVGSGYLAWYQQRPGQ
CoV2
CoV2
(2021) 184(12): 3205-

MGRIISMFGIANNAQKFQGRLTITA

APRLLIYGASSRATGIPDRFSGS

3221.e24

DTSTSTAYMELSSLRSEDTAVYYC

GSGTDFTLTISRLEPEDFAVYY

ARGPYYYDSGGYYLDYWGQGTL

CQQYAGSPRTFGQGTRLEIK

VTVSS

306
EVQLVESGGGLIQPGGSLRLSCAA
307
EIVLTQSPGTLSLSPGERATLSC
SARS-
SARS-
Scheid et al., 2021,

SGITVVRNYMTWVRQAPGKGLEW

RASQSVPSSYLAWYQQKPGQ
CoV2
CoV2
Cell 184, 3205-3221

VSVIYSGGTTYYADSVKGRFTISRD

APRLLIYGASSRATGIPDRFSGS

NSKNTMYLQMNSLRAEDTAIYYC

GSGTDFTLTISRLEPEDFAVYY

ARDLEVVGAMDVWGQGTTVTVS

CQQYGSPMYTFGQGTKLEIK

S

308
QVQLVQSGAEVKKPGASVKVSCK
309
EIVLTQSPGTLSLSPGERATLSC
SARS-
SARS-
Scheid et al., 2021,

ASGYTFTSYAISWVRQAPGQGLE

RASQSVSGTFLAWYQQKPGQ
CoV2
CoV2
Cell 184, 3205-3221

WMGWVSAYNGNTNYAQKLQGR

APRLLISGASSRATGIPDRFSGS

VTMTTDTSTNTAYMELRSLRSDDT

GSGTDFTLTISRLEPEDFAVYY

AIYYCAIPYSSVTFDCWGQGTLVT

CQQYGSSRPTFGQGTKLEIK

VSS

310
QVQLVQSGAEVKKAGASVKVSCK
311
QSVLTQPPSVSGAPGQRVTISC
SARS-
SARS-
Scheid et al., 2021,

ASGYTFTSYDINWVRQASGQGLE

TGSSSNIGAGYDVHWYHQLPG
CoV2
CoV2
Cell 184, 3205-3221

WMGWMNPISGNTGYAQKFQGRV

TAPKFLIYGNSNRPSGVPDRFS

TMTRNTSITTAYMELSSLRSEDTA

GSKSGTSASLAITRLQAEDEAD

VYFCARGGRYCSSTTCYSGVGMD

YYCQSYDSSLSGWVFGGGTKL

VWGQGTTVTVPSA

TVL

312
EVQLVQSGAEVKKPGASVKVSCK
313
DIVMTQTPLSSPVTLGQPASIS
SARS-
SARS-
Noy-Porat et al.,

VSGYTLTELSMHWVRQAPGKGLE

CRSSQSLVHSDGNTYLSWLQQ
CoV2
CoV2
2021, iScience

WMGGFDPEDAETIYAQKFQGRVT

RPGQPPRLLIYKISNRFSGVPD

24, 102479

MTEDTSTDTAYMELSSLRSEDTAV

RFSGSGAGTDFTLKISRVEAED

YYCVTAPAITGSPEAYSYYYGMD

VGVYYCMQATQFPYTFGQGT

VWGQGTTVTVSS

KLEIK

314
QVQLVQSGAEVKKPGASVKVSCK
315
SYELIQEPSVSVSPGQTARITCQ
SARS-
SARS-
Noy-Porat et al.,

VSGYTLPELSMHWVRQAPGKGLE

GDSLRSYYASWYQQKPGQAP
CoV2
CoV2
2021, iScience

WMGGFDPEDGETIYAQKFQGRVT

VLVIYNRNKRPSGIPDRFSGSS

24, 102479

MTEDTSTDTAYMELSSLRSEDTAV

SGNTASLTITGAQADDEADYY

YYCATGPAIAAAATGWFDPWGQG

CNSRDNSGNHPFGGGTKVTVL

TLVTVSS

316
QVQLQQSGAEVKKPGASVKVSCK
317
DIVMTQSPLSSPVTLGQPASISC
SARS-
SARS-
Noy-Porat et al.,

VSGYTLTELSMHWVRQAPGKGLE

RSSQSLVHSDGNTYLSWLQQR
CoV2
CoV2
2021, iScience

WMGGFDPEDAETIYAQKFQGRVT

PGQPPRLLIYKISNRFSGVPDRF

24, 102479

MTEDTSTDTAYMELSSLRSEDTAV

SGSGATDFTLKISRVEAEDVG

YYCVTAPVITGSPEAYSYYYGMD

VYYCMQATQFPITFGGGTKVE

VWGQGTTVNVSS

IK

318
QMQLVQSWGRRGPAGRSLRLSCA
319
EIVLTQSPGTLSLSPGERATLSC
SARS-
SARS-
Noy-Porat et al.,

ASGSTFSSYGMHWVRQAPGKGLE

RASQSVSSSYLAWYQQKPGQ
CoV2
CoV2
2021, iScience

WVAVISFDGSNKFYADSVKGRFTI

APRLLIYGASSRATGIPDRFSGS

24, 102479

SRDNSKNTLYLQMNSLRAEDTAV

GSGTDFTLTISRLEPEDFAVYY

YYCAKDHDDGYYFYYYMDVWG

CQQYGSSRTFGGGTRLEIK

KGTTVTVSS

320
EVQLVQSGAEVKKPGASVKVSCK
321
QSVVTQPASVSGSPGQSITISCT
SARS-
SARS-
Noy-Porat et al.,

VSGYTLTELSMHWVRQAPGKGLE

GSSSDIGGYNYVSWYQQHPGK
CoV2
CoV2
2021, iScience

WMGGFDPEDGETIYAQKFQGRVT

APKLMIFEGSKRPSGVPDRFSG

24, 102479

MTEDTSTDTAYMELSSLRSEDTAV

SKSGNTASLTISGLQAEDEADY

YYCAASPAVRGSPSNFYYYHGMD

YCSSYTSSSTLVFGGGTELTVL

VWGQGTMVTVSS

322
QVQLQQSGAEVKKPGASVRVSCK
323
SQSALTQPGSLSGSPGQSITISC
SARS-
SARS-
Noy-Porat et al.,

VSGYTLTELSMHWVRQAPGKGLE

TGTSSDVGSYNLVSWYQQHP
CoV2
CoV2
2021, iScience

WMGGFDPEDAETIYAQKFQGRVT

GQTPKVIIYEVTNRASGVSNRC

24, 102479

MTEDTSTDRAYMELSSLRSEDTAV

SGSQSGNTATLTISRLLADDQA

YYCVAAPVITGSPEAYSYYYGMD

DDYCSSYTRTSTLDVVFGGRT

VWGQGTTVTVSS

ELTVL

324
QLQLQESGPGLVKPSQTLSLTCTVS
325
NILTQPPSASGTPGQRVTISCSG
SARS-
SARS-
Noy-Porat et

GGSISSGSYYWSWIRQPAGKGLEW

SSSNIGSNTVN
CoV2
CoV2
al.,2021, iScience

IGRIYTTGSTSYNPSLKSRVTISVDT

WYQQLPGTAPKLLIYSKNQRP

24,102479

SKNQFSLKLSSVTAADTAVYYCAR

SGVPDRFSGSKSGTSASLAISG

MAYQVYYYDSSGYYDAFDIWGQ

LRSEDEADYYCSAWDDSLRG

GTMVTVSS

YVFGPGTKVTVL

326
QVQLQESGPGLVKPSQTLSLTCTV
327
QSALTQPASASGSPGQSVTISC
SARS-
SARS-
Noy-Porat et al.,

SGGSISSGSYYWSWIRQPAGKGLE

TGSSSDVGGYNFVSWYQQHP
CoV2
CoV2
2021, iScience

WIGRIYTTGSTNYNPSLKSRVTISV

GKAPKLIIYEVSKRPSGVPNRF

24, 102479

DTSKNQFSLKLSSVTAADTAVYYC

SGSKSGNTASLTVSGLQADDE

ARMAYQVYYYDSSGYYDAFDIW

ALYYCSSYAGSNNYVFGPGTK

GQGTMVTVSS

VTVL

328
EVQLVQSGAEVKKPGASVKVSCK
329
QSVLTQPASVSGSPGQSITISCT
SARS-
SARS-
Noy-Porat et al.,

VSGYTLPELSMHWVRQAPGKGLE

GTSSDVGGYNYVSWYQQHPG
CoV2
CoV2
2021, iScience

WMGGFDPEDGGTIYAQKFQGRVT

KAPKLMIYDVSNRPSGVPDRF

24, 102479

MTEDTSTDTAYMELSSLRSEDTAV

SGSKSGNTASLTISGLQAEDEA

YYCATSRVAGTPNWFHPWGQGTL

DYYCSSYTSSSTLVFGTGTKVT

VTVSS

VL

330
EVQLLESGGGVVQPGRSLRLSCAA
331
NFMLTQPPSVSVSPGQTASITC
SARS-
SARS-
Noy-Porat et al.,

SGFTFSSYAMHWVRQAPGKGLQW

SGDKLGDKYASWYQQKPGQS
CoV2
CoV2
2021, iScience

VALISYDGSNKYYADSVKGRFTIS

PVLVIYQDSKRPSGIPERFSGSN

24, 102479

RDNSKNTLYLQMNSLRAEDTAVY

SGNTATLTISGTQAMDEADYY

YCARDLGSGWYPWGQGTLVTVSS

CQAWDSSTVVFGGGTELTVL

332
QVQLVQSGAGVKKPGASVKVSCK
333
QSALTQPVSVSGSPGQSITISCT
SARS-
SARS-
Noy-Porat et al.,

VSGYTLPELSMHWVRQAPGKGLE

GTSSDVGRYNYVSWYQQHPG
CoV2
CoV2
2021, iScience

WMGGFDPEDGETIYAQKFQGRVT

KAPKLITYDVKNRPSGVPDRFS

24, 102479

MTEDTSTDTAYMELSSLRSEDTAV

GSKSGNTASLTISGLQAEDEAD

YYCATSRVAGTPNWFHPWGQGTL

YYCSSYTRSSTLDVVFGGGTE

VTVSS

LTVL

334
EVQLVESGGGLVQPGGSLRLSCAA
335
AIQMTQSPSFLSASVGDRVTIT

Andreano et al.,

SGLTVSSNYMSWVRQAPGKGLEW

CRASQGISSYLAWYQQKPGKA

2021, Cell,

VSVIYSGGSTFYADSVKDRFTISRD

PKLLIYAASTLQSGVPSRFSGS

184(7): 1821-1835

NSKNTLYLQMNSLRAEDTAVYYC

GSGTEFTLTISSLQPEDFATYY

VRDLYSYGMDVWGQGTTVTVSS

CQQVNSYPTFGQGTRLEIK

336
EVQLQQWGAGLLKPSETLSLTCAV
337
EIVLTQSPATLSLSPGERATLSC
SARS-
SARS-
Song et al., 2021,

YGGSFSGYYWSWIRQPPGKGLEWI

RASQSVSSYLAWYQQKPGQA
CoV2
CoV2
Communications

GEVNHSGSTNYNPSLKSRVTISVD

PRLLIYDASNRATGIPARFSGS

Biology volume 4,

TSKNQLSLKLNSVTAADTAVYYC

GSGTDFTLTISSLEPEDFAVYY

Article number: 500

ARGNTMVRGVIIPFEYWDKGTLVT

CQQRSNWPLTFGGGTKVEIK

(2021)

VSS

338
EVQLLESGGGLVQPGGSLRLSCAA
339
SYELTQPPSVSVSPGQTARITC
SARS-
SARS-
Panpan Zhou et al.,

SGFTFSSYVMTWARQAPGKGLEW

SGDALPKRYAYWYQQKSGQA
CoV2
CoV2
2021

VSAISGTGYTYYADSVKGRFTVSR

PILVIYEDKKRPSGIPERLSGSK

(biorxiv.org/content/

DNSKNTLFLQMSSLRAEDTAVYY

SGTVATLTISGAQVEDEADYY

10.1101/

CAITMAPVVWGQGTTVTVSS

CYSTDSSGNHAVFGGGTQLTV

2021.03.30.437769v1)

L

340
QVQLVESGGGLVKPGGSLRLSCAA
341
EIVLTQSPATLSLSPGERATLSC
SARS-
SARS-
Voss et al., 2021,

SGFTFSDYYMSWIRQAPGKGLEW

RASQSVSTYLAWYQQKPGQA
CoV2
CoV2
Science, 372(6546):

