Patent Application
20210046182
The sequence listing of the present application is submitted electronically as an ASCII formatted sequence listing with a file name “10643seqlist”, creation date of Aug. 11, 2020, and a size of 136 Kb. This sequence listing submitted is part of the specification and is hereby incorporated by reference in its entirety.
The field of the disclosure relates to pharmaceutical formulations comprising antibodies and antigen-binding fragments thereof and methods of treatment using such formulations.
Pharmaceutical formulations for delivering a high dose of antibody or other polypeptide in a moderate volume present a challenge due to the high viscosities that result. As the concentration of antibody increases, the viscosity of the formulation typically increases exponentially. Yadav et al., J Pharm Sci. 99 (12) 4812-29 (2010). For example, Cimzia contains the PEGylated Fab′ fragment at a concentration of 200 mg/ml and a viscosity of about 80 cP (a relatively high viscosity). See “Innovative Drug Delivery Technology to Meet Evolving Need of Biologics & Small Molecules,” ONdrugDelivery Magazine, Issue 56 (March 2015), pp 4-6.
Viscous solutions require high injection force, through a needle, to administer the drug and may also require a prolonged injection time. Pain and discomfort experienced by the patient during long injection times can have a negative impact on compliance and adherence to the medication. Moreover, the potential for product loss that could result from highly viscous solutions sticking to the contact surface of the primary packaging can also be a problem. If drug delivery is through an autoinjector, the challenge will be to ensure that the device can produce the required force to function properly throughout its shelf life, hence necessitating extensive modeling and accelerated aging to simulate the high stress placed on the device.
Acceptable subcutaneous (SQ or SC) anti-C5 therapeutic antibody formulations are particularly difficult to develop. Because the concentration of C5 in plasma is relatively high (approximately 80 μg/mL), large amounts of antibody are typically needed to block at a therapeutic level. Holers, Annu Rev Immunol 32: 433-459 (2014). Subcutaneous administration is typically preferred due to patient convenience. SQ injections can usually be done by the patient himself whereas intravenous (IV) administration must be done by a doctor/in the clinic. For example, eculizumab has been approved for treatment of various C5-mediated diseases. Patients are dosed with a large amount (900-1200 mg) of eculizumab every other week, and this huge dosage requires IV administration. Holers (2014). Another approved therapeutic anti-C5 antibody, ravulizumab (sold as Ultomoris), is dosed, IV at even higher levels, at 2400-3000 mg. SQ Ultomoris is dosed weekly at 700 mg from a 100 mg/ml formulation (7 ml dosage volume given in two separate injections). Alexion Pharmaceuticals, Inc., Investor Day presentation (Mar. 20, 2019). As discussed, high SQ dosage volumes present problems, for example, due to the extended period of time required for the full dose to be injected. With a device capable of a 1 ml/minute injection rate, 7 minutes would be required. During this time, errors can occur during injection, for example, interruption of the injection.
The present invention provides a pharmaceutical formulation comprising about 150 or 200 mg/ml or more antigen-binding protein (e.g., antibody or antigen-binding fragment thereof) that binds specifically to C5 (H2M11683N; H2M11686N; H4H12159P; H4H12161P; H4H12163P; H4H12164P; H4H12166P; H4H12166P2; H4H12166P3; H4H12166P4; H4H12166P5; H4H12166P6; H4H12166P7; H4H12166P8; H4H12166P9; H4H12166P10; H4H12167P; H4H12168P; H4HI2169P; H4H12170P; H4H12171P; H4H12175P; H4H12176P2; H4H12177P2; H4H12183P2; H2M11682N; H2M11684N; H2M11694N; H2M11695N; ravulizumab; crovalimab, eculizumab; tesidolumab or mubodina); and a pharmaceutically acceptable carrier comprising: buffer (e.g., phosphate buffer, acetate buffer, citrate buffer, histidine buffer or imidazole buffer); arginine (for example, L-arginine HCl, e.g., 50-100 mM, e.g., 100 mM); water; and, optionally, an oligosaccharide (for example, sucrose, mannitol, dextrose, glycerol, TMAO (trimethylamine N-oxide), trehalose, ethylene glycol, glycine betaine, xylitol or sorbitol, e.g., 2%); and optionally, a non-ionic detergent (e.g., a polyoxyethylene-based detergent or a glycosidic compound-based detergent, polysorbate-20, polysorbate-80 or tween-20), pH of up to about 6.1, e.g., 5-6, e.g., 5.8; and a viscosity of about 14, 14.3 or 15 cP (20° C.) or less. In an embodiment of the invention, the anti-C5 antigen-binding protein is pozelimab. In an embodiment of the invention, the formulation comprises about 200 mg/ml antibody that binds specifically to human C5 (e.g., pozelimab); about 20 mM histidine buffer; about 100 mM L-arginine; about 2% sucrose; about 0.15% polysorbate-80 and water, pH 5.8±0.2. In an embodiment of the invention, the pharmaceutical formulation is aqueous (e.g., suitable for intravenous and/or subcutaneous administration) and comprises H4H12166P (e.g., about 200 mg/mL), histidine (e.g., histidine-HCl; e.g., about 20 mM), pH about 5.8, arginine (e.g., about 100 mM; e.g., L-arginine or L-arginine hydrochloride), a polyol such as sucrose (e.g., about 2% (w/v)), and a non-ionic surfactant such as polysorbate (e.g., polysorbate 80; e.g., about 0.15% (w/v)). In an embodiment of the invention, the pharmaceutical formulation is aqueous (e.g., suitable for intravenous and/or subcutaneous administration) and comprises H4H12166P (e.g., about 200 mg/mL, 200 mg/ml±20 mg/ml or 180-210 mg/ml), histidine (e.g., histidine-HCl; e.g., about 10-20 or 10-24 mM), pH about 5.5±0.6, and arginine (e.g., about 100 mM±20 mM; e.g., L-arginine, L-arginine HCl or L-arginine monohydrochloride), optionally, a polyol such as sucrose (e.g., about 2% (w/v)), and optionally, a non-ionic surfactant such as polysorbate (e.g., polysorbate 80; e.g., about 0.15% (w/v)). In an embodiment of the invention, the pharmaceutical formulation is aqueous (e.g., suitable for intravenous and/or subcutaneous administration) and comprises about 200 mg/mL or 274 mg/ml antibody that binds specifically to C5 wherein the antibody comprises a heavy chain immunoglobulin comprising the amino acid sequence:
and a light chain immunoglobulin comprising the amino acid sequence:
about 20 mM histidine (e.g., histidine-HCl), pH about 5.8, about 100 mM L-arginine (e.g., L-arginine HCl or L-arginine monohydrochloride), about 2% (w/v) sucrose, and about 0.15% (w/v) polysorbate 80 (PS-80). In an embodiment of the invention, the formulation includes one or more further therapeutic agents, e.g., an RNA interference agent that binds to an mRNA sequence that encodes C5 partially or fully, for example, comprising an RNA strand comprising the ribonucleotide sequence 5′-
The present invention also provides a method for making a pharmaceutical formulation of the present invention comprising admixing the antigen-binding protein and the carrier components. A pharmaceutical formulation which is a product of such a method also forms part of the present invention.
The present invention also provides a pharmaceutical formulation of the present invention including a vessel or injection device comprising a pharmaceutical formulation of the present invention, e.g., a vial, syringe, pre-filled syringe or autoinjector.
The present invention also provides an intravenous formulation (e.g., a sterile intravenous formulation) comprising a pharmaceutical formulation comprising an anti-C5 antigen-binding protein (e.g., H2M11683N; H2M11686N; H4H12159P; H4H12161P; H4H12163P; H4H12164P; H4H12166P; H4H12166P2; H4H12166P3; H4H12166P4; H4H12166P5; H4H12166P6; H4H12166P7; H4H12166P8; H4H12166P9; H4H12166P10; H4H12167P; H4HI2168P; H4HI2169P; H4H12170P; H4H12171P; H4H12175P; H4H12176P2; H4H12177P2; H4H12183P2; H2M11682N; H2M11684N; H2M11694N; H2M11695N; ravulizumab; eculizumab; crovalimab, tesidolumab or mubodina) and an aqueous intravenous solution (e.g., 0.9% Normal Saline, Lactated Ringers, Dextrose 5% in Water or 0.45% Normal Saline). For example, in an embodiment of the invention, the aqueous intravenous solution has a volume of about 250 ml, 500 ml, 750 ml or 1000 ml. Such an intravenous formulation may include any one or more of NaCl, dextrose, potassium salt, potassium chloride, calcium salt, calcium chloride, sodium lactate and/or lactate salt. A plastic intravenous bag or glass bottle containing an intravenous formulation also forms part of the present invention. Such intravenous formulations can be constituted such that, when administered to a subject, a dose of about 30 mg/kg body weight is achieved. Methods for making such an intravenous formulation comprising the step of introducing a pharmaceutical formulation that is set forth herein into the aqueous intravenous solution are part of the present invention along with intravenous formulations which are products of such a method.
The present invention also provides a method for reducing the viscosity of an aqueous composition that comprises water and about 150 mg/ml or more (e.g., about 200 mg/ml) of anti-C5 antigen-binding protein (for example, about 150 mg/ml, 175 mg/ml, 200 mg/ml, 211 mg/ml, 220 mg/ml, 242 mg/ml or 274 mg/ml, at least about 150 mg/ml, at least about 175 mg/ml, at least about 200 mg/ml, at least about 211 mg/ml, at least about 220 mg/ml, at least about 242 mg/ml or at least about 274 mg/ml, e.g., an anti-C5 antibody or antigen-binding fragment thereof) comprising combining the water and antigen-binding protein with arginine (e.g., 50 mM or 100 mM), and, optionally, one or more additional carrier components (e.g., buffer, non-ionic detergent and/or oligosaccharide). In an embodiment of the invention, the antigen-binding protein is H2M11683N; H2M11686N; H4H12159P; H4H12161P; H4H12163P; H4H12164P; H4H12166P; H4H12166P2; H4H12166P3; H4H12166P4; H4H12166P5; H4H12166P6; H4H12166P7; H4H12166P8; H4H12166P9; H4H12166P10; H4H12167P; H4HI2168P; H4HI2169P; H4H12170P; H4H12171P; H4H12175P; H4H12176P2; H4H12177P2; H4H12183P2; H2M11682N; H2M11684N; H2M11694N; H2M11695N; ravulizumab; eculizumab; crovalimab, tesidolumab or mubodina. In an embodiment of the invention, the formulation viscosity is reduced by about 30% or about 30-42%, e.g., wherein viscosity is in units of cP as measured at 20° C.
The present invention also provides a method for administering a pharmaceutical formulation of the present invention to a subject (e.g., a human) comprising introducing (e.g., parenterally, e.g., intravenously, intramuscularly or subcutaneously) the formulation into the body of the subject (e.g., wherein the subject suffers from a C5-associated disease).
The present invention also provides a method for treating or preventing a C5-associated disease (e.g., atypical hemolytic uremic syndrome (aHUS), paroxysmal nocturnal hemoglobinuria (PNH) or CHAPLE disease) in a subject (e.g., a human) in need thereof comprising administering a therapeutically effective amount of antigen-binding protein (e.g., antibody or antigen-binding fragment thereof) that binds specifically to C5 (e.g., human C5) in a pharmaceutical formulation of the present invention to the subject. In an embodiment of the invention, the C5-associated disease is one or more selected from the group consisting of adult respiratory distress syndrome; age-related macular degeneration (AMD); allergy; Alport's syndrome; Alzheimer's disease; antiphospholipid syndrome (APS); asthma; atherosclerosis; atypical hemolytic uremic syndrome (aHUS); autoimmune disease; autoimmune hemolytic anemia (AIHA); balloon angioplasty; bronchoconstriction; bullous pemphigoid; burns; C3 glomerulopathy; capillary leak syndrome; cardiovascular disorder; catastrophic antiphospholipid syndrome (CAPS); cerebrovascular disorder; CHAPLE disease; chemical injury; chronic obstructive pulmonary disease (COPD); cold agglutinin disease (CAD); corneal and/or retinal tissue; Crohn's disease; Degos disease; dense deposit disease (DDD); dermatomyositis; diabetes; diabetic angiopathy; diabetic macular edema (DME); diabetic nephropathy; diabetic retinopathy; dilated cardiomyopathy; disorder of inappropriate or undesirable complement activation; dyspnea; emphysema; epidermolysis bullosa; epilepsy; fibrogenic dust disease; frostbite; geographic atrophy (GA); glomerulonephritis; glomerulopathy; Goodpasture's Syndrome; Graves' disease; Guillain Barre Syndrome; Hashimoto's thyroiditis; hemodialysis complications; hemolysis-elevated liver enzymes—and low platelets (HELLP) syndrome; hemolytic anemia; hemoptysis; Henoch-Schonlein purpura nephritis; hereditary angioedema; hyperacute allograft rejection; hypersensitivity pneumonitis; idiopathic thrombocytopenic purpura (ITP); IgA nephropathy; immune complex disorder; immune complex vasculitis; immune complex-associated inflammation; infectious disease; inflammation caused by an autoimmune disease; inflammatory disorder; inherited CD59 deficiency; injury due to inert dusts and/or minerals; interleukin-2 induced toxicity during IL-2 therapy; ischemia-reperfusion injury; Kawasaki's disease; lung disease or disorder; lupus nephritis; membrane proliferative glomerulonephritis; membrano-proliferative nephritis; mesenteric artery reperfusion after aortic reconstruction; mesenteric/enteric vascular disorder; multifocal motor neuropathy (MMN); multiple sclerosis; myasthenia gravis; myocardial infarction; myocarditis; neurological disorder; neuromyelitis optica; obesity; ocular angiogenesis; ocular neovascularization affecting choroidal; organic dust disease; parasitic disease; Parkinson's disease; paroxysmal nocturnal hemoglobinuria (PNH); Pauci-immune vasculitis; pemphigus; percutaneous transluminal coronary angioplasty (PTCA); peripheral vascular disorder; pneumonia; post-ischemic reperfusion condition; post-pump syndrome in cardiopulmonary bypass; post-pump syndrome in renal bypass; progressive kidney failure; proliferative nephritis; proteinuric kidney disease; psoriasis; pulmonary embolism; pulmonary fibrosis; pulmonary infarction; pulmonary vasculitis; recurrent fetal loss; renal disorder; renal ischemia; renal ischemia-reperfusion injury; renovascular disorder; restenosis following stent placement; rheumatoid arthritis; rotational atherectomy; schizophrenia; sepsis; septic shock; SLE nephritis; smoke injury; spinal cord injury; spontaneous fetal loss; stroke; systemic inflammatory response to sepsis; systemic lupus erythematosus (SLE); systemic lupus erythematosus-associated vasculitis; Takayasu's disease; thermal injury; thrombotic thrombocytopenic purpura (TTP); traumatic brain injury; type I diabetes; typical hemolytic uremic syndrome; uveitis; vasculitis; vasculitis associated with rheumatoid arthritis; venous gas embolus (VGE); and xenograft rejection.
The present invention also provides a method for reducing complement activity in the body of a subject (e.g., a human) in need thereof comprising administering a therapeutically effective amount anti-C5 antigen-binding protein (e.g., antibody or antigen-binding fragment thereof) in a pharmaceutical formulation of the present invention to the subject.
