Multispecific antigen-binding molecules having blood coagulation factor viii (fviii) cofactor function-substituting activity and pharmaceutical formulations containing such a molecule as an active ingredient

{
  "publication_number": "US2026103540A1",
  "country": "US",
  "kind": "A1",
  "title": "Multispecific antigen-binding molecules having blood coagulation factor viii (fviii) cofactor function-substituting activity and pharmaceutical formulations containing such a molecule as an active ingredient",
  "abstract": "Bispecific antibodies whose FIX activation-inhibiting activity is not elevated and whose FVIII cofactor function-substituting activity is elevated have been successfully discovered.",
  "claims": [
    "1. A multispecific antigen-binding molecule which has a function to substitute for the function of blood coagulation factor VIII, wherein the molecule comprises a first antigen-binding site which binds to blood coagulation factor IX and/or activated blood coagulation factor IX, and a second antigen-binding site which binds to blood coagulation factor X, wherein the first antigen-binding site comprises a heavy chain variable domain and a light chain variable domain, wherein the heavy chain variable domain (Q499) comprises HVR-H1 comprising the amino acid sequence of SEQ ID NO: 1, HVR-H2 comprising the amino acid sequence of SEQ ID NO: 2, and HVR-H3 comprising the amino acid sequence of SEQ ID NO: 3, and the light chain variable domain (QNK131) comprises HVR-L1 comprising the amino acid 1 sequence of SEQ ID NO: 162, HVR-L2 comprising the amino acid sequence of SEQ ID NO: 163, and HVR-L3 comprising the amino acid sequence of SEQ ID NO: 164; and wherein the second antigen-binding site comprises a heavy chain variable domain and a light chain variable domain, wherein the heavy chain variable domain (J327) comprises HVR-H1 comprising the amino acid sequence of SEQ ID NO: 4, HVR-H2 comprising the amino acid sequence of SEQ ID NO: 5, and HVR-H3 comprising the amino acid sequence of SEQ ID NO: 6, and the light chain variable domain (JNL095) comprises HVR-L1 comprising the amino acid sequence of SEQ ID NO: 165, HVR-L2 comprising the amino acid sequence of SEQ ID NO: 166, and HVR-L3 comprising the amino acid sequence of SEQ ID NO: 167; wherein one or more amino acid residues are substituted with other amino acids, deleted, or inserted in at least one of the HVRs. 2. The multispecific antigen-binding molecule of claim 1, wherein: at least one amino acid residue selected from amino acid residues at positions 31, 34, 97, 98, 100, 100a, 100b, and 100e according to Kabat numbering is substituted with another amino acid or deleted in the heavy chain variable domain of the first antigen-binding site, at least one amino acid residue selected from amino acid residues at positions 26, 27, 30, 31, 32, 53, 55, 92, 93, 95, and 96 according to Kabat numbering is substituted with another amino acid or inserted in the light chain variable domain of the first antigen-binding site, at least one amino acid residue selected from amino acid residues at positions 31, 51, 56, 57, 59, 61, 62, 65, and 102 according to Kabat numbering is substituted with another amino acid in the heavy chain variable domain of the second antigen-binding site, at least one amino acid residue selected from amino acid residues at positions 24, 26, 27, 29, 30, 31, 32, 50, 92, 94, 95, 95a, and 96 according to Kabat numbering is substituted or deleted in the light chain variable domain of the second antigen-binding site. 3. The multispecific antigen-binding molecule of claim 1 or 2, wherein: in the heavy chain variable domain of the first antigen-binding site, the amino acid residue at position 31 is histidine, the amino acid residue at position 34 is alanine, the amino acid residue at position 97 is aspartic acid, the amino acid residue at position 98 is serine, the amino acid residue at position 100 is aspartic acid or glutamic acid, the amino acid residue at position 100a is aspartic acid or deleted, the amino acid residue at position 100b is alanine or histidine, or the amino acid residue at position 100e is histidine or isoleucine, said position being according to Kabat numbering; in the light chain variable domain of the first antigen-binding site, the amino acid residue at position 26 is threonine, the amino acid residue at position 27 is arginine, the amino acid residue at position 30 is arginine, the amino acid residue at position 31 is arginine, the amino acid