VSSIDGSTSYTKYADSVKGRFTISR

PRLLIFDASNRATGIPARFSGSG

1108-1112

DNAKNSLYLQMNSLRAEDTAVYY

SGTDFTLTISSLEPEDFAVYYC

CARVGPAVAGSPFDSWGQGTLVT

QQRSNWLFSFGPGTKVDIK

VSS

342
QVQLVQSGPEVKKPGASVKVSCQ
343
QSVLTQPASVSASPGQSITISCT
SARS-
SARS-
Voss et al., 2021,

TSGYSFSDHYLHWVRQTPGQGFE

GTSSDVGGYDYVSWYQHHPD
CoV2
CoV2
Science,

WMGWIKPKSGATNSADNFQDRVT

NAPKLLIFEVSNRPSGVSNRFS

372(6546): 1108-1112

MTADASVNTAYMELSSLRPDDTA

GSKSGNAASLTISGLLAEDEAD

VYYCARGHRIPSAISDKYDFWGQG

YFCTSYSSGRTPYVFGTGTKV

TLVTVSS

TVL

344
EVQLVESGGGLIQPGGSLRLSCAA
345
DVVMTQSPGTLSLSPGERATL
SARS-
SARS-
Dejnirattisai et al.,

SGLTVSSNYMSWVRQAPGKGLEW

SCRASQSVPSSYLAWYQQKPG
CoV2
CoV2
2021, Cell,

VSVIYSGGSTFYADSVKGRFTISRD

QAPRLLIYGASTRATGIPDRFS

184(11): 2939-2954

NSKNTLYLQMNSLGAEDTAVYYC

GSGSGTDFTLTISRLEPEDFAV

ARGEGSPGNWFDPWGQGTLVTVS

YYCQHYDTSPRFGGGTKVDIK

S

346
EVQLVESGGGLVQPGGSLRLSCAA
347
AIQMTQSPSSLSASVGDRVTIT
SARS-
SARS-
Andreano et al.,

SGFTVSINYMSWVRQAPGKGLEW

CRASQDIRNNLGWFQQKPGK
CoV2
CoV2
2021, Cell,

VSVIYSGGSTYYADSVKGRFTISRD

APKRLIYAASTLQRGVPSRFSG

184(7): 1821-1835

NSKNTLYLQMNSLRAEDTAVYYC

SGSGTEFTLTISSLQPEDFATYY

AAPLLWADSYYMDVWGKGTTVT

CLQHNSYLWTFGQGTKVEIK

VSS

348
QVQLVQSGAEVKKPGPSVKVSCK
349
DIVMTQSPAALSVSPGERATLS
SARS-
SARS-
Andreano et al.,

ASGGTFSSYTINWVRQAPGQGLE

CRASQSVSSNLAWYQQKPGQ
CoV2
CoV2
2021, Cell,

WMGRIIPMLGIAKYAQKFQGRVTI

APRLLIYGASTRATGIPARFSG

184(7): 1821-1835

TADKSTSTAYMELSSLRSEDTAVY

SWSGTEFTLTISSLQSEDLAVY

YCARGIVGATPGYFDYWGQGTLV

YCQQYNNWLTFGGGTKVEIK

TVSS

350
QVQLVQSGAEVKKPGSSVKVSCK
351
EIVMTQSPATLSLSPGERATLS
SARS-
SARS-
Andreano et al.,

ASGGTFSSYAISWVRQAPGQGLEW

CRASQSVSSYLAWYQQKPGQ
CoV2
CoV2
2021, Cell,

MGGITPIFHTANYAQKFQGRVTIT

APRLLIYDASNRATGIPARFSG

184(7): 1821-1835

ADESTSTVYMELSSLSSEDTAVYY

SGSGTDFTLTISSLEPEDFAVY

CARETGDQGVTAPFDLWGRGTLV

YCQLRGNWPPWTFGQGTKVEI

TVSS

K

352
QVQLVQSGPEVKKPGTSVKVSCK
353
EIVMTQSPGTLSLAPGERATLS
SARS-
SARS-
Andreano et al.,

ASGFTFTSSAMQWVRQARGQRLE

CRASQSVSSSYLGWYQQKPGQ
CoV2
CoV2
2021, Cell,

WIGWIVVGSGNTDYVQKFQGRVTI

APRLLIYGASSRATGIPDRFSGS

184(7): 1821-1835

TRDMSTSTAYMELSSLRSEDTAVY

GSGTDFTLTISRLEPEDFAVYY

YCAAPYCSSTTCHDGFDIWGQGT

CQQYGRSPWTFGQGTKVEIK

MVTVSS

354
QVQLVQSGAEVKKPGSSVKVSCK
355
EIVMTQSPATLSLSPGERATLS
SARS-
SARS-
Andreano et al.,

ASGGTFSSYTISWVRQAPGQGLEW

CRASQSVSSYLAWYQQKPGQ
CoV2
CoV2
2021, Cell,

MGRIIPILDRVMYAQKFQGRVTITA

APSLLIYDASNRATGIPARFSG

184(7): 1821-1835

DKSTSTAYMELSSLRSEDTAVYYC

SGSGTDFTLTISSLEPEDFAVY

ARRAIDSDTYVEQSHFDYWGQGT

YCQQPLTFGGGTKVEIK

LVTVSS

356
QVQLQESGAEVKKPGSSVKVSCK
357
EIVMTQSPATLSLSPGERATLS
SARS-
SARS-
Andreano et al.,

ASGGTFSSYAINWVRQAPGQGLE

CRASQSVSSFLAWYQQKPGQA
CoV2
CoV2
2021, Cell,

WMGGLIPIFGTANYAQKFQGRVTI

PRLLIYDASNRATGIPARFSGS

184(7): 1821-1835

TADESTSTAYMELSSLRSEDTAVY

GSGTDFTLTISSLEPEDFAVYY

YCANFIGDGYNYEEDYMDVWGK

CQQRSNWPPFTFGPGTKVDIK

GTTVTVSS

358
EVQLVESGGGLVKPGGSLRLFCAA
359
DIVMTQSPSSLSASVGDRVTIT
SARS-
SARS-
Andreano et al.,

SGFTFSDYYMSWFRQAPGKGLEW

CQASQDISNYLNWYQQKPGK
CoV2
CoV2
2021, Cell,

VSYISSSGSNIYYADSVKGRFTVSR

APKLLIYDASNLQTGVPSRFSG

(weak)
184(7): 1821-1835

DNAKNSLYLQMNSLRAEDTAVYF

SGSGTDFTFTISSLQPEDIATYY

CARGRLWGWFDPWGQGTLVTVSS

CQQYDHLLITFGQGTRLEIK

360
QITLKESGPTLVKPTQTLTLTCTFS
361
QSALTQPASVSGSPGQSITISCT
SARS-
SARS-
Kathryn Westendorf

GFSLSISGVGVGWLRQPPGKALEW

ATSSDVGDYNYVSWYQQHPG
CoV
CoV2
et al., 2021

LALIYWDDDKRYSPSLKSRLTISKD

KAPKLMIFEVSDRPSGISNRFS

(biorxiv.org/content/

TSKNQVVLKMTNIDPVDTATYYC

GSKSGNTASLTISGLQAEDEAD

10.1101/

AHHSISTIFDHWGQGTLVTVSS

YYCSSYTTSSAVFGGGTKLTVL

2021.04.30.442182v3)

362
QVQVVQSGAEVKKPGASVKVSCK
363
QSALTQPASVSGSPGQSITISCT
SARS-
SARS-
Cao et al., 2021,

VSGYTLIEISIHWVRQAPGKGLEW

GTSSDVGSYNYVSWYQQHPG
CoV2
CoV2
Cell Research (2021)

MGGFDPEAGETIYAQKFQGRVTM

KAPKLMIYDVTKRPSGVPDRF

0: 1-10; doi:

TEDTSTDTAYMEVSSLRSEDTAVY

SGSKSGNTASLTISGLQAEDEA

10.1038/s41422-021-

YCATGPAIAAAETNWFDLWGQGT

DYYCSSYTSSSTWVFGGGTKL

00514-9

LVTVSS

TVL

364
EVQLVESGGGLVKPGGSLRLSCAA
365
SYELTQPPSVSVSPGQTATITCS
SARS-
SARS-
Cao et al., 2021, Cell

SEFTFSSYSMNWVRQAPGKGLEW

GDKLGDKYACWYQQRPGQSP
CoV2
CoV2
Research (2021) 0: 1-

VSSISSSGSQIYYADSVKGRFTISRD

VLVIYQDSKRPSGIPERFSGSNS

10; doi:

NAKKSLYLQMNSLRVEDTAVYYC

GNTATLTIGGTQAMDEAAYFC

10.1038/s41422-021-

ATNGGAHSSTWSFYGMDVWGQG

QAWDSNTGVFGGGTKLTVL

00514-9

TTVTVSS

366
EVQLVESGGGLVKPGGSLRLSCAA
367
AIRMTQSPSSLSASVGDRVTIT
SARS-
SARS-
Rosa et al., 2021,

SGFSFSSYSMNWVRQAPGKGLEW

CQASQDISNYLNWYQQKPGK
CoV2
CoV2
Science Advances

VSSISSNSNYIYYADSMKGRFTISR

APKLLIYDASNLETGVPSRFSG

(2021): Vol. 7, no.

DNAKNSLYLQMNSLRAEDTAVYY

SGSGTDFTFTISSLQPEDIATYY

22, eabg7607

CASNRSPYDSSNYYFDYWGQGTR

CQHHDSLPLTFGGGTKVEIK

VTISS

368
EVQLVESGGGVVQPGRSLRLSCAA
369
DIVMTQSPLSLPVTPGEPASISC
SARS-
SARS-
Fu et al., PLOS

SGFTFSYYGMHWVRQAPGKGLEW

RSSQSLLHSNGYNYLDWYLQ
CoV2
CoV2
Biology, (2021), doi:

VAVIWYDGSNRFYADSVKGRFTIS

KPGQSPQLLIYLGSNRASGVPD

10.1371/journal.pbio.

RDNSKSTLYLQMNSLRAEDTAVY

RFSGSGSGTDFTLKISRVEAED

3001209

YCATDPPGLRFRFDYWGQGTLVT

VGVYYCMQGLQTPLTFGGGT

VSS

KVEIK

370
EVQLQQSGPELVKPGASVKISCKT
371
DIVMTQSQKFMSTSVGDRVSV
SARS-
SARS-
Fu et al., PLOS

SGYTFTEYTMHWVKQSHGKSLEW

TCKASQNVGTNVAWYQQKPG
CoV2
CoV2
Biology, (2021), doi:

IGGINPNNGDNTYNQKLKGKATLT

QSPKPLIYSASSRYSGVPDRFT

10.1371/journal.pbio.

VHKSSSTAYMELRSLTSEDSAVYY

GSGSGTDFTLTISNVQSEDLAE

3001209

CARDGYPYYYALDYWGQGTSVT

YFCQQYNNYPWTFGGGTKLEI

VSS

K

372
QVQLVQSGAEVKKPGASVKLSCK
373
DIVLTQSPASLAVSPGQRATIT
SARS-
SARS-
Fu et al., PLOS

ASGYSFTSYWVNWVRQAPGQGLE

CRASESVDSYGNSFMHWYQQ
CoV2
CoV2
Biology, (2021), doi:

WIGMIHPSDSETRLNQKFKDRVTIT

KPGQPPKLLIYRASNLESGIPA

10.1371/journal.pbio.

VDKSTSTAYMELSSLRSEDTAVYY

RFSGSGSGTDFTLTINPVEAND

3001209

CARADGYEWYFDVWGRGTLVTV

VANYYCQQSNEDPWTFGQGT

SS

KVEIK

374
QVQLQQSGAELVKPGASVKLSCK
375
DIVLTQSPASLAVSLGQRATIS
SARS-
SARS-
Guo et al., JBC

ASGYTFTSYYIYWMKQRPGQGLE

CRASESVEYYGTGLMQWYQQ
CoV2
CoV2
(2021), 296

WIGEINPNNGGTNFNEKFKSKATL

KPGQPPKLLIYAASNVESGVPA

(100346): 1-9

TVDKSSSTAYMQLSSLTSEDSAVY

RFSGSGSGTDFSLNIHPVEEDDI

YCTRGHSDYWGQGTTLTVSS

AMYFCQQTRKVPYTFGGGTK

LEIK

376
EVQLVESGGGLVNPGGSLRLSCAA
377
VTQPASVSGSPGQSITISCTGTS
SARS-
SARS-
rcsb.org/structure/

SGFTFSDYTIHWVRQAPGKGLEW

SDVGGYNYVSWYQQHPGKAP
CoV2
CoV2
7LXX

VSSISSSSNYIYYADSVKGRFTISRD

KLMIYDVSDRPSGVSNRFSGS

NAKNSLSLQMNSLRAEDTAVYYC

KSGNTASLTISGLQAEDEADY

ARDGNAYKWLLAENVRFDYWGQ

YCSSYTSSSTPNWVFGGGTKL

GTLVTVSS

T

378
VQLVESGGGVVQPGRSLRLSCAAS
379
YELTQPPSVSVSPGQTARITCS
SARS-
SARS-
rcsb.org/structure/

GFTFSSYGMHWVRQAPGKGLEWV

GDALAKHYAYWYRQKPGQAP
CoV2
CoV2
71y0

TVIWYDGSNRYYADSVKGRFTISR

VLVIYKDSERPSGIPERFSGSSS

DNSKNTLYLQMDSLRAEDTAVYY

GTTVTLTISGVQAEDEADYYC

CARAVAGEWYFDYWGQGTLVTV

QSADSIGSSWVFGGGTKLTV

S

380
VQLVESGGGVVQPGRSLRLSCAAS
381
YELTQPPSVSTARITCGGNNIE
SARS-
SARS-
rcsb.org/structure/

GFTFSNYGMHWVRQAPGKGLEW

RKSVHWCQQKPGQAPALVVY
CoV2
CoV2
7LXW

VAVIWYDGSNKFYADSVKGRFTIS

DDSDRPSGIPERFSGSNSGNTA

RDNSKNSLYLQMNSLRAEDTAVY

TLTISRVEAGDEADYYCQVWD

FCARAFPDSSSWSGFTIDYWGQGT

SGSDQVIFGGGTKLT

LVTV

382
QVRLVQSGAEVKKSGESLKISCKG
383
QSVLTQPASVSGSPGQSITISCT
SARS-
SARS-
rcsb.org/structure/

SGYSFTSYWIGWVRQMPGKGLEW

GISSDVGGYNSVSWYQQHPGK
CoV2
CoV2
7M7W; Starr, TN, et

MGIIYPGDSDTRYSPSFQGQVTISA

APKLMIYDVTNRPSGVSNRFS

al., Nature, 2021

DKSISTVYLQWSSLKASDTAMYYC

GSKSGNTASLTISGLQAEDEAD

Jul 14. doi:

ARQWSHYTYDYYYWGQGTLVTIS

YYCSSYTSSSTPPYVFGTGTKV

10.1038/s41586-

S

SVL

021-03807-6.

384
QVQLVQSGAEVKKPGSSVKVSCK
385
QTVLTQPPSVSGAPGQRVTISC
SARS-
SARS-
rcsb.org/structure/

ASGGIFNTYTISWVRQAPGQGLEW

TGSNSNIGAGYDVHWYQQLP
CoV2,
CoV2,
7MKL; Tortorici et

MGRIILMSGMANYAQKIQGRVTIT

GTAPKLLICGNSNRPSGVPDRF
SARS-
SARS-
al., Nature doi:

ADKSTSTAYMELTSLRSDDTAVYY

SGSKSGTSASLAITGLQAEDEA
CoV1
CoV1
10.1038/s41586-021-

CARGFNGNYYGWGDDDAFDIWG

DYYCQSYDSSLSGPNWVFGG

03817-4(2021)

QGTLVTVYS

GTKLTVL

386
QVQLVQSGAEVKKPGASVKVSCK
387
DIVMTQTPLSSPVTLGQPASIS
SARS-
SARS-
Peter et al., 2021,

VSGYTLTEVSVHWVRQAPEKGLE

CRSSQSLVHSDGNTYLSWLQQ
CoV2
CoV2
BioRxiv, doi:

WMGGFDPEDAETIYAQKFQGRVT

RPGQPPRLIIYKVSNRFCGVPD

10.1101/

MTEDTSTDTAYMELSSLRSEDTAV

RFSGSGAGTDFTLKISRVEAED

2021.04.16.440101

YFCATAPAVAGPFYYYYYGMDV

VGVYYCTQATQFPHTFGQGTK

WGQGTTVTVSS

LEIK

388
QVQLVQSGAEVKKPGASVKVSCK
389
DIVMTQTPLSSPVTLGQPASIS
SARS-
SARS-
Peter et al., 2021,

VSGYTLTEVSVHWVRQAPGKGLE

CRSSQSLVHSDGNTYLSWLQQ
CoV2
CoV2
BioRxiv, doi:

WMGGFDPEDAKTIYAQKFQGRVT

RPGQPPRLLIYKVSNRFSGVPD

10.1101/

MTEDTSTDTAYMELSSLSSEDTAV

RFSGSGAGTDFTLKISRVEAED

2021.04.16.440101

YFCATAPAVAGPFYYYYYGMDV

VGVYYCTQATQFPHTFGQGTK

WGQGTTVTVSS

LEIK

390
QVQLVQSGAEVKKPGASVKVSCK
391
DIVMTQTPLSSPVTLGQPASIS
SARS-
SARS-
Peter et al., 2021,

VSGYSLIEVSVHWVRQAPGKGLE

CRSSQSLVHSDGNTYLSWLQQ
CoV2
CoV2
BioRxiv, doi:

WMGGFDPENAETIYARGFRGRVT

RPGQPPRLLIYKVSNRFSGVPD

10.1101/

MTEDTSTDTAYMELSSLKYEDTA

RFSGSGAGTEFTLKISRVEAED

2021.04.16.440101

VYFCATAPAVAGPFYYYYYGMDV

VGVYYCTQATQFPHTFGQGTK

WGQGTTVTVSS

LEIK

392
QVQVVESGGGVVQPGRSLRLSCA
393
NIQMTQSPSAMSASVGDSVTIT
SARS-
SARS-
Peter et al., 2021,

ASGFTFSGYGMHWVRQAPGKGLE

CRARQDINNYLAWFQQKPGK
CoV2
CoV2
BioRxiv, doi:

WVAVIWYDGSNQYYADSVKGRFT

VPKHLIYAASSLLSGVPSRFSG

10.1101/

ISRDNSKNTLYLQMNSLRVEDTAV

SGSGTEFTLTISSLQPEDFATYY

2021.04.16.440101

YHCVRETVDGMDVWGQGTTVTV

CLQHNSYPYTFGQGTKLEIK

SS

394
QHQLVQSGAEVKKPGASVKVSCK
395
DIVMTQTPLSSPVTLGQPASIS
SARS-
SARS-
Peter et al., 2021,

VSGYTLVEVSVHWVRQAPGKGFE

CRSSQSLVHSDGNTYLSWLQQ
CoV2
CoV2
BioRxiv, doi:

WMGGFDPENAATIYAQKFQGRVT

RPGQPPRLLIYKVSNRFSGVPD

10.1101/

MTEDTSTDTAYMELSSLRYEDTAV

RFSGSGAGTEFTLKISRVEAED

2021.04.16.440101

YFCATAPAVAGPLYYYYYGMDV

VGVYYCTQATQFPHTFGQGTK

WGQGTTVTVSS

LEIK

396
QVQLVQSGAEVKKPGASVKVSCK
397
DIVMTQTPLSSPVTLGQPASIS
SARS-
SARS-
Peter et al., 2021,

VSGYTLTEVSVHWVRQAPGKGLE

CRSSQSLVHSDGNTYLSWLQQ
CoV2
CoV2
BioRxiv, doi:

WMGGFDPEDAETIYAQKFQGRVT

RPGQPPRLLIYKVSNRFSGVPD

10.1101/

MTEDTSTDTAYMELSSLRYEDTAV

RFSGSGAGTEFTLKISRVEAED

2021.04.16.440101

YFCATAPAVAGPFYYYYYGMDV

VGVYYCTQATQFPHTFGQGTK

WGQGTTVTVSS

LEIK

398
QVQVVESGGGVVQPGRSLRLSCA
399
NIQMTQSPSAMSASVGDSVTIT
SARS-
SARS-
Peter et al., 2021,

ASGFTFSSYGMHWVRQAPGKGLE

CRARQDINNYLAWFQQKPGK
CoV2
CoV2
BioRxiv, doi:

WVAVIWYDGSNKYYADSVKGRFT

VPKHLIYAASSLLSGVPSRFSG

10.1101/

ISRDNSKNTLYLQMNSLRVEDTAV

SGSGTEFTLTISSLQPEDFATYY

2021.04.16.440101

YYCVRETVDGMDVWGQGTTVTV

CLQHNSYPYTFGQGTKLEIK

SS

400
QVQVVESGGGVVQPGRSLRLSCA
401
NIQMTQSPSAMSASVGDSVTIT
SARS-
SARS-
Peter et al., 2021,

ASGFTFSSYGMHWVRQAPGKGLE

CRARQDINNYLAWFQQKPGK
CoV2
CoV2
BioRxiv, doi:

WVAVIWYDGSNKYYADSVKGRFT

VPKHLIYAASSLLSGVPSRFSG

10.1101/

ISRDNSKNTLYLQMNSLRVEDTAV

SGSGTEFTLTISSLQPEDFATYY

2021.04.16.440101

YYCVRETVDGMDVWGQGTTVTV

CLQHNSYPYTFGQGTKLEIK

SS

402
QVQLVQSGAEVKKPGASVKVSCK
403
DIVMTQTPLSSPVTLGQPASIS
SARS-
SARS-
Peter et al., 2021,

VSGYTLTEVSVHWVRQAPGKGLE

CRSSQSLVHSDGNTYLSWLQQ
CoV2
CoV2
BioRxiv, doi:

WMGGFDPEDAETIYAQKFQGRVT

RPGQPPRLLIYKVSNRFSGVPD

10.1101/

MTEDTSTDTAYMELSSLRSEDTAV

RFSGSGAGTDFTLKISRVEAED

2021.04.16.440101

YFCATAPAVAGPFYNFYYGIDVW

VGVYYCTQATQFPHTFGQGTK

GQGTTVTVSS

LEIK

404
QVQLVQSGAEVKKPGASVKVSCK
405
SYELTQPPSVSVSPGQTARITC
SARS-
SARS-
Wang et al., 2021,

ASGYTFTSYGISWVRQAPGQGLE

SGDALPKQYAYWYQQKPGQA
CoV2
CoV2
Science Translational

WMGWISAYNGNTNYAQKLQGRV

PVLVIYKDSERPSGIPERFSGSS

(weak)
Medicine,

TMTTDTSTSTAYMELRSLRSDDTA

SGTTVTLTISGVQAEDEADYY

13(577): eabf1555

VYYCARVPASYGDDDYYYYYGM

CQSADSSGTLWVFGGGTKLTV

DVWGQGTTVTVSS

L

406
EVQLLESGGGLVQPGGSLRLSCAA
407
QTVVTQEPSLTVSPGGTVTLTC
SARS-
SARS-
Wang et al., 2021,

SGFTFSNYAMSWVRQAPGKGLEW

GSSTGAVTSGHYPYWFQQKSG
CoV2
CoV2
Science Translational

VSGISNSGGSTYYEDSVKGRFTISR

QAPRTLIYETNIKHSWTPARFS

Medicine,

DNSKNTLYLQMNSLRAEDTAVYY

GSLLGGKAALTLSGAQPDDEA

13(577): eabf1555

CAKVGEYCGDDCYRGLDYWGQG

DYYCLLSYSGARPVFGGGTKL

TLVTVSS

TVL

408
EVQLVESGGGLVQPGGSQRLSCAA
409
EIVMTQSPATLSVSPGERATLS
SARS-
SARS-
Wang et al., 2021,

SGFTVSSNYMSWIRQAPGKGLEW

CRASQSVSSHLAWYQQKPGQ
CoV2
CoV2
Science Translational

VSVIYSGGSAYYVDSVKGRFTISR

APRLLIYGASTRATGIPTRFSGS

(weak)
Medicine,

DNSKNTLYLQMNSLRPEDTAVYY

GSGTEFTLTISSLQSEDFAVYY

13(577): eabf1555

CARIANYMDVWGKGTTVTVSS

CQQYNNWPPLTFGGGTKVEIK

410
QVQLVESGGGLIQPGGSLRLSCAA
411
EIVLTQSPGTLSLSPGERATLSC
SARS-
SARS-
Wang et al., 2021,

SGLTVSSNYMTWVRQAPGKGLEW

RASQSVSSNYLAWYQQKPGQ
CoV2
CoV2
Science Translational

VSVIYSGGSTFYADSVKGRFTISRD

APRLLIYGASSRATGIPDRFSGS

Medicine,

NSKNTLYLQMNSLRAEDTAVYYC

GSGTDFTLTISRLEPEDFAVYY

13(577): eabf1555

ARETYGMDVWGQGTTVTVSS

CQQYGSSPWTFGQGTKVEIK

412
QLQLQESGPGLVKPSETLSLTCTVS
413
QSALTQPASVSGSPGQSITISCT
SARS-
SARS-
Wang et al., 2021,

GGSISRSDYYWGWIRQPPGKGLE

GTSSDVGSYNLVSWYQQHPG
CoV2
CoV2
Science Translational

WIGTIYYSGSTYYNPSLKSRVTISV

KAPKLMIYEGSKRPSGVSSRFS

Medicine,

DTSKNQFSLKLGSVTAADTAVYY

GSKSGNTASLTISGLQGEDEAD

13(577): eabf1555

CARQARTDASTYGHNFDSWGQGT

YYCCSYAGSSTWVFAGGTKLT

LVT

VL

414
QLQLQESGPGLVKPSETLSLTCTVS
415
QSALTQPASVSGSPGQSITISCT
SARS-
SARS-
Wang et al., 2021,

GGSISRSDFYWGWIRQPPGKGLEW

GTSSDVGSYNLVSWYQQHPG
CoV2
CoV2
Science Translational

IGTIYYSGSTYYNPSLKSRVTISVDT

KAPKLMIYEGSKRPSGVSSRFS

Medicine,

SKNQFSLKLDSVTAADTAVYYCA

GSKFGNTASLTIYGLQGEDEA

13(577): eabf1555

RQARTDGSTYGHNFDYWGQGTLV

DYYCCSYAGSITWVFGGGTKL

TVSS

TVL

416
QVQLVQSGAEVKKPGASVKVSCK
417
QSVLTQPASVSGSPGQSITISCT
SARS-
SARS-
Wang et al., 2021,

ASGYTFTGYYMHWVRQAPGQGLE

GTSSDVGGYNYVSWYQQHPG
CoV2
CoV2
Science Translational

WMGWINPNSGGTNYAQKFQGWV

KAPKLMIYDVSNRPSGVSNRF

Medicine,

TMTRDTSISTAYMELSRLRSDDTA

SGSKSGNTASLTISGLQAEDEA

13(577): eabf1555

VYYCARESHGGVWSAPGYYYGM

DYYCSSYTNSSAVVFGGGTKL

DVWGQGT

TVL

418
EVQLVESGGGLVKPGGSLRLSCAA
419
EIVLTQSPGTLSLSPGERATLSC
SARS-
SARS-
Wang et al., 2021,

SGFTFSSYSMNWVRQAPGKGLEW

RASQSVSSSYLAWYQQKPGQ
CoV2
CoV2
Science Translational

VSSISRDSKYIYYAESVKGRFTISR

APRLLIYGASRRATGIPDRFSG

Medicine,

DNAKNSLYLQMNSLIVEDTAVYY

SGSGTDFTLTISRLEPEDFAVY

13(577): eabf1555

CARDDGIAAASDYWGQGTLVTVSS

YCQQYGSSPLLTFGGGTKVEIK

420
QVQLQQWGAGLLKPSETLSRTCA
421
QSALTQPASVSGSPGQSITISCT
SARS-
SARS-
Wang et al., 2021,

VYGGSFSGYYWSWIRQSPGKGLE

GTSSDVGDYNYVSWYQQHPG
CoV2
CoV2
Science Translational

WIGEINDSGSTNYNPSLKSRVTISV

KAPKLMIYDVSNRPSGVSNRF

Medicine,

DTSKNQFSLRLSSVTAADTAVYYC

SGSKSGNTASLTISGLQAEDEA

13(577): eabf1555

ARGHTQEKWELREGYYFDYWDQ

DYYCSSYASGSTLYYVFGTGT

GTLVTVSS

KVTVL

422
EVQLLESGGGLVKPGGSLRLSCAA
423
NFMLTQPHSVSESPGKTVTISC
SARS-
SARS-
Wang et al., 2021,

SGFTFSSYNMNWVRQAPGKGLEW

TGSSGSIASNYVQWYQQRPGS
CoV2
CoV2
Science Translational

VSSISSSSSHIYYADSVKGRFTISRD

APTTVIYEDNQRPSGVPDRFSG

(weak)
Medicine,

NAKNSLYLQMNSLRAEDTAVYYC

SIDSSSNSASLTISGLKTEDEAD

13(577): eabf1555

ARERGYHGGKTSPFLGGQGTLVT

YYCQSYDSSNYWVFGGGTKL

VSS

TVL

424
QVQLVESGAEVKKPGASVKVSCK
425
EIVLTQSPATLSLSPGERATLSC
SARS-
SARS-
Wang et al., 2021,

ASGYTFTAYYMHWVRQAPGQGLE

RASQSVSSYLAWYQQKPGQA
CoV2
CoV2
Science Translational

WMGWINPNSGGTNYAQKFQGRV

PRLLIYDASNRATGIPARFSGS

Medicine,

TMTRDTSISTAYMELSRLRSDDTA

GPGTDFTLTISSLEPEDFAVYY

13(577): eabf1555

VYYCARPPRDYYDSSGYQIRDDHF

CQQRSNCLFTFGPGTKVDIK

DYWGQGTLVTVSS

426
EVQLVQSGAEVKKPGASVRVSCK
427
QSALTQPASVSGSPGQSITISCT
SARS-
SARS-
Wang et al., 2021,

ASGYTFTSYDINWVRQATGQGLE

GTSSDVGSYNLVSWYQQHPG
CoV2
CoV2
Science Translational

WMGWMNPNSGNTGYAQKFQGRV

KAPKLMIYEVSKRPSGVSNRFS

Medicine,

TMTRNTSISTVYMELSSLRSEDTA

GSKSGNTASLTISGLQAEDEAD

13(577): eabf1555

VYYCARFPKVPAAIFPGDYYYGM

YYCCSYAGSSTLVFGGGTKLT

DVWGQGTTVTVSS

VL

428
QVQLVESGGGVVQPGRSLRLSCA
429
DIQMTQSPSSLSASVGDRVTIS
SARS-
SARS-
Wang et al., 2021,

ASGFTFSSYAMHWVRQAPGKGLE

PKLLIYAASSLQSGVPSRFSGS
CoV2
CoV2
Science Translational

CRASQSISSYLNWFQQKPGKA

GSGTDFTLTISTLQPEDFATYY

Medicine,

WVAVIWYDGSNKHYADSVKGRFT

CQQSYGTPPWTFGQGTKVEIK

13(577): eabf1555

ISRDNSKNTLYLQMNSLRAEDTAM

YYCARDEGSLTTTFDYWGQGTLV

TVSS

430
EVQLVESGGGLVQPGGSLRLSCAA
431
QSALTQPPSVSGAPGQRVTISC
SARS-
SARS-
Wang et al., 2021,

SGFTFSTYDMSWARQAPGKGLEW

TGSSSNIGAGYDVHWYQQLPG
CoV2
CoV2
Science Translational

VANIKQDGSEKYYVDSVKGRFTIS

TAPKLLIYGNSNRPSGVPDRFS

Medicine,

RDNAKNSLYLQMNSLRAEDTAVY

GSKSGTSASLAITGLQAEDEAD

13(577): eabf1555

YCARDTIPFWSGYYTSPDYYFDY

YYCQSYDSSLSGVVFGGGTKL

WGQGTLVTVSS

TVL

432
QVQLQESGPGLVKPSQTLSLTCTV
433
QSALTQPPSASGSPGQSVTISC
SARS-
SARS-
Wang et al., 2021,

SGGSISSGGYYWSWIRQHPGKGLE

TGTSSDVGGYNYVSWYQQHP
CoV2
CoV2
Science Translational

WIGYIYYSGTTYYNPSLKSRVTISV

GKAPKLMIYEVSKRPSGVPDR

Medicine,

DTSKNQFSLKLSSVTAADTAVYYC

FSGSKSGNTASLTVSGLQAED

13(577): eabf1555

ASSRYDFWSGSFDYWGQGTLVTV

EADYYCSSYAGSNNWVFGGG

SS

TKLTVL

434
QVQLVQSGAEVKKPGASVKVSCK
435
QSALTQPASVSGSPGQSITISCT
SARS-
SARS-
Wang et al., 2021,

TSGYIFTDYSMHWVRQAPGQGLE

GTSSDVGGYNFVSWYQQHPG
CoV2
CoV2
Science Translational

WMGWVNPNSGGTNYAQKFQGW

KAPKLMIYEVSDRPSGVSNRFS

Medicine,

VTMARDTSITTVYMELSRLRSDDT

GSKSGNTASLTISGLQAEDEAD

13(577): eabf1555

AVYYCARGPLPHRLVYDFWSGFH

YYCSSYTSSSTWVFGGGTKLT

DAFDIWGQGTMVTVSS

VL

436
QVQLVESGGGVVQPGRSLRLSCA
437
DIQMTQSPSTLSASVGDRVTIT
SARS-
SARS-
Wang et al., 2021,

ASGFTFSNYGMHWVRQAPGKGLE

CRASQSISSWLAWYQQKPGKA
CoV2
CoV2
Science Translational

WVAVIRYNGNNIYYADFVKGRFTI

PKLLIYEASSLKSGVPSRFSGS

(weak)
Medicine,

SRDNSKNTLYLQMNSLRGEDTAV

GSGTEFTLTISSLQPDDFATYY

13(577): eabf1555

YYCAREGDGPDAFDIWGQGTMV

CQQYNNYGITFGQGTRLEIK

438
EVQLVESGGGLIQPGGSLRLSCAA
439
DIQLTQSPSFLSASVGDRVTITC
SARS-
SARS-
Wang et al., 2021,

SGLTVSSNYMSWVRQAPGKGLEW

RASQGVGSYLAWYQQKPGKA
CoV2
CoV2
Science Translational

VSVIYSGGSTYYADSVRGRFTISRD

PNLLIYAASTLQSGVPSRFSGS

Medicine,

NSENTLYLQMNSLRAEDTAVYYC

GSGTEFTLKITSLQPEDIATYY

13(577): eabf1555

ARVGDWYFSWGQGTLVTVSS

CQQLNSYPPLTFGGGTKVEIK

440
QVQLQESGPGLVKPSETLSLTCTFS
441
EIVLTQSPGTLSLSPGERVTLSC
SARS-
SARS-
Wang et al., 2021,

GGSISSYSWNWIRQPPGKGLEWIG

RASQSITSTYLTWYQQKPGQA
CoV2
CoV2
Science Translational

YIYTSGSTNYNPSLKSRVTMSVDT

PRLLIYGASNRATGIPDRFSSSG

(weak)
Medicine,

SKNQFSLKLNSVTAADAAVYFCA

SGTDFTLTISRLEPEDFAVYYC

13(577): eabf1555

RGLFYNSGGYYSSNYYYYIDVWG

QHYDRSPLCSFGQGTKLEIK

KGTTVTVSS

442
EVQLVQSAAEVKKPGESLRISCKG
443
EIVLTQSPGILSLSPGERATLSC
SARS-
SARS-
Wang et al., 2021,

SGYSFTNYWINWVRQMPGKGLEW

RASQSVSSSYLAWYQQKPGQ
CoV2
CoV2
Science Translational

MGRIDPSDSYTNYSPSFQGHVTISA

APRLLIYGASSRAAGIPDRFSG

Medicine,

DKSISTAYLQWSSLKASDTAMYYC

SGSGTDFTLTISRLEPEDSAVY

13(577): eabf1555

ARLNTDLRSRFGELYYYFDYWGQ

YCQQYGSSLTWTFGQGTKVEI

GTLV

K

444
QVQLVQSGAEVKKPGASVKVSCK
445
DIQMTQSPSSLSASVGDRVTIT
SARS-
SARS-
Wang et al., 2021,

ASGYTFTTYYLHWVRQAPGQGLE

CQASQDITNHLNWYQQKPGK
CoV2
CoV2
Science Translational

WMGIIDPSGGSTSYAQKFQGRVTM

APKLLIYYASNLETGVPSRFSG

Medicine,

TKDTSTSTVYMELSSLRSEDTAVY

IGSGTDFTFTISSLQPEDIATYY

13(577): eabf1555

YCARVGRGFSYGYFDYWGQGAL

CQQYDNLPPLTFGGGTKVEIK

VTVSS

446
QVQLVQSGAEVKKPGSSVKVSCK
447
DIVMTQSPLSLPVTPGEPASISC
SARS-
SARS-
Wang et al., 2021,

ASGGTFNSYAISWVRQAPGQGLE

RSSQSLLHSNGYNYLDWYLQ
CoV2
CoV2
Science Translational

WMGGIIPIFGTANYAQKFQGRVTIT

KPGQSPQLLIYLGSNRASGVPD

(weak)
Medicine,

ADESTSTAYMELSSLRSEDTAVYY

RFSGSGSGTDFTLKISRVEAED

13(577): eabf1555

CARVGAEWPRDHKYYYYGMDV

VGVYYCMQALQTPLTFGGGT

WGQGTTVTVSS

KVEIK

448
QVQLVESGGGLVQPGGSLRLSCAA
449
DIQMTQSPSSLSASVGDRVTIT
SARS-
SARS-
Wang et al., 2021,

SGFTFSNYDMHWVRQATGRGLEW

CRASQSISSYLNWYQQKPGKA
CoV2
CoV2
Science Translational

VSTIGTAGDTYYPGSVKGRFTISRE

PKLLIYAASSLQSGVPSRFSGS

(weak)
Medicine,

NAKNSLYLQMNSLRAGDTAVYYC

GSGTDFTLTISSLQPEDFATYY

13(577): eabf1555

ARVKYGGYVGYFDYWGQGTLVT

CQQSYSTPELTFGGGTKVEIK

VSS

450
EVQLVESGGGLVQPGGSLRLSCAA
451
DIQMTQSPSSLSASVGDRVTIT
SARS-
SARS-
Wang et al., 2021,

SGFTVSSNYMSWVRQAPGKGLEW

CQASQDISNYLNWYQQKPGK
CoV2
CoV2
Science Translational

VSLIYSGGTTYYADSVKGRFTISRD

APKLLIYDASNLETGVPSRFSG

Medicine,

NSKNTLYLQMNSLRAEDTAVYYC

SGSGTDFTFTISSLQPEDIATYY

13(577): eabf1555

ARETLGRGGDYWGQGTLVTVSS

CQQYDNLPRSFGQGTKLEIK

452
EVQLVESGGGLVQPGRSLRLSCAA
453
QSVLTQPPSASGTPGQRVTISC
SARS-
SARS-
Wang et al., 2021,

SGFTFDDYAMHWVRQAPGKGLE

SGSSSNIGSNTVNWYQQLPGT
CoV2
CoV2
Science Translational

WVSGVSWNSGTIGYADSVKGRFTI

APKLLIYSNNQRPSGVPDRFSG

Medicine,

SRDNAKNSLYLQMNSLRAEDTAL

SKSGTSASLAISGLQSEDEADY

13(577): eabf1555

YYCAKIADIVRAYDFWSGQHFDAF

YCAAWDDSLVVFGGGTKLTV

DIWGQGTMVT

L

454
EVQLVESGGGLVQPGRSLRLSCAA
455
DIQMTQSPSTLSASVGDRVTIT
SARS-
SARS-
Wang et al., 2021,

SGFTFDDYAMHWVRQAPGKGLE

CRASQSISSWLAWYQQKPGKA
CoV2
CoV2
Science Translational

WVSIISWNSDNIGYADSVKGRFTIS

PNLLIYTASNLESGVPSRYSGS

Medicine,

RDNARNSLYLQMNSLRVEDTALY

GSGTEFTLSISSLQPEDSATYFC

13(577): eabf1555

YCAKDKGSGSGYGMDVWGRGTT

QRYNSYPYSFGQGTKLEIK

VTVSS

456
QLQLQESGPGLVKPSETLSLTCTVS
457
DIQMTQSPSSLSASVGDRVTIT
SARS-
SARS-
Wang et al., 2021,

GGSISSSYYYWGWIRQPPGKGLEW

CQASQDISNYLNWYQQKPGK
CoV2
CoV2
Science Translational

IGSIYYSGSTYYNPSLKSRVTISVDT

APKLLIYDASNLETGVPSRFSG

(weak)
Medicine,

SKNQFSLTLSSVTAADTAVYYCAT

SGSGTDFTFTISSLQPEDIATYY

13(577): eabf1555

GGRFWGWFDPWGQGTLVTVSS

CQQYDNLPPKLTFGGGTKVEIK

458
EVQLVQSGAEVKKPGESLKISCKG
459