The pharmaceutical formulations of the present invention are characterized by a number of particularly advantageous properties. The formulations have both high protein concentration and low viscosity. The particularly low viscosity of the formulations contrast with that of several commercially available anti-C5 antibody products. The low viscosity of the formulations of the present invention facilitate the delivery of a large amount of anti-C5 antibody in a low volume. Moreover, the pharmaceutical formulations of the present invention exhibit a high degree of stability-resistance to meaningful increases in high molecular weight (HMW) species under highly oxidizing conditions and only minimal increases in HMW species after several hours of agitation.
A “high molecular weight” (HMW) species as used herein, for example, with reference to a pharmaceutical formulation containing a given anti-C5 antibody or antigen-binding fragment thereof, refers to any species of antibody or antigen-binding fragment thereof in the formulation which elutes from a size exclusion column (e.g., SE-UPLC) ahead of (e.g., with a higher molecular weight than) that of a single species of such antibody (a tetrameric complex with two heavy and two light chains) or an antigen-binding fragment thereof. The percentage of HMW species refers to the percentage of such species relative to the overall quantity of antibody or antigen-binding fragment thereof in the formulation, e.g., by SE-UPLC analysis.
A “low molecular weight” (LMW) species as used herein, for example, with reference to a pharmaceutical formulation containing a given anti-C5 antibody or antigen-binding fragment thereof, refers to any species of antibody or antigen-binding fragment thereof in the formulation which elutes from a size exclusion column (e.g., SE-UPLC) behind (e.g., with a lower molecular weight than) that of a single species of such antibody (a tetrameric complex with two heavy and two light chains) or an antigen-binding fragment thereof. The percentage of LMW species refers to the percentage of such species relative to the overall quantity of antibody or antigen-binding fragment thereof in the formulation, e.g., by SE-UPLC analysis.
Concentrations of the excipients in the formulations of the present invention may be expressed in percentages (%) which are weight/volume (w/v) units. Weight/volume refers to the mass of a component/volume of solution×100.
The term “C5”, also called “complement component 5” or “complement factor 5” refers to the serum protein of the complement cascade. The C5 protein is a 1676 amino acid protein comprising two chains, alpha and beta. The protein represents the convergence point for three complement activation pathways: classical pathway, alternative pathway and the mannose binding lectin pathway. The amino acid sequence of full-length C5 protein is exemplified by the amino acid sequence provided in GenBank as accession number NP001726.2.
In accordance with the present invention there may be employed conventional molecular biology, microbiology, and recombinant DNA techniques within the skill of the art. Such techniques are explained fully in the literature. See, e.g., Sambrook, Fritsch & Maniatis, Molecular Cloning: A Laboratory Manual, Second Edition (1989) Cold Spring Harbor Laboratory Press, Cold Spring Harbor, N.Y. (herein “Sambrook, et al., 1989”); DNA Cloning: A Practical Approach, Volumes I and II (D. N. Glover ed. 1985); Oligonucleotide Synthesis (M. J. Gait ed. 1984); Nucleic Acid Hybridization (B. D. Hames & S. J. Higgins eds. (1985)); Transcription And Translation (B. D. Hames & S. J. Higgins, eds. (1984)); Animal Cell Culture (R. I. Freshney, ed. (1986)); Immobilized Cells And Enzymes (IRL Press, (1986)); B. Perbal, A Practical Guide To Molecular Cloning (1984); F. M. Ausubel, et al. (eds.), Current Protocols in Molecular Biology, John Wiley & Sons, Inc. (1994).
The present invention provides pharmaceutical formulations comprising anti-C5 antigen-binding proteins (e.g., antibodies and antigen-binding fragments thereof) and a pharmaceutically acceptable carrier.
In an embodiment of the invention, the anti-C5 antigen-binding protein binds to the beta chain or the alpha chain of C5 or both, e.g., at residues 591-599 and/or 775-794, e.g.,
In an embodiment of the invention, the anti-C5 antigen-binding protein binds C5 at residues
In an embodiment of the invention, the anti-C5 antigen-binding protein binds the beta chain of C5 thereof, e.g., at residues 332-398, 332-378, 332-364, 332-348, 350-420, 369-409, 379-398 and/or 386-392.
In an embodiment of the invention, the anti-C5 antigen-binding protein binds C5a, e.g., at residues
In an embodiment of the invention, the anti-C5 antigen-binding protein binds the beta chain of C5, e.g., residues 19-180. In an embodiment of the invention, binding to C5 is reduced by E48A, D51A and/or K109A C5 mutations.
Immunoglobulin polypeptides in anti-C5 antigen binding proteins (e.g., antibody or antigen-binding fragment thereof) of the pharmaceutical formulations of the present invention are set forth in Table A. See International patent application publication no. WO2017/218515.
In an embodiment of the invention, the anti-C5 antigen-binding protein is eculizumab (sold as Soliris), crovalimab, ravulizumab (ALXN1210; sold as Ultomiris), tesidolumab (see U.S. Pat. No. 8,241,628; WO 2010/015608; or WO2017/212375) or mubodina (see U.S. Pat. No. 7,999,081). In an embodiment of the invention, the anti-C5 antigen-binding protein is pozelimab (REGN3918; H4H12166P) antibody. Pozelimab (REGN3918; H4H12166P) antibody comprises a heavy chain immunoglobulin comprising the amino acid sequence:
and a light chain immunoglobulin comprising the amino acid sequence:
In an embodiment of the invention, the anti-C5 antigen-binding protein comprises a heavy chain immunoglobulin comprising the amino acid sequence:
or the HCDR1, HCDR2 and HCDR3 thereof; or the VH thereof (or a variant thereof);
and a light chain immunoglobulin comprising the amino acid sequence:
or the LCDR1, LCDR2 and LCDR3 thereof; or the VL thereof (or a variant thereof).
The present invention includes pharmaceutical formulations comprising antibodies and antigen-binding fragments thereof that include the variable regions and CDRs which are specifically discussed herein as well as variable regions and CDRs which are variants of those discussed herein.
A “variant” of a polypeptide, such as an immunoglobulin chain (e.g., the H2M11683N; H2M11686N; H4H12159P; H4H12161P; H4H12163P; H4H12164P; H4H12166P; H4H12166P2; H4H12166P3; H4H12166P4; H4H12166P5; H4H12166P6; H4H12166P7; H4H12166P8; H4H12166P9; H4H12166P10; H4H12167P; H4HI2168P; H4HI2169P; H4H12170P; H4H12171P; H4H12175P; H4H12176P2; H4H12177P2; H4H12183P2; H2M11682N; H2M11684N; H2M11694N; H2M11695N; ravulizumab, eculizumab, crovalimab, tesidolumab or mubodina VH, VL, HC or LC or CDR thereof comprising the amino acid sequence specifically set forth herein), refers to a polypeptide comprising an amino acid sequence that is at least about 70-99.9% (e.g., at least 70, 72, 74, 75, 76, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 99.5 or 99.9%) identical or similar to a referenced amino acid sequence that is set forth herein (e.g., any of SEQ ID NOs: 2; 4; 6; 8; 10; 12; 14; 16; 18; 20; 22; 24; 26; 28; 30; 32; 34; 36; 38; 40; 42; 44; 46; 48; 50; 52; 54; 56; 58; 60; 62; 64; 66; 68; 70; 72; 74; 76; 78; 80; 82; 84; 86; 88; 90; 92; 94; 96; 98; 98; 98; 100; 100; 100; 102; 102; 102; 104; 104; 104; 106; 106; 106; 106; 108; 108; 108; 108; 110; 110; 110; 110; 112; 112; 112; 112; 114; 114; 116; 116; 118; 118; 120; 120; 122; 122; 124; 124; 126; 126; 128; 128; 130; 130; 130; 130; 132; 132; 132; 132; 134; 134; 134; 134; 136; 136; 136; 136; 138; 138; 140; 140; 142; 142; 144; 144; 146; 146; 146; 148; 148; 148; 150; 150; 150; 152; 152; 152; 154; 156; 158; 160; 162; 164; 166; 168; 170; 172; 174; 176; 178; 180; 182; 184; 186; 188; 190; 192; 194; 196; 198; 200; 202; 204; 206; 208; 210; 212; 214; 216; 218; 220; 222; 224; 226; 228; 230; 232; 234; 236; 238; 240; 242; 244; 246; 248; 250; 252; 254; 256; 258; 258; 260; 260; 262; 262; 264; 264; 266; 268; 270; 272; 274; 276; 278; 280; 282; 284; 286; 288; 290; 292; 294; 296; 298; 300; 302; 304; 306; 308; 310; 312; 314; 316; 318; 320; 322; 324; 326; 328; 330; 332; 334; 336; 338; 340; 342; 344; 346; 348; 350, 352, 353, 354, 355, 356, 357, 362, 363, 364, 365, 366, 367, 368 and/or 369), see e.g., Table A; when the comparison is performed by a BLAST algorithm wherein the parameters of the algorithm are selected to give the largest match between the respective sequences over the entire length of the respective reference sequences (e.g., expect threshold: 10; word size: 3; max matches in a query range: 0; BLOSUM 62 matrix; gap costs: existence 11, extension 1; conditional compositional score matrix adjustment).
Moreover, a variant of a polypeptide may include a polypeptide such as an immunoglobulin chain (e.g., the H2M11683N; H2M11686N; H4H12159P; H4H12161P; H4H12163P; H4H12164P; H4H12166P; H4H12166P2; H4H12166P3; H4H12166P4; H4H12166P5; H4H12166P6; H4H12166P7; H4H12166P8; H4H12166P9; H4H12166P10; H4H12167P; H4HI2168P; H4HI2169P; H4H12170P; H4H12171P; H4H12175P; H4H12176P2; H4H12177P2; H4H12183P2; H2M11682N; H2M11684N; H2M11694N; H2M11695N; ravulizumab, eculizumab, crovalimab, tesidolumab or mubodina VH, VL, HC or LC or CDR thereof) may include the amino acid sequence of the reference polypeptide whose amino acid sequence is specifically set forth herein but for one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10) mutations, e.g., one or more missense mutations (e.g., conservative substitutions), non-sense mutations, deletions, or insertions. For example, the present invention includes pharmaceutical formulations including one or more anti-C5 antigen-binding proteins which include an immunoglobulin light chain (or VL) variant comprising the amino acid sequence set forth in SEQ ID NO: 106 but having one or more of such mutations and/or an immunoglobulin heavy chain (or VH) variant comprising the amino acid sequence set forth in SEQ ID NO: 98 but having one or more of such mutations. In an embodiment of the invention, the anti-C5 antigen-binding protein includes an immunoglobulin light chain variant comprising CDR-L1, CDR-L2 and CDR-L3 wherein one or more (e.g., 1 or 2 or 3) of such CDRs has one or more of such mutations (e.g., conservative substitutions) and/or an immunoglobulin heavy chain variant comprising CDR-H1, CDR-H2 and CDR-H3 wherein one or more (e.g., 1 or 2 or 3) of such CDRs has one or more of such mutations (e.g., conservative substitutions).
The following references relate to BLAST algorithms often used for sequence analysis: BLAST ALGORITHMS: Altschul et al. (2005) FEBS J. 272(20): 5101-5109; Altschul, S. F., et al., (1990) J. Mol. Biol. 215:403-410; Gish, W., et al., (1993) Nature Genet. 3:266-272; Madden, T. L., et al., (1996) Meth. Enzymol. 266:131-141; Altschul, S. F., et al., (1997) Nucleic Acids Res. 25:3389-3402; Zhang, J., et al., (1997) Genome Res. 7:649-656; Wootton, J. C., et al., (1993) Comput. Chem. 17:149-163; Hancock, J. M. et al., (1994) Comput. Appl. Biosci. 10:67-70; ALIGNMENT SCORING SYSTEMS: Dayhoff, M. O., et al., “A model of evolutionary change in proteins.” in Atlas of Protein Sequence and Structure, (1978) vol. 5, suppl. 3. M. O. Dayhoff (ed.), pp. 345-352, Natl. Biomed. Res. Found., Washington, D.C.; Schwartz, R. M., et al., “Matrices for detecting distant relationships.” in Atlas of Protein Sequence and Structure, (1978) vol. 5, suppl. 3.” M. O. Dayhoff (ed.), pp. 353-358, Natl. Biomed. Res. Found., Washington, D.C.; Altschul, S. F., (1991) J. Mol. Biol. 219:555-565; States, D. J., et al., (1991) Methods 3:66-70; Henikoff, S., et al., (1992) Proc. Natl. Acad. Sci. USA 89:10915-10919; Altschul, S. F., et al., (1993) J. Mol. Evol. 36:290-300; ALIGNMENT STATISTICS: Karlin, S., et al., (1990) Proc. Natl. Acad. Sci. USA 87:2264-2268; Karlin, S., et al., (1993) Proc. Natl. Acad. Sci. USA 90:5873-5877; Dembo, A., et al., (1994) Ann. Prob. 22:2022-2039; and Altschul, S. F. “Evaluating the statistical significance of multiple distinct local alignments.” in Theoretical and Computational Methods in Genome Research (S. Suhai, ed.), (1997) pp. 1-14, Plenum, N.Y.
“H2M11683N”; “H2M11686N”; “H4H12159P”; “H4H12161P”; “H4H12163P”; “H4H12164P”; “H4H12166P”; “H4H12166P2”; “H4H12166P3”; “H4H12166P4”; “H4H12166P5”; “H4H12166P6”; “H4H12166P7”; “H4H12166P8”; “H4H12166P9”; “H4H12166P10”; “H4H12167P”; “H4HI2168P”; “H4HI2169P”; “H4H12170P”; “H4H12171P”; “H4H12175P”; “H4H12176P2”; “H4H12177P2”; “H4H12183P2”; “H2M11682N”; “H2M11684N”; “H2M11694N” or “H2M11695N”, unless otherwise stated, refer to anti-C5 antigen-binding proteins, e.g., antibodies and antigen-binding fragments thereof (including multispecific antigen-binding proteins), that bind specifically to C5, comprising an immunoglobulin heavy chain or variable region thereof (VH) comprising the amino acid sequence specifically set forth herein corresponding, in Table A herein or Table 1 of WO2017/218515 (and the sequences set forth therein), to H2M11683N; H2M11686N; H4H12159P; H4H12161P; H4H12163P; H4H12164P; H4H12166P; H4H12166P2; H4H12166P3; H4H12166P4; H4H12166P5; H4H12166P6; H4H12166P7; H4H12166P8; H4H12166P9; H4H12166P10; H4H12167P; H4HI2168P; H4HI2169P; H4H12170P; H4H12171P; H4H12175P; H4H12176P2; H4H12177P2; H4H12183P2; H2M11682N; H2M11684N; H2M11694N; or H2M11695N (e.g., SEQ ID NO: 2; 18; 34; 50; 66; 82; 98; 98; 122; 98; 138; 146; 122; 146; 146; 138; 154; 170; 186; 202; 218; 234; 250; 266; 274; 290; 306; 322 or 338) (or a variant thereof), and/or an immunoglobulin light chain or variable region thereof (VL) comprising the amino acid sequence specifically set forth herein corresponding, in Table A herein or Table 1 of WO2017/218515 (and the sequences set forth therein), to H2M11683N; H2M11686N; H4H12159P; H4H12161P; H4H12163P; H4H12164P; H4H12166P; H4H12166P2; H4H12166P3; H4H12166P4; H4H12166P5; H4H12166P6; H4H12166P7; H4H12166P8; H4H12166P9; H4H12166P10; H4H12167P; H4HI2168P; H4HI2169P; H4H12170P; H4H12171P; H4H12175P; H4H12176P2; H4H12177P2; H4H12183P2; H2M11682N; H2M11684N; H2M11694N or H2M11695N (e.g., SEQ ID NO: 10; 26; 42; 58; 74; 90; 106; 114; 106; 130; 106; 106; 130; 114; 130; 130; 162; 178; 194; 210; 226; 242; 258; 258; 282; 298; 314; 330 or 346) (or a variant thereof), respectively; and/or that comprise a heavy chain or VH that comprises the CDRs thereof (CDR-H1 (or a variant thereof), CDR-H2 (or a variant thereof) and CDR-H3 (or a variant thereof)) and/or a light chain or VL that comprises the CDRs thereof (CDR-L1 (or a variant thereof), CDR-L2 (or a variant thereof) and CDR-L3 (or a variant thereof)). In an embodiment of the invention, the VH is linked to an IgG constant heavy chain domain (e.g., IgG1 or IgG4 (e.g., IgG4 (S228P mutant))) and/or the VL is linked to a lambda or kappa constant light chain domain.