residue at position 32 is aspartic acid or glutamic acid, the amino acid residue at position 53 is arginine, the amino acid residue at position 55 is glutamic acid, the amino acid residue at position 92 is arginine, the amino acid residue at position 93 is serine or aspartic acid, the amino acid residue at position 95 is proline, or the amino acid residue at position 96 is glycine, said position being according to Kabat numbering; in the heavy chain variable domain of the second antigen-binding site, the amino acid residue at position 31 is asparagine, glutamine, or histidine, the amino acid residue at position 51 is serine, the amino acid residue at position 56 is threonine or arginine, the amino acid residue at position 57 is valine, the amino acid residue at position 59 is serine, the amino acid residue at position 61 is arginine, the amino acid residue at position 62 is lysine, the amino acid residue at position 65 is asparagine or glutamine, or the amino acid residue at position 102 is valine, said position being according to Kabat numbering; and in the light chain variable domain of the second antigen-binding site, the amino acid residue at position 24 is threonine, the amino acid residue at position 26 is glutamic acid, the amino acid residue at position 27 is glutamine, the amino acid residue at position 29 is serine, the amino acid residue at position 30 is glutamine, serine, or glutamic acid, the amino acid residue at position 31 is arginine, the amino acid residue at position 32 is glutamine or glutamic acid, the amino acid residue at position 50 is glutamine, the amino acid residue at position 92 is alanine, the amino acid residue at position 94 is aspartic acid, the amino acid residue at position 95 is aspartic acid or alanine, the amino acid residue at position 95a is tyrosine or deleted, or the amino acid residue at position 96 is threonine, said position being according to Kabat numbering. 4. The multispecific antigen-binding molecule of any one of claims 1-3, wherein the first antigen-binding site comprises a heavy chain variable domain and a light chain variable domain, wherein the heavy chain variable domain comprises: 1) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 168, HVR-H2 comprising the amino acid sequence of SEQ ID NO: 169, and HVR-H3 comprising the amino acid sequence of SEQ ID NO: 170 (QH01); 2) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 171, HVR-H2 comprising the amino acid sequence of SEQ ID NO: 172, and HVR-H3 comprising the amino acid sequence of SEQ ID NO: 173 (QH02); 3) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 174, HVR-H2 comprising the amino acid sequence of SEQ ID NO: 175, and HVR-H3 comprising the amino acid sequence of SEQ ID NO: 176 (QH03); 4) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 177, HVR-H2 comprising the amino acid sequence of SEQ ID NO: 178, and HVR-H3 comprising the amino acid sequence of SEQ ID NO: 179 (QH04); 5) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 180, HVR-H2 comprising the amino acid sequence of SEQ ID NO: 181, and HVR-H3 comprising the amino acid sequence of SEQ ID NO: 182 (QH06); or 6) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 183, HVR-H2 comprising the amino acid sequence of SEQ ID NO: 184, and HVR-H3 comprising the amino acid sequence of SEQ ID NO: 185 (QH07); and the light chain variable domain comprises: 1) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 186, HVR-L2 comprising the amino acid sequence of SEQ ID NO: 187, and HVR-L3 comprising the amino acid sequence of SEQ ID NO: 188 (QL21); 2) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 189, HVR-L2 comprising the amino acid sequence of SEQ ID NO: 190, and HVR-L3 comprising the amino acid sequence of SEQ ID NO: 191 (QL22); 3) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 192, HVR-L2 comprising the amino acid sequence of SEQ ID NO: 193, and HVR-L3 comprising the amino acid sequence of SEQ ID NO: 194 (QL23); 4) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 195, HVR-L2 comprising the amino acid sequence of SEQ ID NO: 196, and HVR-L3 comprising the amino acid sequence of SEQ ID NO: 197 (QL24); 5) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 198, HVR-L2 comprising the amino acid sequence of SEQ ID NO: 199, and HVR-L3 comprising the amino acid sequence of SEQ ID NO: 200 (QL25); 6) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 201, HVR-L2 comprising the amino acid sequence of SEQ ID NO: 202, and HVR-L3 comprising the amino