QSVLTQPPSASGTPGQRVTISC
SARS-
SARS-
Wang et al., 2021,

SGYSFISYWIGWVRQMPGKGLEW

SGSSSNIGSNTVNWYQQLPGT
CoV2
CoV2
Science Translational

MGIIYPGDSDTRYSPSFQGQVTISA

APKLLIYSNNQRPSGVPDRFSG

Medicine,

DKSINTAYLQWSSLKASDTAMYY

SKSGTSASLAISGLQSEDEADY

13(577): eabf1555

CARRVTIPNGWFDPWGQGTLVTV

YCAAWDDSLNGVVFGGGTKL

SS

TVL

460
QVQLVQSGAEVKKPGSSVKVSCK
461
DIQMTQSPSSVSASVGDRVTIT
SARS-
SARS-
Wang et al., 2021,

ASGGTFSSYAINWVRQAPGQGLE

CRASQGISRWLAWYQQKPGK
CoV2
CoV2
Science Translational

WMGGIIPIFGTANYAQKFQGRVTIT

APKLLIYAAFSLQSGVPSRFSG

Medicine,

ADESTSTAYMELSSLRSEDTALYY

SGSGTDFTLTISSLQPEDFATY

13(577): eabf1555

CARNRAVSEREDYYYGMDVWGQ

YCQQANSFPLTFGGGTKVEIK

GTTVTVSS

462
QVQLVQSGAEVKKPGASVKVSCK
463
QSVLTQPASVSGSPGQSITISCT
SARS-
SARS-
Wang et al., 2021,

ASGYIFTDYSMITWVRQAPGQGLE

GTSSDVGGYKFVSWYQQHPG
CoV2
CoV2
Science Translational

WIGWVNPNSGGTNYAQKFQGWV

KAPKLMIYEVSNRPSGVSNRFS

Medicine,

TMARDTSITTVYMELSRLKSDDTA

GSKSGNTASLTISGLQAEDEAD

13(577): eabf1555

VYFCARGPLFHRLVYDFWSGYHD

YYCNSYTSSSTWVFGGGTKLT

GFDMWGQGTMVTVSS

VL

464
EVQLVESGGGLIQPGGSLRLSCAA
465
EIVLTQSPGTLSLSPGERATLSC
SARS-
SARS-
Wang et al., 2021,

SGLTVSRNYMNWVRQAPGKGLE

RASQSFSSTYLAWYQQKPGQA
CoV2
CoV2
Science Translational

WVSVMYSGGSTFYADSVKGRFTIS

PRLLIYGASSRATGIPDRFSGSG

Medicine,

RDNSKNTLYLQMNSLRAEDTAVY

SGTDFTLTISRLEPEDFAVYYC

13(577): eabf1555

YCARESYGMDVWGQGTTVTVSS

QQYVTSPWTFGQGTKVEIK

466
QVQLQQWGAGLLKPSETLSRTCA
467
QSALTQPASVSGSPGQSITISCT
SARS-
SARS-
Wang et al., 2021,

VYGGSFSGYYWSWIRQSPGKGLE

GTSSDVGDYNYVSWYQQHPG
CoV2
CoV2
Science Translational

WIGEINDSGSTNYNPSLKSRVTISV

KAPKLMIYDVSNRPSGVSNRF

Medicine,

DTSKNQFSLRLSSVTAADTAVYYC

SGSKSGNTASLTISGLQAEDEA

13(577): eabf1555

ARGHTQEKWELREGYYFDYWDQ

DYYCSSYASGSTLYYVFGTGT

GTLVTVSS

KVTVL

468
QVQLVESGGGVVQPGRSLRLSCA
469
DIQMTQSPSSLSASVGDRVTIT
SARS-
SARS-
Wang et al., 2021,

ASGFPFSIYGMHWVRQAPGKGLE

CRASQSISSYLNWYQQKPGKA
CoV2
CoV2
Science Translational

WVAVISYDGGNKYYADSVKGRFT

PKLLIYAASSLQSGVPSRFSGS

Medicine,

ISRDNSKNTLYLQMNSLRAEDTAV

VSGTDFTLTISSLLPEDFATYY

13(577): eabf1555

YYCAKEGRPSDIVVVVAFDYWGQ

CQQSYSTPRTFGQGTKVEIK

GTLVTVSS

470
QVQLVQSGPEVKKPGTSVKVSCK
471
EIVLTQSPGTLSLSPGERATLSC
SARS-
SARS-
Wang et al., 2021,

ASGFTFTSSAVQWVRQARGQRLE

RASQSVSSSYLAWYQQKPGQ
CoV2
CoV2
Science Translational

WIGWIVVGSGNTNYAQKFQERVTI

APRLLIYGASSRATGIPDRFSGS

Medicine,

TRDMSTSTAYMELSSLRSEDTAVY

GSGTDFTLTISRLEPEDFAVYY

13(577): eabf1555

YCAAPHCSGGSCYDAFDIWGQGT

CQQYGSSPWTFGQGTKVEIK

MVTVSS

472
QVQLVQSGPEVKKPGTSVKVSCK
473
EIVLTQSPGTLSLSPGERATLSC
SARS-
SARS-
Wang et al., 2021,

ASGFTFTSSAVQWVRQARGQRLE

RASQSVSSSYLAWYQQKPGQ
CoV2
CoV2
Science Translational

WIGWIVVGSGNTNYAQKFQERVTI

APRLLIYGASSRATGIPDRFSGS

(weak)
Medicine,

TRDMSTSTAYMELSSLRSEDTAVY

GSGTDFTLTISRLEPEDFAVYY

13(577): eabf1555

YCAAPHCSGGSCYDAFDIWGQGT

CQQYGSSPWTFGQGTKVEIK

MVTVSS

474
EVQLVESGGGLIQPGGSLRLSCAA
475
QSALTQPASVSGSPGQSITISCT
SARS-
SARS-
Wang et al., 2021,

SGFTVSSNYMSWVRQAPGKGLEW

GTSSDVGGYNYVSWYQQHPG
CoV2
CoV2
Science Translational

VSVIYSGGSTYYADSVKGRFTISRD

KAPKLMIYDVSNRPSGVSNRF

Medicine,

NSKNTLYLQMNSLRAEDTAVYYC

SGSKSGNTASLTISGLQAEDEA

13(577): eabf1555

AREGDVEGYYDFWSGYSRDRYYF

DYYCSSYTSSSTRVFGTGTKV

DYWGQGTLVTVSS

TVL

476
QVQLVQSGAEVKKPGASVKVSCK
477
QSALTQPPSASGSPGQSVTISC
SARS-
SARS-
Wang et al., 2021,

ASGYTFTGYYMHWVRQAPGQGLE

TGTSSDVGGYNYVSWYQQRP
CoV2
CoV2
Science Translational

WMGWINPNSGGTNYAQKFQGRV

GKAPKLMIDEVTKRPSGVPDR

Medicine,

TMTRETSISTVYMELSRLRSDDTA

FSGSKSGNTASLTVSGLQAED

13(577): eabf1555

VYYCARDLGWSRLHGAFDIWGQG

EADYYCSSYAGSNNWVFGGG

TMVTVSS

TKLTVL

478
QVQLQESGPGLVKPSGTLSLTCTV
479
QSVLTQPPSASGTPGQRVTISC
SARS-
SARS-
Wang et al., 2021,

SSDSVSSYYWNWIRQTTGKGMEW

SGISSNLGSNTVNWFQQLPGT
CoV2
CoV2
Science Translational

IGRIDTGGRTNYNPSLSSRVAMSM

APKLLIYNSNRRPSGVPDRFSG

Medicine,

ATSKNQFSLKLSSVTAADTAVYFC

SKSGTSASLAISGLQSEDEGDY

13(577): eabf1555

ARGLSYYPLYGSHINYIDYWGQGT

YCAEWDDSLSTWVFGGGTHL

LVTVSS

TVL

480
QVQLQESGPGLVKPSGTLSLTCTV
481
QSVLTQPPSASGTPGQRVTISC
SARS-
SARS-
Wang et al., 2021,

SSDSVSSYYWNWIRQTTGKGMEW

SGISSNLGSNTVNWFQQLPGT
CoV2
CoV2
Science Translational

IGRIDTGGRTNYNPSLSSRVAMSM

APKLLIYNSNRRPSGVPDRFSG

Medicine,

ATSKNQFSLKLSSVTAADTAVYFC

SKSGTSASLAISGLQSEDEGDY

13(577): eabf1555

ARGLSYYPLYGSHINYIDYWGQGT

YCAEWDDSLSTWVFGGGTHL

LVTVSS

TVL

482
QVQLQESGPGLVKPSGTLSLTCAV
483
EIVLTQSPATLSLSPGERATLSC
SARS-
SARS-
Wang et al., 2021,

SGGSISSSNWWSWVRQPPGKGLE

RASQSVSSYLAWYQQKPGQA
CoV2
CoV2
Science Translational

WIGEIYHSGSTNYNPSLKSRVTISV

PRLLIYDASNRATGIPARFSGS

(weak)
Medicine,

DKSKNQFSLKLSSVTAADTAVYYC

GSGTDFSLTISSLEPEDFAVYY

13(577): eabf1555

ATHLRLGELRGVDYWGQGTLVTV

CQQRSNWPPWTFGQGTKVEIK

SS

484
EVQLLESGGGLVKPGGSLRLSCAA
485
NFMLTQPHSVSESPGKTVTISC
SARS-
SARS-
Wang et al., 2021,

SGFTFSSYSMNWVRQAPGKGLEW

TGSSGSIASNYVQWYQQRPGS
CoV2
CoV2
Science Translational

VSSISSSSSYIYYADSVKGRFTISRD

APTTVIYEDNQRPSGVPDRFSG

Medicine,

NAKNSLYLQMNSLRAEDTAVYYC

SIDSSSNSASLTISGLKTEDEAD

13(577): eabf1555

ARERGYYGGKTPPFLGGQGTLVT

YYCQSYDSSNYWVFGGGTKL

VSS

TVL

486
QVQLVQSGAEVKKPGSSVKVSCK
487
EIVLTQSPATLSLSPGERATLSC
SARS-
SARS-
Wang et al., 2021,

ASGGTFSSYAISWVRQAPGQGLEW

RASQSVSSYLAWYQQKPGQA
CoV2
CoV2
Science Translational

MGGIIPIFGTANYAQKFQGRVTITA

PRLLIYDASNRATGIPARFSGS

Medicine,

DESTSTAYMELSSLRSEDTAVYYC

GSGTDFTLTISSLEPEDFAVYY

13(577): eabf1555

ARGNRLLYCSSTSCYLDAVRQGY

CQQRSNWPLTFGGGTKVEIK

YYYYYMDVWGKGTTVTVSS

488
QVQLVQSGAEVKKPGASVKVSCK
489
QSALTQPASVSGSPGQSITISCT
SARS-
SARS-
Wang et al., 2021,

ASGYTFTGYYMHWVRQAPGQGLE

GTSSDVGGYNYVSWYQQHPG
CoV2
CoV2
Science Translational

WMGWINPNSGGTNYAQKFQGRV

KAPKLMIYDVSNRPSGVSNRF

Medicine,

TMTRDTSIITAYMELSRLRSDDTA

SGSKSGNTASLTISGLQAEDEA

13(577): eabf1555

VYYCARAPPFYDFWSGIDYWGQG

DYYCSSYTSSSTLVFGGGTKLT

TLVTVSS

V

490
QVQLVQSGAEVKKPGSSVKVSCK
491
DIQMTQSPSSLSASVGDRVTIT
SARS-
SARS-
Wang et al., 2021,

ASGGTFSTYAISWVRQAPGQGLE

CRASQSISSYLNWYQQKPGKA
CoV2
CoV2
Science Translational

WMGGIIPIFGTANYAQKFQGRVTIT

PKLLIYVASSLQSGVPSRFSGS

(weak)
Medicine,

ADESTSTAYMELSSLRSEDTAVYY

GSGTDFTLTISSLQPEDFATYY

13(577): eabf1555

CARDLRNCSSTSCYYWFDPWGQG

CQQSYSTRTFGQGTKVEIK

TLVTVSS

492
QVQLVQSGAEVKKPGSSVKVSCK
493
EIVLTQSPATLSLSPGERATLSC
SARS-
SARS-
Wang et al., 2021,

ASGGTFSSYAISWVRQAPGQGLEW

RASQSVSSYLAWYQQKPGQA
CoV2
CoV2
Science Translational

MGGIIPIFGTANYAQKFQGRVTITA

PRLLIYDASNRATGIPARFSGS

Medicine,

DESTSTAYMELSSLRSEDTAVYYC

GSGTDFTLTISSLEPEDFAVYY

13(577): eabf1555

ARGNRLLYCSSTSCYLDAVRQGY

CQQRSNWPLTFGGGTKVEIK

YYYYYMDVWGKGTTVTVSS

494
QVQLVQSGAEVKKPGASVKVSCK
495
DIQMTQSPSSLSASVGDRVTIT
SARS-
SARS-
Wang et al., 2021,

ASGYTFTGYYMHWVRQAPGQGLE

CQASQDISNYLNWYQQKPGK
CoV2
CoV2
Science Translational

WMGWINPISGGTNYAQKFQGRVT

APKLLIYDASNLETGVPSRFSG

Medicine,

MTRDTSISTAYMELSRLRSDDTAV

SGSGTDFTFTISSLQPEDIATYY

13(577): eabf1555

YYCASPASRGYSGYDHGYYYYMD

CQQYDNLPITFGQGTRLEIK

VWGKGTTVTVSS

496
QVQLVQSGAEVKKPGASVKVSCK
497
QSALTQPASVSGSPGQSITISCT
SARS-
SARS-
Wang et al., 2021,

ASGYTFTGYFMHWVRQAPGQGLE

GTSSDVGGYNYVSWYQQHPG
CoV2
CoV2
Science Translational

WMGWINPNSGGTNYAQKFQGRV

KAPKVMIYDVSNRPSGVSNRF

(weak)
Medicine,

TMTRDTSITTAYMELSRLRSDDTA

SGSKSGNTASLTISGLQAEDEA

13(577): eabf1555

VYYCARDDTLLRYSDWLPTTSFG

DYYCSSYTSSSTNVFGTGTKV

GMDVWGQGTTVTVSS

TVL

498
QVQLVESGGGVVQPGRSLRLSCA
499
QSALTQPRSVSGSPGQSVTISC
SARS-
SARS-
Wang et al., 2021,

ASGFTFSSYGMHWVRQAPGKGLE

TGTSSDVGGYNYVSWYQQHP
CoV2
CoV2
Science Translational

WVAVIRYDGSNKYYADSVKGRFT

GKAPKLMIYDVSKRPSGVPDR

Medicine,

ISRDNSKNKLYLQMNSLRAEDTAV

FSGSKSGNTASLTISGLQAEDE

13(577): eabf1555

YYCAREDYYDSSGSLDYWGQGTL

ADYYCCSYAGSPWVFGGGTK

VTVSS1

LTVL

500
QVQLVQSGPEVKKPGTSVKVSCK
501
EIVLTQSPGTLSLSPGERATLSC
SARS-
SARS-
Wang et al., 2021,

ASGFTFTSSAVQWVRQARGQRLE

RASQSVSSSYLAWYQQKPGQ
CoV2
CoV2
Science Translational

WIGWIVVGSGNTNYAQKFQERVTI

APRLLIYGASSRATGIPDRFSGS

Medicine,

TRDMSTSTAYMELSSLRSEDTAVY

GSGTDFTLTISRLEPEDFAVYY

13(577): eabf1555

YCAAPHCSGGSCYDAFDIWGQGT

CQQYGSSPYTFGQGTKLEIK

MVTVSS

502
QVQLVQSGAEVKKPGASVKVSCK
503
QSALTQPASVSGSPGQSITISCT
SARS-
SARS-
Wang et al., 2021,

ASGYTFTGYFLHWVRQAPGQGLE

GTSSDVGYYNFVSWYQQHPG
CoV2
CoV2
Science Translational

WVGWISPISGGTNYALKFQGRVT

KAPKLMIFDVSNRPSGVSNRFS

Medicine,

MTRDTSSTTAYMDLSRLRSDDTA

GSKSGNTASLTISGLQAEDEAD

13(577): eabf1555

VYYCAREALGYGDFPHDGFDLWG

YYCSSYTSSSARVFGGGTKVT

KGTMVTVSS

VL

504
QVQLVESGGGVVQPGRSLRLSCA
505
DIQMTQSPSSLSASVGDRVTIT
SARS-
SARS-
Wang et al., 2021,

ASGFTFSSYTMHWVRQAPGKGLE

CRASQGISNYLAWYQQKPGK
CoV2
CoV2
Science Translational

WVAVISYDGSNKYYADSVKGRFTI

VPKLLIYAASTLQSGVPSRFSG

Medicine,

SRDNSKNTLYLQMNSLRAEDTAV

SGSGTDFTLTISSLQPEDVATY

13(577): eabf1555

YYCARGPRGYYDFWSGYENEYYF

YCQKYNSAPLTFGQGTRLEIK

DYWGQGTLVTVSS

506
QVQLVESGGGVVQPGRSLRLSCA
507
EIVLTQSPATLSLSPGERATLSC
SARS-
SARS-
Wang et al., 2021,

ASGFTFSSYAMHWVRQAPGKGLE

RASQSVSSYLAWYQQKPGQA
CoV2
CoV2
Science Translational

WVAVISYDGSNKYYADSVKGRFTI

PRLLIYDASNRATGIPARFSGS

Medicine,

SRDNSKNTLYLQMNSLRAEDTAV

GSGTDFTLTISSLEPEDFAVYY

13(577): eabf1555

YYCAREGAGPYYYDSSGYYTLFD

CQQRSNWPTFGQGTRLEIK

DWGQGTLVTVSS

508
QVQLVQSGAEVKKPGSSVRVSCK
509
QLVLTQPASVSGSPGQSIIVSCT
SARS-
SARS-
Wang et al., 2021,

ASGGTFSTYPISWVRQAPGQGLEW

GTSSDVGGYKFVSWYQQHPG
CoV2
CoV2
Science Translational

MGGIIPIFGTAKSAQKFQGRVTITA

KAPRVMIYDVSNRPSGVSNRF

Medicine,

DEFTSTAYMEMSSLRSEDTAMYY

SGSKSGNTASLTISGLQADDEA

13(577): eabf1555

CAREGRRYGSGWYISTGYFDYWG

DYYCSSYTNSSTVVFGGGTKV

QGTLVTVSS

TVL

510
QVQLVQSGGGVVQPGRSLRLSCV
511
SYELTQPPSVSVSPGQTATITCS
MERS-
MERS-
Tang, X. et al., 2014,

ASEFTFNTYGMHWVRQAPGKGLE

GDELGDKFAFWYQQKPGQSP
CoV
CoV
PNAS,

WVAAISYDGTKKFYADSLKGRFTI

VLVIYQDSKRPSGIPERFSGSNS

111(19): E2018-26

SRDNSKNTLYLQMNSLRSEDTAV

GNTATLTISGTQALDEADYYC

YYCARSGDSDAFDIWGQGTMVTV

QAWDSNSYVFGTGTKVTVL

SS

512
EVQLVQSGAEVKEPGSSVKVSCKA
513
QPVLTQPPSASGTPGQRVTISC
MERS-
MERS-
Tang, X. et al., 2014,

SGGTFGSYAINWVRQAPGQRLEW

SGSSSNIGSNYVFWYQQLPGM
CoV
CoV
PNAS,

MGWIDAANGNTKYSQKFQGRVTI

APKLLISRNNQRPSGVPDRFSG

111(19): E2018-26

TGDTSASTAYMELSSLRSEDTAVY

