US2012045443A1PendingUtilityA1
Agonist anti-trk-c monoclonal antibodies
Est. expiryJun 22, 2020(expired)· nominal 20-yr term from priority
A61P 9/00A61P 25/28A61P 25/00A61P 25/02A61K 2039/505C07K 2317/34C07K 2317/21C07K 16/2863C07K 16/32A61P 21/00C07K 16/28
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Claims
Abstract
The invention concerns agonist anti-trkC monoclonal antibodies which mimic certain biological activities of NT-3, the native ligand of trkC. The invention further concerns the use of such antibodies in the prevention and/or treatment of cellular degeneration, including nerve cell damage associated with acute nervous cell system injury and chronic neurodegenerative diseases, including peripheral neuropathy.
Claims
exact text as granted — not AI-modified1 . An agonist anti-trkC monoclonal antibody which
(a) shows no significant cross-reactivity with trkA or trkB; and (b) recognizes an epitope in domain 5 of trkC.
2 . The antibody of claim 1 which further recognizes an epitope in domain 4 of trkC.
3 . The antibody of claim 1 which binds both human and rat trkC.
4 . The antibody of claim 1 which is a human antibody.
5 . The antibody of claim 1 which is a murine antibody.
6 . The antibody of claim 5 which is humanized.
7 . The antibody of claim 1 effective in the treatment of cisplatin- or pyridoxine-induced neuropathy.
8 . The antibody of claim 1 effective in the treatment of diabetic neuropathy.
9 . The antibody of claim 1 which does not cause hyperalgesia when administered to a patient.
10 . The antibody of claim 1 which has increased bioavailability as compared to NT-3.
11 . The antibody of claim 1 which has a higher specific activity than NT-3.
12 . An anti-trkC antibody heavy chain comprising the following CDRs: a CDR1 selected from the group consisting of SEQ ID NOs: 1, 2, 3, 4 and 5; a CDR2 selected from the group consisting of SEQ ID NOs: 6, 7, 8, 9, 10 and 11; and a CDR3 selected from the group consisting of SEQ ID NOs: 12, 13, 14, 15, 16 and 17.
13 . An anti-trkC antibody light chain comprising the following CDRs: a CDR1 selected from the group consisting of SEQ ID NOs: 18, 19, 20, 21, 22, 23 and 24; a CDR2 selected from the group consisting of SEQ ID NOs: 25, 26, 27, 28, 29 and 30; and a CDR3 selected from the group consisting of SEQ ID NOs: 31, 32, 33, 34, 35 and 36.
14 . A murine anti-trkC antibody heavy chain comprising the following CDRs:
(a) a CDR1 of the formula XaaWXaaXaaWVK (SEQ ID NO: 37), wherein Xaa at position 1 is F or Y; Xaa at position 3 is I or M; and Xaa at position 4 is E or H; (b) a CDR2 of the formula EIXaaPXaaXaaXaaXaaTNYNEKFKXaa (SEQ ID NO: 38), wherein Xaa at position 3 is L or Y; Xaa at position 5 is G or S; Xaa at position 6 is S or N; Xaa at position 7 is D or G; Xaa at position 8 is N or R and Xaa at position 17 is G or S; and (c) a CDR3 of the formula KNRNYYGNYVV (SEQ ID NO: 12) or KYYYGNSYRSWYFDV (SEQ ID NO: 13).
15 . A human anti-trkC antibody heavy chain comprising the following CDRs:
(a) a CDR1 of the formula XaaXaaXaaYYWXaa (SEQ ID NO: 39), wherein Xaa at position 1 is S or I; Xaa at position 2 is G or S; Xaa at position 3 is G, T or Y, and Xaa at position 7 is S or N; (b) a CDR2 of the formula XaaIXaaXaaSGSXaaTXaaNPSLKS (SEQ ID NO: 40), wherein Xaa at position 1 is Y or R; Xaa at position 3 is Y or F; Xaa at position 4 is Y or T; Xaa at position 8 is S or R; and Xaa at position 10 is N or Y; and (c) a CDR3 of the formula selected from the group consisting of DRDYDSTGDYYSYYGMDV (SEQ ID NO: 14); DGGYSNPFD (SEQ ID NO: 15); ERIAAAGXaaDYYYNGLXaaV (SEQ ID NO: 41), wherein Xaa at position 8 is A or T and Xaa at position 16 is D or A.
