ANTI-TMPRSS6 ANTIBODIES AND USES THEREOF

Abstract

Antibodies and antigen-binding fragments thereof that bind type II transmembrane serine protease 6 (TMPRSS6) on the surface of a cell and increase hepcidin expression, and methods for treating disorders of iron metabolism and myeloproliferative disorders using anti TMPRSS6 antibodies and fragments, are provided.

Description

Claims

1. A method of treating a myeloproliferative disorder in a subject in need thereof, comprising administering an effective amount of an anti-TMPRSS6 antibody comprising an antibody or an antigen-binding fragment thereof that specifically binds human TMPRSS6 and increases the activity of the hepcidin promoter, wherein the antibody is capable of binding human TMPRSS6 on the surface of a cell expressing human TMPRSS6, and comprises one of: i. (a) a heavy chain polypeptide comprising a heavy chain complementarity determining region 1 (HC CDR1) having the sequence GYTFTSYW as set forth in SEQ ID NO: 2, an HC CDR2 having the sequence IYPGSGST as set forth in SEQ ID NO: 3, an HC CDR3 having the sequence APYDSDYAMDY as set forth in SEQ ID NO: 4, and (b) a light chain polypeptide comprising a complementarity determining region 1 (LC CDR1) having the sequence QDINNY as set forth in SEQ ID NO: 7, an LC CDR2 having the sequence RAN as set forth in SEQ ID NO: 8, an LC CDR3 having the sequence LQYDEFPLT as set forth in SEQ ID NO: 9;ii. (a) a heavy chain polypeptide comprising an HC CDR1 having the sequence GYTFTSYW as set forth in SEQ ID NO: 32, an HC CDR2 having the sequence IYPGSGST as set forth in SEQ ID NO: 33, an HC CDR3 having the sequence APYDADYAMDY as set forth in SEQ ID NO: 34, and (b) a light chain polypeptide comprising an LC CDR1 having the sequence QDISNY of SEQ ID NO: 37, an LC CDR2 having the sequence RAN as set forth in SEQ ID NO: 38, an LC CDR3 having the sequence LQYDEFPLT as set forth in SEQ ID NO: 39;iii. (a) a heavy chain polypeptide comprising an HC CDR1 having the sequence GFNIKDYY as set forth in SEQ ID NO: 12, an HC CDR2 having the sequence IDPEDGES as set forth in SEQ ID NO: 13, an HC CDR3 having the sequence TRGDSMMVTYFDY as set forth in SEQ ID NO: 14, and (b) a light chain polypeptide comprising an LC CDR1 having the sequence QDVSTA as set forth in SEQ ID NO: 17, an LC CDR2 having the sequence WAF as set forth in SEQ ID NO: 18, an LC CDR3 having the sequence QQHYRSPWT as set forth SEQ ID NO: 19;iv. (a) a heavy chain polypeptide comprising an HC CDR1 having the sequence GFNIKDYY as set forth in SEQ ID NO: 42, an HC CDR2 having the sequence IDPEDAES as set forth in SEQ ID NO: 43, an HC CDR3 having the sequence TRGDSMMVTYFDY as set forth in SEQ ID NO: 44, and (b) a light chain polypeptide comprising an LC CDR1 having the sequence QDVSTA as set forth in SEQ ID NO: 47, an LC CDR2 having the sequence WAF as set forth in SEQ ID NO: 48, an LC CDR3 having the sequence QQHYRSPWT as set forth in SEQ ID NO: 49;v. (a) a heavy chain polypeptide comprising an HC CDR1 having the sequence GFNIEDYY as set forth in SEQ ID NO: 22, an HC CDR2 having the sequence IDPEDGET as set forth in SEQ ID NO: 23, an HC CDR3 having the sequence ARSIYLDPMDY as set forth in SEQ ID NO: 24, and (b) a light chain polypeptide comprising an LC CDR1 having the sequence QDVTTA as set forth in SEQ ID NO: 27 or SEQ ID NO: 57, an LC CDR2 having the sequence WAT as set forth in SEQ ID NO: 58, an LC CDR3 having the sequence QQHYSTPYT as set forth in SEQ ID NO: 29; orvi. (a) a heavy chain polypeptide comprising an HC CDR1 having the sequence GFNIEDYY as set forth in SEQ ID NO: 52, an HC CDR2 having the sequence IDPEDAET as set forth in SEQ ID NO: 53, an HC CDR3 having the sequence ARSIYLDPMDY as set forth in SEQ ID NO: 54, and (b) a light chain polypeptide comprising an LC CDR1 having the sequence QDVTTA as set forth in SEQ ID NO: 57, an LC CDR2 having the sequence WAT as set forth in SEQ ID NO: 58, an LC CDR3 having the sequence QQHYSTPYT as set forth in SEQ ID NO: 59.