SKSGTSASLAISGPQSEDEADY

YCARDRWMTTRAFDIWGQGTMV

YCAAWDDSLRGPVFGGGTRV

TVSS

TVL

514
QVQLVQSGAEVKKPGSSVKVSCK
515
ETTLTQSPATLSVSPGERATLS
MERS-
MERS-
Tang, X. et al., 2014,

ASGGTFSSYAVSWVRQAPGQLEW

CRASESVGSNLAWYQQKPGQ
CoV
CoV
PNAS,

VGRIIPIFGKANYAQKFQGRVTITA

APSLLIYGASTRATGIPDRFSGS

111(19): E2018-26

DKSTSTAYMELSSLRPEDTAVYYC

GSGTDFTLTISSLQSEDFAAYY

ARDQGISANFKDAFDIWGQGTTVT

CQQYNNWPLTFGPGTKVEIK

VSS

516
QVQLVQSGAEVKKPGSSVKVSCK
517
ETTLTQSPGTLSLSPGERATLS
MERS-
MERS-
Tang, X. et al., 2014,

ASGGTFSSYAISWVRQAPGQGLEW

CRASQSVSSSIAWYQQKPGQA
CoV
CoV
PNAS,

MGGIIPIFGTANYAQKFQGRVTITA

PRLLMFDSSTRATGIPDRFSGS

111(19): E2018-26

DKSTSTAYMELSSLRSEDTAVYYC

GSGTDFTLNISSLEPEDFAVYY

ARVGYCSSTSCHIGAFDIWGQGTT

CQQYSSSPYTFGQGTKLEIK

VTVSS

518
QVQLVQSGAEVKKPGSSVKVSCK
519
DIQMTQSPDSLAVSLGERATIN
MERS-
MERS-
Tang, X. et al., 2014,

ASGGTFSSYAISWVRQAPGQGLEW

CKSSQSVLYSSNNKNYLAWY
CoV
CoV
PNAS,

MGGIIPIFGTANYAQKFQGRVTITA

QQKPGQPPKLLIYWASARESG

111(19): E2018-26

DKSTSTAYMELSSLRSEDTAVYYC

VPDRFSGSGSGTDFTLTISSLQP

ARASYCSTTSCASGAFDIWGQGTL

EDVAIYYCQQYYSVPFTFGPG

VTVSS

TKVEIK

520
EVQLVQSGAEVKKPGASVKVSCK
521
QPGLTQPPSVSKGLRQTATLTC
MERS-
MERS-
Tang, X. et al., 2014,

ASGYTFNVYAINWVRQAPGQGLE

TGNSNNVGNQGAAWLQQHQ
CoV
CoV
PNAS,

WMGRIIPILGIANYAQKFQGRVTIT

GHPPKLLSYTNNNRPSGISERL

111(19): E2018-26

ADKSTSTAYMELSSLRSEDTAVYY

SASRSGNTASLAITGLQPEDEA

CARDYYGSGARGFDYWGQGTLVT

DYYCASWDSSLSVWVIGGGT

VSS

KLTVL

522
DVKLVESGGGLVKPGGSLKLSCA
523
DIQMTQTTSSLSASLGDRVTIS
MERS-
MERS-
Li, Y. et al., 2015,

ASGFTFSSYTMSWVRQTPEKRLEW

CRASQDISNYLNWYQQKPDGT
CoV
CoV
Cell Research,

VATISSGGSYTYYPDSVKGRFTISR

VKLLIYYTSRLHSGVPSRFSGS

25: 1237-1249

DNAKNTLYLQMSSLKSEDTAMYY

GSGTDYSLTISNLEQEDIATYF

CTRDGNDYDYWGQGTTLTVSS

CQQGNTLPRTFGGGTKLEIK

524
QVQLVQSGAEVKKPGSSVKVSCK
525
QSALTQPPSASGTPGQRVTISC
MERS-
MERS-
Choi et al.,

ASGGTFRSHAISWVRQAPGQGLE

SGSSSNIGSNTVNWYQQLPGT
CoV
CoV
WO2019/039891

WMGGIIPFASANYAQKFQGRVTIT

APKLLIYSNNQRPSGVPDRFSG

ADESTSTAYMDLSSLRSDDTAVYY

SKSGTSASLAISGLQSEDEADY

CAKNVSPKSYSGRYSISYFYGVDV

YCAAWDDSLSGHYVFGTGTK

WGQGTTVTVSS

VTVL

526
EVQLLESGGGLVQPGGSLRLSCAD
527
QSALTQPPSVSAAPGQKVTISC
MERS-
MERS-
Choi et al.,

SGLTFSSYAMSWVRQAPGKGLEW

SGSSSNIGNNYVSWYQHLPGT
CoV
CoV
WO2019/039891

VSAISVSGGSTYYSDSVKGRFTISR

APKLLIYDNMRPSGIPDRFSGS

DNSKNTLSLQMNSLRAEDTAVYY

KSGTSATLGITGLQTGDEADY

CVKARSIVGPFDYWGQGTLVTVSS

YCGTWDTSLSAVVFGGGTKLT

VL

528
EVQLVESGAEVVKPGASVKMSCK
529
DIVMTQSPASLTVSLGQRATIS
MERS-
MERS-
Zhou et al., 2019,

ASGYPFTSYNIHWIKQTPGQGLEW

CRASKSVSASGYNYLHWYQQ
CoV
CoV
Nature

IGAIYPGNGDTSYTQKFKVKATLT

RPGQPPKLLIYLAFNLESGVPA

Communications,

SDKSSSTAYMQLSSLTSEDSAVYF

RFNGSGSGTDFTLNIHPVEEED

10: 3068

CARYGNYPSYAMDYWGQGTSVT

AATYYCQHSRDLPFTFGSGTK

VSS

LEIK

530
QVQLVQSGAEVKKPGSSVKVSCK
531
QSVLTQPPSVSGAPGQRVTISC
MERS-
MERS-
Choi et al.,

ASGGTFSSYTINWVRQAPGQGLE

TGSSSNIGAGYDVHWYQQLPG
CoV
CoV
WO2019/039891

WMGGIIPIFGTANYAQKFQGRVTIT

TAPKVLIYGNSNRPSGVPDRFS

ADASTSTAYMELSSLRSEDTAVYY

GSKSDTSASLAITGLQAEDEAD

CARVLLRSSSWFSSNWFDPWGQG

YYCQSYDSSLSVVFGGGTKLT

TLVTVSS

VL

532
QVQLVQSGAEVKRPGSSVKVSCK
533
EIVLTQSPATLSLSPGERATLSC
MERS-
MERS-
Choi et al.,

TSGGTFNNNAINWVRQAPGQGLE

GASQSVSSSYLAWYQQKPGLA
CoV
CoV
WO2019/039891

WMGGIIPFFGIAKYAQKFQGRVTIT

PRLLIYDASSRATGIPDRFSGSG

ADESTSTAYMELSSLRSEDTAVYY

SGTDFTLTISRLEPEDFAVYYC

CARDLPRESSYGSGSYYTHYYAM

QQYGSSPLTFGGGTKVEIK

DVWGQGTTVTVSS

534
QVQLVQSGAEVKKPGASVKVSCK
535
DIQMTQSPSTLSASVGDRVTIT
MERS-
MERS-
Choi et al.,

ASGYTFTTYYMHWVRQAPGQGLE

CRASQTISTWLAWYQQKPGK
CoV
CoV
WO2019/039891

WMGIINPSGGSTSYAQKFQGRVTM

APKLLIYKASSLESGVPSRFSG

TRDTSTSTVYMELSSLRSEDTAVY

SGSGTEFTLTISSLQPDDFATY

YCARGAVVVILDYWGQGTLVTVS

YCQQYNSYSYTFGQGTKLEIK

S

536
EVQLLESGAEVKKPGSSVKVSCRA
537
QSVLTQPPSVSGAPGQRVTPSC
MERS-
MERS-
Niu et al., 2018, J.

SGGTFSSYAISWVRQAPGQGLEW

TGSSSNIGAGYDVHWYQQLPG
CoV
CoV
Infectious Diseases,

MGRIIPILGIANYAQKFQGRVTITA

TAPKLLIYGNSNRPSGVPDRFS

218: 1249-1260

DKATSTAYMELSSLRSEDTAVYYC

GSKSGTSASLAITGLQAEDEAD

ATRSGDYYGSGSYSAFDIWGQGT

YYCQSYDSSLSGLMFGGGTKL

MVTVSS

TVL

538
QVQLVQSGAEVEKAGASVKVSCK
539
QSVLTQPPSVSAAPGQKVTISC
MERS-
MERS-
Niu et al., 2018, J.

ASGGTFSSYAISWVRQAPGQGLEW

SGSRSNIGNNYVSWYQQLPGT
CoV
CoV
Infectious Diseases,

MGRIIPILGIANYAQKFQGRVTITA

APKLLIYDNNKRPSGIPDRSSG

218: 1249-1260

DKSTSTAYMELSSLRSEDTAVYYC

SKSGTSAALGITGLQTGDEAD

ARRSGDYYGSGSYSAFDIWGQGT

YYCGTWDNSLSAVVFGGGTK

MVTVSS

LTVL

540
QVQLVQSGAEVKKPGSSVKVSCK
541
QSVLTQPPSVSGAPGQRVTPSC
MERS-
MERS-
Niu et al., 2018, J.

ASGGTFSSYAISWVRQAPGQGLEW

TGSSSNIGAGYDVHWYQQLPG
CoV
CoV
Infectious Diseases,

MGRIIPILGIANYAQKFQGRVTITA

TAPKLLIYGNSNRPSGVPDRFS

218: 1249-1260

DKSTSTAYMELSSLRSEDTAVYYC

GSKSGTSASLAITGLQAEDEAD

ARRSGDYYGSGSYSAFDIWGQGT

YYCQSYDSSLSGLMFGGGTKL

MVTVSS

TVL

542
QVQLVQSGAEVKKPGSSVKVSCK
543
QSVLTQPPSVSGAPGQRVTISC
MERS-
MERS-
Niu et al., 2018, J.

ASGGTFSSYAISWVRQAPGQGLEW

TGSSSNIGAGYDVHWYQQLPG
CoV
CoV
Infectious Diseases,

MGRIIPILGIANYAQKFQGRVTITA

TAPKLLIYGNSNRPSGVPDRFS

218: 1249-1260

DKSTSTAYMELSSLRSEDTAVYYC

GSKSGTSASLAITGLQAEDEAD

ARRSGDYYGSGSYSAFDIWGQGT

YYCGTWDSSLSAYVVFGGGT

MVTVSS

KLTVL

544
QVQLVQSGAEVKKPGSSVKVSCK
545
SYELTQPASVSGSPGQSITISCT
MERS-
MERS-
Niu et al., 2018, J.

ASGGTFSSYAISWVRQAPGQGLEW

GSSTDVGSSIYVSWYQQHPGK
CoV
CoV
Infectious Diseases,

MGRIIPILGIANYAQKFQGRVTITA

APQLILYDVTNRPSGVSTRFSG

218: 1249-1260

DKSTSTAYMELSSLRSEDTAVYYC

SKSGNTASLTISGLRAEDEADY

ARATRSDYYGSGSYSAFDIWGQGT

YCNSYTTSNTLVFGGGTKLTV

MVTVSS

L

546
QMQLVQSGAEVKKPGASVKVSCK
547
NFMLTQPPSVSGAPGQRVTISC
MERS-
MERS-
Niu et al., 2018, J.

ASGGTFSSYAISWVRQAPGQGLEW

TGSSSNIGAGYDVHWYQQLPG
CoV
CoV
Infectious Diseases,

MGRIIPILGIANYAQKFQGRVTITA

TAPKLLIYGNSNRPSGVPDRFS

218: 1249-1260

DKSTSTAYMELSSLRSEDTAVYYC

GSKSGTSASLAISGLRSEDEAD

ARRSGDYYGSGSYSAFDIWGQGT

YYCAAWDDSLSGYVFGTGTK

MVTVSS

VTVL

548
QMQLVQSGAEVKKPGASVKVSCK
549
QSVLTQPPSVSGAPGQRVTISC
MERS-
MERS-
Niu et al., 2018, J.

ASGGTFSSYAISWVRQAPGQGLEW

TGSSSNIGAGYDVHWYQQLPG
CoV
CoV
Infectious Diseases,

MGRIIPILGIANYAQKFQGRVTITA

TAPKLLIYGNSNRPSGVPDRFS

218: 1249-1260

DKSTSTAYMELSSLRSEDTAVYYC

GSKSGTSASLAITGLQAEDEAD

ARRSGDYYGSGSYSAFDIWGQGT

YYCGTWDSSLSAYVVFGGGT

MVTVSS

KLTVL

550
QVQLVQSGAEVKKPGSSVKVSCK
551
DVVMTQSPLSLPVTPGEPASIS
MERS-
MERS-
Niu et al., 2018, J.

ASGGTFSSYAISWVRQAPGQGLEW

CRSSQSLLHSNGYNYLDWYLQ
CoV
CoV
Infectious Diseases,

MGRIIPILGIANYAQKFQGRVTITA

KPGQSPQLLIYLGSNRASGVPD

218: 1249-1260

DKSTSTAYMELSSLRSEDTAVYYC

RFSGSGSGTDFTLKISRVEAED

ARDSYGDYTGSGYYYGMDVWGQ

VGVYYCMQALQTPLTFGGGT

GTTVTVSS

KVEIK

552
EVQLVQSGAEVKKPGSSVKVSCK
553
DIVMTQSPLSLPVTPGEPASISC
MERS-
MERS-
Niu et al., 2018, J.

ASGGTFSSYAISWVRQAPGQGLEW

RSSQSLLHSNGYNYLDWYLQ
CoV
CoV
Infectious Diseases,

MGRIIPILGIANYAQKFQGRVTITA

KPGQSPQLLIYLGSNRASGVPD

218: 1249-1260

DKSTSTAYMELSSLRSEDTAVYYC

RFSGSGSGTDFTLKISRVEAED

ARDSYGDYTGSGYYYGMDVWGQ

VGVYYCMQALQTPLTFGGGT

GTTVTVSS

KVEIK

554
EVRLVQSGAEVEKAGASVKVSCK
555
QSVLTQPPSVSAAPGQKVTISC
MERS-
MERS-
Niu et al., 2018, J.

ASGGTFSSYAISWVRQAPGQGLEW

SGSRSNIGNNYVSWYQRPPGT
CoV
CoV
Infectious Diseases,

MGRIIPILGIANYAQKFQGRVTITA

APKLLIYDNNKRPSGIPDRFSG

218: 1249-1260

DKSTSTAYMELSSLRSEDTAVYYC

SKSGTSATLGITGLQTGDEAD

ARRSGDYYGSGSYSAFDIWGQGT

YYCGTWDNSLSAVVNGGGTK

MVTVSS

NTVV

556
QVQLVQSGAEVKKPGASVKVSCK
557
QSVLTQPPSVSGAPGQRVTISC
MERS-
MERS-
Niu et al., 2018, J.

ASGGTFSSYAISWVRQAPGQGLEW

TGSSSNIGAGYDVHWYQQLPG
CoV
CoV
Infectious Diseases,

MGRIIPILGIANYAQKFQGRVTITA

TAPKLLIYGNSNRPSGVPDRFS

218: 1249-1260

DKSTSTAYMELSSLRSEDTAVYYC

GSKSGTSASLAITGLQAEDEAD

ARRSGDYYGSGSYSAFDIWGQGT

YYCGTWDSSLSAYVVFGGGT

MVTVSS

KLTVL

558
QVQLVQSGAEVKKPGSSVKVSCK
559
QYALTQPASVSGSPGQSITISCT
MERS-
MERS-
Niu et al., 2018, J.

ASGGTFSSYAISWVRQAPGQGLEW

GSSTDVGSSIYVSWYQQHPGK
CoV
CoV
Infectious Diseases,

MGRIIPILGIANYAQKFQGRVTITA

APQLILYDVTNRPSGVSTRFSG

218: 1249-1260

DKSTSTAYMELSSLRSEDTAVYYC

SKSGNTASLTISGLRAEDEADY

ARRSGDYYGSGSYSAFDIWGQGT

YCNSYTTSNTLVFGGGTKLTV

MVTVSS

L

560
QVQLVQSGAEVKKPGSSVKVSCK
561
QSALTQPRSVSGSPGQSVTISC
MERS-
MERS-
Niu et al., 2018, J.

ASGGTFSTYALSWVRQAPGQGLE

TGTSSDVGGYNYVSWYQQHP
CoV
CoV
Infectious Diseases,

WMGGIIPIFGTANYAQKFQGRVTIT

GKAPKLMIYDVSKRPSGVPDR

218: 1249-1260

ADESTSTAYMELNSLRSEDTAVYY

FSGSKSGNTASLTISGLQAEDE

CARGSRSSSSAEYFQHWGQGTLVT

ADYYCCSYAGSYTLEWFGGG

VSS

TKLTVL

562
QVQLVESGGGLVKPGGSLRLSCAA
563
QSALTQPPSVSGAPGQRVTISC
MERS-
MERS-
Niu et al., 2018, J.

SGFTFSDYYMSWIRQAPGKGLEW

TGSSSNIGASYDVHWYQHLPG
CoV
CoV
Infectious Diseases,

VSYISSSGSTIYYADSVKGRFTISRD

TAPKLLIYGNTNRPSGVPDRFS

218: 1249-1260

NAKNSLYLQMNSLRAEDTAVYYC

GSKSGTSASLAITGLQAEDEAD

ARVGLGSGWYDWFDPWGQGTLV

YYCQSYDSSLSGWFSGGTKLT

TVSS

VL

564
QVQLVQSGAEVKKPGSSVKVSCK
565
DVVMTQSPLSLPVTPGEPASIS
MERS-
MERS-
Niu et al., 2018, J.

ASGGTFSIYAISWVRQAPGQGLEW

CRSSQSLLHSNGYNYLDWYLQ
CoV
CoV
Infectious Diseases,

MGGIIPIFGTANYAQKFQGRVTITA

KPGQSPQLLIYLGSNRASGVPD

218: 1249-1260

DKSTSTAYMELSSLRSEDTAVYYC

RFSGSGSGTDFTLKISRVEAED

AREGGHQGYCSGGSCYDFDYWG

VGVYYCMQALQTPAFGGGTK

QGTLVTVSS

LEIK

566
QLQLQESGPGLVKPSETLSLTCTVS
567
QSALTQPASVSGSPGQSITISCT
MERS-
MERS-
Niu et al., 2018, J.

GGSISSSSYYWGWIRQPPGKGLEW

GTSSDVGGYNYVSWCQQHPG
CoV
CoV
Infectious Diseases,

IGSIYYSGSTYYNPSLKSRVTISVDT

KAPKLMIYEVSNRPSGVSNRFS

218: 1249-1260

SKNQFSLKLSSVTAADTAVYYCAS

GSKSGNTASLTISGLQAEDEAD

LLRPLIYCSGGSCTDYWGQGTLVT

YYCSSYTSNITLVFGTGTKVTV

VSS

L

568
EVKLVESGGGLVKPGGSLKLSCAA
569
DIQMTQTTSSLSASLGDRVTIIC
MERS-
MERS-
Wang et al., 2015,

SGFTFSSYAMSWVRQTPEKRLEW

RASQDINNYLNWYQQKPDGT
CoV
CoV
Nature

VATISSGGTYTYYPDSVKGRFTISR

VKLLIYYTSRLHSGVPSRFSGS

Communications,

DNAENTLYLQMSSLRSEDTAMYY

GSGSDYSLTISNLEQEDIATYF

6: 7712

CVRDGNSMDYWGQGTSVTVSS

CQQANTLPPTFGAGTKLELR

570
EVKLEESGGGLVKPGGSLKLSCAA
571
DVIMTQIPLSLPVSLGDQASISC
MERS-

Wang et al., 2015,

SGFTFSRYAMSWWQTPEKRLEWV

RSSQSIVHSNGNTYLEWYLQK
CoV

Nature

ATINNGGSYSYYPDSVKGRLTISRD

PGQSPKPLIYKVSNRISGVPDR

Communications,

NAKNTLYLQMSSLRSEDTALYYC

FSGSGSGTDFTLKISRVEAEDL

6: 7712

ARHYDYDGYYYTMDFWGQGTSV

GVYYCFQGSHVPYTFGGGTNL

TVSS

EIK

572
QVQLQESGPGLVKPSETLSLTCAV
573
DIQMSQTPSSLSASVGDRVTIT
MERS-

Wang et al.