In an embodiment of the invention, the antigen-binding protein, H2M11683N, comprises an HCVR that comprises the amino acid sequence set forth in SEQ ID NO: 2 and an LCVR that comprises the amino acid sequence set forth in SEQ ID NO: 10 (e.g., wherein the antigen-binding protein is an antibody or antigen-binding fragment thereof).
In an embodiment of the invention, the antigen-binding protein, H2M11686N, comprises an HCVR that comprises the amino acid sequence set forth in SEQ ID NO: 18 and an LCVR that comprises the amino acid sequence set forth in SEQ ID NO: 26 (e.g., wherein the antigen-binding protein is an antibody or antigen-binding fragment thereof).
In an embodiment of the invention, the antigen-binding protein, H4H12159P, comprises an HCVR that comprises the amino acid sequence set forth in SEQ ID NO: 34 and an LCVR that comprises the amino acid sequence set forth in SEQ ID NO: 42 (e.g., wherein the antigen-binding protein is an antibody or antigen-binding fragment thereof).
In an embodiment of the invention, the antigen-binding protein, H4H12161P, comprises an HCVR that comprises the amino acid sequence set forth in SEQ ID NO: 50 and an LCVR that comprises the amino acid sequence set forth in SEQ ID NO: 58 (e.g., wherein the antigen-binding protein is an antibody or antigen-binding fragment thereof).
In an embodiment of the invention, the antigen-binding protein, H4H12163P, comprises an HCVR that comprises the amino acid sequence set forth in SEQ ID NO: 66 and an LCVR that comprises the amino acid sequence set forth in SEQ ID NO: 74 (e.g., wherein the antigen-binding protein is an antibody or antigen-binding fragment thereof).
In an embodiment of the invention, the antigen-binding protein, H4H12164P, comprises an HCVR that comprises the amino acid sequence set forth in SEQ ID NO: 82 and an LCVR that comprises the amino acid sequence set forth in SEQ ID NO: 90 (e.g., wherein the antigen-binding protein is an antibody or antigen-binding fragment thereof).
In an embodiment of the invention, the antigen-binding protein, H4H12166P, comprises an HCVR that comprises the amino acid sequence set forth in SEQ ID NO: 98 and an LCVR that comprises the amino acid sequence set forth in SEQ ID NO: 106 (e.g., wherein the antigen-binding protein is an antibody or antigen-binding fragment thereof).
In an embodiment of the invention, the antigen-binding protein, H4H12166P2, comprises an HCVR that comprises the amino acid sequence set forth in SEQ ID NO: 98 and an LCVR that comprises the amino acid sequence set forth in SEQ ID NO: 114 (e.g., wherein the antigen-binding protein is an antibody or antigen-binding fragment thereof).
In an embodiment of the invention, the antigen-binding protein, H4H12166P3, comprises an HCVR that comprises the amino acid sequence set forth in SEQ ID NO: 122 and an LCVR that comprises the amino acid sequence set forth in SEQ ID NO: 106 (e.g., wherein the antigen-binding protein is an antibody or antigen-binding fragment thereof).
In an embodiment of the invention, the antigen-binding protein, H4H12166P4, comprises an HCVR that comprises the amino acid sequence set forth in SEQ ID NO: 98 and an LCVR that comprises the amino acid sequence set forth in SEQ ID NO: 130 (e.g., wherein the antigen-binding protein is an antibody or antigen-binding fragment thereof).
In an embodiment of the invention, the antigen-binding protein, H4H12166P5, comprises an HCVR that comprises the amino acid sequence set forth in SEQ ID NO: 138 and an LCVR that comprises the amino acid sequence set forth in SEQ ID NO: 106 (e.g., wherein the antigen-binding protein is an antibody or antigen-binding fragment thereof).
In an embodiment of the invention, the antigen-binding protein, H4H12166P6, comprises an HCVR that comprises the amino acid sequence set forth in SEQ ID NO: 146 and an LCVR that comprises the amino acid sequence set forth in SEQ ID NO: 106 (e.g., wherein the antigen-binding protein is an antibody or antigen-binding fragment thereof).
In an embodiment of the invention, the antigen-binding protein, H4H12166P7, comprises an HCVR that comprises the amino acid sequence set forth in SEQ ID NO: 122 and an LCVR that comprises the amino acid sequence set forth in SEQ ID NO: 130 (e.g., wherein the antigen-binding protein is an antibody or antigen-binding fragment thereof).
In an embodiment of the invention, the antigen-binding protein, H4H12166P8, comprises an HCVR that comprises the amino acid sequence set forth in SEQ ID NO: 146 and an LCVR that comprises the amino acid sequence set forth in SEQ ID NO: 114 (e.g., wherein the antigen-binding protein is an antibody or antigen-binding fragment thereof).
In an embodiment of the invention, the antigen-binding protein, H4H12166P9, comprises an HCVR that comprises the amino acid sequence set forth in SEQ ID NO: 146 and an LCVR that comprises the amino acid sequence set forth in SEQ ID NO: 130 (e.g., wherein the antigen-binding protein is an antibody or antigen-binding fragment thereof).
In an embodiment of the invention, the antigen-binding protein, H4H12166P10, comprises an HCVR that comprises the amino acid sequence set forth in SEQ ID NO: 138 and an LCVR that comprises the amino acid sequence set forth in SEQ ID NO: 130 (e.g., wherein the antigen-binding protein is an antibody or antigen-binding fragment thereof).
In an embodiment of the invention, the antigen-binding protein, H4H12167P, comprises an HCVR that comprises the amino acid sequence set forth in SEQ ID NO: 154 and an LCVR that comprises the amino acid sequence set forth in SEQ ID NO: 162 (e.g., wherein the antigen-binding protein is an antibody or antigen-binding fragment thereof).
In an embodiment of the invention, the antigen-binding protein, H4H12168P, comprises an HCVR that comprises the amino acid sequence set forth in SEQ ID NO: 170 and an LCVR that comprises the amino acid sequence set forth in SEQ ID NO: 178 (e.g., wherein the antigen-binding protein is an antibody or antigen-binding fragment thereof).
In an embodiment of the invention, the antigen-binding protein, H4H12169P, comprises an HCVR that comprises the amino acid sequence set forth in SEQ ID NO: 186 and an LCVR that comprises the amino acid sequence set forth in SEQ ID NO: 194 (e.g., wherein the antigen-binding protein is an antibody or antigen-binding fragment thereof).
In an embodiment of the invention, the antigen-binding protein, H4H12170P, comprises an HCVR that comprises the amino acid sequence set forth in SEQ ID NO: 202 and an LCVR that comprises the amino acid sequence set forth in SEQ ID NO: 210 (e.g., wherein the antigen-binding protein is an antibody or antigen-binding fragment thereof).
In an embodiment of the invention, the antigen-binding protein, H4H12171P, comprises an HCVR that comprises the amino acid sequence set forth in SEQ ID NO: 218 and an LCVR that comprises the amino acid sequence set forth in SEQ ID NO: 226 (e.g., wherein the antigen-binding protein is an antibody or antigen-binding fragment thereof).
In an embodiment of the invention, the antigen-binding protein, H4H12175P, comprises an HCVR that comprises the amino acid sequence set forth in SEQ ID NO: 234 and an LCVR that comprises the amino acid sequence set forth in SEQ ID NO: 242 (e.g., wherein the antigen-binding protein is an antibody or antigen-binding fragment thereof).
In an embodiment of the invention, the antigen-binding protein, H4H12176P2, comprises an HCVR that comprises the amino acid sequence set forth in SEQ ID NO: 250 and an LCVR that comprises the amino acid sequence set forth in SEQ ID NO: 258 (e.g., wherein the antigen-binding protein is an antibody or antigen-binding fragment thereof).
In an embodiment of the invention, the antigen-binding protein, H4H12177P2, comprises an HCVR that comprises the amino acid sequence set forth in SEQ ID NO: 266 and an LCVR that comprises the amino acid sequence set forth in SEQ ID NO: 258 (e.g., wherein the antigen-binding protein is an antibody or antigen-binding fragment thereof).
In an embodiment of the invention, the antigen-binding protein, H4H12183P2, comprises an HCVR that comprises the amino acid sequence set forth in SEQ ID NO: 274 and an LCVR that comprises the amino acid sequence set forth in SEQ ID NO: 282 (e.g., wherein the antigen-binding protein is an antibody or antigen-binding fragment thereof).
In an embodiment of the invention, the antigen-binding protein, H2M11682N, comprises an HCVR that comprises the amino acid sequence set forth in SEQ ID NO: 290 and an LCVR that comprises the amino acid sequence set forth in SEQ ID NO: 298 (e.g., wherein the antigen-binding protein is an antibody or antigen-binding fragment thereof).
In an embodiment of the invention, the antigen-binding protein, H2M11684N, comprises an HCVR that comprises the amino acid sequence set forth in SEQ ID NO: 306 and an LCVR that comprises the amino acid sequence set forth in SEQ ID NO: 314 (e.g., wherein the antigen-binding protein is an antibody or antigen-binding fragment thereof).
In an embodiment of the invention, the antigen-binding protein, H2M11694N, comprises an HCVR that comprises the amino acid sequence set forth in SEQ ID NO: 322 and an LCVR that comprises the amino acid sequence set forth in SEQ ID NO: 330 (e.g., wherein the antigen-binding protein is an antibody or antigen-binding fragment thereof).
In an embodiment of the invention, the antigen-binding protein, H2M11695N, comprises an HCVR that comprises the amino acid sequence set forth in SEQ ID NO: 338 and an LCVR that comprises the amino acid sequence set forth in SEQ ID NO: 346 (e.g., wherein the antigen-binding protein is an antibody or antigen-binding fragment thereof).
In an embodiment of the invention, an anti-C5 antigen-binding protein, e.g., antibody or antigen-binding fragment, comprises a heavy chain constant domain, e.g., of the type IgA (e.g., IgA1 or IgA2), IgD, IgE, IgG (e.g., IgG1, IgG2, IgG3 and IgG4 (e.g., comprising a S228P mutation)) or IgM. Silva et al., J Biol Chem. 290(9):5462-9 (2015). In an embodiment of the invention, an antigen-binding protein, e.g., antibody or antigen-binding fragment, comprises a light chain constant domain, e.g., of the type kappa or lambda. The present invention includes pharmaceutical formulations including antigen-binding proteins comprising the variable domains set forth herein and in the art (e.g., H2M11683N; H2M11686N; H4H12159P; H4H12161P; H4H12163P; H4H12164P; H4H12166P; H4H12166P2; H4H12166P3; H4H12166P4; H4H12166P5; H4H12166P6; H4H12166P7; H4H12166P8; H4H12166P9; H4H12166P10; H4H12167P; H4HI2168P; H4HI2169P; H4H12170P; H4H12171P; H4H12175P; H4H12176P2; H4H12177P2; H4H12183P2; H2M11682N; H2M11684N; H2M11694N; H2M11695N; ravulizumab, eculizumab, crovalimab, tesidolumab, mubodina, IFX-1 (see e.g., US2017/0137499), olendalizumab) which are linked to a heavy and/or light chain constant domain, e.g., as set forth above (e.g., an IgG4 heavy chain constant region and a kappa light chain constant region).
The term “antibody”, as used herein, refers to immunoglobulin molecules comprising four polypeptide chains, two heavy chains (HCs) including three H-CDRs and two light chains (LCs) including three L-CDRs inter-connected by disulfide bonds (i.e., “full antibody molecules”) (e.g., IgG4)—for example H2M11683N; H2M11686N; H4H12159P; H4H12161P; H4H12163P; H4H12164P; H4H12166P; H4H12166P2; H4H12166P3; H4H12166P4; H4H12166P5; H4H12166P6; H4H12166P7; H4H12166P8; H4H12166P9; H4H12166P10; H4H12167P; H4HI2168P; H4HI2169P; H4H12170P; H4H12171P; H4H12175P; H4H12176P2; H4H12177P2; H4H12183P2; H2M11682N; H2M11684N; H2M11694N; or H2M11695N. In an embodiment of the invention, the assignment of amino acids to each CDR domain within an immunoglobulin chain is in accordance with the definitions of Sequences of Proteins of Immunological Interest, Kabat, et al.; National Institutes of Health, Bethesda, Md.; 5th ed.; NIH Publ. No. 91-3242 (1991); Kabat (1978) Adv. Prot. Chem. 32:1-75; Kabat, et al., (1977) J. Biol. Chem. 252:6609-6616; Chothia, et al., (1987) J Mol. Biol. 196:901-917 or Chothia, et al., (1989) Nature 342:878-883. Thus, the present invention includes antibodies and antigen-binding fragments including the CDRs of a VH and the CDRs of a VL, which VH and VL comprise amino acid sequences as set forth herein (or a variant thereof), wherein the CDRs are as defined according to Kabat and/or Chothia.
The terms “antigen-binding portion” or “antigen-binding fragment” of an antibody or antigen-binding protein, and the like, as used herein, include any naturally occurring, enzymatically obtainable, synthetic, or genetically engineered polypeptide or glycoprotein that specifically binds an antigen to form a complex. Non-limiting examples of antigen-binding fragments include: (i) Fab fragments; (ii) F(ab′)2 fragments; (iii) Fd fragments (heavy chain portion of a Fab fragment cleaved with papain); (iv) Fv fragments (a VH or VL); and (v) single-chain Fv (scFv) molecules; consisting of the amino acid residues that mimic the hypervariable region of an antibody (e.g., an isolated complementarity determining region (CDR) such as a CDR3 peptide), or a constrained FR3-CDR3-FR4 peptide. Other engineered molecules, such as domain-specific antibodies, single domain antibodies, domain-deleted antibodies, chimeric antibodies, CDR-grafted antibodies, diabodies, triabodies, tetrabodies, minibodies and small modular immunopharmaceuticals (SMIPs), are also encompassed within the expression “antigen-binding fragment,” as used herein. In an embodiment of the invention, the antigen-binding fragment comprises three or more CDRs of H2M11683N; H2M11686N; H4H12159P; H4H12161P; H4H12163P; H4H12164P; H4H12166P; H4H12166P2; H4H12166P3; H4H12166P4; H4H12166P5; H4H12166P6; H4H12166P7; H4H12166P8; H4H12166P9; H4H12166P10; H4H12167P; H4HI2168P; H4HI2169P; H4H12170P; H4H12171P; H4H12175P; H4H12176P2; H4H12177P2; H4H12183P2; H2M11682N; H2M11684N; H2M11694N; or H2M11695N (e.g., CDR-H1, CDR-H2 and CDR-H3; and/or CDR-L1, CDR-L2 and CDR-L3).
