ANTI-MCAM ANTIBODIES AND ASSOCIATED METHODS OF USE
Described herein are anti-MCAM antibodies and antigen binding fragments thereof that are capable of inhibiting the interaction between MCAM and its ligand, a protein comprising a laminin α-4 chain. These anti-MCAM antibodies and antigen binding fragments thereof may be useful for, for example, treating inflammatory conditions characterized by the infiltration of MCAM-expressing cells into a site of inflammation in the body.
1 . An isolated anti-MCAM antibody, or antigen binding fragment thereof, said antibody or antigen binding fragment thereof comprising three light chain hypervariable regions (HVR-L1, HVR-L2, and HVR-L3) and three heavy chain hypervariable regions (HVR-H1, HVR-H2, and HVR-H3), wherein:
(a) HVR-L1 comprises the amino acid sequence of SEQ ID NO:31, HVR-L2 comprises the amino acid sequence of SEQ ID NO:32, HVR-L3 comprises the amino acid sequence of SEQ ID NO:33, HVR-H1 comprises the amino acid sequence of SEQ ID NO:36, HVR-H2 comprises the amino acid sequence of SEQ ID NO:37, and HVR-H3 comprises the amino acid sequence of SEQ ID NO:38;
(b) HVR-L1 comprises the amino acid sequence of SEQ ID NO:41, HVR-L2 comprises the amino acid sequence of SEQ ID NO:42, HVR-L3 comprises the amino acid sequence of SEQ ID NO:43, HVR-H1 comprises the amino acid sequence of SEQ ID NO:46, HVR-H2 comprises the amino acid sequence of SEQ ID NO:47, and HVR-H3 comprises the amino acid sequence of SEQ ID NO:48;
(c) HVR-L1 comprises the amino acid sequence of SEQ ID NO:51, HVR-L2 comprises the amino acid sequence of SEQ ID NO:52, HVR-L3 comprises the amino acid sequence of SEQ ID NO:53, HVR-H1 comprises the amino acid sequence of SEQ ID NO:56, HVR-H2 comprises the amino acid sequence of SEQ ID NO:57, and HVR-H3 comprises the amino acid sequence of SEQ ID NO:58;
(d) HVR-L1 comprises the amino acid sequence of SEQ ID NO:61, HVR-L2 comprises the amino acid sequence of SEQ ID NO:62, HVR-L3 comprises the amino acid sequence of SEQ ID NO:63, HVR-H1 comprises the amino acid sequence of SEQ ID NO:66, HVR-H2 comprises the amino acid sequence of SEQ ID NO:67, and HVR-H3 comprises the amino acid sequence of SEQ ID NO:68;
(e) HVR-L1 comprises the amino acid sequence of SEQ ID NO:73, HVR-L2 comprises the amino acid sequence of SEQ ID NO:74, HVR-L3 comprises the amino acid sequence of SEQ ID NO:75, HVR-H1 comprises the amino acid sequence of SEQ ID NO:78, HVR-H2 comprises the amino acid sequence of SEQ ID NO:79, and HVR-H3 comprises the amino acid sequence of SEQ ID NO:80; or
(f) HVR-L1 comprises the amino acid sequence of SEQ ID NO:85, HVR-L2 comprises the amino acid sequence of SEQ ID NO:86, HVR-L3 comprises the amino acid sequence of SEQ ID NO:87, HVR-H1 comprises the amino acid sequence of SEQ ID NO:90, HVR-H2 comprises the amino acid sequence of SEQ ID NO:91, and HVR-H3 comprises the amino acid sequence of SEQ ID NO:92.
2 . The isolated anti-MCAM antibody or antigen binding fragment of claim 1 , wherein HVR-L1 comprises the amino acid sequence of SEQ ID NO:31, HVR-L2 comprises the amino acid sequence of SEQ ID NO:32, HVR-L3 comprises the amino acid sequence of SEQ ID NO:33, HVR-H1 comprises the amino acid sequence of SEQ ID NO:36, HVR-H2 comprises the amino acid sequence of SEQ ID NO:37, and HVR-H3 comprises the amino acid sequence of SEQ ID NO:38.