acid sequence of SEQ ID NO: 203 (QL26); 7) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 204, HVR-L2 comprising the amino acid sequence of SEQ ID NO: 205, and HVR-L3 comprising the amino acid sequence of SEQ ID NO: 206 (QL28); 8) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 207, HVR-L2 comprising the amino acid sequence of SEQ ID NO: 208, and HVR-L3 comprising the amino acid sequence of SEQ ID NO: 209 (QL29); 9) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 210, HVR-L2 comprising the amino acid sequence of SEQ ID NO: 211, and HVR-L3 comprising the amino acid sequence of SEQ ID NO: 212 (QL30); 10) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 213, HVR-L2 comprising the amino acid sequence of SEQ ID NO: 214, and HVR-L3 comprising the amino acid sequence of SEQ ID NO: 215 (QL31); 11) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 216, HVR-L2 comprising the amino acid sequence of SEQ ID NO: 217, and HVR-L3 comprising the amino acid sequence of SEQ ID NO: 218 (QL32); or 12) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 219, HVR-L2 comprising the amino acid sequence of SEQ ID NO: 220, and HVR-L3 comprising the amino acid sequence of SEQ ID NO: 221 (QL33), and wherein the second antigen-binding site comprises a heavy chain variable domain and a light chain variable domain, wherein the heavy chain variable domain comprises: 1) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 222, HVR-H2 comprising the amino acid sequence of SEQ ID NO: 223, and HVR-H3 comprising the amino acid sequence of SEQ ID NO: 224 (JH01); 2) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 225, HVR-H2 comprising the amino acid sequence of SEQ ID NO: 226, and HVR-H3 comprising the amino acid sequence of SEQ ID NO: 227 (JH02); 3) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 228, HVR-H2 comprising the amino acid sequence of SEQ ID NO: 229, and HVR-H3 comprising the amino acid sequence of SEQ ID NO: 230 (JH03); 4) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 231, HVR-H2 comprising the amino acid sequence of SEQ ID NO: 232, and HVR-H3 comprising the amino acid sequence of SEQ ID NO: 233 (JH04); 5) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 234, HVR-H2 comprising the amino acid sequence of SEQ ID NO: 235, and HVR-H3 comprising the amino acid sequence of SEQ ID NO: 236 (JH05); 6) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 237, HVR-H2 comprising the amino acid sequence of SEQ ID NO: 238, and HVR-H3 comprising the amino acid sequence of SEQ ID NO: 239 (JH06); 7) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 240, HVR-H2 comprising the amino acid sequence of SEQ ID NO: 241, and HVR-H3 comprising the amino acid sequence of SEQ ID NO: 242 (JH07); 8) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 243, HVR-H2 comprising the amino acid sequence of SEQ ID NO: 244, and HVR-H3 comprising the amino acid sequence of SEQ ID NO: 245 (JH08); 9) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 246, HVR-H2 comprising the amino acid sequence of SEQ ID NO: 247, and HVR-H3 comprising the amino acid sequence of SEQ ID NO: 248 (JH09); 10) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 249, HVR-H2 comprising the amino acid sequence of SEQ ID NO: 250, and HVR-H3 comprising the amino acid sequence of SEQ ID NO: 251 (JH10); or 11) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 252, HVR-H2 comprising the amino acid sequence of SEQ ID NO: 253, and HVR-H3 comprising the amino acid sequence of SEQ ID NO: 254 (JH11), and the light chain variable domain comprises: 1) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 255, HVR-L2 comprising the amino acid sequence of SEQ ID NO: 256, and HVR-L3 comprising the amino acid sequence of SEQ ID NO: 257 (JL01); 2) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 258, HVR-L2 comprising the amino acid sequence of SEQ ID NO: 259, and HVR-L3 comprising the amino acid sequence of SEQ ID NO: 260 (JL02); 3) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 261, HVR-L2 comprising the amino acid sequence of SEQ ID NO: 262, and HVR-L3 comprising the amino acid sequence of SEQ ID NO: 263 (JL03); 4) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 264, HVR-L2 comprising the amino acid sequence of SEQ ID NO: 265, and HVR-L3 comprising the amino acid sequence of SEQ ID NO: 266 (JL04); 5) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 267, HVR-L2 comprising the amino acid sequence of SEQ ID NO: 268, and HVR-L3 comprising the amino acid sequence