MCAM ANTAGONISTS AND METHODS OF TREATMENT
Described herein are MCAM antagonists, including MCAM antagonist antibodies capable of inhibiting the interaction between MCAM and it ligand, a laminin α4 chain, e.g., an α4 chain of laminin 411. These MCAM antagonists, e.g., anti-MCAM antibodies, may be useful to treat neuroinflammatory conditions, for example, multiple sclerosis and Parkinson's disease, by inhibiting the infiltration of MCAM-expressing cells into the central nervous system (CNS), e.g., extravasation of TH17 cells into the CNS.
1 . A method for the treatment of a central nervous system (CNS) inflammatory disorder characterized by infiltration of MCAM-expressing cells into the CNS, the method comprising administering to a mammalian subject in need thereof an effective amount of a MCAM antagonist which inhibits binding of MCAM to a laminin α4 chain.
2 . The method of claim 1 , wherein the mammalian subject is a human.
3 . The method of claim 2 , the human having been determined to have CNS infiltration by MCAM-expressing cells.
4 . The method of claim 2 , wherein the MCAM-expressing cells are TH17 cells.
5 . The method of claim 4 , wherein the laminin α4 chain is expressed on the surface of endothelial cells.
6 . The method of claim 5 , wherein the inhibition of MCAM binding to laminin α4 chain prevents extravasation of the MCAM-expressing cell into the CNS.
7 . The method of claim 2 , wherein said MCAM antagonist binds to MCAM or laminin α4 chain.
8 . The method of claim 7 , wherein said MCAM antagonist binds to an immunoglobulin domain of MCAM comprising the amino acid sequence shown as SEQ ID NO:22.
9 . The method of claim 7 , wherein said MCAM antagonist binds to an immunoglobulin domain of MCAM comprising the amino acid sequence shown as SEQ ID NO:23.
10 . The method of claim 7 , wherein said MCAM antagonist binds to a domain of MCAM comprising the amino acid sequences shown as SEQ ID NOS: 22 and 23.
11 . The method of claim 2 , wherein the MCAM antagonist competes with MCAM for binding to laminin α4 chain.
12 . The method of claim 11 , wherein the MCAM antagonist competes with the immunoglobulin domain of MCAM comprising the amino acid sequence shown as SEQ ID NO:22 for binding to a laminin α4 chain.
13 . The method of claim 11 , wherein the MCAM antagonist competes with the immunoglobulin domain of MCAM comprising the amino acid sequence shown as SEQ ID NO:23 for binding to a laminin α4 chain.
14 . The method of claim 11 , wherein the MCAM antagonist competes with the domain of MCAM comprising the amino acid sequences shown as SEQ ID NOS:22 and 23 for binding to a laminin α4 chain.
15 . The method of any one of claims 7 - 10 , wherein said MCAM antagonist is an anti MCAM antibody.
16 . The method of any one of claims 11 - 14 , wherein said MCAM antagonist is an anti laminin α4 chain antibody.
17 . The method of claim 15 , wherein said antibody is an antibody fragment.
18 . The method of claim 16 , wherein said antibody is an antibody fragment.
19 . The method of claim 17 , wherein said antibody fragment is selected from the group consisting of Fv, Fab, Fab′, and F(ab′)2.
20 . The method of claim 15 , wherein said antibody is a full-length antibody, wherein the antibody is a chimeric, humanized, or human antibody.
21 . The method of claim 16 , wherein said antibody is a full-length antibody, wherein the antibody is a chimeric, humanized, or human antibody.
22 - 25 . (canceled)
26 . The method of claim 2 , wherein the mammalian subject is suffering from a neuro inflammatory condition or an autoimmune disease.
27 . The method of claim 26 , wherein the neuroinflammatory condition is multiple sclerosis.
28 . The method of claim 26 , wherein the neuroinflammatory condition is Parkinson's disease.
29 . (canceled)
30 . An isolated anti-MCAM antibody, or antigen binding fragment thereof, that binds to an immunoglobulin domain of MCAM comprising the amino acid sequence shown as SEQ ID NO:22.
31 . An isolated anti-MCAM antibody, or antigen binding fragment thereof, that binds to an immunoglobulin domain of MCAM comprising the amino acid sequence shown as SEQ ID NO:23.
32 . An isolated anti-MCAM antibody, or antigen binding fragment thereof, that binds to a domain of MCAM comprising the amino acid sequences shown as SEQ ID NOS:22 and 23.
33 . An isolated anti-MCAM antibody, or antigen binding fragment thereof, comprising
a) the following hypervariable regions (HVRs):
(i) an HVR-L1 comprising the amino acid sequence KASKNIDTYLA (SEQ ID NO:3);
(ii) an HVR-L2 comprising the amino acid sequence SGSTL (SEQ ID NO:4);
(iii) an HVR-L3 comprising the amino acid sequence QQHNEYPLT (SEQ ID NO:5);
(iv) an HVR-H1 comprising the amino acid sequence GFTFSNYYMA (SEQ ID NO:8)
(v) an HVR-H2 comprising the amino acid sequence SISFEGNRNHYGDSVK (SEQ ID NO:9); and
(vi) an HVR-H3 comprising the amino acid sequence HRGYSTNFYHDVLDAWGQG (SEQ ID NO:10);
or
b) the following hypervariable regions (HVRs):
(i) an HVR-L1 comprising the amino acid sequence KSSQSLLYSGTQKNYLA (SEQ ID NO:14);
(ii) an HVR-L2 comprising the amino acid sequence WASTRQS (SEQ ID NO:15);
(iii) an HVR-L3 comprising the amino acid sequence QQYYDTLTDT (SEQ ID NO:16);
(iv) an HVR-H1 comprising the amino acid sequence GFKFSNYYMS (SEQ ID NO:19);
(v) an HVR-H2 comprising the amino acid sequence SISDGGGDTFCRDLVKG (SEQ ID NO:20); and
(vi) an HVR-H3 comprising the amino acid sequence RGAAMGGVMDAWGQG (SEQ ID NO:21).
34 . An isolated anti-MCAM antibody, or antigen binding fragment thereof, comprising
(a) a light chain variable domain comprising the amino acid sequence shown as SEQ ID NO:2 and a heavy chain variable domain comprising the amino acid sequence shown as SEQ ID NO:7; or
(b) a light chain variable domain comprising the amino acid sequence shown as SEQ ID NO:13 and a heavy chain variable domain comprising the amino acid sequence shown as SEQ ID NO:18.
35 . An isolated anti-MCAM antibody, or antigen binding fragment thereof, which binds to substantially the same epitope as an antibody according to claim 30 .
36 . An isolated anti-MCAM antibody, or antigen binding fragment thereof, that competes for binding to human MCAM with an antibody according to claim 30 .
37 . A pharmaceutical composition comprising an antibody, or antigen binding fragment thereof, according to claim 30 .
38 . (canceled)
39 . The method of claim 18 , wherein said antibody fragment is selected from the group consisting of Fv, Fab, Fab′, and F(ab′)2.
40 . The method of claim 26 , wherein the autoimmune disease is psoriatic arthritis.
41 . The method of claim 26 , wherein the autoimmune disease is rheumatoid arthritis.
42 . The method of claim 26 , wherein the autoimmune disease is psoriasis.