The present application is directed to heterodimeric antibodies and methods of use.
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1. method of treating a bone gap defect in a mammalian subject comprising administering to the subject an antibody that binds to a region of sclerostin comprising amino acids 86-111 of SEQ ID NO: 1, wherein the antibody comprises a first heavy chain and a first light chain comprising a sclerostin-bi
1. method of treating a bone gap defect in a mammalian subject comprising administering to the subject an antibody that binds to a region of sclerostin comprising amino acids 86-111 of SEQ ID NO: 1, wherein the antibody comprises a first heavy chain and a first light chain comprising a sclerostin-binding portion and a second heavy chain and a second light chain comprising a DKK1-binding portion, wherein the first heavy chain comprises amino acid substitutions at EU positions 183, 356 and 399, wherein the second heavy chain comprises amino acid substitutions at EU positions 183 , 392 and 409, and wherein the first and second light chains comprise an amino acid substitution at EU position 176, wherein the amino acid substitutions introduce a charged amino acid at said positions, wherein the substitution introduce charged amino acids that are electrostatically unfavorable to homodimer formation and electrostatically favorable to heterodimer formation, wherein the antibody is administered in an amount effective to treat the gap defect in the subject. 2. The method of claim 1, wherein the negative charged amino acid at one or more of EU positions D399, E356 and E357 in the CH3 domain are substituted with a positive charged amino acid. 3. The method of claim 1, wherein the positive charged amino acids at one or more of EU positions K370, K392 and K409 in the CH3domain are each substituted with a negative charged amino acid. 4. The method of claim 1, wherein the antibody comprises a set of six CDRs selected from the group consisting of a) CDR sequences of SEQ ID NOs:54, 55, and 56 and CDR sequences of SEQ ID NOs:51, 52, and 53; b) CDR sequences of SEQ ID NOs:60, 61, and 62 and CDR sequences of SEQ ID NOs:57, 58, and 59; c) CDR sequences of SEQ ID NOs:48, 49, and 50 and CDR sequences of SEQ ID NOs: 45, 46, and 47; d) CDR sequences of SEQ ID NOs:42, 43, and 44 and CDR sequences of SEQ ID NOs:39, 40, and 41; e) CDR sequences of SEQ ID NOs:275, 276, and 277and CDR sequences of SEQ ID NOs:287, 288, and 289; f) CDR sequences of SEQ ID NOs:278, 279, and 280 and CDR sequences of SEQ ID NOs:290, 291, and 292; g) CDR sequences of SEQ ID NOs:78, 79, and 80 and CDR sequences of SEQ ID NOs: 245, 246, and 247; h) CDR sequences of SEQ ID NOs:81, 99, and 100 and CDR sequences of SEQ ID NOs:248, 249, and 250; i) CDR sequences of SEQ ID NOs:101, 102, and 103 and CDR sequences of SEQ ID NOs:251, 252, and 253; j) CDR sequences of SEQ ID NOs:104, 105, and 106 and CDR sequences of SEQ ID NOs:254, 255, and 256; k) CDR sequences of SEQ ID NOs:107, 108, and 109 and CDR sequences of SEQ ID NOs:257, 258, and 259; I) CDR sequences of SEQ ID NOs:110, 111, and 112 and CDR sequences of SEQ ID NOs:260, 261, and 262; m) CDR sequences of SEQ ID NOs:281, 282, and 283 and CDR sequences of SEQ ID NOs:293, 294, and 295; n) CDR sequences of SEQ ID NOs:113, 114, and 115 and CDR sequences of SEQ ID NOs:263, 264, and 265; o) CDR sequences of SEQ ID NOs:284, 285, and 286 and CDR sequences of SEQ ID NOs:296, 297, and 298; p) CDR sequences of SEQ ID NOs:116, 237, and 238 and CDR sequences of SEQ ID NOs:266, 267, and 268; q) CDR sequences of SEQ ID NOs:239, 240, and 241 and CDR sequences of SEQ ID NOs:269, 270, and 271) CDR sequences of SEQ ID NOs:242, 243, and 244 and CDR sequences of SEQ ID NOs:272, 273, and 274; and s) CDR sequences of SEQ ID NOs:351, 352, and 353and CDR sequences of SEQ ID NOs:358, 359, and 360. 