SGGSISSNYWYWIRQSPVKGLEWI

CRASQGINDYLNWYQQKPGK
CoV

WO2016138160

GYIYGGSGGTEYNPSLKSRVTISTD

APKLLIYYGNSLASGVPSRFSG

TSKNQFFLKLSSVTAADTAVYYCA

SGSGTDFSLTISSLQPEDFATY

RSFYSWNGESWGQGVWTVSS

YCQQGDSFPLTFGGGTKVDIK

574
EVQLVQSGAEVKKPGASVKVSCK
575
QSALTQPPSLSASPGASARLPC
MERS-CoV
MERS-CoV
Wang et al.

ASGHIFTSYVINWLQAEPGQGFEW

TLSSDLSVGSKNMYWYQQKP

WO2016138160

MGGIHPGNGGRDYAQKFQGRVTI

GSAPRLFLYYYSDSDKQLGPG

TADMSTSTVYMELRSLRSEDMAV

VPNRVSGSKETSSNTAFLLISG

YYCAASSGSYGVSSLDVWGRGVL

LQPEDEADYYCQVYDSSANW

VTVSS

VFGGGTRLTVL

576
QVQLQQSGGELVKPGASVKLSCK
577
QLVLTQSPASLAVSLGQRATIS
MERS-
MERS-
Wang et al., 2019,

TSGFTFSSSYISWLKQKPGQSLEWI

CRASESVDNYGISFMNWF'QQK
CoV
CoV
Cell Reports,

AWIYAGTGGTEYNQKFTGKAQVT

PGQPPKLLIHTASNQGSGVPAR

28(13): 3395-3405

VDTSSSTAYMQFSSLTTEDSAIYYC

FSGSGSGTDFSLNIHPVEDDDT

ARGGSSFAMDYWGQGTSVTVSS

AMYFCQQSEEVPLTFGAGTKL

EIK

578
QVQLQQSGPELVRPGVSVKISCKG
579
DIVLTQSPASLAVSLGQRATIS
MERS-
MERS-
Pallesen et al.,

SGYTFTDYAIHWVKQSHAKSLEWI

CRASESVDNYGISFMNWFQQK
CoV
CoV
PNAS, 2017,

GVFSTYYGNTNYNQKFKGRATMT

PGQPPKLLISATSNQGSGVPAR

114(35): E7348-E7357

VDKSSSTAYMELARLTSEDSAIYY

FIGSGSGTDFSLNIHPVEEDDT

CARKSYYVDYVDAMDYWGQGTS

AMYFCQQSKEVPRTFGGGTKL

VTVSS

EIK

580
EVQLVESGGGLVQPGGSLRLSCSA
581
DIQMTQSPSTLSASVGDRVTIT
MERS-
MERS-
WO2015179535

SGFYFSSYDMSWVRQAPGKGLEW

CRASQTISSWLAWYQQKPGK
CoV
CoV

VSAIRGSGHTTYYADSVKGRFTISR

APKLLIYKASSLESGVPSRFSG

DNSKNTLYLEMNSLRAEDTAVYY

SGSGTEFTLTISSLQPDDFATY

CVKDGSIVGFDPWGQGTLVTVSS

YCQQYNSYSYTFGQGTKLEIK

582
QVQLVQSGAEVKKPGSSVKVSCK
583
DIVMTQSPLSLPVTPGEPASISC
MERS-
MERS-
WO2015179535

ASGGSFSVYAISWVRQAPGQGLE

RSSQSLLHGNGYNYLDWYLQ
CoV
CoV

WMGGIIPIFGTANYAQKFQDRFTIT

KPGQSPQLLIYLVSHRASGVPD

TDESTSTAYMELSSLRSEDTAMYY

RFSGSGSGTDFTLKISRVEAED

CAREGDIVVLPAGKGGMDVWGQ

VGVYYCMQALQSPWTFGQGT

GTTVTVSS

KVEIK

584
EVQLVESGGGLVQPGGSLRLSCVV
585
DIQMTQSPSALSASVGDRVTIT
MERS-
MERS-
WO2015179535

SGFTFSNYDMSWVRQAPGRGLEW

CRASQSISSWLAWYQQKPGKA
CoV
CoV

VSAIRGSGFNTYYADSVKGRFTISR

PKLLIYKASSLESGVPSRFSGS

DNSKNTLYLQMNSLRAEDTAVYY

GSGTEFTLTISSLQPDDFATYY

CAKDGSIVSMDYWGQGTLVTVSS

CQQYNSYSWTFGQGTKVEIK

586
QVQLQESGPGLVKPSETLSLTCTVS
587
EIVMTQSPATLSLSPGERATLS
MERS-
MERS-
WO2015179535

GGSISSYYWSWIRQPPGKGLEWIG

CRASQSVSSNLAWYQQKPGQ
CoV
CoV

YIYYSGSPNYNPSLKSRVTISVDTS

APRLLIYGASTRATGIPARFSG

KNQFSLKLTSVTAADTAVYYCARS

SGSGTEFTLTISSLQSEDFAVY

LNWGPPFDYWGQGTLVTVSS

YCQQFNNWPYTFGQGTKLEIK

588
EVQLLESGGGLVQPGGSLRLSCAA
589
DIQMTQSPSSLSASVGDRVTIT
MERS-
MERS-
WO2015179535

SGFTFSSYAMSWVRQAPGKGLEW

CQASQDISNYLNWYQQKPGK
CoV
CoV

VSAISGRGGNTYYADSVKGRFTIS

APKFLIYDASNLETGVPSRFSG

RDNSKNTLFLQMNTLRAEDTAVY

SGSGTDFTFTISSLQPEDIATYY

YCAKDRGFGFFDIWGRGTLATVSS

CQQYDNLPFTFGPGTKINIK

590
EVQLLESGPGVVRPSETLSLSCAVS
591
EIVMTQSPATLSLSPGERATLS
MERS-
MERS-
WO2016138160

GGSISDSYRWSWIRQPPGKGLEWV

CRASQSVSSNLAWYQQKPGQ
CoV
CoV

GYIFATGTTTNYNPSLKSRVTISKD

APRLLIHSASSRATGIPDRFSGS

TSKNQFSLKLSSVTAADTAVYYCA

GSGTEFSLTISSLEAEDVGVYH

REPFKYCSGGVCYAHKDNSLDVW

CYQHSSGYTFGPGTKLDIK

GQGVLVTVSS

592
QVQLQESGPGLVKPSETLSLTCAV
593
DIVMTQTPFTLPVTPGEAASIS
MERS-
MERS-
WO2016138160

SGGSISSNYWNWIRQSPGKGLEWI

CRSSQSLFDSDYGNTYLDWYL
CoV
CoV

GYIYGGSGSTTYNPSLKSRVAISTD

QKPGQSPQLLIYMLSNRASGV

TSKDQFSLKLSSVTAADTAVYYCA

PDRFSGSGSGTDFTLKISRVEA

RLLPLGGGYCFDYWGQGVLVTVS

EDVGLYYCMQSVEYPFTFGPG

S

TKLDIK

594
QVQLQESGPGLVKPSETLSLTCAV
595
DIQMTQSPSSLSASVGDRVTIT
MERS-
MERS-
WO2016138160

SGDSISSNYWSWIRQPPGKGLEWI

CRASQDINNYLSWYQQKPGK
CoV
CoV

GRFSGSGGSTDFNPSLKSRVTISTD

APKPLIYYASSLETGVPSRFSG

TSKNQFSLNLRSVTAADTAVYYCA

SRSGTDYTLTISSLQLEDFATY

KTYSGTFDYWGQGVLVTVSS

YCQQYNNSPYSFGQGTKVEIK

596
EVQLVESGGGLVKPGGSLRLSCAA
597
ELVLTQPPSASGTPGQRVNISC
MERS-
MERS-
KR101828794

SGFAFSSYSMIWVRQAPGKGLEW

SGSRSNVGSNAVTWYQQVPG
CoV
CoV

VSSISTSSGYIYYADSVKGRFTISRD

TAPKLLIYNNSKRPSGVPDRFS

NAKNSLYLQMNSLRAEDTAVYYC

GSKSGTSASLAISGLQSEEEAD

ARAPIDAVAFDIWGQGTMVTVSS

YYCAAWDDSLNGPVFGGGTK

VTVL

598
EVQLLESGGGLVKPGGSLRLSCEA
599
QSALTQPASVSGSPGQSITISCT
MERS-
MERS-
Corti et al., PNAS,

SGLTFSNVWMSWVRQAPGKGLE

GTSSDVGTYDLVSWYQQHPG
CoV
CoV
2015, 112(33): 10473-

WVGRIKRKSEGAFIDYGAPVKGR

KSPKLMIYADIKRPSGVSHRFS

10478

FTLSRDDSKNTVYLQMNSLKIDDT

GSKSGNTASLTISGLQSADEAD

AVYYCSTLTRGGDVWSSSYYFDY

YYCCLYAGSSTSVIFGGGTKVT

WGQGALVTVSS

600
QVQLKGSGPGLVAPSQSLSITCTVS
601
DIQMTQSPASLSASVGETVTIT
MERS-
MERS-
Li et al., Cell Res.,

GFSLTGYGVNWVRQPPGKGLEWL

CRASENIYSYLAWYQQKQGKS
CoV
CoV
2015,

GMIWGDGSTDYNSALKSRLSISKD

PQLLVYNAKTLAEGVPSRFSG

NSKSQVFLKMNSLQTDDTARYYC

SGSGTQFSLKINSLQPEDFGSY

ARVGDYGDYFDYWGQGTTLTVSS

YCQHHYGTPWFGGGTKLEIK

602
EVQLVQSGAEVKKPGSSVKVSCK
603
ETTLTQSPATLSVSPGERAILSC
MERS-
MERS-
Tang et al., PNAS,

ASGGTFSSYAISWVRQAPGQGLEW

RASQSISNDLAWYQQKPGQAP
CoV
CoV
2014, E2018-E2026.