2. The method of claim 1, wherein the myeloproliferative disorder is a myeloproliferative neoplasm.

3. The method of claim 2, wherein the myeloproliferative neoplasm is polycythemia vera (PV).

4. The method of claim 1, wherein administration of the effective amount of anti-TMPRSS6 antibody has at least one effect selected from reducing red blood cell count (RBC), reducing hematocrit (HCT), reducing hemoglobin (HGB), reducing mean corpuscular volume (MCV), and reducing red cell distribution width (RDW), when administered to a subject known or suspected to have a myeloproliferative disorder.

5. The method of claim 3, wherein administration of the effective amount of anti-TMPRSS6 antibody has at least one effect selected from reducing red blood cell count (RBC), reducing hematocrit (HCT), reducing hemoglobin (HGB), reducing mean corpuscular volume (MCV), and reducing red cell distribution width (RDW), when administered to a subject known or suspected to have polycythemia vera (PV).

6. The method of claim 1, wherein the anti-TMPRSS6 antibody is selected from at least one of a monoclonal antibody, a chimeric antibody, a humanized antibody, a recombinant antibody, and an antigen-binding fragment.

7. The method of claim 1, further comprising a pharmaceutically acceptable carrier.

8. The method of claim 1, wherein the subject is human.

9. The method of claim 1, wherein the anti-TMPRSS6 antibody comprises at least one polypeptide having an amino acid sequence that is at least about 85%, 90%, 92%, 95%, 97%, or 98%, 99% or 100% identical to an amino acid sequence selected from: SEQ ID NO: 1; SEQ ID NO: 2; SEQ ID NO: 3; SEQ ID NO: 4; SEQ ID NO: 6; SEQ ID NO: 7; SEQ ID NO: 8; SEQ ID NO: 9; SEQ ID NO: 11; SEQ ID NO: 12; SEQ ID NO: 13; SEQ ID NO: 14; SEQ ID NO: 16; SEQ ID NO: 17; SEQ ID NO: 18; SEQ ID NO: 19; SEQ ID NO: 21; SEQ ID NO: 22; SEQ ID NO: 23; SEQ ID NO: 24; SEQ ID NO: 26; SEQ ID NO: 27; SEQ ID NO: 28; SEQ ID NO: 29; SEQ ID NO: 31; SEQ ID NO: 32; SEQ ID NO: 33; SEQ ID NO: 34; SEQ ID NO: 36; SEQ ID NO: 37; SEQ ID NO: 38; SEQ ID NO: 39; SEQ ID NO: 41; SEQ ID NO: 42; SEQ ID NO: 43; SEQ ID NO: 44; SEQ ID NO: 46; SEQ ID NO: 47; SEQ ID NO: 48; SEQ ID NO: 49; SEQ ID NO: 51; SEQ ID NO: 52; SEQ ID NO: 53; SEQ ID NO: 54; SEQ ID NO: 56; SEQ ID NO: 57; SEQ ID NO: 58; SEQ ID NO: 59; SEQ NO: 61; SEQ ID NO: 63; SEQ ID NO: 65; SEQ ID NO: 67; SEQ ID NO: 69; SEQ ID NO: 71; SEQ ID NO: 73; SEQ ID NO: 75; SEQ ID NO: 77; SEQ ID NO: 79; SEQ ID NO: 81; or SEQ ID NO: 83.