5. The method of claim 1, wherein the antibody comprises a light chain comprising a variable region amino acid sequence selected from the group consisting of SEQ ID NO: 364, SEQ ID NO: 376, SEQ ID NO: 75, SEQ ID NO: 384, SEQ ID NO: 388, SEQ ID NO: 380, SEQ ID NO: 299, SEQ ID NO: 303, SEQ ID NO: 314, SEQ ID NO: 311, SEQ ID NO: 315 and SEQ ID NO: 368. 6. The method of claim 1, wherein the antibody comprises a heavy chain comprising a variable region amino acid sequence selected from the group consisting of SEQ ID NO: 366, SEQ ID NO: 378, SEQ ID NO: 77, SEQ ID NO: 386, SEQ ID NO: 390, SEQ ID NO: 382, SEQ ID NO: 301, SEQ ID NO: 305, SEQ ID NO: 327, SEQ ID NO: 313, SEQ ID NO: 317 and SEQ ID NO: 370. 7. The method of claim 1, wherein the antibody comprises a first heavy chain and a first light chain comprising a sclerostin-binding portion and a second heavy chain and a second light chain comprising a DKK1-binding portion, wherein the first heavy chain comprises amino acid substitutions at AHo position 46 and EU positions 183, 356 and 399, wherein the second heavy chain comprises amino acid substitutions at AHo position 46 and EU positions 183, 392 and 409, wherein the first and second light chains comprise an amino acid substitution at AHo position 46 and EU position 176, and wherein the amino acid substitutions introduce a charged amino acid at said positions. 8. The method of claim 1, wherein the sclerostin-binding portion comprises a set of six CDRs selected from the group consisting of a) CDR sequences of SEQ ID NOs:54, 55, and 56 and CDR sequences of SEQ ID NOs:51, 52, and 53; b) CDR sequences of SEQ ID NOs:60, 61, and 62 and CDR sequences of SEQ ID NOs:57, 58, and 59; c) CDR sequences of SEQ ID NOs:48, 49, and 50 and CDR sequences of SEQ ID NOs: 45, 46, and 47; d) CDR sequences of SEQ ID NOs:42, 43, and 44 and CDR sequences of SEQ ID NOs:39, 40, and 41; e) CDR sequences of SEQ ID NOs:275, 276, and 277 and CDR sequences of SEQ ID NOs:287, 288, and 289; f) CDR sequences of SEQ ID NOs:278, 279, and 280 and CDR sequences of SEQ ID NOs:290, 291, and 292; g) CDR sequences of SEQ ID NOs:78, 79, and 80 and CDR sequences of SEQ ID NOs: 245, 246, and 247; h) CDR sequences of SEQ ID NOs:81, 99, and 100 and CDR sequences of SEQ ID NOs:248, 249, and 250; i) CDR sequences of SEQ ID NOs:101, 102, and 103and CDR sequences of SEQ ID NOs:251, 252, and 253; j) CDR sequences of SEQ ID NOs:104, 105, and 106 and CDR sequences of SEQ ID NOs:254, 255, and 256; k) CDR sequences of SEQ ID NOs:107, 108, and 109 and CDR sequences of SEQ ID NOs:257, 258, and 259; I) CDR sequences of SEQ ID NOs:110, 111, and 112 and CDR sequences of SEQ ID NOs:260, 261, and 262; m) CDR sequences of SEQ ID NOs:281, 282, and 283 and CDR sequences of SEQ ID NOs:293, 294, and 295; n) CDR sequences of SEQ ID NOs:113, 114, and 115and CDR sequences of SEQ ID NOs:263, 264, and 265; o) CDR sequences of SEQ ID NOs:284, 285, and 286 and CDR sequences of SEQ ID NOs:296, 297, and 298; p) CDR sequences of SEQ ID NOs:116, 237, and 238 and CDR sequences of SEQ ID NOs:266, 267, and 268; q) CDR sequences of SEQ ID NOs:239, 240, and 241 and CDR sequences of SEQ ID NOs:269, 270, and 271) CDR sequences of SEQ ID NOs:242, 243, and 244and CDR sequences of SEQ ID NOs:272, 273, and 274; or s) CDR sequences of SEQ ID NOs:351, 352, and 353 and CDR sequences of SEQ ID NOs:358, 359, and 360. 9. The method of claim 1, wherein the sclerostin-binding portion comprises a set of six CDRs selected from the group consisting of a) CDR-L1 of SEQ ID NO: 284, CDR-L2 of SEQ ID NO: 285, CDR-L3 of SEQ ID NO: 286, CDR-H1 of SEQ ID NO: 296, CDR-H2 of SEQ ID NO: 297, and CDR-H3 of SEQ ID NO: 298; b) CDR-L1 of SEQ ID NO: 48, CDR-L2 of SEQ ID NO: 49, CDR-L3 of SEQ ID NO: 50, CDR-H1 of SEQ ID NO: 45, CDR-H2 of SEQ ID NO: 46, and CDR-H3 of SEQ ID NO: 47; or c) CDR-L1 of SEQ ID NO: 42, CDR-L2 of SEQ ID NO: 43, CDR-L3 of SEQ ID NO: 44, CDR-H1of SEQ ID NO: 39, CDR-H2 of SEQ ID NO: 40, and CDR-H3 of SEQ ID NO: 41. 