The term “recombinant” antigen-binding proteins, such as antibodies or antigen-binding fragments thereof, refers to such molecules created, expressed, isolated or obtained by technologies or methods known in the art as recombinant DNA technology which include, e.g., DNA splicing and transgenic expression. The term includes antibodies expressed in a non-human mammal (including transgenic non-human mammals, e.g., transgenic mice), or a host cell (e.g., Chinese hamster ovary (CHO) cell) or cellular expression system or isolated from a recombinant combinatorial human antibody library. The present invention includes recombinant antigen-binding proteins as set forth herein (e.g., H2M11683N; H2M11686N; H4H12159P; H4H12161P; H4H12163P; H4H12164P; H4H12166P; H4H12166P2; H4H12166P3; H4H12166P4; H4H12166P5; H4H12166P6; H4H12166P7; H4H12166P8; H4H12166P9; H4H12166P10; H4H12167P; H4HI2168P; H4HI2169P; H4H12170P; H4H12171P; H4H12175P; H4H12176P2; H4H12177P2; H4H12183P2; H2M11682N; H2M11684N; H2M11694N; or H2M11695N).
The present invention includes formulations comprising monoclonal anti-C5 antigen-binding proteins (e.g., antibodies and antigen-binding fragments thereof). The term “monoclonal antibody” or “mAb”, as used herein, refers to an antibody from a population of substantially homogeneous antibodies, i.e., the antibody molecules comprising the population are identical in amino acid sequence except for possible naturally occurring mutations that may be present in minor amounts. The modifier “monoclonal” is not to be construed as requiring production of the antibody by any particular method. Monoclonal antibodies may be made by the hybridoma method of Kohler et al. (1975) Nature 256: 495, or may be made by recombinant DNA methods (see, e.g., U.S. Pat. No. 4,816,567).
“Isolated” antigen-binding proteins (e.g., antibodies or antigen-binding fragments thereof), polypeptides, polynucleotides and vectors, are at least partially free of other biological molecules from the cells or cell culture from which they are produced. Such biological molecules include nucleic acids, proteins, other antibodies or antigen-binding fragments, lipids, carbohydrates, or other material such as cellular debris and growth medium. An isolated antigen-binding protein may further be at least partially free of expression system components such as biological molecules from a host cell or of the growth medium thereof. Generally, the term “isolated” is not intended to be limited to a complete absence of such biological molecules (e.g., minor or insignificant amounts of impurity may remain) or to an absence of water, buffers, or salts or to components of a pharmaceutical formulation that includes the antigen-binding proteins (e.g., antibodies or antigen-binding fragments).
An “anti-C5” antigen-binding protein specifically binds to C5. The term “specifically binds” refers to those antigen-binding proteins (e.g., mAbs) having a binding affinity to an antigen, such as human C5 protein at 25° C., expressed as KD, of at least about 10−9 M or less (a lower number) (e.g., about 10−10 M, about 10−11 M or about 10−12 M), as measured by real-time, label free bio-layer interferometry assay, for example, at 25° C. or 37° C., e.g., an Octet® HTX biosensor, or by surface plasmon resonance, e.g., BIACORE™, or by solution-affinity ELISA. In some embodiments of the invention, an anti-C5 antigen-binding protein also binds to a variant of C5, e.g., comprising a mutation such as R885H or R885C.
The present invention provides pharmaceutical formulations that comprise high concentrations (at least 150 mg/ml or at least 200 mg/ml) of anti-C5 antigen-binding proteins (e.g., H2M11683N; H2M11686N; H4H12159P; H4H12161P; H4H12163P; H4H12164P; H4H12166P; H4H12166P2; H4H12166P3; H4H12166P4; H4H12166P5; H4H12166P6; H4H12166P7; H4H12166P8; H4H12166P9; H4H12166P10; H4H12167P; H4HI2168P; H4HI2169P; H4H12170P; H4H12171P; H4H12175P; H4H12176P2; H4H12177P2; H4H12183P2; H2M11682N; H2M11684N; H2M11694N; H2M11695N; ravulizumab, eculizumab, crovalimab, tesidolumab or mubodina) having a low viscosity (e.g., less than about 15 cP, e.g., about 14 or 14.3) optionally in association with a C5 si-RNA such as cemdisiran. For example, the invention includes a pharmaceutical formulation comprising, consisting of or consisting essentially of: 200 mg/ml pozelimab; 20 mM histidine buffer; 100 mM L-arginine hydrochloride; 2% (w/v) sucrose; 0.15% (w/v) polysorbate-80; and water, pH 5.8.
A pharmaceutical formulation or pharmaceutical composition, as used herein, refers to a formulation/composition including an anti-C5 antigen-binding protein and a pharmaceutically acceptable carrier. A pharmaceutically acceptable carrier includes one or more excipients. In an embodiment of the invention, a pharmaceutical formulation of the present invention is aqueous, i.e., includes water.
Pharmaceutical formulations including anti-C5 antigen-binding proteins may be prepared by admixing the antigen-binding protein with one or more excipients (see, e.g., Hardman, et al. (2001) Goodman and Gilman's The Pharmacological Basis of Therapeutics, McGraw-Hill, New York, N.Y.; Gennaro (2000) Remington: The Science and Practice of Pharmacy, Lippincott, Williams, and Wilkins, New York, N.Y.; Avis, et al. (eds.) (1993) Pharmaceutical Dosage Forms: Parenteral Medications, Marcel Dekker, NY; Lieberman, et al. (eds.) (1990) Pharmaceutical Dosage Forms: Tablets, Marcel Dekker, NY; Lieberman, et al. (eds.) (1990) Pharmaceutical Dosage Forms: Disperse Systems, Marcel Dekker, NY; Weiner and Kotkoskie (2000) Excipient Toxicity and Safety, Marcel Dekker, Inc., New York, N.Y.).
In an embodiment of the invention, a pharmaceutical formulation of the present invention comprises:
In an embodiment of the invention, the pharmaceutical formulation of the present invention is aqueous (e.g., suitable for intravenous and/or subcutaneous administration) and comprises an anti-C5 antibody or antigen-binding fragment thereof (e.g., pozelimab) (e.g., about 200 mg/mL or about 180-210 mg/ml), histidine (e.g., histidine-HCl; e.g., about 20 mM or 20 mM±4 mM), pH about 5.8 or 5.8±0.3, arginine (e.g., about 100 mM or 100 mM±20 mM; e.g., L-arginine, L-arginine HCl or L-arginine monohydrochloride), a polyol such as sucrose (e.g., about 2% or 2%±0.4% (w/v)), and a non-ionic surfactant such as polysorbate (e.g., polysorbate 80; e.g., about 0.15% or 0.15%±0.075% (w/v))—e.g.,
200 mg/ml pozelimab;
20 mM histidine buffer;
100 mM L-arginine hydrochloride;
2% (w/v) sucrose;
0.15% (w/v) polysorbate-80;
and water,
pH 5.8.
“Arginine” or “L-arginine” includes any pharmaceutically acceptable salt form thereof, e.g., L-arginine hydrochloride.
Buffers control the pH of formulations and in some cases contribute to the overall stability of a protein product. In an embodiment of the invention, the buffer is a phosphate buffer, acetate buffer, citrate buffer, histidine buffer or imidazole buffer.
An amino acid can be any one of the 20 essential amino acids. In an embodiment of the invention, the amino acid is glycine, arginine, aspartic acid, glutamic acid, lysine, asparagine, glutamine, proline or histidine.
In an embodiment of the invention, the oligosaccharide is sucrose, mannitol, dextrose, glycerol, TMAO (trimethylamine N-oxide), trehalose, ethylene glycol, glycine betaine, xylitol or sorbitol.
Non-ionic detergents contain molecules with head groups that are uncharged. In an embodiment of the invention, the non-ionic detergent is polyoxyethylene-based or glycosidic compound-based. In an embodiment of the invention, the non-ionic detergent is polysorbate-20 (PS20), polysorbate-80 (PS80) or tween-20.
In an embodiment of the invention,
The present invention includes embodiments wherein any one or more selected from the foregoing characterize any of the anti-C5 antigen-binding proteins which are described herein.
In an embodiment of the invention, the formulation comprises:
The present invention includes a pharmaceutical formulation comprising about 200 mg/ml H2M11683N; about 20 mM histidine buffer; about 100 mM L-arginine; about 2% (w/v) sucrose; about 0.15% (w/v) polysorbate-80 (PS-80) and water, pH 5.8±0.2.
The present invention includes a pharmaceutical formulation comprising about 200 mg/ml H2M11686N; about 20 mM histidine buffer; about 100 mM L-arginine; about 2% (w/v) sucrose; about 0.15% (w/v) polysorbate-80 and water, pH 5.8±0.2.
The present invention includes a pharmaceutical formulation comprising about 200 mg/ml H4H12159P; about 20 mM histidine buffer; about 100 mM L-arginine; about 2% (w/v) sucrose; about 0.15% (w/v) polysorbate-80 and water, pH 5.8±0.2.
The present invention includes a pharmaceutical formulation comprising about 200 mg/ml H4H12161P; about 20 mM histidine buffer; about 100 mM L-arginine; about 2% (w/v) sucrose; about 0.15% (w/v) polysorbate-80 and water, pH 5.8±0.2.
The present invention includes a pharmaceutical formulation comprising about 200 mg/ml H4H12163P; about 20 mM histidine buffer; about 100 mM L-arginine; about 2% (w/v) sucrose; about 0.15% (w/v) polysorbate-80 and water, pH 5.8±0.2.
The present invention includes a pharmaceutical formulation comprising about 200 mg/ml H4H12164P; about 20 mM histidine buffer; about 100 mM L-arginine; about 2% (w/v) sucrose; about 0.15% (w/v) polysorbate-80 and water, pH 5.8±0.2.
The present invention includes a pharmaceutical formulation comprising about 200 mg/ml H4H12166P; about 20 mM histidine buffer; about 100 mM L-arginine; about 2% (w/v) sucrose; about 0.15% (w/v) polysorbate-80 and water, pH 5.8±0.2.
The present invention includes a pharmaceutical formulation comprising about 200 mg/ml H4H12166P2; about 20 mM histidine buffer; about 100 mM L-arginine; about 2% (w/v) sucrose; about 0.15% (w/v) polysorbate-80 and water, pH 5.8±0.2.
The present invention includes a pharmaceutical formulation comprising about 200 mg/ml H4H12166P3; about 20 mM histidine buffer; about 100 mM L-arginine; about 2% (w/v) sucrose; about 0.15% (w/v) polysorbate-80 and water, pH 5.8±0.2.
The present invention includes a pharmaceutical formulation comprising about 200 mg/ml H4H12166P4; about 20 mM histidine buffer; about 100 mM L-arginine; about 2% (w/v) sucrose; about 0.15% (w/v) polysorbate-80 and water, pH 5.8±0.2.
The present invention includes a pharmaceutical formulation comprising about 200 mg/ml H4H12166P5; about 20 mM histidine buffer; about 100 mM L-arginine; about 2% (w/v) sucrose; about 0.15% (w/v) polysorbate-80 and water, pH 5.8±0.2.
The present invention includes a pharmaceutical formulation comprising about 200 mg/ml H4H12166P6; about 20 mM histidine buffer; about 100 mM L-arginine; about 2% (w/v) sucrose; about 0.15% (w/v) polysorbate-80 and water, pH 5.8±0.2.
The present invention includes a pharmaceutical formulation comprising about 200 mg/ml H4H12166P7; about 20 mM histidine buffer; about 100 mM L-arginine; about 2% (w/v) sucrose; about 0.15% (w/v) polysorbate-80 and water, pH 5.8±0.2.
The present invention includes a pharmaceutical formulation comprising about 200 mg/ml H4H12166P8; about 20 mM histidine buffer; about 100 mM L-arginine; about 2% (w/v) sucrose; about 0.15% (w/v) polysorbate-80 and water, pH 5.8±0.2.
The present invention includes a pharmaceutical formulation comprising about 200 mg/ml H4H12166P9; about 20 mM histidine buffer; about 100 mM L-arginine; about 2% (w/v) sucrose; about 0.15% (w/v) polysorbate-80 and water, pH 5.8±0.2.
The present invention includes a pharmaceutical formulation comprising about 200 mg/ml H4H12167P; about 20 mM histidine buffer; about 100 mM L-arginine; about 2% (w/v) sucrose; about 0.15% (w/v) polysorbate-80 and water, pH 5.8±0.2.
The present invention includes a pharmaceutical formulation comprising about 200 mg/ml H4H12168P; about 20 mM histidine buffer; about 100 mM L-arginine; about 2% (w/v) sucrose; about 0.15% (w/v) polysorbate-80 and water, pH 5.8±0.2.
The present invention includes a pharmaceutical formulation comprising about 200 mg/ml H4H12169P; about 20 mM histidine buffer; about 100 mM L-arginine; about 2% (w/v) sucrose; about 0.15% (w/v) polysorbate-80 and water, pH 5.8±0.2.
The present invention includes a pharmaceutical formulation comprising about 200 mg/ml H4H12170P; about 20 mM histidine buffer; about 100 mM L-arginine; about 2% (w/v) sucrose; about 0.15% (w/v) polysorbate-80 and water, pH 5.8±0.2.
The present invention includes a pharmaceutical formulation comprising about 200 mg/ml H4H12171P; about 20 mM histidine buffer; about 100 mM L-arginine; about 2% (w/v) sucrose; about 0.15% (w/v) polysorbate-80 and water, pH 5.8±0.2.
The present invention includes a pharmaceutical formulation comprising about 200 mg/ml H4H12175P; about 20 mM histidine buffer; about 100 mM L-arginine; about 2% (w/v) sucrose; about 0.15% (w/v) polysorbate-80 and water, pH 5.8±0.2.
The present invention includes a pharmaceutical formulation comprising about 200 mg/ml H4H12176P2; about 20 mM histidine buffer; about 100 mM L-arginine; about 2% (w/v) sucrose; about 0.15% (w/v) polysorbate-80 and water, pH 5.8±0.2.
The present invention includes a pharmaceutical formulation comprising about 200 mg/ml H4H12177P2; about 20 mM histidine buffer; about 100 mM L-arginine; about 2% (w/v) (w/v) sucrose; about 0.15% (w/v) (w/v) polysorbate-80 and water, pH 5.8±0.2.
The present invention includes a pharmaceutical formulation comprising about 200 mg/ml H4H12183P2; about 20 mM histidine buffer; about 100 mM L-arginine; about 2% (w/v) sucrose; about 0.15% (w/v) polysorbate-80 and water, pH 5.8±0.2.
The present invention includes a pharmaceutical formulation comprising about 200 mg/ml H2M11682N; about 20 mM histidine buffer; about 100 mM L-arginine; about 2% (w/v) sucrose; about 0.15% (w/v) polysorbate-80 and water, pH 5.8±0.2.
The present invention includes a pharmaceutical formulation comprising about 200 mg/ml H2M11684N; about 20 mM histidine buffer; about 100 mM L-arginine; about 2% (w/v) sucrose; about 0.15% (w/v) polysorbate-80 and water, pH 5.8±0.2.
The present invention includes a pharmaceutical formulation comprising about 200 mg/ml H2M11694N; about 20 mM histidine buffer; about 100 mM L-arginine; about 2% (w/v) sucrose; about 0.15% (w/v) polysorbate-80 and water, pH 5.8±0.2.
The present invention includes a pharmaceutical formulation comprising about 200 mg/ml H2M11695N; about 20 mM histidine buffer; about 100 mM L-arginine; about 2% (w/v) sucrose; about 0.15% (w/v) polysorbate-80 and water, pH 5.8±0.2.