3 . The isolated anti-MCAM antibody or antigen binding fragment of claim 1 , wherein HVR-L1 comprises the amino acid sequence of SEQ ID NO:41, HVR-L2 comprises the amino acid sequence of SEQ ID NO:42, HVR-L3 comprises the amino acid sequence of SEQ ID NO:43, HVR-H1 comprises the amino acid sequence of SEQ ID NO:46, HVR-H2 comprises the amino acid sequence of SEQ ID NO:47, and HVR-H3 comprises the amino acid sequence of SEQ ID NO:48.
4 . The isolated anti-MCAM antibody or antigen binding fragment of claim 1 , wherein HVR-L1 comprises the amino acid sequence of SEQ ID NO:51, HVR-L2 comprises the amino acid sequence of SEQ ID NO:52, HVR-L3 comprises the amino acid sequence of SEQ ID NO:53, HVR-H1 comprises the amino acid sequence of SEQ ID NO:56, HVR-H2 comprises the amino acid sequence of SEQ ID NO:57, and HVR-H3 comprises the amino acid sequence of SEQ ID NO:58.
5 . The isolated anti-MCAM antibody or antigen binding fragment of claim 1 , wherein HVR-L1 comprises the amino acid sequence of SEQ ID NO:61, HVR-L2 comprises the amino acid sequence of SEQ ID NO:62, HVR-L3 comprises the amino acid sequence of SEQ ID NO:63, HVR-H1 comprises the amino acid sequence of SEQ ID NO:66, HVR-H2 comprises the amino acid sequence of SEQ ID NO:67, and HVR-H3 comprises the amino acid sequence of SEQ ID NO:68.
6 . The isolated anti-MCAM antibody or antigen binding fragment of claim 1 , wherein HVR-L1 comprises the amino acid sequence of SEQ ID NO:73, HVR-L2 comprises the amino acid sequence of SEQ ID NO:74, HVR-L3 comprises the amino acid sequence of SEQ ID NO:75, HVR-H1 comprises the amino acid sequence of SEQ ID NO:78, HVR-H2 comprises the amino acid sequence of SEQ ID NO:79, and HVR-H3 comprises the amino acid sequence of SEQ ID NO:80.
7 . The isolated anti-MCAM antibody or antigen binding fragment of claim 1 , wherein HVR-L1 comprises the amino acid sequence of SEQ ID NO:85, HVR-L2 comprises the amino acid sequence of SEQ ID NO:86, HVR-L3 comprises the amino acid sequence of SEQ ID NO:87, HVR-H1 comprises the amino acid sequence of SEQ ID NO:90, HVR-H2 comprises the amino acid sequence of SEQ ID NO:91, and HVR-H3 comprises the amino acid sequence of SEQ ID NO:92.
8 . The isolated antibody of claim 1 which is a chimeric or humanized antibody.
9 . The isolated antibody of claim 1 which is an IgG1 antibody.
10 . The isolated antibody of claim 1 which is produced in bacteria or CHO cells.
11 . An isolated anti-MCAM antibody, or antigen binding fragment thereof, said antibody or antigen binding fragment thereof comprising a light chain variable region and a heavy chain variable region, wherein:
(a) the light chain variable region comprises the amino acid sequence of SEQ ID NO:30 and the heavy chain variable region comprises the amino acid sequence of SEQ ID NO:35;
(b) the light chain variable region comprises the amino acid sequence of SEQ ID NO:40 and the heavy chain variable region comprises the amino acid sequence of SEQ ID NO:45;
(c) the light chain variable region comprises the amino acid sequence of SEQ ID NO:50 and the heavy chain variable region comprises the amino acid sequence of SEQ ID NO:55;
(d) the light chain variable region comprises the amino acid sequence of SEQ ID NO:60 and the heavy chain variable region comprises the amino acid sequence of SEQ ID NO:65;
(e) the light chain variable region comprises the amino acid sequence of any one of SEQ ID NOS:70, 71, or 72 and the heavy chain variable region comprises the amino acid sequence of SEQ ID NO:77; or
(f) the light chain variable region comprises the amino acid sequence of any one of SEQ ID NOS:83 or 84 and the heavy chain variable region comprises the amino acid sequence of SEQ ID NO:89.