10. The method of claim 1, wherein the sclerostin-binding portion comprises a heavy chain and a light chain comprising CDR-H1 of SEQ ID NO: 269, CDR-H2 of SEQ ID NO: 270, CDR-H3 of SEQ ID NO: 271, CDR-L1 of SEQ ID NO: 239, CDR-L2 of SEQ ID NO: 240 and CDR-L3 of SEQ ID NO: 241. 11. The method of claim 1, wherein the first light chain comprises a variable region amino acid sequence selected from the group consisting of SEQ ID NO: 364, SEQ ID NO: 376, SEQ ID NO: 75, SEQ ID NO: 384, SEQ ID NO: 388, SEQ ID NO: 380, SEQ ID NO: 299, SEQ ID NO: 303, SEQ ID NO: 314, SEQ ID NO: 311, SEQ ID NO: 315 and SEQ ID NO: 368. 12. The method of claim 1, wherein the first heavy chain comprises a variable region amino acid sequence selected from the group consisting of SEQ ID NO: 366, SEQ ID NO: 378, SEQ ID NO: 77, SEQ ID NO: 386, SEQ ID NO: 390, SEQ ID NO: 382, SEQ ID NO: 301, SEQ ID NO: 305, SEQ ID NO: 327, SEQ ID NO: 313, SEQ ID NO: 317 and SEQ ID NO: 370. 13. The method of claim 1, wherein the DKK1-binding portion comprises a set of six CDRs selected from the group consisting of (a) SEQ ID NOs: 820-825, (b) SEQ ID NOs: 828-833, (c) SEQ ID NOs: 836-841, (d) SEQ ID NOs: 844-849, (e) SEQ ID NOs: 852-857, (f) SEQ ID NOs: 860-865, (g) SEQ ID NOs: 868-873, (h) SEQ ID NOs: 876-881, (i) SEQ ID NOs: 884-889, (j) SEQ ID NOs: 892-897, (k) SEQ ID NOs: 900-905, (I) SEQ ID NOs: 908-913, (m) SEQ ID NOs: 916-921, (n) SEQ ID NOs: 924-929, (o) SEQ ID NOs: 932-937, (p) SEQ ID NOs: 940-945, (q) SEQ ID NOs: 948-953, (r) SEQ ID NOs: 956-961, (s) SEQ ID NOs: 964-969, (t) SEQ ID NOs: 972-977, (u) SEQ ID NOs: 980-985, (v) SEQ ID NOs: 988-993, (w) SEQ ID NOs: 996-1001, and (x) SEQ ID NOs: 1004-1009. 14. The method of claim 1, wherein the DKK1-binding portion comprises a set of six CDRs selected from the group consisting of SEQ ID NOs: 980-985 and SEQ ID NOs: 1004-1009. 15. The method of claim 1, wherein the second light chain comprises a variable region amino acid sequence selected from the group consisting of SEQ ID NO: 818, SEQ ID NO: 826, SEQ ID NO: 834, SEQ ID NO: 842, SEQ ID NO: 850, SEQ ID NO: 866, SEQ ID NO: 874, SEQ ID NO: 882, SEQ ID NO: 890, SEQ ID NO: 898, SEQ ID NO: 906, SEQ ID NO: 814, SEQ ID NO: 822, SEQ ID NO: 830, SEQ ID NO: 938, SEQ ID NO: 946, SEQ ID NO: 954, SEQ ID NO: 962, SEQ ID NO: 970, SEQ ID NO: 978, SEQ ID NO: 988, SEQ ID NO: 994 and SEQ ID NO: 1002. 16. The method of claim 1, wherein the second heavy chain comprises a variable region amino acid sequence selected from the group consisting of SEQ ID NO: 819, SEQ ID NO: 827, SEQ ID NO: 835, SEQ ID NO: 843, SEQ ID NO: 851, SEQ ID NO: 859, SEQ ID NO: 867, SEQ ID NO: 875, SEQ ID NO: 883, SEQ ID NO: 891, SEQ ID NO: 899, SEQ ID NO: 907, SEQ ID NO: 915, SEQ ID NO: 923, SEQ ID NO: 931, SEQ ID NO: 939, SEQ ID NO: 947, SEQ ID NO: 955, SEQ ID NO: 963, SEQ ID NO: 971, SEQ ID NO: 979, SEQ ID NO: 987, SEQ ID NO: 995 and SEQ ID NO: 1003. 17. The method of claim 1, wherein the antibody comprises a first heavy chain comprising a variable region amino acid sequence selected from the group consisting of SEQ ID NOs: 378 and 366 and comprising amino acid substitutions at EU positions 183, 356 and 399 of the first heavy chain,a second heavy chain comprising a variable region amino acid sequence selected from the group consisting of SEQ ID NOs: 1003 and 979 and comprising amino acid substitutions at EU positions 183, 392 and 409 of the second heavy chain,a first light chain comprising a variable region amino acid sequence selected from the group consisting of SEQ ID NOs: 376 and 364 and comprising an amino acid substitution at EU position 176 of the first light chain, anda second light chain comprising a variable region amino acid sequence selected from the group consisting of SEQ ID NOs: 1002 and 978 and comprising an amino acid substitution at EU position 176 of the second light chain;wherein the amino acid substitutions introduce a charged amino acid at said positions. 