US2012082662A1PendingUtilityA1
Anti-cmet antagonists
Individually held — no corporate assignee on recordPriority: Aug 5, 2004Filed: Jul 28, 2011Published: Apr 5, 2012
Est. expiryAug 5, 2024(expired)· nominal 20-yr term from priority
A61P 43/00C07K 2317/73C07K 16/2863C07K 2317/55C07K 16/005C07K 16/32A61K 2039/505C07K 2317/24C07K 2317/92C07K 2319/30A61P 35/00C07K 16/46A61K 39/395C07K 16/00
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Claims
Abstract
The invention provides therapeutic anti-c-met antibodies, and compositions comprising and methods of using these antibodies.
Claims
exact text as granted — not AI-modified1 . An anti-c-met antibody comprising:
(a) at least one HVR sequence selected from the group consisting of:
(i) HVR-L1 comprising sequence A1-A17, wherein A1-A17 is KSSQSLLYTSSQKNYLA (SEQ ID NO:1)
(ii) HVR-L2 comprising sequence B1-B7, wherein B1-B7 is WASTRES (SEQ ID NO:2)
(iii) HVR-L3 comprising sequence C1-C9, wherein C1-C9 is QQYYAYPWT (SEQ ID NO:3)
(iv) HVR-H1 comprising sequence D1-D10, wherein D1-D10 is GYTFTSYWLH (SEQ ID NO:4)
(v) HVR-H2 comprising sequence E1-E18, wherein E1-E18 is GMIDPSNSDTRFNPNFKD (SEQ ID NO:5)
(vi) HVR-H3 comprising sequence F1-F 11, wherein F1-F11 is XYGSYVSPLDY (SEQ ID NO:6) and X is not R; and
(b) at least one variant HVR, wherein the variant HVR comprises modification of at least one residue of the sequence depicted in SEQ ID NO: 1, 2, 3, 4, 5 or 6.
2 . The antibody of claim 1 , wherein Fl in a variant HVR-H3 is T or S, F3 is R or S and F7 is T.
3 . The antibody of claim 1 , wherein the antibody is humanized.
4 . The antibody of claim 1 , wherein at least a portion of the framework sequence is a human consensus framework sequence.
5 . The antibody of claim 1 , wherein said modification is substitution, insertion or deletion.
6 . The antibody of claim 1 , wherein a HVR-L2 variant comprises 1-5 (1, 2, 3, 4 or 5) substitutions in any combination of the following positions: B1 (M or L), B2 (P, T, G or S), B3 (N, G, R or T), B4 (I, N or F), B5 (P, I, L or G), B6 (A, D, T or V) and B7 (R, I, M or G).
7 . The antibody of claim 1 , wherein a HVR-H1 variant comprises 1-5 (1, 2, 3, 4 or 5) substitutions in any combination of the following positions: D3 (N, P, L, S, A, I), D5 (I, S or Y), D6 (G, D, T, K, R), D7 (F, H, R, S, T or V) and D9 (M or V).
8 . The antibody of claim 1 , wherein a HVR-H2 variant comprises 1-4 (1, 2, 3 or 4) substitutions in any combination of the following positions: E7 (Y), E9 (I), E10 (I), E14 (T or Q), E15 (D, K, S, T or V), E16 (L), E17 (E, H, N or D) and E18 (Y, E or H).
9 . The antibody of claim 1 , wherein a HVR-H3 variant comprises 1-5 (1, 2, 3, 4 or 5) substitutions in any combination of the following positions: F1 (T, S), F3 (R, S, H, T, A, K), F4 (G), F6 (R, F, M, T, E, K, A, L, W), F7 (L, I, T, R, K, V), F8 (S, A), F10 (Y, N) and F11 (Q, S, H, F).
10 . The antibody of claim 1 comprising an HVR-L1 having the sequence of SEQ ID NO:1.
11 . The antibody of claim 1 comprising an HVR-L3 having the sequence of SEQ ID NO:3.
12 . The antibody of claim 1 , wherein F1 in a variant HVR-H3 is T.
13 . The antibody of claim 1 , wherein F3 in a variant HVR-H3 is R or S.
14 . The antibody of claim 1 , wherein F7 in a variant HVR-H3 is T.
15 . A humanized anti-c-met antibody wherein monovalent affinity of the antibody to human c-met is substantially the same as monovalent affinity of a murine antibody comprising a light chain and heavy chain variable sequence as depicted in FIG. 7 (SEQ ID NO: 9 and 10).
16 . A humanized anti-c-met antibody wherein monovalent affinity of the antibody to human c-met is at least 3-fold greater than monovalent affinity of a murine antibody comprising a light chain and heavy chain variable sequence as depicted in FIG. 7 (SEQ ID NO: 9 and 10).
17 . The humanized antibody of claim 15 or 16 wherein the murine antibody is produced by hybridoma cell line deposited under American Type Culture Collection Accession Number ATCC with designation HB-11894 (hybridoma 1A3.3.13) or HB-11895 (hybridoma 5D5.11.6).
18 . The antibody of any of claims 15 - 17 wherein the binding affinity is expressed as a Kd value.
19 . The antibody of any of claim 15 - 18 wherein the binding affinity is measured by Biacore or radioimmunoassay.