12 . The isolated anti-MCAM antibody, or antigen binding fragment thereof, of claim 11 , wherein the light chain variable region comprises the amino acid sequence of SEQ ID NO:30 and the heavy chain variable region comprises the amino acid sequence of SEQ ID NO:35.
13 . The isolated anti-MCAM antibody, or antigen binding fragment thereof, of claim 11 , wherein the light chain variable region comprises the amino acid sequence of SEQ ID NO:40 and the heavy chain variable region comprises the amino acid sequence of SEQ ID NO:45.
14 . The isolated anti-MCAM antibody, or antigen binding fragment thereof, of claim 11 , wherein the light chain variable region comprises the amino acid sequence of SEQ ID NO:50 and the heavy chain variable region comprises the amino acid sequence of SEQ ID NO:55.
15 . The isolated anti-MCAM antibody, or antigen binding fragment thereof, of claim 11 , wherein the light chain variable region comprises the amino acid sequence of SEQ ID NO:60 and the heavy chain variable region comprises the amino acid sequence of SEQ ID NO:65.
16 . The isolated anti-MCAM antibody, or antigen binding fragment thereof, of claim 11 , wherein the light chain variable region comprises the amino acid sequence of any one of SEQ ID NOS:70, 71, or 72 and the heavy chain variable region comprises the amino acid sequence of SEQ ID NO:77.
17 . The isolated anti-MCAM antibody, or antigen binding fragment thereof, of claim 11 , wherein the light chain variable region comprises the amino acid sequence of any one of SEQ ID NOS:83 or 84 and the heavy chain variable region comprises the amino acid sequence of SEQ ID NO:89.
18 . The isolated antibody of claim 11 which is a chimeric or humanized antibody.
19 . The isolated antibody of claim 11 which is an IgG1 antibody.
20 . The isolated antibody of claim 11 which is produced in bacteria or CHO cells.
21 . An isolated anti-MCAM antibody, or antigen binding fragment thereof, that binds substantially the same epitope as, or competes for binding with, an antibody of claim 1 .
22 . An isolated anti-MCAM antibody, or antigen binding fragment thereof, that binds substantially the same epitope as, or competes for binding with, an antibody of claim 11 .
23 . An isolated anti-MCAM antibody, or antigen binding fragment thereof, that blocks the interaction between an MCAM protein comprising the amino acid sequence of SEQ ID NO:22 and a protein comprising a laminin α-4 chain.
24 . An isolated anti-MCAM antibody, or antigen binding fragment thereof, that blocks the interaction between an MCAM protein comprising the amino acid sequences of SEQ ID NOS:22 and 23 and a protein comprising a laminin α-4 chain.
25 . The isolated anti-MCAM antibody or antigen binding fragment of claim 24 which is the antibody of claim 1 or 11 .
26 . The isolated anti-MCAM antibody or antigen binding fragment of claim 24 which does not block the interaction between an MCAM protein consisting of the amino acid sequence of SEQ ID NO:22 and a protein comprising a laminin α-4 chain.
27 . An isolated anti-MCAM antibody, or antigen binding fragment thereof, that blocks the interaction between an MCAM protein comprising the amino acid sequences of SEQ ID NOS:22, 23, and 24 and a protein comprising a laminin α-4 chain.
28 . The isolated anti-MCAM antibody or antigen binding fragment of claim 27 which is the antibody of claim 1 or 11 .
29 . The isolated anti-MCAM antibody or antigen binding fragment of claim 27 which does not block the interaction between an MCAM protein consisting of the amino acid sequence of SEQ ID NO:22 and a protein comprising a laminin α-4 chain.
30 . An isolated anti-MCAM antibody or antigen binding fragment thereof, which binds to amino acids 244-321 of the human MCAM protein.
31 . The isolated anti-MCAM antibody or antigen binding fragment of claim 30 which blocks the binding interaction between human MCAM and a laminin α-4 chain.