10. The method of claim 1, wherein the anti-TMPRSS6 antibody comprises one of: a. (a) a heavy chain (HC) polypeptide wherein the variable region comprises an amino acid sequence that is at least about 85%, 90%, 92%, 95%, 97%, or 98%, 99% or 100% identical to the amino acid sequence of SEQ ID NO: 1; and (b) a light chain (LC) polypeptide wherein the variable region comprises an amino acid sequence that is at least about 85%, 90%, 92%, 95%, 97%, or 98%, 99% or 100% identical to the amino acid sequence of SEQ ID NO: 6;b. (a) an HC polypeptide wherein the variable region comprises an amino acid sequence that is at least about 85%, 90%, 92%, 95%, 97%, or 98%, 99% or 100% identical to the amino acid sequence of SEQ ID NO: 31 and (b) a light chain (LC) polypeptide wherein the variable region comprises an amino acid sequence that is at least about 85%, 90%, 92%, 95%, 97%, or 98%, 99% or 100% identical to the amino acid sequence of SEQ ID NO: 36;c. (a) an HC polypeptide wherein the variable region comprises an amino acid sequence that is at least about 85%, 90%, 92%, 95%, 97%, or 98%, 99% or 100% identical to the amino acid sequence of SEQ ID NO: 11 and (b) an LC polypeptide wherein the variable region comprises an amino acid sequence that is at least about 85%, 90%, 92%, 95%, 97%, or 98%, 99% or 100% identical to the amino acid sequence of SEQ ID NO: 16;d. (a) an HC polypeptide wherein the variable region comprises an amino acid sequence that is at least about 85%, 90%, 92%, 95%, 97%, or 98%, 99% or 100% identical to the amino acid sequence of SEQ ID NO: 41 and (b) an LC polypeptide wherein the variable region comprises an amino acid sequence that is at least about 85%, 90%, 92%, 95%, 97%, or 98%, 99% or 100% identical to the amino acid sequence of SEQ ID NO: 46;e. (a) an HC polypeptide wherein the variable region comprises an amino acid sequence that is at least about 85%, 90%, 92%, 95%, 97%, or 98%, 99% or 100% identical to the amino acid sequence of SEQ ID NO: 21 and (b) an LC polypeptide wherein the variable region comprises an amino acid sequence that is at least about 85%, 90%, 92%, 95%, 97%, or 98%, 99% or 100% identical to the amino acid sequence of SEQ ID NO: 26; orf. (a) an HC polypeptide wherein the variable region comprises an amino acid sequence that is at least about 85%, 90%, 92%, 95%, 97%, or 98%, 99% or 100% identical to the amino acid sequence of SEQ ID NO: 51 and (b) a light chain (LC) polypeptide wherein the variable region comprises an amino acid sequence that is at least about 85%, 90%, 92%, 95%, 97%, or 98%, 99% or 100% identical to the amino acid sequence of SEQ ID NO: 56.

11. The method of claim 1, wherein the anti-TMPRSS6 antibody comprises: (a) a heavy chain polypeptide comprising an HC CDR1 having the sequence GFNIEDYY as set forth in SEQ ID NO: 22, an HC CDR2 having the sequence IDPEDGET as set forth in SEQ ID NO: 23, an HC CDR3 having the sequence ARSIYLDPMDY as set forth in SEQ ID NO: 24, and(b) a light chain polypeptide comprising an LC CDR1 having the sequence QDVTTA as set forth in SEQ ID NO: 27 or SEQ ID NO: 57, an LC CDR2 having the sequence WAT as set forth in SEQ ID NO: 58, an LC CDR3 having the sequence QQHYSTPYT as set forth in SEQ ID NO: 29.

12. The method of claim 1, wherein the anti-TMPRSS6 antibody comprises (a) a heavy chain polypeptide comprising an HC CDR1 having the sequence GFNIEDYY as set forth in SEQ ID NO: 52, an HC CDR2 having the sequence IDPEDAET as set forth in SEQ ID NO: 53, an HC CDR3 having the sequence ARSIYLDPMDY as set forth in SEQ ID NO: 54, and(b) a light chain polypeptide comprising an LC CDR1 having the sequence QDVTTA as set forth in SEQ ID NO: 57, an LC CDR2 having the sequence WAT as set forth in SEQ ID NO: 58, an LC CDR3 having the sequence QQHYSTPYT as set forth in SEQ ID NO: 59.

13. The method of claim 10, wherein the anti-TMPRSS6 antibody comprises (a) an HC polypeptide wherein the variable region comprises an amino acid sequence that is at least about 85%, 90%, 92%, 95%, 97%, or 98%, 99% or 100% identical to the amino acid sequence of SEQ ID NO: 21 and(b) an LC polypeptide wherein the variable region comprises an amino acid sequence that is at least about 85%, 90%, 92%, 95%, 97%, or 98%, 99% or 100% identical to the amino acid sequence of SEQ ID NO: 26.

14. The method of claim 10, wherein the anti-TMPRSS6 antibody comprises (a) an HC polypeptide wherein the variable region comprises an amino acid sequence that is at least about 85%, 90%, 92%, 95%, 97%, or 98%, 99% or 100% identical to the amino acid sequence of SEQ ID NO: 51 and(b) a light chain (LC) polypeptide wherein the variable region comprises an amino acid sequence that is at least about 85%, 90%, 92%, 95%, 97%, or 98%, 99% or 100% identical to the amino acid sequence of SEQ ID NO: 56.