16 . An anti-trkC agonist monoclonal antibody comprising a heavy chain comprising the CDRs of the murine anti-trkC antibody heavy chain of claim 14 associated with a light chain.
17 . The antibody of claim 16 comprising human framework residues.
18 . The antibody of claim 17 which shows no significant cross-reactivity with trkA or trkB.
19 . The antibody of claim 17 having a homo-tetrameric structure composed of two disulfide-bonded antibody heavy chain-light chain pairs.
20 . The antibody of claim 17 which is an antibody fragment selected from the group consisting of Fv, Fab, Fab′ and F(ab′) 2 fragments.
21 . An anti-trkC agonist monoclonal antibody comprising a human anti-trkC antibody heavy chain of claim 15 associated with a human antibody light chain.
22 . The antibody of claim 21 which shows no significant cross-reactivity with trkA or trkB.
23 . The antibody of claim 22 having a homo-tetrameric structure composed of two disulfide-bonded antibody heavy chain-light chain pairs.
24 . The antibody of claim 22 which is an antibody fragment selected from the group consisting of Fv, Fab, Fab′ and F(ab′) 2 fragments.
25 . The antibody of claim 22 which is an IgG.
26 . The antibody of claim 25 which is an IgG-2 or IgG-4.
27 . A murine anti-trkC agonist antibody selected from the group consisting of antibodies 2248, 2250, 2253 and 2256.
28 . A human anti-trkC agonist antibody selected from the group consisting of antibodies 6.1.2, 6.4.1, 2345, 2349, 2.5.1 and 2344.
29 . (canceled)
30 . An isolated nucleic acid molecule encoding a murine anti-trkC agonist antibody of claim 27 or a human anti-trkC agonist antibody selected from the group consisting of antibodies 6.1.2, 6.4.1, 2345, 2349, 2.5.1 and 2344.
31 . (canceled)
32 . A nucleic acid molecule deposited with ATCC on Jun. 21, 2000 under an accession number selected from the group consisting of PTA-2136, PTA-2137, PTA-2138, PTA-2133, PTA-2134, PTA-2135, PTA-2139, PTA-2140, PTA-2141, PTA-2142 and PTA-2143.
33 . (canceled)
34 . A vector comprising a nucleic acid molecule of claim 30 or a nucleic acid molecule selected from the group consisting of nucleic acid molecules deposited with ATCC on Jun. 21, 2000 under an accession number selected from the group consisting of PTA-2136, PTA-2137, PTA-2138, PTA-2133, PTA-2134, PTA-2135, PTA-2139, PTA-2140, PTA-2141, PTA-2142 and PTA-2143.
35 . A host cell line transformed with a nucleic acid molecule of claim 30 or a nucleic acid molecule selected from the group consisting of nucleic acid molecules deposited with ATCC on Jun. 21, 2000 under an accession number selected from the group consisting of PTA-2136, PTA-2137, PTA-2138, PTA-2133, PTA-2134, PTA-2135, PTA-2139, PTA-2140, PTA-2141, PTA-2142 and PTA-2143.
36 . A hybridoma cell line transformed with a nucleic acid molecule of claim 30 , or a nucleic acid molecule selected from the group consisting of nucleic acid molecules deposited with ATCC on Jun. 21, 2000 under an accession number selected from the group consisting of PTA-2136, PTA-2137, PTA-2138, PTA-2133, PTA-2134, PTA-2135, PTA-2139, PTA-2140, PTA-2141, PTA-2142 and PTA-2143.
37 . An antibody produced by a hybridoma cell line of claim 36 .
38 . An isolated nucleic acid molecule encoding a heavy chain of an anti-trkC agonist monoclonal antibody, said nucleic acid molecule selected from the group consisting of SEQ ID NO: 58, SEQ ID NO: 60, SEQ ID NO: 62, SEQ ID NO: 64, SEQ ID NO: 66, SEQ ID NO. 68 and SEQ ID NO: 70.