MGGIIPIFGIANYAQKFQGRVTITA

RLLIYGASSRATGIPDRFSGSGS

DKSTSTAYMELSSLRSEDTAVYYC

GTDFTFTISRLESEDFAVYYCQ

ASSNYYGSGSYYPRSAFDIWGQGT

QYGVSPLTFGGGTKVEIK

TVTVSS

604
QVQLVQSGAEVKKPGSSVKVSCK
605
DIQLTQSPSSLSASVGDRVTITC
MERS-
MERS-
Ying et al, J. of

ASGGTFSSYAISWVRQAPGQGLEW

RASQGIRNDLGWYQQKPGKA
CoV
CoV
Virology, 2014,

MGGIIPIFGTASYAQKFQGRVTITA

PKLLIYAASSLQSGVPSRFSGS

88(14)7796-7805

DKSTSTAYMELSSLRSEDTAVYYC

GSGTDFTLTISSLQPEDFATYY

ARVGYCSSTSCNRGAFDIWGQGT

CQQLNSYPLTFGGGTKVEIK

MVTVSS

606
QVQLQQSGAEVKKPGSSVKVSCK
607
EIVLTQSPLSLPVTPGEPASISC
MERS-
MERS-
Ying et al, J. of

ASGGTFSSYTISWVRQAPGQGLEW

RSSQSLLHSNGYNYLDWYLQ
CoV
CoV
Virology, 2014,

MGRIIPIFGTANYAQKFQGRVTITA

KPGKSPQLLIYLGSNRASGVPD

88(14): 7796-7805

DKSTSTAYMELSSLRSEDTAVYYC

RFSGSGSGTDFTLKISRVEAED

ARDLGPGGDSSGYYYGPGAFDIW

VGVYYCMQALQTPLTFGGGT

GQGTMVTVSS

KVEIK

608
QVQLQQSGAEVKKRGSSVKVSCK
609
EIVMTQSPVTLSLSPGERATLS
MERS-
MERS-
Ying et al, J. of

ASGGTFSSYTISWVRQAPGQGLEW

CRASQSVSSYLAWYQQKPGQ
CoV
CoV
Virology, 2014,

MGRIIPILGIANYAQKFQGRVTITA

APRLLIYDASNRATGIPARFSG

88(14): 7796-7805

DKSTSTAYMELSSLRSEDTAVYYC

SGSGTDFTLTISSLEPEDFAVY

ARDLYDSSGYYRNTDAFDIWGQG

YCQQYGSSPWTFGQGTKVEIK

TMVTVSS

610
ATRLEESGAEVKKPGSSVKVSCKA
611
DVELTQSPGTLSLSPGERATLS
MERS-
MERS-
Chen et al., J. of

SGGTFSSYAISWVRQAPGQGLEW

CRASQSVSSSYLAWYQQKPGQ
CoV
CoV
Infectious Diseases,

MGRIIPILGIANYAQKFQGRVTITA

APRLLIYGASSRATGIPDRFSGS

2017, 215(12): 1807-

DKSTSTAYMELSSLRSEDTAVYYC

GSGTDFTLTISRLEPEDFAVYY

1815

ASKQGDYYDRTSYAFDIWGQGTM

CQQYGSSPITFGQGTRLEIK

VTVSS

612
VQLLETGGGLVKPGGSLRLSCAAS
613
DIRLTQSPSFLSASVGDRVTITC
MERS-
MERS-
Jiang et al., Science

GFSLSDYYMNWIRQAPGKGLEWV

RASQDINSFLAWYQQRPGKAP
CoV
CoV
Translational

AYISSSSGYTNYGDSVKGRFTISRD

KLLIYGASNLETGVPSRFSGGG

Medicine, 2014,

HAKNSLYLQMNSLRVEDTAVYYC

SGTDFTLTISSLQPEDIATYYCQ

6(234): 234ra59

VRDRDDFWSGYYKHWGLGTLVT

QYDKLPTFGQGTRLEIK

VSS

614
VQLVESGGGLVQPGRSLRLSCAAS
615
QPVLTQSPSASGTPGQRVTISC
MERS-
MERS-
Zhang et al., 2018

GFTFSNYAMYWVRQAPGKGLEW

SGSSSNIGNNYVYWYQQLPGT
CoV
CoV
Cell Reports,

VALISYDISTDYYADSVKGRFTISR

APKLLIYWNDQRPSGVPDRFS

24(2): 441-452

DNSKNTIYLQMNNLRTEDTALYY

GSKSGTSASLAISGLRSEDEAD

CAGNDYWGQGTLVTVSS

YYCAAWDDSLSGAVFGGGTQ

LTVL

616
EVQLVESGGGLVQPGRSLRLSCAA
617
GSQPVLTQSPSASGTPGQRVTI
MERS-
MERS-
Zhang et al., 2018

SGFTFSNYAMYWVRQAPGKGLEW

SCSGSSSNIGNNYVYWYQQLP
CoV
CoV
Cell Reports,

VALISYDISTDYYADSVKGRFTISR

GTAPKLLIYWNDQRPSGVPDR

24(2): 441-452

DNSKNTIYLQMNNLRTEDTALYY

FSGSKSGTSASLAISGLRSEDE

CTNTYYWGQGTLVTVS

ADYYCAAWDDSLSGAVFGGG

TQLTVL

618
EVQLLESGGGLVQPGGSLRLSCAA
619
DIQMTQSPSSLSASVGDRVTIT
MERS-
MERS-
Pascal et al, PNAS,

SGFTFSSYAMSWVRQAPGKGLEW

CQASQDISNYLNWYQQKPGK
CoV
CoV
2015, 112(28): 8738-

VSAISGRGGNTYYADSVKGRFTIS

APKFLIYDASNLETGVPSRFSG

8743

RDNSKNTLFLQMNTLRAEDTAVY

SGSGTDFTFTISSLQPEDIATYY

YCAKDRGFGFFDIWGRGTLATVSS

CQQYDNLPFTFGPGTKINIK

620
EVQLVESGGGLVQPGGSLRLSCVV
621
DIQMTQSPSALSASVGDRVTIT
MERS-
MERS-
Pascal et al, PNAS,

SGFTFSNYDMSWVRQAPGRGLEW

CRASQSISSWLAWYQQKPGKA
CoV
CoV
2015, 112(28): 8738-

VSAIRGSGFNTYYADSVKGRFTISR

PKLLIYKASSLESGVPSRFSGS

8743

DNSKNTLYLQMNSLRAEDTAVYY

GSGTEFTLTISSLQPDDFATYY

CAKDGSIVSMDYWGQGTLVTVSS

CQQYNSYSWTFGQGTKVEIK

622
EVQLVESGGGLVQPGGSLRLSCAA
623
DIQMTQSPSSLSASVGDRVTIT
MERS-
MERS-
KR101828794

SGFTFSSYAMHWVRQAPGKGLEW

CRASQSISNYLNWYQQKPGKA
CoV
CoV

VSSIYSSGGYIYYADSVKGRFTISR

PKLLIYDASRLQSGVPSRFSGS

DNSKNTLYLQMNSLRAEDTAVYY

GSGTDFTLTISSLQPEDFATYY

CAKDQYVSTDFDIWGQGTLVTVSS

CQQSYSYPWTFGQGTKVEIK

624
EVQLVESGGGLVQPGGSLRLSCAA
625
DIQMTQSPSSLSASVGDRVTIT
MERS-
MERS-
KR101828794

SGFTFSSYGMSWVRQAPGKGLEW

CRASQSIGSYLNWYQQKPGKA
CoV
CoV

VSAISQSGGYIYYADSVKGRFTISR

PKLLIYAASNLQSGVPSRFSGS

DNSKNTLYLQMNSLRAEDTAVYY

GSGTDFTLTISSLQPEDFATYY

CAKHLYGSWAFDIWGQGTLVTVSS

CQQSYSFPFTFGQGTKVEIK

626
EVQLVESGGGLVQPGGSLRLSCAA
627
DIQMTQSPSSLSASVGDRVTIT
MERS-
MERS-
KR101828794

SGFTFSDYAMSWVRQAPGKGLEW

CRASQSISSYLNWYQQKPGKA
CoV
CoV

VSAISQSGSYTNYADSVKGRFTISR

PKLLIYGASSLQSGVPSRFSGS

DNSKNTLYLQMNSLRAEDTAVYY

GSGTDFTLTISSLQPEDFATYY

CAKVSSQTLRFDYWGQGTLVTVSS

CQQSYSFPFTFGQGTKVEIK

628
QVQLQESGPGLVKPSETLSLTCSVS
629
EIVMTQSPATLSVSPGERATLS
SARS-
SARS-
Wang et al., Nature

GGSISSHYWSWIRQPPGKGLEWIG

CRASQSVSSSLAWYQQKPGQA
CoV1,
CoV2 and
Communications,

YIYYSGSTNHNPSLKSRVTISVDTS

PRLLIYGASTRAPGIPARFSGSG
SARS-
SARS-
(2020) 11: 2251

KNQFSLKLSSVTAADTAVYYCAR

SGTEFTLTISSLQSEDFAVYYC
CoV2
CoV1

GVLLWFGEPIFEIWGQGTMVTVSS

QQYNNWPLTFGGGTKVEI

630
EVQLQQSGPVLVKPGASVRMSCK
631
NIMMTQSPSSLAVSAGEKVTM
SARS-
MERS-
Sauer et al., Nature

ASGYTITDYYLNWVKQSHGKSLE

SCKSSQSVLHSSDQKNYLAWY
CoV2,
CoV,
Structural &

WLGVLNPYSGGSLYSQTFKGKAT

QQKPGQSPKLLIYWASTRESG
MERS-
HKU4,
Molecular Biology

LTVDRSSSTAYLELNSLTSEDSAVY

VPDRFTGSGSGTDFTLTISSVQ
CoV,
OC43
28: 478-486(2021)

YCARQLGRGNGLDYWGQGTSVT

AEDLAVYFCHQYLSSYTFGGG
HKU4,

VSS

TKLEIK
OC43

632
EVQLVQSGAEVKKPGESLKISCKG
633
QSVLTQPPSASGTPGQRVTISC
SARS-
SARS-
Scheid et al., 2021

SGYSFTSYWIGWVRQMPGKGLEW

SGSSSNIGSDHVYWYQQLPGT
CoV2;
CoV2;
(sciencedirect.com/

MGVIYPGDSDTRYSPSFQGQVTISA

APKLFIYRNNQRPSGVPDRFSG
SARS-
SARS-
science/article/pii/

DKSISTAYLQWSSLKASDTAMYYC

SKSGTSASLAISGLRSEDEADY
CoV1
CoV1
S0092867421005353)

ARTQWGYNYGSHFFYMDVWGKG

YCAAWDASLSGYVFGTGTKV

TTVTVSS

TVL

634
QVQLVQSGAEVKKPGSSVKVSCK
635
EIVLTQSPGTLSLSPGERATLSC
SARS-
SARS-
Rogers et al., 2020

ASGGTFSSSAISWVRQAPGQGLEW

RASQSVSSSYLAWYQQKPGQ
CoV1,
CoV2
(science.sciencemag.

MGGIIPILDITNYAQKFQGRVTITA

APRLLIYGASSRATGIPDRFSGS
SARS-
and
org/content/early/

DKSTSTAFMELSSLRSEDTAVYYC

GSGTDFTLTISRLEPEDFAVYY
CoV2
SARS-
2020/06/15/

ALRNQWDLLVYWGQGTLVTVSS

CQHYGSSLWTFGQGTKLEIK

CoV1
science.abc7520)

636
VQLQQESGPGLVKPSETLSLTCTVS
637
DIVMTQSPSSLSASVGDRVTIT
SARS-
SARS-
Brouwer et al., 2020

GGSISSSSYYWGWIRQPPGKGLEW

CRASQSISNYLNWYQQKPGKA
CoV1,
CoV1,
(science.sciencemag.

IGSIYYSGSTYYNPSLKSRVTISVDT

PKLLLYAASDLQSGVPSRFSGS
SARS-
SARS-
org/content/early/

SKNQFSLKLSSVTAADTAVYYCAR

GSGTDFTLTISSLQPEDFATYY
CoV2
CoV2
2020/06/15/science.

RSTSRWGYYYMDVWGKGTRVTV

CQQSYSTHMSTFGQGTKVDIK

(weak)
abc5902)

SS

638
QVQLQESGPGLVKPSETLSLTCTVS
639
SYVLTQPPSVSVAPGQTARITC
SARS-
SARS-
Jennewein et al.,

GGSISSYYWSWIRQPPGKGLEWIG

GGNNIGSKTVHWYQQKPGQA
CoV2;
CoV2;
2021(biorxiv.org/

YVYYSGSTNYNPSLKSRVTISVDTS

PVLVVYDDSDRPSGIPERFSGS
SARS-
SARS-
content/10.1101/2021.

KNEFSLKLSSVTAADTAVYYCASS

NSGNTATLTISRVEAGDEADY
CoV1
CoV1
03.23.436684v1)

QRPDGNLYYFDYWGQGTLVTVSS

YCQVWDSSSDHYVFGTGTKV

TVL

640
EVQLVQSGAEVKKPGATVKISCKV
641
IVLTQSPFQSVSPKEKVTITCRA
SARS-
SARS-
Zhe Lv et al., 2020

SGYSFSNYYIHWVKQAPGKSLEWI

SQSISSNLHWYQQKPDQSPKL
CoV1,
CoV1,
(Science, doi:

GYIDPFNGGTSDNLKFKGAATLTA

LIKYASQSISGIPSRFSGSGSGT
SARS-
SARS-
10.1126/science.

DTSTDTAYMELSSLRSEDTAVYYC

DFTLTINSLEAEDFGIYFCQQT
CoV2
CoV2
abc5881)

ARSEYDPYYVMDYWGQGTTVTVSS

NFWPYIFGQGTKLEIL

642
QVQLQQSGAEVKKPGSSVKVSCK
643
SYELTQPPSVSVAPGKTARITC
SARS-
SARS-
Rouet et al., 2021

ASGGTFSTYSISWVRQAPGQGLEW

GGNNIGSKSVHWYQQKPGQA
CoV1,
CoV1,
(MAbs doi:

MGGIAPSHGFANYAQKFQGRVTIT

PVLVVYDDSDRPSGIPERFSGS
SARS-
SARS-
10.1080/19420862.

TDESTSTAYMELSSLRSEDTAVYY

NSGNTATLTISRVEAGDEADY
CoV2
CoV2
2021.1922134)

CARDTATGGMDVWGQGTTVTVSS

YCQVWDTYSDYVFGTGTKVT

VL

644
VQLVESGGGLVQPGGSLRLSCAAS
645
DIEMTQSPSSLSAAVGDRVTIT
SARS-
SARS-
Pinto et al., Nature

GFTFSSYDMHWVRQTTGKGLEWV

CRASQSIGSYLNWYQQKPGKA
CoV1,
CoV1,
583: 290-295 (2020)

STIGTAGDTYYPDSVKGRFTISRED

PKLLIYAASSLQSGVPSRFSGS
SARS-
SARS-

AKNSLYLQMNSLRAGDTAVYYCA

GSGTDFTLTISSLQPEDFAIYYC
CoV2
CoV2

RGDSSGYYYYFDYWGQGTLLTVSS

QQSYVSPTYTFGPGTKVDIK

(weak)

646
QVQLVQSGPEVKKPGTSVRVSCK
647
DIVLTQTPGTLSLSPGERATLS
SARS-
SARS-
Starr, TN, et al.,

ASGFTFTSSAVQWVRQARGQRLE

CRASQSVSSSYLAWYQQKPGQ
CoV2,
CoV2,
Nature, 2021 Jul 14.

WVGWIVVGSGNTNYAQKFHERVT

APRLLIYGASSRATGIPDRFSGS
SARS-
SARS-
doi: 10.1038/s41586-

ITRDMSTSTAYMELSSLRSEDTAV

GSGTDFTLTISRLEPEDFAVYY
CoV1
CoV1
021-03807-6.

YYCASPYCSGGSCSDGFDIWGQGT

CQQYVGLTGWTFGQGTKVEIK

MVTVSS

648
EVQLVESGGGLVNPGGSLRLSCAA
649
VTQPASVSGSPGQSITISCTGTS
SARS-
SARS-
PDB: 7LXX;

SGFTFSDYTIHWVRQAPGKGLEW

SDVGGYNYVSWYQQHPGKAP
CoV2
CoV2
McCallum et al.,

VSSISSSSNYIYYADSVKGRFTISRD

KLMIYDVSDRPSGVSNRFSGS

(2021) Cell 184:

NAKNSLSLQMNSLRAEDTAVYYC

KSGNTASLTISGLQAEDEADY

2332

ARDGNAYKWLLAENVRFDYWGQ

YCSSYTSSSTPNWVFGGGTKLT

GTLVTVSS

650
VQLVESGGGVVQPGRSLRLSCAAS
651
YELTQPPSVSVSPGQTARITCS
SARS-
SARS-
PDB: 7LY2;

GFTFSSYGMHWVRQAPGKGLEWV

GDALAKHYAYWYRQKPGQAP
CoV2
CoV2
McCallum et al.,

TVIWYDGSNRYYADSVKGRFTISR

VLVIYKDSERPSGIPERFSGSSS

(2021) Cell 184:

DNSKNTLYLQMDSLRAEDTAVYY

GTTVTLTISGVQAEDEADYYC

2332

CARAVAGEWYFDYWGQGTLVTVS

QSADSIGSSWVFGGGTKLTV

652
VQLVESGGGVVQPGRSLRLSCAAS
653
YELTQPPSVSTARITCGGNNIE
SARS-
SARS-
PDB: 7LXW;

GFTFSNYGMHWVRQAPGKGLEW

RKSVHWCQQKPGQAPALVVY
CoV2
CoV2
McCallum et al.,

VAVIWYDGSNKFYADSVKGRFTIS

DDSDRPSGIPERFSGSNSGNTA

(2021) Cell 184:

RDNSKNSLYLQMNSLRAEDTAVY

TLTISRVEAGDEADYYCQVWD

2332

FCARAFPDSSSWSGFTIDYWGQGT

SGSDQVIFGGGTKLT

LVTV

654
EVQLVESGGGLVKPGGSLRLSCAA
655
QPVLTQPPSVSGAPGQRITISCT
SARS-
SARS-
Rappazzo, et al

SGFTFSSYYMNWVRQAPGKGLEW

GSSSNIGAGYDVHWYQQLPGT
CoV2
CoV2
Science 371: 823-829

VSSISSDGYNTYYPDSLKGRFTISR

APKLLIYGSSSRPSGVPDRFSG

DOI: 10.1126/

DSAKNSLYLQMNSLRADDTAVYY

SKSGTSASLAITGLQAEDEADY

science.abf4830

CARDFSGHTAVAGTGFEYWGQGT

YCQSYDSSLSVLYVFGTGTKV

LVTVSS

TVL

*Sequence, binding, and neutralization data derived from the CoV-AbDab database: opig.stats.ox.ac.uk/webapps/covabdab/(last visited July 22, 2021)(Raybould, MIJ, et al., Bioinformatics doi = 10.1093/bioinformatics/btaa739(2020)).

Number	Date	Country
63057244	Jul 2020	US
63133153	Dec 2020	US
63133276	Jan 2021	US
63150491	Feb 2021	US

MULTIMERIC CORONAVIRUS BINDING MOLECULES AND USES THEREOF

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CROSS-REFERENCE TO RELATED APPLICATIONS

Provisional Applications (4)