of SEQ ID NO: 269 (JL05); 6) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 270, HVR-L2 comprising the amino acid sequence of SEQ ID NO: 271, and HVR-L3 comprising the amino acid sequence of SEQ ID NO: 272 (JL06); 7) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 273, HVR-L2 comprising the amino acid sequence of SEQ ID NO: 274, and HVR-L3 comprising the amino acid sequence of SEQ ID NO: 275 (JL07); 8) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 276, HVR-L2 comprising the amino acid sequence of SEQ ID NO: 277, and HVR-L3 comprising the amino acid sequence of SEQ ID NO: 278 (JL08); 9) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 279, HVR-L2 comprising the amino acid sequence of SEQ ID NO: 280, and HVR-L3 comprising the amino acid sequence of SEQ ID NO: 281 (JL09); 10) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 282, HVR-L2 comprising the amino acid sequence of SEQ ID NO: 283, and HVR-L3 comprising the amino acid sequence of SEQ ID NO: 284 (JL10); or 11) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 285, HVR-L2 comprising the amino acid sequence of SEQ ID NO: 286, and HVR-L3 comprising the amino acid sequence of SEQ ID NO: 287 (JL11). 5. The multispecific antigen-binding molecule of claim 1, wherein the first antigen-binding site comprises a heavy chain variable domain of SEQ ID NO: 45 (Q499) and a light chain variable domain of SEQ ID NO: 13 (QNK131), and the second antigen-binding site comprises a heavy chain variable domain of SEQ ID NO: 46 (J327) and a light chain variable domain of SEQ ID NO: 31 (JNL095), wherein one or more amino acid residues are substituted with other amino acids, deleted, or inserted in at least one of the heavy chain variable domains or the light chain variable domains. 6. The multispecific antigen-binding molecule of claim 5, wherein: at least one amino acid residue selected from amino acid residues at positions 31, 34, 39, 97, 98, 100, 100a, 100b, and 100e according to Kabat numbering is substituted with another amino acid or deleted in the heavy chain variable domain of the first antigen-binding site, at least one amino acid residue selected from amino acid residues at positions 26, 27, 30, 31, 32, 38, 45, 53, 55, 60, 70, 76, 79, 80, 83, 85, 92, 93, 95, and 96 according to Kabat numbering is substituted with another amino acid or inserted in the light chain variable domain of the first antigen-binding site, at least one amino acid residue selected from amino acid residues at positions 28, 31, 39, 51, 56, 57, 59, 61, 62, 65, 67, 73, 82b, and 102 according to Kabat numbering is substituted with another amino acid in the heavy chain variable domain of the second antigen-binding site, and at least one amino acid residue selected from amino acid residues at positions 3, 8, 15, 24, 26, 27, 29, 30, 31, 32, 38, 48, 49, 50, 79, 92, 94, 95, 95a, and 96 according to Kabat numbering is substituted with another amino acid or deleted in the light chain variable domain of the second antigen-binding site. 7. The multispecific antigen-binding molecule of claim 5 or 6, wherein: in the heavy chain variable domain of the first antigen-binding site, the amino acid residue at position 31 is histidine, the amino acid residue at position 34 is alanine, the amino acid residue at position 39 is glutamic acid, the amino acid residue at position 97 is aspartic acid, the amino acid residue at position 98 is serine, the amino acid residue at position 100 is aspartic acid or glutamic acid, the amino acid residue at position 100a is aspartic acid or deleted, the amino acid residue at position 100b is alanine or histidine, or the amino acid residue at position 100e is histidine or isoleucine, said position being according to Kabat numbering, in the light chain variable domain of the first antigen-binding site, the amino acid residue at position 26 is threonine, the amino acid residue at position 27 is arginine, the amino acid residue at position 30 is arginine, the amino acid residue at position 31 is arginine, the amino acid residue at position 32 is aspartic acid or glutamic acid, the amino acid residue at position 38 is lysine, the amino acid residue at position 45 is glutamic acid, the amino acid residue at position 53 is arginine, the amino acid residue at position 55 is glutamic acid, the amino acid residue at position 60 is aspartic acid, the amino acid residue at position 70 is aspartic acid, the amino acid residue at position 76 is asparagine, the amino acid residue at position 79 