32 . An isolated anti-MCAM antibody or antigen binding fragment thereof, which binds to amino acids 19-242 of the human MCAM protein but which does not bind to amino acids 19-129 of the human MCAM protein.
33 . The isolated anti-MCAM antibody or antigen binding fragment of claim 32 which blocks the binding interaction between human MCAM and a laminin α-4 chain.
34 . A pharmaceutical composition comprising an antibody, or antigen binding fragment thereof, according to any of claims 1 , 11 , 21 , 22 , 23 , 24 , 27 , 30 , or 32 .
35 . An article of manufacture comprising the pharmaceutical composition of claim 34 .
36 . Use of an anti-MCAM antibody, or antigen binding fragment thereof, according to any of claims 1 , 11 , 21 , 22 , 23 , 34 , 27 , 30 , or 32 , in the manufacture of a medicament for the treatment of an inflammatory disorder characterized by infiltration of MCAM-expressing cells into a site of inflammation in the body.
37 . Use of an anti-MCAM antibody, or antigen binding fragment thereof, according to any of claims 1 , 11 , 21 , 22 , 23 , 24 , 27 , 30 , or 32 , in the manufacture of a medicament for the treatment of a central nervous system (CNS) inflammatory disorder characterized by infiltration of MCAM-expressing cells into the CNS.
38 . Use of an anti-MCAM antibody, or antigen binding fragment thereof, according to any of claims 1 , 11 , 21 , 22 , 23 , 24 , 27 , 30 , or 32 , in the manufacture of a medicament for the treatment of multiple sclerosis.
39 . Use of an anti-MCAM antibody, or antigen binding fragment thereof, according to any of claims 1 , 11 , 21 , 22 , 23 , 24 , 27 , 30 , or 32 , in the manufacture of a medicament for the treatment of psoriasis.
40 . Use of an anti-MCAM antibody, or antigen binding fragment thereof, according to any of claims 1 , 11 , 21 , 22 , 23 , 24 , 27 , 30 , or 32 , in the manufacture of a medicament for the treatment of a solid tumor, such as melanoma.
41 . Use of an anti-MCAM antibody, or antigen binding fragment thereof, according to any of claims 1 , 11 , 21 , 22 , 23 , 24 , 27 , 30 , or 32 , in the manufacture of a medicament for the treatment of sarcoidosis.
42 . Use of an anti-MCAM antibody, or antigen binding fragment thereof, according to any of claims 1 , 11 , 21 , 22 , 23 , 24 , 27 , 30 , or 32 , in the manufacture of a medicament for the treatment of any of psoriatic arthritis.
43 . Use of an anti-MCAM antibody, or antigen binding fragment thereof, according to any of claims 1 , 11 , 21 , 22 , 23 , 24 , 27 , 30 , or 32 , in the manufacture of a medicament for the treatment of Parkinson's disease.
44 . Use of an anti-MCAM antibody, or antigen binding fragment thereof, according to any of claims 1 , 11 , 21 , 22 , 23 , 24 , 27 , 30 , or 32 , in the manufacture of a medicament for the treatment of allergic contact dermatitis.
45 . A method for the treatment of an inflammatory disorder characterized by infiltration of MCAM-expressing cells to a site of inflammation, the method comprising administering to a mammalian subject in need thereof an effective amount of an anti-MCAM antibody or antigen binding fragment thereof that inhibits the binding of MCAM to a protein comprising a laminin α-4 chain.
46 . The method or use of any of claims 36 - 45 , wherein the mammalian subject is a human.
47 . The method of claim 45 , wherein the MCAM-expressing cells are TH17 cells.
48 . The method of claim 45 , wherein the anti-MCAM antibody or antigen binding fragment thereof is an antibody according to any of claims 1 , 11 , 21 , 22 , 23 , 24 , 27 , 30 , or 32 .