The present invention includes a pharmaceutical formulation comprising about 200 mg/ml ravulizumab; about 20 mM histidine buffer; about 100 mM L-arginine; about 2% (w/v) sucrose; about 0.15% (w/v) polysorbate-80 and water, pH 5.8±0.2.
The present invention includes a pharmaceutical formulation comprising about 200 mg/ml crovalimab; about 20 mM histidine buffer; about 100 mM L-arginine; about 2% (w/v) sucrose; about 0.15% (w/v) polysorbate-80 and water, pH 5.8±0.2.
The present invention includes a pharmaceutical formulation comprising about 200 mg/ml eculizumab; about 20 mM histidine buffer; about 100 mM L-arginine; about 2% (w/v) sucrose; about 0.15% (w/v) polysorbate-80 and water, pH 5.8±0.2.
The present invention includes a pharmaceutical formulation comprising about 200 mg/ml tesidolumab; about 20 mM histidine buffer; about 100 mM L-arginine; about 2% (w/v) sucrose; about 0.15% (w/v) polysorbate-80 and water, pH 5.8±0.2.
The present invention includes a pharmaceutical formulation comprising about 200 mg/ml mubodina; about 20 mM histidine buffer; about 100 mM L-arginine; about 2% (w/v) sucrose; about 0.15% (w/v) polysorbate-80 and water, pH 5.8±0.2.
The present invention includes a pharmaceutical formulation comprising about 200 mg/ml H4H12166P, about 5 mM histidine, about 2.5% (w/v) proline, about 5% (w/v) sucrose, about 150 mM L-arginine-HCl, about 0.2% (w/v) PS-80, and water, pH about 5.7.
The present invention includes a pharmaceutical formulation comprising about 135 mg/ml H4H12166P, about 20 mM histidine, about 5% (w/v) proline, about 10% (w/v) sucrose, about 150 mM L-arginine-HCl, about 0.02% (w/v) PS-80, and water, pH about 5.7.
The present invention includes a pharmaceutical formulation comprising about 160 mg/ml H4H12166P, about 5 mM histidine, about 5% (w/v) sucrose, about 75 mM L-arginine-HCl, about 0.02% (w/v) PS-80, and water, pH about 6.2.
The present invention includes a pharmaceutical formulation comprising about 120 mg/ml H4H12166P, about 40 mM histidine, about 5% (w/v) proline, about 0.02% (w/v) PS-80, and water, pH about 6.8.
The present invention includes a pharmaceutical formulation comprising about 120 mg/ml H4H12166P, about 40 mM histidine, about 0.02% (w/v) PS-80, and water, pH about 5.7.
The present invention includes a pharmaceutical formulation comprising about 160 mg/ml H4H12166P, about 5 mM histidine, about 2.5% (w/v) proline, about 10% (w/v) sucrose, about 0.2% (w/v) PS-80, and water, pH about 6.8.
The present invention includes a pharmaceutical formulation comprising about 120 mg/ml H4H12166P, about 40 mM histidine, about 5% (w/v) proline, about 150 mM L-arginine-HCl, about 0.02% (w/v) PS-80, and water, pH about 5.7.
The present invention includes a pharmaceutical formulation comprising about 200 mg/ml H4H12166P, about 5 mM histidine, about 0.2% (w/v) PS-80, and water, pH about 5.7.
The present invention includes a pharmaceutical formulation comprising about 200 mg/ml H4H12166P, about 20 mM histidine, about 5% (w/v) proline, about 10% (w/v) sucrose, about 0.2% (w/v) PS-80, and water, pH about 6.2.
The present invention includes a pharmaceutical formulation comprising about 120 mg/ml H4H12166P, about 40 mM histidine, about 150 mM L-arginine-HCl, about 0.02% (w/v) PS-80, and water, pH about 6.8.
The present invention includes a pharmaceutical formulation comprising about 200 mg/ml H4H12166P, about 5 mM histidine, about 5% (w/v) proline, about 150 mM L-arginine-HCl, about 0.2% (w/v) PS-80, and water, pH about 6.2.
The present invention includes a pharmaceutical formulation comprising about 120 mg/ml H4H12166P, about 20 mM histidine, about 5% (w/v) proline, about 5% (w/v) sucrose, about 150 mM L-arginine-HCl, about 0.2% (w/v) PS-80, and water, pH about 6.8.
The present invention includes a pharmaceutical formulation comprising about 120 mg/ml H4H12166P, about 5 mM histidine, about 10% (w/v) sucrose, about 0.2% (w/v) PS-80, and water, pH about 5.7.
The present invention includes a pharmaceutical formulation comprising about 120 mg/ml H4H12166P, about 5 mM histidine, about 0.2% (w/v) PS-80, and water, pH about 6.8.
The present invention includes a pharmaceutical formulation comprising about 120 mg/ml H4H12166P, about 5 mM histidine, about 150 mM L-arginine-HCl, about 0.2% (w/v) PS-80, and water, pH about 5.7.
The present invention includes a pharmaceutical formulation comprising about 175 mg/ml H4H12166P, about 40 mM histidine, about 5% (w/v) proline, about 0.2% (w/v) PS-80, and water, pH about 5.7.
The present invention includes a pharmaceutical formulation comprising about 200 mg/ml H4H12166P, about 5 mM histidine, about 10% (w/v) sucrose, about 150 mM L-arginine-HCl, about 0.2% (w/v) PS-80, and water, pH about 6.8.
The present invention includes a pharmaceutical formulation comprising about 185 mg/ml H4H12166P, about 40 mM histidine, about 10% (w/v) sucrose, about 0.02% (w/v) PS-80, and water, pH about 5.7.
The present invention includes a pharmaceutical formulation comprising about 120 mg/ml H4H12166P, about 40 mM histidine, about 10% (w/v) sucrose, about 150 mM L-arginine-HCl, about 0.2% (w/v) PS-80, and water, pH about 5.7.
The present invention includes a pharmaceutical formulation comprising about 120 mg/ml H4H12166P, about 40 mM histidine, about 10% (w/v) sucrose, about 0.02% (w/v) PS-80, and water, pH about 6.8.
The present invention includes a pharmaceutical formulation comprising about 120 mg/ml H4H12166P, about 5 mM histidine, about 5% (w/v) proline, about 0.02% (w/v) PS-80, and water, pH about 5.7.
The present invention includes a pharmaceutical formulation comprising about 170 mg/ml H4H12166P, about 40 mM histidine, about 5% (w/v) proline, about 10% (w/v) sucrose, about 150 mM L-arginine-HCl, about 0.02% (w/v) PS-80, and water, pH about 6.8.
The present invention includes a pharmaceutical formulation comprising about 120 mg/ml H4H12166P, about 40 mM histidine, about 5% (w/v) proline, about 10% (w/v) sucrose, about 0.02% (w/v) PS-80, and water, pH about 5.7.
The present invention includes a pharmaceutical formulation comprising about 120 mg/ml H4H12166P, about 5 mM histidine, about 2.5% (w/v) proline, about 10% (w/v) sucrose, about 150 mM L-arginine-HCl, about 0.02% (w/v) PS-80, and water, pH about 6.2.
The present invention includes a pharmaceutical formulation comprising about 200 mg/ml H4H12166P, about 5 mM histidine, about 5% (w/v) proline, about 10% (w/v) sucrose, about 75 mM L-arginine-HCl, about 0.2% (w/v) PS-80, and water, pH about 5.7.
The present invention includes a pharmaceutical formulation comprising about 120 mg/ml H4H12166P, about 5 mM histidine, about 5% (w/v) proline, about 10% (w/v) sucrose, about 75 mM L-arginine-HCl, about 0.2% (w/v) PS-80, and water, pH about 6.8.
The present invention includes a pharmaceutical formulation comprising about 160 mg/ml H4H12166P, about 5 mM histidine, about 5% (w/v) proline, about 150 mM L-arginine-HCl, about 0.2% (w/v) PS-80, and water, pH about 6.8.
The present invention includes a pharmaceutical formulation comprising about 200 mg/ml H4H12166P, about 20 mM histidine, about 2.5% (w/v) proline, about 75 mM L-arginine-HCl, about 0.02% (w/v) PS-80, and water, pH about 6.8.
The present invention includes a pharmaceutical formulation comprising about 170 mg/ml H4H12166P, about 35 mM histidine, about 150 mM L-arginine-HCl, about 0.02% (w/v) PS-80, and water, pH about 5.7.
The present invention includes a pharmaceutical formulation comprising about 183 mg/ml H4H12166P, about 40 mM histidine, about 0.2% (w/v) PS-80, and water, pH about 6.8.
The present invention includes a pharmaceutical formulation comprising about 200 mg/ml H4H12166P, about 5 mM histidine, about 5% (w/v) proline, about 5% (w/v) sucrose, about 0.02% (w/v) PS-80, and water, pH about 6.8.
The present invention includes a pharmaceutical formulation comprising about 160 mg/ml H4H12166P, about 40 mM histidine, about 2.5% (w/v) proline, about 5% (w/v) sucrose, about 75 mM L-arginine-HCl, about 0.2% (w/v) PS-80, and water, pH about 6.2.
The present invention includes a pharmaceutical formulation comprising about 187 mg/ml H4H12166P, about 40 mM histidine, about 0.02% (w/v) PS-80, and water, pH about 5.7.
See, for example,
The present invention provides a vessel (e.g., a plastic or glass vial, e.g., with a cap, or a chromatography column, hollow bore needle or a syringe cylinder) comprising a pharmaceutical formulation of the present invention that includes an anti-C5 antigen-binding protein, e.g., H2M11683N; H2M11686N; H4H12159P; H4H12161P; H4H12163P; H4H12164P; H4H12166P; H4H12166P2; H4H12166P3; H4H12166P4; H4H12166P5; H4H12166P6; H4H12166P7; H4H12166P8; H4H12166P9; H4H12166P10; H4H12167P; H4HI2168P; H4HI2169P; H4H12170P; H4H12171P; H4H12175P; H4H12176P2; H4H12177P2; H4H12183P2; H2M11682N; H2M11684N; H2M11694N; H2M11695N; ravulizumab, eculizumab, crovalimab, tesidolumab or mubodina.
The present invention also provides an injection device comprising a pharmaceutical formulation of the present invention including an anti-C5 antigen-binding protein, e.g., H2M11683N; H2M11686N; H4H12159P; H4H12161P; H4H12163P; H4H12164P; H4H12166P; H4H12166P2; H4H12166P3; H4H12166P4; H4H12166P5; H4H12166P6; H4H12166P7; H4H12166P8; H4H12166P9; H4H12166P10; H4H12167P; H4HI2168P; H4HI2169P; H4H12170P; H4H12171P; H4H12175P; H4H12176P2; H4H12177P2; H4H12183P2; H2M11682N; H2M11684N; H2M11694N; H2M11695N; ravulizumab, eculizumab, crovalimab tesidolumab or mubodina. The injection device may be packaged into a kit. An injection device is a device that introduces a substance into the body of a subject via a parenteral route, e.g., intraocular, intravitreal, intramuscular, subcutaneous or intravenous. For example, an injection device may be a syringe or an auto-injector (e.g., pre-filled with the pharmaceutical formulation) which, for example, includes a cylinder or barrel for holding fluid to be injected (e.g., comprising the antibody or fragment or a pharmaceutical formulation thereof), a needle for piecing skin, blood vessels or other tissue for injection of the fluid; and a plunger for pushing the fluid out of the cylinder and through the needle bore and into the body of the subject.
The present invention also includes a kit comprising a vessel (e.g., a vial) or injection device comprising (a) a pharmaceutical formulation of the present invention including an anti-C5 antigen-binding protein, e.g., H2M11683N; H2M11686N; H4H12159P; H4H12161P; H4H12163P; H4H12164P; H4H12166P; H4H12166P2; H4H12166P3; H4H12166P4; H4H12166P5; H4H12166P6; H4H12166P7; H4H12166P8; H4H12166P9; H4H12166P10; H4H12167P; H4HI2168P; H4HI2169P; H4H12170P; H4H12171P; H4H12175P; H4H12176P2; H4H12177P2; H4H12183P2; H2M11682N; H2M11684N; H2M11694N; H2M11695N; ravulizumab, eculizumab, crovalimab, tesidolumab or mubodina; and (b) a vessel (e.g., a vial) or injection device comprising an oligonucleotide, for example, cemdisiran, or a pharmaceutical formulation thereof that comprises a pharmaceutically acceptable carrier and, optionally, one or more additional materials such as, for example, written materials (e.g., instructions for use).
To prepare pharmaceutical formulations of the present invention, an anti-C5 antigen-binding protein, e.g., antibody or antigen-binding fragment thereof (e.g., H2M11683N; H2M11686N; H4H12159P; H4H12161P; H4H12163P; H4H12164P; H4H12166P; H4H12166P2; H4H12166P3; H4H12166P4; H4H12166P5; H4H12166P6; H4H12166P7; H4H12166P8; H4H12166P9; H4H12166P10; H4H12167P; H4HI2168P; H4HI2169P; H4H12170P; H4H12171P; H4H12175P; H4H12176P2; H4H12177P2; H4H12183P2; H2M11682N; H2M11684N; H2M11694N; H2M11695N; ravulizumab, eculizumab, crovalimab, tesidolumab or mubodina), is mixed with the required excipients (e.g., histidine, arginine, sucrose, PS-80 and water) and, optionally, a further therapeutic agent. Optionally, the pharmaceutical composition is then lyophilized. Such methods and pharmaceutical formulations, which are the product of such methods, are also part of the present invention.
In an embodiment of the invention, a pharmaceutical formulation of the present invention includes no more than one anti-C5 antigen-binding protein. In an embodiment of the invention, a pharmaceutical formulation of the present invention includes more than one anti-C5 antigen-binding protein, e.g., 2 or 3. In an embodiment of the invention, when two or more anti-C5 antigen-binding proteins are in a pharmaceutical formulation of the present invention, two or more of the antigen-binding proteins do not compete for binding to C5 (e.g., H4H12176P2+H4H12177P2; H4H12166P8+H4H12170P; H4H12166P+H4H12170P; H4H12166P+H4H12161P; H4H12166P+H4H12171P; H4H12166P+H4H12175P; H4H12166P+H4H12176P2 or H4H12166P+H4H12177P2). In an embodiment of the invention, when two or more anti-C5 antigen-binding proteins are present, they do compete for binding to C5.
The present invention provides pharmaceutical formulations that include an anti-C5 antigen-binding protein (e.g., H2M11683N; H2M11686N; H4H12159P; H4H12161P; H4H12163P; H4H12164P; H4H12166P; H4H12166P2; H4H12166P3; H4H12166P4; H4H12166P5; H4H12166P6; H4H12166P7; H4H12166P8; H4H12166P9; H4H12166P10; H4H12167P; H4HI2168P; H4HI2169P; H4H12170P; H4H12171P; H4H12175P; H4H12176P2; H4H12177P2; H4H12183P2; H2M11682N; H2M11684N; H2M11694N; H2M11695N; ravulizumab, eculizumab, crovalimab, tesidolumab or mubodina) in association with one or more further therapeutic agents; as well as methods of use thereof and methods of making such compositions.