is glutamic acid, the amino acid residue at position 80 is proline or alanine, the amino acid residue at position 83 is methionine or alanine, the amino acid residue at position 85 is threonine, the amino acid residue at position 92 is arginine, the amino acid residue at position 93 is serine or aspartic acid, the amino acid residue at position 95 is proline, or the amino acid residue at position 96 is glycine, said position being according to Kabat numbering, in the heavy chain variable domain of the second antigen-binding site, the amino acid residue at position 28 is glutamic acid, the amino acid residue at position 31 is asparagine, glutamine, or histidine, the amino acid residue at position 39 is lysine, the amino acid residue at position 51 is serine, the amino acid residue at position 56 is threonine or arginine, the amino acid residue at position 57 is valine, the amino acid residue at position 59 is serine, the amino acid residue at position 61 is arginine, the amino acid residue at position 62 is lysine, the amino acid residue at position 65 is asparagine or glutamine, the amino acid residue at position 67 is leucine, the amino acid residue at position 73 is isoleucine, the amino acid residue at position 82b is glutamic acid, or the amino acid residue at position 102 is valine, said position being according to Kabat numbering, and in the light chain variable domain of the second antigen-binding site, the amino acid residue at position 3 is glutamic acid, the amino acid residue at position 8 is proline, the amino acid residue at position 15 is leucine, the amino acid residue at position 24 is threonine, the amino acid residue at position 26 is glutamic acid, the amino acid residue at position 27 is glutamine, the amino acid residue at position 29 is serine, the amino acid residue at position 30 is glutamine, serine, or glutamic acid, the amino acid residue at position 31 is arginine, the amino acid residue at position 32 is glutamine or glutamic acid, the amino acid residue at position 38 is glutamic acid, the amino acid residue at position 48 is isoleucine, the amino acid residue at position 49 is tyrosine, the amino acid residue at position 50 is glutamine, the amino acid residue at position 79 is glutamic acid, the amino acid residue at position 92 is alanine, the amino acid residue at position 94 is aspartic acid, the amino acid residue at position 95 is aspartic acid or alanine, the amino acid residue at position 95a is tyrosine or deleted, or the amino acid residue at position 96 is threonine, said position being according to Kabat numbering. 8. The multispecific antigen-binding molecule of any one of claims 1-7, wherein the first antigen-binding site comprises: a heavy chain variable domain (QH) comprising the amino acid sequence of SEQ ID NO: 56, SEQ ID NO: 57, SEQ ID NO: 58, SEQ ID NO: 59, or SEQ ID NO: 60, and a light chain variable domain (QL) comprising the amino acid sequence of SEQ ID NO: 61, SEQ ID NO: 62, SEQ ID NO: 63, SEQ ID NO: 64, SEQ ID NO: 65, SEQ ID NO: 66, SEQ ID NO: 67, SEQ ID NO: 68, SEQ ID NO: 69, SEQ ID NO: 70, SEQ ID NO: 71 or SEQ ID NO: 72; and the second antigen-binding site comprises: a heavy chain variable domain (JH) comprising the amino acid sequence of SEQ ID NO: 73, SEQ ID NO: 74, SEQ ID NO: 75, SEQ ID NO: 76, SEQ ID NO: 77, SEQ ID NO: 78, SEQ ID NO: 79, SEQ ID NO: 80, SEQ ID NO: 81, SEQ ID NO: 82 or SEQ ID NO: 83, and a light chain variable domain (JL) comprising the amino acid sequence of SEQ ID NO: 84, SEQ ID NO: 85, SEQ ID NO: 86, SEQ ID NO: 87, SEQ ID NO: 88, SEQ ID NO: 89, SEQ ID NO: 90, SEQ ID NO: 91, SEQ ID NO: 92, SEQ ID NO: 93 or SEQ ID NO: 94. 9. The multispecific antigen-binding molecule of any one of claims 1-8, wherein the first antigen-binding site comprises constant regions comprising the amino acid sequences set forth in (1) or (2) below, and the second antigen-binding site comprises constant regions comprising the amino acid sequences set forth in (1) or (2) below which are different from the constant regions comprised in the first antigen-binding site: (1) SEQ ID NO: 119 as a heavy chain constant region and SEQ ID NO: 100 as a light chain constant region (2) SEQ ID NO: 118 as a heavy chain constant region and SEQ ID NO: 102 as a light chain constant region. 10. The multispecific antigen-binding molecule of any one of claims 1-9, which is a multispecific antibody or a bispecific antibody. 