39 . An isolated nucleic acid molecule encoding a light chain of an anti-trkC agonist monoclonal antibody, said nucleic acid molecule selected from the group consisting of SEQ ID NO: 59, SEQ ID NO: 61, SEQ ID NO: 63, SEQ ID NO: 65, SEQ ID NO: 67, SEQ ID NO: 69 and SEQ ID NO: 71.
40 . A vector comprising a nucleic acid molecule of claim 38 or a nucleic acid molecule selected from the group consisting of SEQ ID NO: 59, SEQ ID NO: 61, SEQ ID NO: 63, SEQ ID NO: 65, SEQ ID NO: 67, SEQ ID NO: 69 and SEQ ID NO: 71.
41 . A host cell transformed with a nucleic acid molecule of claim 38 or a nucleic acid molecule selected from the group consisting of SEQ ID NO: 59, SEQ ID NO: 61, SEQ ID NO: 63, SEQ ID NO: 65, SEQ ID NO: 67, SEQ ID NO: 69 and SEQ ID NO: 71.
42 . A host cell transformed with both a nucleic acid molecule of claim 38 and a nucleic acid molecule selected from the group consisting of SEQ ID NO: 59, SEQ ID NO: 61, SEQ ID NO: 63, SEQ ID NO: 65, SEQ ID NO: 67, SEQ ID NO: 69 and SEQ ID NO: 71.
43 . A hybridoma cell line transformed with a nucleic acid molecule of claim 38 or a nucleic acid molecule selected from the group consisting of SEQ ID NO: 59, SEQ ID NO: 61, SEQ ID NO: 63, SEQ ID NO: 65, SEQ ID NO: 67, SEQ ID NO: 69 and SEQ ID NO: 71.
44 . A hybridoma cell line transformed with a nucleic acid molecule of claim 38 and a nucleic acid molecule selected from the group consisting of SEQ ID NO: 59, SEQ ID NO: 61, SEQ ID NO: 63, SEQ ID NO: 65, SEQ ID NO: 67, SEQ ID NO: 69 and SEQ ID NO: 71.
45 . An antibody produced by a hybridoma cell line of claim 43 .
46 . An antibody produced by a hybridoma cell line of claim 44 .
47 . A polypeptide encoded by a nucleic acid molecule of claim 38 or by nucleic acid molecule selected from the group consisting of SEQ ID NO: 59, SEQ ID NO: 61, SEQ ID NO: 63, SEQ ID NO: 65, SEQ ID NO: 67, SEQ ID NO: 69 and SEQ ID NO: 71.
48 . A polypeptide comprising polypeptide chains encoded by a nucleic acid molecule of claim 38 and a nucleic acid molecule selected from the group consisting of SEQ ID NO: 59, SEQ ID NO: 61, SEQ ID NO: 63, SEQ ID NO: 65, SEQ ID NO: 67, SEQ ID NO: 69 and SEQ ID NO: 71.
49 . A pharmaceutical composition comprising an effective amount of an agonist anti-trkC monoclonal antibody of any one of claims 1 , 16 , and 21 , in admixture with a pharmaceutically acceptable carrier.
50 . A method for treating a neuropathy or neurodegenerative disease, or repairing a damaged nerve cell comprising administering to a mammal an effective amount of an antibody of claim 1 .
51 - 57 . (canceled)
58 . A method for enhancing the proliferation, maintenance or regeneration of peripheral neurons comprising contacting said neurons with an effective amount of an antibody of claim 1 , claim 16 , or claim 21 .
59 . A method for the treatment of a disease or condition involving cell degeneration in a mammalian subject by introducing nucleic acid encoding an anti-trkC antibody of claim 1 into a cell of such subject.
60 - 63 . (canceled)
64 . A method of inducing angiogenesis comprising delivering an anti-trkC antibody of claim 1 in an amount effective to induce angiogenesis.
65 . A method of making an agonist anti-trkC antibody comprising preparing an antibody specifically binding trkC at a site overlapping with the binding site of a native NT-3 ligand of said trkC.
66 - 69 . (canceled)Cited by (0)
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