In an embodiment of the invention, the further therapeutic agent is an oligonucleotide (e.g., DNA or RNA or a duplex of both), e.g., that binds to DNA or mRNA encoding C5. In an embodiment of the invention, the oligonucleotide is up to about 23, about 19-22, about 19-23 or about 19, about 20, about 21, about 22 or about 23 nucleotides in length (e.g., a 19-23 nucleotide RNA molecule). In an embodiment of the invention, the oligonucleotide is single stranded (e.g., in anti-sense orientation) or double stranded. A double stranded oligonucleotide includes a strand in sense orientation and a strand in an anti-sense orientation. In an embodiment of the invention, the double stranded oligonucleotide (e.g., RNA) has a 3′ overhang and/or a 5′ overhang, for example, of at least two nucleotides. In an embodiment of the invention, the oligonucleotide is naked and in another embodiment the oligonucleotide is chemically modified.
In an embodiment of the invention, the further therapeutic agent is an RNAi agent that binds to an RNA encoding C5 or a portion thereof. An RNAi agent refers to an agent that contains RNA and which mediates the targeted cleavage of an RNA transcript via an RNA-induced silencing complex (RISC) pathway. RNAi directs the sequence-specific degradation of mRNA through a process known as RNA interference. The RNAi modulates, e.g., inhibits, the expression of C5 in a cell, e.g., a cell within a subject, such as a mammalian subject.
In one embodiment of the invention, an RNAi agent of the invention includes a single stranded RNA that interacts with a target RNA sequence, e.g., a C5 target mRNA sequence, to direct the cleavage of the target RNA. Without wishing to be bound by theory it is believed that long double stranded RNA introduced into cells is broken down into siRNA by a Type III endonuclease known as Dicer (Sharp et al. (2001) Genes Dev. 15:485). Dicer, a ribonuclease-III-like enzyme, processes the dsRNA into 19-23 base pair short interfering RNAs with characteristic two base 3′ overhangs (Bernstein, et al., (2001) Nature 409:363). The siRNAs are then incorporated into an RNA-induced silencing complex (RISC) where one or more helicases unwind the siRNA duplex, enabling the complementary antisense strand to guide target recognition (Nykanen, et al., (2001) Cell 107:309). Upon binding to the appropriate target mRNA, one or more endonucleases within the RISC cleave the target to induce silencing (Elbashir, et al., (2001) Genes Dev. 15:188). Thus, in one aspect the invention relates to a single stranded RNA (siRNA) generated within a cell and which promotes the formation of a RISC complex to effect silencing of the target gene, i.e., a C5 gene. Accordingly, the term “siRNA” is also used herein to refer to an RNAi as described herein.
In another embodiment, the RNAi agent may be a single-stranded siRNA that is introduced into a cell or organism to inhibit a target mRNA. In an embodiment of the invention, single-stranded RNAi agents bind to the RISC endonuclease, Argonaute 2, which then cleaves the target mRNA. The single-stranded siRNAs are, in an embodiment of the invention, 15-30 nucleotides and are chemically modified. The design and testing of single-stranded siRNAs are described in U.S. Pat. No. 8,101,348 and in Lima et al., (2012) Cell 150: 883-894, the entire contents of each of which are hereby incorporated herein by reference. Any of the antisense nucleotide sequences described herein may be used as a single-stranded siRNA as described herein or as chemically modified by the methods described in Lima et al., (2012) Cell 150:883-894.
In another embodiment of the invention, an RNAi agent is a double-stranded RNA (dsRNA). A dsRNA, refers to a complex of ribonucleic acid molecules, having a duplex structure comprising two anti-parallel and substantially complementary nucleic acid strands, referred to as having “sense” and “antisense” orientations with respect to a target RNA, i.e., a C5 gene. In some embodiments of the invention, a double-stranded RNA (dsRNA) triggers the degradation of a target RNA, e.g., an mRNA, through a post-transcriptional gene-silencing mechanism referred to as RNA interference.
In an embodiment of the invention, the oligonucleotide (e.g., RNAi) is conjugated to another molecule such as a sugar, such as an N-acetylgalactosamine (GalNAc) derivative such as
In an embodiment of the invention, the oligonucleotide (e.g., RNAi) is conjugated to another molecule as shown in the following schematic:
wherein X is O or S.
In an embodiment of the invention, the further therapeutic agent is cemdisiran. In an embodiment of the invention, the further therapeutic agent is a double stranded RNA comprising the anti-sense strand nucleotide sequence:
and/or the sense strand comprises the nucleotide sequence:
In an embodiment of the invention, the further therapeutic agent is a double-stranded ribonucleic acid (dsRNA) agent for inhibiting expression of complement component C5, wherein said dsRNA agent comprises a sense strand and an antisense strand, wherein the sense strand comprises:
and the antisense strand comprises:
wherein a, g, c and u are 2′-O-methyl (2′-OMe) A, G, C, and U, respectively; Af, Gf, Cf and Uf are 2′-fluoro A, G, C and U, respectively; dT is a deoxy-thymine nucleotide; and s is a phosphorothioate linkage; and wherein said sense strand is conjugated at the 3′-terminus to the ligand:
See U.S. Pat. No. 9,249,415.
In an embodiment of the invention, the RNAi is in a pharmaceutical formulation comprising a lipid nanoparticle (LNP). An LNP is a vesicle comprising a lipid layer encapsulating a pharmaceutically active molecule such as RNAi. LNPs are described in, for example, U.S. Pat. Nos. 6,858,225, 6,815,432, 8,158,601, and 8,058,069, the entire contents of which are hereby incorporated by reference.
In an embodiment of the invention, the further therapeutic agent is an anti-coagulant, warfarin, aspirin, heparin, phenindione, fondaparinux, idraparinux, a thrombin inhibitor, argatroban, lepirudin, bivalirudin, dabigatran, an anti-inflammatory drug, a corticosteroid, a non-steroidal anti-inflammatory drug (NSAID), an antihypertensive, an angiotensin-converting enzyme inhibitor, an immunosuppressive agent, vincristine, cyclosporine A, or methotrexate, a fibrinolytic agent ancrod, E-aminocaproic acid, antiplasmin-a1, prostacyclin, defibrotide, a lipid-lowering agent, an inhibitor of hydroxymethylglutaryl CoA reductase, an anti-CD20 agent, rituximab, an anti-TNFalpha agent, infliximab, an anti-seizure agent, magnesium sulfate, a C3 inhibitor and/or an anti-thrombotic agent.
The term “in association with” indicates that components of a pharmaceutical formulation, (1) an anti-C5 antigen-binding protein and pharmaceutically acceptable carrier components, along with (2) one or more further therapeutic agents, such as cemdisiran, can be formulated into a single composition, e.g., for simultaneous delivery, or formulated separately into two or more compositions (e.g., a kit including each component, for example, wherein the further therapeutic agent is in a separate formulation). Components administered in association with each another can be administered to a subject at the same time or at a different time than when the other component is administered; for example, each administration may be given simultaneously (e.g., together in a single composition or essentially simultaneously during the same administration session) or non-simultaneously at one or more intervals over a given period of time. Moreover, the separate components administered in association with each another may be administered to a subject by the same or by a different route.
The pharmaceutical formulations of the present invention are useful for the treatment or prevention of a C5-associated disease and/or for ameliorating at least one sign or symptom associated with such C5-associated disease.
The term “C5-associated disease” refers to a disease, disorder, condition or syndrome which is caused, maintained or exacerbated, or whose signs and/or symptoms are caused, maintained or exacerbated, directly or indirectly, by complement system activity wherein the complement system activity can be reduced or stabilized or eliminated by inhibition of C5 activity. Such C5 activity can be inhibited by preventing, for example, cleavage of C5 precursor into C5a and C5b chains and/or formation of membrane attack complex (MAC).
Treatment of a C5-associated disease refers to the reduction, stabilization or elimination of the disease and/or one or more of its signs and/or symptoms thereof.
Subjective evidence of a disease, disorder, condition or syndrome is a symptom. A sign is objective evidence of the disease, disorder, condition or syndrome. For example, blood coming out a nostril is a sign insofar as it is apparent to the patient, physician, and others. Anxiety, low back pain, and fatigue are symptoms insofar as only the patient can perceive them.
The term “subject” includes a mammal such as a human, mouse, goat, rabbit, rat, dog, non-human primate or monkey. In an embodiment of the invention, amino acid Arginine 885 is mutated in the subject's C5 to another amino acid, e.g., R885H or R885C.
The pharmaceutical formulations of the present invention are useful for treating or preventing a C5-associated disease which is one or more of:
Thus, the present invention includes methods for treating or preventing a C5-associated disease (e.g., PNH, aHUS or CHAPLE), in a subject in need thereof e.g., in a subject suffering from the C5-associated disease, comprising administering a therapeutically effective amount of pharmaceutical formulation of the present invention that includes an anti-C5 antigen-binding protein (e.g., H2M11683N; H2M11686N; H4H12159P; H4H12161P; H4H12163P; H4H12164P; H4H12166P; H4H12166P2; H4H12166P3; H4H12166P4; H4H12166P5; H4H12166P6; H4H12166P7; H4H12166P8; H4H12166P9; H4H12166P10; H4H12167P; H4HI2168P; H4HI2169P; H4H12170P; H4H12171P; H4H12175P; H4H12176P2; H4H12177P2; H4H12183P2; H2M11682N; H2M11684N; H2M11694N; H2M11695N; ravulizumab, crovalimab or eculizumab) to the subject, optionally in association with a further therapeutic agent (e.g., cemdisiran). In an embodiment of the invention, the subject had previously received a different anti-C5 antigen-binding protein, e.g., ravulizumab, crovalimab or eculizumab.
Paroxysmal nocturnal hemoglobinuria (PNH) is a rare acquired, life-threatening disease of the blood. The disease is characterized by destruction of red blood cells (hemolytic anemia), blood clots (thrombosis), and impaired bone marrow function (not making enough of the three blood components). Signs and symptoms of PNH can include significant fatigue or weakness, bruising or bleeding easily, shortness of breath, recurring infections and/or flu-like symptoms, difficulty in controlling bleeding, even from very minor wounds, the appearance of small red dots on the skin that indicates bleeding under the skin, severe headache, fever due to infection and blood clots (thrombosis). Thus, the present invention provides a method for treating or preventing PNH in a subject in need thereof comprising administering a therapeutically effective amount of anti-C5 antigen-binding protein (e.g., H2M11683N; H2M11686N; H4H12159P; H4H12161P; H4H12163P; H4H12164P; H4H12166P; H4H12166P2; H4H12166P3; H4H12166P4; H4H12166P5; H4H12166P6; H4H12166P7; H4H12166P8; H4H12166P9; H4H12166P10; H4H12167P; H4H12168P; H4HI2169P; H4H12170P; H4H12171P; H4H12175P; H4H12176P2; H4H12177P2; H4H12183P2; H2M11682N; H2M11684N; H2M11694N; H2M11695N; ravulizumab, crovalimab or eculizumab) in a pharmaceutical formulation of the present invention to the subject. The present invention includes a method for reducing, stabilizing and/or eliminating one or more signs and/or symptoms of PNH (e.g., hemolytic anemia) in a subject suffering from PNH and said signs and/or symptoms comprising administering a therapeutically effective amount of pharmaceutical formulation of the present invention comprising an anti-C5 antigen-binding protein to the subject.
Atypical hemolytic uremic syndrome (aHUS) is a rare disease characterized by low levels of circulating red blood cells due to their destruction (hemolytic anemia), low platelet count (thrombocytopenia) due to their consumption and inability of the kidneys to process waste products from the blood and excrete them into the urine (acute kidney failure), a condition known as uremia. Signs and symptoms of aHUS can include, for example, feelings of illness, fatigue, irritability, and lethargy, anemia, thrombocytopenia, acute kidney failure, hypertension and organ damage. Thus, the present invention provides a method for treating or preventing aHUS in a subject in need thereof comprising administering a therapeutically effective amount of anti-C5 antigen-binding protein (e.g., H2M11683N; H2M11686N; H4H12159P; H4H12161P; H4H12163P; H4H12164P; H4H12166P; H4H12166P2; H4H12166P3; H4H12166P4; H4H12166P5; H4H12166P6; H4H12166P7; H4H12166P8; H4H12166P9; H4H12166P10; H4H12167P; H4H12168P; H4HI2169P; H4H12170P; H4H12171P; H4H12175P; H4H12176P2; H4H12177P2; H4H12183P2; H2M11682N; H2M11684N; H2M11694N; H2M11695N; ravulizumab, crovalimab or eculizumab) in a pharmaceutical formulation of the present invention to the subject. The present invention includes a method for reducing, stabilizing and/or eliminating one or more signs and/or symptoms of aHUS (e.g., hemolytic anemia) in a subject suffering from aHUS and said signs and/or symptoms comprising administering a therapeutically effective amount of pharmaceutical formulation of the present invention comprising an anti-C5 antigen-binding protein to the subject.
CHAPLE disease is an autosomal recessive disorder caused by loss of function mutations in CD55 (also known as decay accelerating factor, DAF). Signs and symptoms of CHAPLE can include hypoproteinemia (low serum levels of albumin and immunoglobulins)-hypoproteinemia leads to facial and extremity edema and recurrent infections, malabsorption syndrome (chronic diarrhea, failure to thrive, anemia, and micronutrient deficiencies), complement overactivation, intestinal lymphangiectasia (IL) and bowel inflammation; and/or increased susceptibility to visceral thrombosis. Thus, the present invention provides a method for treating or preventing CHAPLE disease in a subject in need thereof comprising administering a therapeutically effective amount of anti-C5 antigen-binding protein (e.g., H2M11683N; H2M11686N; H4H12159P; H4H12161P; H4H12163P; H4H12164P; H4H12166P; H4H12166P2; H4H12166P3; H4H12166P4; H4H12166P5; H4H12166P6; H4H12166P7; H4H12166P8; H4H12166P9; H4H12166P10; H4H12167P; H4H12168P; H4HI2169P; H4H12170P; H4H12171P; H4H12175P; H4H12176P2; H4H12177P2; H4H12183P2; H2M11682N; H2M11684N; H2M11694N; H2M11695N; ravulizumab, crovalimab or eculizumab) in a pharmaceutical formulation of the present invention to the subject. The present invention includes a method for reducing, stabilizing and/or eliminating one or more signs and/or symptoms of CHAPLE (e.g., hypoproteinemia) in a subject suffering from CHAPLE and said signs and/or symptoms comprising administering a therapeutically effective amount of pharmaceutical formulation of the present invention comprising an anti-C5 antigen-binding protein to the subject.
Antiphospholipid syndrome (APS) is an autoimmune disease characterized by arterial and venous thrombosis due to antiphospholipid antibodies. The disorder is referred to as primary when it occurs in the absence of another autoimmune disease. Secondary APS occurs in the context of an autoimmune disorder such as systemic lupus erythematosus. The catastrophic APS (CAPS) is a rare life-threatening form of APS in which widespread intravascular thrombosis results in multiorgan ischemia and failure. Thus, the present invention provides a method for treating or preventing APS (e.g., primary or secondary or CAPS) in a subject in need thereof comprising administering a therapeutically effective amount of anti-C5 antigen-binding protein (e.g., H2M11683N; H2M11686N; H4H12159P; H4H12161P; H4H12163P; H4H12164P; H4H12166P; H4H12166P2; H4H12166P3; H4H12166P4; H4H12166P5; H4H12166P6; H4H12166P7; H4H12166P8; H4H12166P9; H4H12166P10; H4H12167P; H4H12168P; H4HI2169P; H4H12170P; H4H12171P; H4H12175P; H4H12176P2; H4H12177P2; H4H12183P2; H2M11682N; H2M11684N; H2M11694N; H2M11695N; ravulizumab, crovalimab or eculizumab) in a pharmaceutical formulation of the present invention to the subject. The present invention includes a method for reducing, stabilizing and/or eliminating one or more signs and/or symptoms of APS (e.g., primary, secondary or CAPS) in a subject suffering from APS and said signs and/or symptoms comprising administering a therapeutically effective amount of pharmaceutical formulation of the present invention comprising an anti-C5 antigen-binding protein to the subject.