49 . An isolated anti-MCAM antibody, or antigen binding fragment thereof, said antibody or antigen binding fragment thereof comprising three light chain hypervariable regions (HVR-L1, HVR-L2, and HVR-L3) and three heavy chain hypervariable regions (HVR-H1, HVR-H2, and HVR-H3), wherein HVR-L1 comprises the amino acid sequence of SEQ ID NO: 61, HVR-L2 comprises the amino acid sequence of SEQ ID NO:62, HVR-L3 comprises the amino acid sequence of SEQ ID NO:63, HVR-H1 comprises the amino acid sequence of SEQ ID NO:66, HVR-H2 comprises the amino acid sequence of SEQ ID NO:67, HVR-H3 comprises the amino acid sequence of SEQ ID NO:68.
50 . The isolated anti-MCAM antibody, or antibody binding fragment thereof, of claim 49 wherein the antibody further comprises a heavy chain framework region 2 (FR2) comprising the amino acid sequence of SEQ ID NO: 128.
51 . An isolated anti-MCAM antibody, or antigen binding fragment thereof, said antibody or antigen binding fragment thereof comprising three light chain hypervariable regions (HVR-L1, HVR-L2, and HVR-L3) and three heavy chain hypervariable regions (HVR-H1, HVR-H2, and HVR-H3), wherein HVR-L1 comprises the amino acid sequence of SEQ ID NO:85, HVR-L2 comprises the amino acid sequence of SEQ ID NO:86, HVR-L3 comprises the amino acid sequence of SEQ ID NO:87, HVR-H1 comprises the amino acid sequence of SEQ ID NO:90, HVR-H2 comprises the amino acid sequence of SEQ ID NO:91, and HVR-H3 comprises the amino acid sequence of SEQ ID NO:92.
52 . The isolated anti-MCAM antibody, or antibody binding fragment thereof, further comprising a heavy chain framework region 2 (FR2) comprising the amino acid sequence of SEQ ID NO:134.
53 . The isolated anti-MCAM antibody, or antibody binding fragment thereof, wherein the antibody further comprises a heavy chain framework region 3 (FR3) comprising the amino acid sequence of SEQ ID NO:137.
54 . The isolated anti-MCAM antibody, or antibody binding fragment thereof, wherein the antibody further comprises a light chain framework region 2 (FR2) comprising the amino acid sequence of SEQ ID NO:146.
55 . The isolated anti-MCAM antibody, or antibody binding fragment thereof, wherein the antibody further comprises a light chain framework region 3 (FR3) comprising the amino acid sequence of SEQ ID NO:144.
56 . An isolated anti-MCAM antibody, or antigen binding fragment thereof, said antibody or antigen binding fragment thereof comprising three light chain hypervariable regions (HVR-L1, HVR-L2, and HVR-L3) and three heavy chain hypervariable regions (HVR-H1, HVR-H2, and HVR-H3),
wherein HVR-L1 comprises the amino acid sequence of SEQ ID NO:73, HVR-L2 comprises the amino acid sequence of SEQ ID NO:74, HVR-L3 comprises the amino acid sequence of SEQ ID NO:75, HVR-H1 comprises the amino acid sequence of SEQ ID NO:141, HVR-H2 comprises the amino acid sequence of SEQ ID NO:79, and HVR-H3 comprises the amino acid sequence of SEQ ID NO:80.
57 . The isolated anti-MCAM antibody, or antibody binding fragment thereof, wherein the antibody further comprises a heavy chain framework region 2 (FR2) comprising the amino acid sequence of SEQ ID NO:134.
58 . The isolated anti-MCAM antibody, or antibody binding fragment thereof, wherein the antibody further comprises a heavy chain framework region 3 (FR3) comprising the amino acid sequence of SEQ ID NO:135.
59 . The isolated anti-MCAM antibody, or antibody binding fragment thereof, wherein the antibody further comprises a light chain framework region 1 (FR1) comprising the amino acid sequence of SEQ ID NO:147.
60 . The isolated anti-MCAM antibody, or antibody binding fragment thereof, wherein the antibody further comprises a light chain framework region 2 (FR2) comprising the amino acid sequence of SEQ ID NO:148.
61 . The isolated anti-MCAM antibody, or antibody binding fragment thereof, wherein the antibody further comprises a light chain framework region 3 (FR3) comprising the amino acid sequence of SEQ ID NO:149.