20 . The antibody of claim 1 comprising human subgroup 1 consensus framework sequence.
21 . The antibody of claim 1 comprising heavy chain human subgroup III consensus framework sequence.
22 . The antibody of claim 21 wherein the framework sequence comprises a substitution at position 71, 73 and/or 78.
23 . The antibody of claim 22 wherein said substitution is R71A, N73T and/or N78A.
24 . A humanized anti-c-met antibody wherein the humanized antibody inhibits binding human hepatocyte growth factor to its receptor better than a reference antibody comprising a chimeric anti-c-met antibody comprising a light chain and heavy chain variable sequence as depicted in FIG. 7 (SEQ ID NO: 9 and 10).
25 . The antibody of claim 24 , wherein the humanized antibody inhibits binding with an IC50 value that is less than half that of the chimeric antibody.
26 . The antibody of claim 25 , wherein the IC50 is determined across an antibody concentration range from about 0.01 nM to around 1000 nM.
27 . A humanized anti-c-met antibody wherein the humanized antibody inhibits human hepatocyte growth factor (HGF) receptor activation better than a reference antibody comprising a chimeric anti-c-met antibody comprising a light chain and heavy chain variable sequence as depicted in FIG. 7 (SEQ ID NO: 9 and 10).
28 . The antibody of claim 27 , wherein the humanized antibody inhibits receptor activation with an IC50 value that is less than half that of the chimeric antibody.
29 . The antibody of claim 28 , wherein the IC50 is determined across an antibody concentration range from about 0.1 nM to about 100 nM.
30 . A humanized anti-c-met antibody wherein the humanized antibody inhibits c-met-dependent cell proliferation better than a reference antibody comprising a chimeric anti-c-met antibody comprising a light chain and heavy chain variable sequence as depicted in FIG. 7 (SEQ ID NO: 9 and 10).
31 . The antibody of claim 30 , wherein the humanized antibody inhibits cell proliferation with an IC50 value that is less than half that of the chimeric antibody.
32 . The antibody of claim 31 , wherein the IC50 is determined across an antibody concentration range from about 0.01 nM to about 100 nM.
33 . The antibody of the preceding claims, wherein both the humanized antibody and chimeric antibody are monovalent.
34 . The antibody of the preceding claims, wherein both the humanized antibody and chimeric antibody comprise a single Fab region linked to an Fc region.
35 . An antibody comprising a heavy chain variable domain comprising HVR1-HC, HVR2-HC and/or HVR3-HC sequence depicted in FIG. 13 (SEQ ID NO: 191-193).
36 . The antibody of claim 35 , wherein the variable domain comprises FR1-HC, FR2-HC, FR3-HC and/or FR4-HC sequence depicted in FIG. 13 (SEQ ID NO: 187-190).
37 . The antibody of claim 35 or 36 , wherein the antibody comprises CH1 and/or Fc sequence depicted in FIG. 13 (SEQ ID NO: 194 and/or 195).
38 . An antibody comprising a light chain variable domain comprising HVR1-LC, HVR2-LC and/or HVR3-LC sequence depicted in FIG. 13 (SEQ ID NO: 183-185).
39 . The antibody of claim 38 , wherein the variable domain comprises FR1-LC, FR2-LC, FR3-LC and/or FR4-LC sequence depicted in FIG. 13 (SEQ ID NO: 179-182).
40 . The antibody of claim 38 or 39 , wherein the antibody comprises CL1 sequence depicted in FIG. 13 (SEQ ID NO: 186).
41 . An antibody comprising a heavy chain variable domain of any of claims 35 - 37 and a light chain variable domain of any of claims 38 - 40 .
42 . The antibody of claim 41 , wherein the antibody is monovalent and comprises an Fc region.
43 . The antibody of claim 42 , wherein the Fc region comprises a first and a second polypeptide, wherein the first and second polypeptide each comprises one or more mutations with respect to wild type human Fc.
44 . The antibody of claim 43 , wherein the first polypeptide comprises the Fc sequence depicted in FIG. 13 (SEQ ID NO: 195) and the second polypeptide comprises the sequence depicted in FIG. 14 (SEQ ID NO: 196).
45 . A method of inhibiting c-met activated cell proliferation, said method comprising contacting a cell or tissue with an effective amount of an antibody of any of the preceding claims.
46 . A method of modulating a disease associated with dysregulation of the HGF/c-met signaling axis, said method comprising administering to a subject an effective amount of an antibody of any of the preceding claims.
47 . A method of treating a subject having cancer, said method comprising administering to the subject an effective amount of an antibody of any of the preceding claims.
48 . The method of claim 47 , wherein the cancer is lung cancer, brain cancer, kidney cancer, gastric cancer, colorectal cancer and/or pancreatic cancer.
49 . A method of treating a proliferative disorder in a subject, said method comprising administering to the subject an effective amount of an antibody of any of the preceding claims.
50 . The method of claim 49 , wherein the proliferative disorder is cancer.
51 . A nucleic acid encoding the antibody of any of claims 1 - 44 .
52 . A host cell comprising the nucleic acid of claim 51 .
53 . A composition comprising the antibody of any of claims 1 - 44 .
54 . The composition of claim 53 , wherein the composition comprises a carrier.Join the waitlist — get patent alerts
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