Myasthenia gravis (MG) is a chronic autoimmune neuromuscular disease that causes weakness in the skeletal muscles, which are responsible for breathing and moving parts of the body, including the arms and legs. Thus, the present invention provides a method for treating or preventing myasthenia gravis in a subject in need thereof comprising administering a therapeutically effective amount of anti-C5 antigen-binding protein (e.g., H2M11683N; H2M11686N; H4H12159P; H4H12161P; H4H12163P; H4H12164P; H4H12166P; H4H12166P2; H4H12166P3; H4H12166P4; H4H12166P5; H4H12166P6; H4H12166P7; H4H12166P8; H4H12166P9; H4H12166P10; H4H12167P; H4H12168P; H4HI2169P; H4H12170P; H4H12171P; H4H12175P; H4H12176P2; H4H12177P2; H4H12183P2; H2M11682N; H2M11684N; H2M11694N; H2M11695N; ravulizumab, crovalimab or eculizumab) in a pharmaceutical formulation of the present invention to the subject. The present invention includes a method for reducing, stabilizing and/or eliminating one or more signs and/or symptoms of MG in a subject suffering from MG and said signs and/or symptoms comprising administering a therapeutically effective amount of pharmaceutical formulation of the present invention comprising an anti-C5 antigen-binding protein to the subject.
Typical hemolytic uremic syndrome (tHUS) may follow a gastrointestinal infection with Shiga toxin-producing Escherichia coli (STEC). Typical HUS (STEC-HUS; Shiga toxin-producing Escherichia coli (STEC)-hemolytic uremic syndrome (HUS)) can be initiated when the Shiga toxin (or Shiga-like toxin), a known potent cytotoxin, binds to cell membrane glycolipid Gb3 (via domain B). Domain A is internalized and subsequently halts protein synthesis and induces apoptosis of the affected cell. The Shiga toxin has several additional effects on endothelial cells, one of which is enhanced expression of functional tissue factor that could contribute to microvascular thrombosis. The toxin causes damage to or activation of endothelium, red cells, and platelets. Thus, the present invention provides a method for treating or preventing tHUS in a subject in need thereof comprising administering a therapeutically effective amount of anti-C5 antigen-binding protein (e.g., H2M11683N; H2M11686N; H4H12159P; H4H12161P; H4H12163P; H4H12164P; H4H12166P; H4H12166P2; H4H12166P3; H4H12166P4; H4H12166P5; H4H12166P6; H4H12166P7; H4H12166P8; H4H12166P9; H4H12166P10; H4H12167P; H4H12168P; H4HI2169P; H4H12170P; H4H12171P; H4H12175P; H4H12176P2; H4H12177P2; H4H12183P2; H2M11682N; H2M11684N; H2M11694N; H2M11695N; ravulizumab, crovalimab or eculizumab) in a pharmaceutical formulation of the present invention to the subject. The present invention includes a method for reducing, stabilizing and/or eliminating one or more signs and/or symptoms of tHUS in a subject suffering from tHUS and said signs and/or symptoms comprising administering a therapeutically effective amount of pharmaceutical formulation of the present invention comprising an anti-C5 antigen-binding protein to the subject.
The present invention also includes a method for switching therapeutic regimens for treating or preventing a C5-associated disease comprising ceasing administering a first such therapeutic regimen and administering a therapeutically effective amount of anti-C5 antigen-binding protein selected from H2M11683N; H2M11686N; H4H12159P; H4H12161P; H4H12163P; H4H12164P; H4H12166P; H4H12166P2; H4H12166P3; H4H12166P4; H4H12166P5; H4H12166P6; H4H12166P7; H4H12166P8; H4H12166P9; H4H12166P10; H4H12167P; H4H12168P; H4H12169P; H4H12170P; H4H12171P; H4H12175P; H4H12176P2; H4H12177P2; H4H12183P2; H2M11682N; H2M11684N; H2M11694N; and H2M11695N in a pharmaceutical formulation of the present invention to the subject.
Certain standard treatments of C5-associated disease are burdensome and present significant dangers due to complications. The present invention also provides methods for avoiding such standard treatments and complications thereof by treating the underlying C5-associated disease (e.g., PNH or aHUS) with a pharmaceutical formulation of the present invention as set forth herein. For example, said standard treatments include blood transfusion, bone marrow transplantation (BMT), renal transplant, hemodialysis and/or balloon angioplasty.
Complications of blood transfusion include for example allergic reaction, fever, acute immune hemolytic reaction and blood-borne infection (e.g., human immunodeficiency virus (HIV), hepatitis C, hepatitis B and/or west nile virus). Thus, the present invention includes a method for avoiding blood transfusions and/or one or more complications of blood transfusions (e.g., allergic reaction, fever, acute immune hemolytic reaction and blood-borne infection) in a subject with a C5-associated disease (e.g., PNH or aHUS) by treating the underlying C5-associated disease (e.g., PNH or aHUS) with an pharmaceutical formulation of the present invention as set forth herein wherein treatment comprises administering a therapeutically effective amount of anti-C5 antigen-binding protein in a pharmaceutical formulation of the present invention to the subject.
Complications of bone marrow transplantation include for example graft-versus-host disease, stem cell (graft) failure, organ damage, infection, cataract, infertility and death. Thus, the present invention includes a method for avoiding bone marrow transplantation and/or one or more complications of bone marrow transplantation (e.g., graft-versus-host disease, stem cell (graft) failure, organ damage, infection, cataract, infertility and death) in a subject with a C5-associated disease (e.g., PNH or aHUS) by treating the underlying C5-associated disease (e.g., PNH or aHUS) with a pharmaceutical formulation of the present invention as set forth herein wherein treatment comprises administering a therapeutically effective amount of anti-C5 antigen-binding protein in a pharmaceutical formulation of the present invention to the subject.
Complications of hemodialysis include for example infection, sepsis, hypotension, muscle cramps, itching, sleep disturbance, sleep apnea, anemia, hypertension, fluid overload, pericarditis, hyperkalemia, amyloidosis or depression. Thus, the present invention includes a method for avoiding hemodialysis and/or one or more complications of hemodialysis (e.g., infection, sepsis, hypotension, muscle cramps, itching, sleep disturbance, sleep apnea, anemia, hypertension, fluid overload, pericarditis, hyperkalemia, amyloidosis or depression) in a subject with a C5-associated disease (e.g., PNH or aHUS) by treating the underlying C5-associated disease (e.g., PNH or aHUS) with a pharmaceutical formulation of the present invention as set forth herein wherein treatment comprises administering a therapeutically effective amount of anti-C5 antigen-binding protein in a pharmaceutical formulation of the present invention to the subject.
Complications of renal transplant include for example blood clots, bleeding, leaking from or blockage of the ureter, infection, kidney failure, kidney rejection, death, heart attack and stroke. Thus, the present invention includes a method for avoiding renal transplant and/or one or more complications of renal transplant (e.g., blood clots, bleeding, leaking from or blockage of the ureter, infection, kidney failure, kidney rejection, death, heart attack and stroke) in a subject with a C5-associated disease (e.g., PNH or aHUS) by treating the underlying C5-associated disease (e.g., PNH or aHUS) with an pharmaceutical formulation of the present invention as set forth herein wherein treatment comprises administering a therapeutically effective amount of anti-C5 antigen-binding protein in a pharmaceutical formulation of the present invention to the subject.
The pharmaceutical formulations of the present invention may be used to treat or prevent a C5-associated disease such as a C5-associated ophthalmologic disease, e.g., age-related macular degeneration (AMD; e.g., wet or dry), diabetic retinopathy (DR), non-infections uveitis, geographic atrophy, Stargardt Macular Dystrophy or optic neuritis.
AMD is the progressive degeneration of the macula (central part of the retina), typically, in people aged over 55 years. Various complement components, including C3, C5b-9, CFB, and CFH, have been detected in drusen as well as in AMD lesions. In addition, increased plasma levels of C3a, C3d, Bb, and C5a have been observed in AMD patients. These results suggest increased local and systemic complement activation in AMD.
DR is a progressive degeneration of retinal vasculature and neurons as a result of diabetes. Choriocapillaris of DR eyes contain significant levels of C3d and the C5b-9 complex. C5b-9 deposition may also be detectable in retinal vessels of patients with >9-year type-2 diabetes and increased C5a may be detected in the vitreous of patients with proliferative DR suggesting that complement activation is involved in retinal vascular damage in DR.
Non-infectious uveitis is inflammation—heat, redness, pain, and swelling—in one or both eyes which is not due to infection.
Geographic atrophy (GA) is a chronic progressive degeneration of the macula, as part of late-stage age-related macular degeneration (AMD). The disease is characterized by localized sharply demarcated atrophy of outer retinal tissue, retinal pigment epithelium and choriocapillaris. It typically starts typically in the perifoveal region and expands to involve the fovea with time, leading to central scotomas and permanent loss of visual acuity. It is bilateral in most cases.
Autosomal recessive Stargardt macular dystrophy (STGD1) is a dystrophy resulting from mutations in the ABCA4 (ABCR) gene. Mutations in ABCA4 also result in cone-rod dystrophy. The age of onset of juvenile and early adult STGD1 is usually 8-25 years with some cases occurring in older adults (lateadult onset STGD1). A hallmark of the disease is premature accumulation of lipofuscin (a brown-yellow autofluorescent pigment associated with aging) in the retinal pigment epithelia (RPE) of the eye, causing a pattern of yellowish flecks that extend outward from the macula.
Optic neuritis is an inflammation that damages the optic nerve. Pain and temporary vision loss in one eye are common symptoms of optic neuritis.
Thus, the present invention includes a method for treating or preventing a C5-associated ophthalmologic disease, e.g., age-related macular degeneration (AMD; e.g., wet or dry), diabetic retinopathy (DR), non-infections uveitis, geographic atrophy, Stargardt Macular Dystrophy or optic neuritis, in a subject in need thereof comprising administering, to the subject, a therapeutically effective amount of anti-C5 antigen binding protein, in a pharmaceutical formulation of the present invention, e.g., by intraocular or intravitreal injection.
The anti-C5 antigen-binding proteins of the present invention also reduce complement activity (e.g., C5-mediated complement activity) in the body of a subject. For example, in an embodiment of the invention, the complement activity is complement-mediated hemolysis (e.g., classical pathway mediated or alternative pathway mediated) or C5 activity (e.g., binding of C5a to C5aR1, generation of C5a and/or C5b from C5 precursor; or formation or deposition of membrane attack complex (MAC) in cells, e.g., endothelial cells). In an embodiment of the invention, complement activity is the capacity of serum taken from a subject's body to lyse sheep erythrocytes coated with anti-sheep antibodies. Thus, the present invention provides a method for reducing complement activity in the body of a subject comprising administering an anti-C5 antigen-binding protein, e.g., a therapeutically effective amount thereof, (e.g., H2M11683N; H2M11686N; H4H12159P; H4H12161P; H4H12163P; H4H12164P; H4H12166P; H4H12166P2; H4H12166P3; H4H12166P4; H4H12166P5; H4H12166P6; H4H12166P7; H4H12166P8; H4H12166P9; H4H12166P10; H4H12167P; H4H12168P; H4H12169P; H4H12170P; H4H12171P; H4H12175P; H4H12176P2; H4H12177P2; H4H12183P2; H2M11682N; H2M11684N; H2M11694N; H2M11695N; ravulizumab, crovalimab or eculizumab) in a pharmaceutical formulation of the present invention to the subject.
In certain embodiments, a therapeutically effective amount of anti-C5 antigen-binding protein in a pharmaceutical formulation of the invention is administered to a subject with a C5-associated disease. A therapeutically effective amount of anti-C5 antigen-binding protein in a pharmaceutical formulation of the present invention may vary depending upon the age and the size of a subject to be administered, target disease, conditions, route of administration, and the like. In an embodiment of the invention, a therapeutically effective amount of an anti-C5 antigen-binding protein in a pharmaceutical formulation of the present invention is about 0.1 to about 100 mg/kg body weight, about 5 to about 80, about 10 to about 70, or about 20 to about 50 mg/kg body weight (e.g., a single or multiple doses thereof). In an embodiment of the invention, a therapeutically effective amount of an anti-C5 antigen-binding protein in a pharmaceutical formulation of the present invention is about 0.1 mg to about 1000 mg, about 1 to about 600 mg, about 5 to about 500 mg, or about 10 to about 400 mg. Depending on the severity of the condition, the frequency and the duration of the treatment can be adjusted. In certain embodiments, the initial dose may be followed by administration of a second or a plurality of subsequent doses of the antigen-binding protein in an amount that can be approximately the same or less than that of the initial dose, wherein the subsequent doses are separated by at least 1 day to 3 days; at least one week, at least 2 weeks; at least 3 weeks or at least 4 weeks.
In an embodiment of the invention, a therapeutically effective amount of anti-C5 antigen-binding protein (e.g., pozelimab) in a pharmaceutical formulation of the invention is about 30 mg/kg body weight administered intravenously (IV) one or more times; optionally further including one or more doses of the formulation administered subcutaneously.
In an embodiment of the invention, a therapeutically effective amount of a further therapeutic agent that is an RNAi (e.g., cemdisiran) is about 0.001 to about 200.0 milligrams per kilogram body weight of the recipient per day, generally in the range of about 1 to 50 mg per kilogram body weight per day. For example, a therapeutically effective amount of RNAi, e.g., dsRNA (e.g., cemdisiran), is about 0.01 mg/kg, about 0.05 mg/kg, about 0.5 mg/kg, about 1 mg/kg, about 1.5 mg/kg, about 2 mg/kg, about 3 mg/kg, about 10 mg/kg, about 20 mg/kg, about 30 mg/kg, about 40 mg/kg, or about 50 mg/kg per single dose.
In a further embodiment of the invention, a further therapeutic agent that is administered to a subject in association with a pharmaceutical formulation of the invention. In an embodiment of the invention, the further therapeutic agent is administered at a dosage in accordance with the Physicians' Desk Reference 2003 (Thomson Healthcare; 57th edition (Nov. 1, 2002)).
The present invention further provides methods for administering a pharmaceutical formulation of the present invention comprising an anti-C5 antigen-binding protein, e.g., H2M11683N; H2M11686N; H4H12159P; H4H12161P; H4H12163P; H4H12164P; H4H12166P; H4H12166P2; H4H12166P3; H4H12166P4; H4H12166P5; H4H12166P6; H4H12166P7; H4H12166P8; H4H12166P9; H4H12166P10; H4H12167P; H4H12168P; H4H12169P; H4H12170P; H4H12171P; H4H12175P; H4H12176P2; H4H12177P2; H4H12183P2; H2M11682N; H2M11684N; H2M11694N; H2M11695N; ravulizumab, crovalimab or eculizumab, to a subject, comprising introducing the pharmaceutical formulation into the body of the subject (e.g., a human), for example, parenterally. For example, the method comprises piercing the body of the subject with a needle of a syringe and injecting the pharmaceutical formulation into the body of the subject, e.g., into the vein, artery, eye, muscular tissue or subcutis of the subject.
The mode of administration of a pharmaceutical formulation of the present invention can vary. Routes of administration include parenteral, non-parenteral, oral, rectal, transmucosal, intestinal, parenteral; intramuscular, subcutaneous, intradermal, intramedullary, intrathecal, direct intraventricular, intravenous, intraperitoneal, intranasal, intraocular, inhalation, insufflation, topical, cutaneous, intraocular, intravitreal, transdermal or intra-arterial.