18. The method of claim 1, wherein the antibody comprises (a) a first heavy chain comprising the amino acid sequence set forth in SEQ ID NO: 1038; a second heavy chain comprising the amino acid sequence set forth in SEQ ID NO: 1034; a first light chain comprising the amino acid sequence set forth in SEQ ID NO: 1039 and a second light chain comprising the amino acid sequence set forth in SEQ ID NO: 1035;(b) a first heavy chain comprising the amino acid sequence set forth in SEQ ID NO: 1038; a second heavy chain comprising the amino acid sequence set forth in SEQ ID NO: 1036; a first light chain comprising the amino acid sequence set forth in SEQ ID NO: 1039and a second light chain comprising the amino acid sequence set forth in SEQ ID NO: 1037;(c) a first heavy chain comprising the amino acid sequence set forth in SEQ ID NO: 1040; a second heavy chain comprising the amino acid sequence set forth in SEQ ID NO: 1034; a first light chain comprising the amino acid sequence set forth in SEQ ID NO: 1041 and a second light chain comprising the amino acid sequence set forth in SEQ ID NO: 1035;(d) a first heavy chain comprising the amino acid sequence set forth in SEQ ID NO: 1040; a second heavy chain comprising the amino acid sequence set forth in SEQ ID NO: 1036; a first light chain comprising the amino acid sequence set forth in SEQ ID NO: 1041 and a second light chain comprising the amino acid sequence set forth in SEQ ID NO: 1037;(e) a first heavy chain comprising the amino acid sequence set forth in SEQ ID NO: 1046; a second heavy chain comprising the amino acid sequence set forth in SEQ ID NO: 1042; a first light chain comprising the amino acid sequence set forth in SEQ ID NO: 1047 and a second light chain comprising the amino acid sequence set forth in SEQ ID NO: 1043;(f) a first heavy chain comprising the amino acid sequence set forth in SEQ ID NO: 1046; a second heavy chain comprising the amino acid sequence set forth in SEQ ID NO: 1044; a first light chain comprising the amino acid sequence set forth in SEQ ID NO: 1047 and a second light chain comprising the amino acid sequence set forth in SEQ ID NO: 1045;(g) a first heavy chain comprising the amino acid sequence set forth in SEQ ID NO: 1048; a second heavy chain comprising the amino acid sequence set forth in SEQ ID NO: 1042; a first light chain comprising the amino acid sequence set forth in SEQ ID NO: 1049 and a second light chain comprising the amino acid sequence set forth in SEQ ID NO: 1043; or(h) a first heavy chain comprising the amino acid sequence set forth in SEQ ID NO: 1048; a second heavy chain comprising the amino acid sequence set forth in SEQ ID NO: 1044; a first light chain comprising the amino acid sequence set forth in SEQ ID NO: 1049 and a second light chain comprising the amino acid sequence set forth in SEQ ID NO: 1045. 19. The method of claim 1, wherein the antibody comprises (a) a heavy chain that comprises an amino acid sequence selected from the group consisting of SEQ ID NO: 1038, SEQ ID NO: 1046, SEQ ID NO: 1040 and SEQ ID NO: 1048, optionally further comprising a light chain amino acid sequence selected from the group consisting of SEQ ID NO: 1039, SEQ ID NO: 1047, SEQ ID NO: 1041 and SEQ ID NO: 1049; or(b) a heavy chain that comprises an amino acid sequence selected from the group consisting of SEQ ID NO: 1034, SEQ ID NO: 1042, SEQ ID NO: 1036 and SEQ ID NO: 1044, optionally further comprising a light chain amino acid sequence selected from the group consisting of SEQ ID NO: 1035, SEQ ID NO: 1043, SEQ ID NO: 1037 and SEQ ID NO: 1045.
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Btzow Ralf (Helsinki CA FIX) Ruoslahti Erkki (Rancho Santa Fe CA), 60 kDa transforming growth factor-b
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