The anti-C5 antigen-binding proteins discussed herein (e.g., H2M11683N; H2M11686N; H4H12159P; H4H12161P; H4H12163P; H4H12164P; H4H12166P; H4H12166P2; H4H12166P3; H4H12166P4; H4H12166P5; H4H12166P6; H4H12166P7; H4H12166P8; H4H12166P9; H4H12166P10; H4H12167P; H4H12168P; H4HI2169P; H4H12170P; H4H12171P; H4H12175P; H4H12176P2; H4H12177P2; H4H12183P2; H2M11682N; H2M11684N; H2M11694N; H2M11695N; ravulizumab, crovalimab or eculizumab) can be administered to a subject by an intravenous (IV) route. The present invention, thus, includes intravenous formulations that include an aqueous intravenous solution (e.g., NS) and a pharmaceutical formulation set forth herein. An intravenous formulation can be prepared by adding a pharmaceutical formulation that is set forth herein (e.g., about 200 mg/ml pozelimab; 20±4 mM histidine buffer; 100±20 mM L-arginine; 2±0.4% (w/v) sucrose; 0.15±0.075% (w/v) polysorbate-80; and water, pH 5.8±0.3) to an aqueous intravenous solution (e.g., NS). A pharmaceutical formulation can be added to an aqueous intravenous solution, for example, by injection through a medication port in the container holding the solution (e.g., a bag). The resulting intravenous formulation can then be administered to a subject. Intravenous formulations that are the result of such a method form part of the present invention along with methods of use thereof as set forth herein.
An aqueous intravenous solution, into which a pharmaceutical formulation can be introduced to produce an intravenous formulation, includes for example, 0.9% Normal Saline (NS, 0.9NaCl, or NSS), Lactated Ringers (LR, Ringers Lactate, or RL), Dextrose 5% in Water (D5 or D5W, an intravenous sugar solution); 0.45% Normal Saline (Half Normal Saline, 0.45NaCl, 0.45NS); 0.33% NaCl; 0.225% NaCl; 2.5% dextrose in water (D2.5W); 3% NaCl; 5% NaCl; dextrose 5% in 0.45% NaCl (D5 ½ NS); 5% dextrose and 0.45% NaCl; dextrose 5% in 0.9% NaCl (D5NS); dextrose 5% in Lactated Ringer's (D5LR); LR that contains 0.6% NaCl; 10% dextrose in water (D10W); 20% dextrose in water (D20W); or 50% dextrose in water (D50W). These solutions are well known in the art and are commercially available.
Vessels and other devices (e.g., sterile plastic or glass intravenous bottle or intravenous plastic bag) comprising such intravenous formulations also form part of the present invention.
Intravenous formulations can be administered into the veins of a subject by any of several methods known in the art. For example, the intravenous formulation can be administered by peripheral intravenous (PIV) line or a central IV line. A PIV introduces an intravenous formulation into the peripheral veins (typically, the veins in the arms, hands, legs and feet) of the subject. Central IV lines have catheters that are advanced through a vein and empty into a large central vein (a vein within the torso), usually the superior vena cava, inferior vena cava or even the right atrium of the heart.
Thus, the present invention provides a method for intravenously administering, to a subject, an intravenous formulation of the present invention which includes a pharmaceutical formulation set forth herein (e.g., about 200 mg/ml pozelimab; 20±4 mM histidine buffer; 100±20 mM L-arginine; 2±0.4% (w/v) sucrose; 0.15±0.075% (w/v) polysorbate-80; and water, pH 5.8±0.3) in an aqueous intravenous solution (e.g., NS) comprising introducing the intravenous formulation into a vein (e.g., a peripheral vein) of the subject, e.g., by IV infusion (e.g., drip infusion or pump infusion). Also provided are methods for administering an intravenous formulation of the present invention which may include the step of adding a pharmaceutical formulation set forth herein (e.g., about 200 mg/ml pozelimab; 20±4 mM histidine buffer; 100±20 mM L-arginine; 2±0.4% (w/v) sucrose; 0.15±0.075% (w/v) polysorbate-80; and water, pH 5.8±0.3) to an aqueous intravenous solution (e.g., NS) and introducing the resulting intravenous formulation into a vein of the subject, e.g., by IV infusion (e.g., drip infusion or pump infusion). Such methods optionally comprise further administering a pharmaceutical formulation by a route other than intravenously, e.g., subcutaneously.
The present invention includes methods for treating or preventing a C5-associated disease (e.g., PNH) in a subject by administering an intravenous formulation comprising intravenously administering anti-C5 antigen-binding protein to the subject (e.g., one or more IV doses of 1, 3, 10, 15 or 30 mg/kg). Optionally, the method further includes the step of administering a pharmaceutical formulation of the present invention to the subject by a route other than IV, for example, subcutaneously, i.e., wherein the pharmaceutical formulation is administered without the step of forming an intravenous formulation.
The following example is provided to further describe the present invention and should not be construed as a limitation thereof. The scope of the present invention includes any of the methods and pharmaceutical formulations which are set forth below in the following examples.
The melting temperatures (Tm) of H4H12166P were determined by TA-differential scanning calorimetry (DSC) and VP-DSC using the parameters set forth in Tables 1-1 and 1-2. Melting temperatures that were determined are summarized in Table 1-3. In addition, the thermal melting profiles of H4H12166P determined by VP-DSC at 1 mg/mL and by TA-DSC at 150 mg/mL and 200 mg/mL are shown in
The first transition (Tm1) in the DSC thermograms observed at lower temperatures most likely represents the thermal unfolding of the CH2 domain in the Fc region, whereas the main transition (larger endotherm) is from the domains of the Fab region. The Tm1 values determined for all samples are similar (61-62° C.), although this peak is not well-defined in the TA-DSC thermogram for the 150 mg/mL H4H12166P (
Temperature, pH and container headspace were evaluated in a Design of Experiment (DoE) study to characterize the degradation pathways of 150 mg/mL H4H12166P. A risk assessment was completed. The factors used in this study are shown in Table 2-1.
Results from the study, designed to characterize 150 mg/mL H4H12166P in 20 mM histidine buffer over a range of temperatures, pH and container headspaces, is illustrated in
The transfer functions obtained from analysis of the DoE study results were used to estimate the rates of formation of molecular size and charge variant species in 150 mg/mL H4H12166P, 20 mM histidine, pH 5.8, at temperatures ranging from 25° C. to 45° C. (Table 2-2); these rates are plotted in
The rationale for including headspace as one of the factors in this characterization study was to evaluate the impact of different amounts of headspace oxygen on the susceptibility of H4H12166P to undergo methionine oxidation. Methionine oxidation was quantified by peptide mapping (LCMS), however, since this is not a high throughput method the test was performed only on the 150 mg/mL H4H12166P, 20 mM histidine, pH 6.2 sample filled in a 10 mL glass vial (largest headspace) at the t=0 and 45° C. 28 day time point, as a worst case scenario. The results, listed in Table 2-3, show only a very small increase (1.3%) in oxidation of Met105, which is in the CDR of H4H12166P, under these incubation conditions. The other Met residues showed lower and negligible changes in oxidation upon thermal incubation. Container headspace showed a minimal impact on other monitored quality attributes over the evaluated range (2.5 mL to 11.5 mL) (
The susceptibility of 150 mg/mL H4H12166P in 20 mM histidine, pH 6.2 to freeze/thaw, agitation and oxidation (H2O2 spiking) stress was evaluated using a single factor study design. The incubation/stress conditions used to assess the stability of H4H12166P are shown in Table 3-1. The concentrations of hydrogen peroxide evaluated in this study are listed in Table 3-2.
Fourteen (14) mL of F1 (control) and ten (10) mL of each subsequent formulation (F2 to F8) listed in Table 3-2 was prepared. Each formulation was filter-sterilized, using a syringe and Millipore Millex GV (PVDF Durapore) 0.2 μM filter, in a laminar flow hood. Formulations F2 to F8 were spiked with H2O2 in a laminar flow hood after being filter-sterilized. The formulations were dispensed as follows:
1. One (1) mL of formulation F1 was filled in ten (10) 2 mL glass vials (also used for F/T and agitation tests).
2. One (1) mL of formulations F2 to F8 were each filled in four (4) 2 mL glass vials.
The analytical testing plan for the F/T, agitation and oxidation stressed samples is shown in Table 3-4.
After being subjected to freeze/thaw and agitation stress, under the conditions described in Table 3-1, 150 mg/mL H4H12166P, 20 mM histidine, pH 6.2 showed increased levels of HMW species (
No changes in charge variants, determined by CEX-UPLC, were observed following freeze/thaw or agitation stress (see
A high throughput hydrophobic interaction chromatography (HIC) HPLC-based method was developed to quantify the levels of methionine oxidation in H4H12166P. This method is not sufficiently sensitive to allow identification of specific methionine residues that undergo oxidation, but distinct peaks, that increased with incubation time, were resolved in the chromatogram. The peak areas for the 500 ppm hydrogen peroxide sample, which represent the change in different oxidized species, are shown in
The H4H12166P samples incubated with hydrogen peroxide were also analyzed for charge variants (CEX-UPLC) and molecular size variants (SE-UPLC). A minimal (˜1%) decrease in acidic charge variants and a comparable increase in basic charge variants was observed only at 100 and 500 ppm hydrogen peroxide (
There was no meaningful increase in formation of HMW species even at the highest tested concentration of hydrogen peroxide (
Viscosity was measured using a Rheosense m-VROC viscometer. Prior to analysis, standards and formulations were filtered through a 0.22 μm PVDF spin filter. Two standards of known viscosities were measured before the unknown sample viscosity analysis: 2 cP and glycerol standards. Viscosity measurements were performed at 20° C.
# All molecules were analyzed in 10 mM histidine, pH 5.5.
Stability studies evaluated the stability of a liquid, aqueous H4H12166P 200 mg/mL formulation under long term storage and stress conditions. Two stability studies were initiated:
(1) 0.5 mL fill in a 2 mL type 1 borosilicate glass vial stored in the upright orientation, and
(2) 2.5 mL fill in a 5 mL type 1 borosilicate glass vial stored in the inverted orientation
The attributes of an aqueous formulation comprising 200 mg/mL H4H12166P, 20 mM histidine, pH 5.8, 100 mM L-arginine hydrochloride, 2% (w/v) sucrose, 0.15% (w/v) polysorbate 80, following 6 months of long term (5° C.) storage in 2 mL Schott Type 1 borosilicate glass vials (stored upright), are set forth in Table 5-2. Table 5-3 and Table 5-4 summarizes the attributes of liquid, aqueous H4H12166P 200 mg/mL formulation after storage at accelerated condition of 25° C., 60% RH and at stressed conditions of 40° C., 75% RH, respectively.
+PASS
+PASS
+PASS
+PASS
+PASS
+PASS
#USP Type 1 clear glass, 2 mL vial with 13 mm gray chlorobutyl rubber stopper with FluroTec. stored upright and containing 200 mg/mL H4H12166P, 20 mM histidine, pH 5.8, 100 mM L-arginine hydrochloride, 2% (w/v) sucrose, 0.15% (w/v) polysorbate 80
+Pass = Clear to pale yellow, and essentially free from visible particulates.
+PASS
+PASS
+PASS
+PASS
+PASS
+Pass = Clear to pale yellow, and essentially free from visible particulates.
+PASS
+PASS
+PASS
+PASS
+PASS
+PASS
~USP Type 1 clear glass, 2 mL vial with 13 mm gray chlorobutyl rubber stopper with FluroTec stored upright and containing 200 mg/mL H4H12166P, 20 mM histidine, pH 5.8, 100 mM L-arginine hydrochloride, 2% (w/v) sucrose, 0.15% (w/v) polysorbate 80.
+Pass = Clear to pale yellow, and essentially free from visible particulates.
A comparison of the results between the 2 mL and 5 mL glass vials revealed that factors such as container size (2 mL and 5 mL) and fill volume (0.5 mL and 2.5 mL) did not have a meaningful impact on the degradation pathways or trends in key quality attributes in the H4H12166P formulation.
Stability studies evaluated the stability of a liquid, aqueous H4H12166P 200 mg/mL formulation under agitation and freeze/thaw conditions.
The attributes of an aqueous formulation comprising 200 mg/mL H4H12166P, 20 mM histidine, pH 5.8, 100 mM L-arginine hydrochloride, 2% (w/v) sucrose, 0.15% (w/v) polysorbate 80, following agitation or freeze/thaw in 6R Type 1 borosilicate glass vials (stored upright), are set forth in Table 6-2 and 6-3.
+PASS
+PASS
+PASS
+Pass = Clear to pale yellow, and essentially free from visible particulates.
+PASS
+PASS
+PASS
+Pass = Clear to pale yellow, and essentially free from visible particulates.
No appreciable change in physical or chemical stability after 48 hr of agitation and of 4 cycles of freeze/thaw for aqueous formulation comprising of 200 mg/mL H4H12166P.
Stability studies evaluated the stability of a liquid, aqueous H4H12166P 274 mg/mL formulation under long term storage (5° C.).
The attributes of an aqueous formulation comprising 274 mg/mL H4H12166P, 20 mM histidine, pH 5.8, 100 mM L-arginine hydrochloride, 2% (w/v) sucrose, 0.15% (w/v) polysorbate 80, following 15.5 months of long term (5° C.) storage 5 mL container, are set forth in Table 7-1. Table 7-2 summarizes the attributes of liquid, aqueous H4H12166P 274 mg/mL formulation after freeze/thaw.
+PASS
+PASS
+PASS
+PASS
+PASS
+PASS
+PASS
+PASS
+PASS
No appreciable change in physical or chemical stability after 15.5 months at 5° C. of 8 cycles of freeze/thaw for aqueous formulation comprising of 274 mg/mL H4H12166P.
Viscosity was measured using a Rheosense Initium automatic viscometer. Prior to analysis, standards and formulations were filtered through a 0.22 μm PVDF spin filter. Two standards of known viscosities were measured before the unknown sample viscosity analysis: 2 cP and glycerol standards. Viscosity measurements were performed at different temperatures (5-40° C.) of aqueous formulations comprising of 161-274 mg/mL H4H12166P, 20 mM histidine, pH 5.8, 100 mM L-arginine hydrochloride, 2% (w/v) sucrose, 0.15% (w/v) polysorbate 80. Table 8-1 summarizes measured viscosity.
#Containing 20 mM histidine, pH 5.8, 100 mM L-arginine hydrochloride, 2% (w/v) sucrose, 0.15% (w/v) polysorbate 80.
All references cited herein are incorporated by reference to the same extent as if each individual publication, database entry (e.g., Genbank sequences or GeneID entries), patent application, or patent, was specifically and individually indicated to be incorporated by reference. This statement of incorporation by reference is intended by Applicants, to relate to each and every individual publication, database entry (e.g., Genbank sequences or GeneID entries), patent application, or patent even if such citation is not immediately adjacent to a dedicated statement of incorporation by reference. The inclusion of dedicated statements of incorporation by reference, if any, within the specification does not in any way weaken this general statement of incorporation by reference. Citation of the references herein is not intended as an admission that the reference is pertinent prior art, nor does it constitute any admission as to the contents or date of these publications or documents.
The present application claims the benefit of U.S. Provisional Patent Application No. 62/888,086, filed Aug. 16, 2019, which is hereby incorporated by reference in its entirety for all purposes.
| Number | Date | Country | |
|---|---|---|---|
| 62888086 | Aug 2019 | US |