11. A bispecific antibody comprising a first antibody heavy chain and a first antibody light chain which bind to blood coagulation factor IX and/or activated blood coagulation factor IX, and a second antibody heavy chain and a second antibody light chain which bind to blood coagulation factor X, wherein the bispecific antibody is any of (a) to (v) below: (a) a bispecific antibody which comprises a first antibody heavy chain comprising the amino acid sequence of SEQ ID NO: 120, a first antibody light chain comprising the amino acid sequence of SEQ ID NO: 126, a second antibody heavy chain comprising the amino acid sequence of SEQ ID NO: 138, and a second antibody light chain comprising the amino acid sequence of SEQ ID NO: 149 (QH01/QL21//JH01/JL01); (b) a bispecific antibody which comprises a first antibody heavy chain comprising the amino acid sequence of SEQ ID NO: 121, a first antibody light chain comprising the amino acid sequence of SEQ ID NO: 127, a second antibody heavy chain comprising the amino acid sequence of SEQ ID NO: 138, and a second antibody light chain comprising the amino acid sequence of SEQ ID NO: 149 (QH02/QL22//JH01/JL01); (c) a bispecific antibody which comprises a first antibody heavy chain comprising the amino acid sequence of SEQ ID NO: 122, a first antibody light chain comprising the amino acid sequence of SEQ ID NO: 128, a second antibody heavy chain comprising the amino acid sequence of SEQ ID NO: 139, and a second antibody light chain comprising the amino acid sequence of SEQ ID NO: 150 (QH03/QL23//JH02/JL02); (d) a bispecific antibody which comprises a first antibody heavy chain comprising the amino acid sequence of SEQ ID NO: 122, a first antibody light chain comprising the amino acid sequence of SEQ ID NO: 129, a second antibody heavy chain comprising the amino acid sequence of SEQ ID NO: 139, and a second antibody light chain comprising the amino acid sequence of SEQ ID NO: 150 (QH03/QL24//JH02/JL02); (e) a bispecific antibody which comprises a first antibody heavy chain comprising the amino acid sequence of SEQ ID NO: 121, a first antibody light chain comprising the amino acid sequence of SEQ ID NO: 127, a second antibody heavy chain comprising the amino acid sequence of SEQ ID NO: 140, and a second antibody light chain comprising the amino acid sequence of SEQ ID NO: 151 (QH02/QL22//JH03/JL03); (f) a bispecific antibody which comprises a first antibody heavy chain comprising the amino acid sequence of SEQ ID NO: 121, a first antibody light chain comprising the amino acid sequence of SEQ ID NO: 127, a second antibody heavy chain comprising the amino acid sequence of SEQ ID NO: 141, and a second antibody light chain comprising the amino acid sequence of SEQ ID NO: 152 (QH02/QL22//JH04/JL04); (g) a bispecific antibody which comprises a first antibody heavy chain comprising the amino acid sequence of SEQ ID NO: 121, a first antibody light chain comprising the amino acid sequence of SEQ ID NO: 127, a second antibody heavy chain comprising the amino acid sequence of SEQ ID NO: 139, and a second antibody light chain comprising the amino acid sequence of SEQ ID NO: 150 (QH02/QL22//JH02/JL02); (h) a bispecific antibody which comprises a first antibody heavy chain comprising the amino acid sequence of SEQ ID NO: 123, a first antibody light chain comprising the amino acid sequence of SEQ ID NO: 130, a second antibody heavy chain comprising the amino acid sequence of SEQ ID NO: 139, and a second antibody light chain comprising the amino acid sequence of SEQ ID NO: 150 (QH04/QL25//JH02/JL02); (i) a bispecific antibody which comprises a first antibody heavy chain comprising the amino acid sequence of SEQ ID NO: 123, a first antibody light chain comprising the amino acid sequence of SEQ ID NO: 131, a second antibody heavy chain comprising the amino acid sequence of SEQ ID NO: 139, and a second antibody light chain comprising the amino acid sequence of SEQ ID NO: 150 (QH04/QL26//JH02/JL02); (j) a bispecific antibody which comprises a first antibody heavy chain comprising the amino acid sequence of SEQ ID NO: 123, a first antibody light chain comprising the amino acid sequence of SEQ ID NO: 131, a second antibody heavy chain comprising the amino acid sequence of SEQ ID NO: 142, and a second antibody light chain comprising the amino acid sequence of SEQ ID NO: 153 (QH04/QL26//JH05/JL05); (k) a bispecific antibody which comprises a first antibody heavy chain comprising the amino acid sequence of SEQ ID NO: 123, a first antibody light chain comprising the amino acid sequence of SEQ ID NO: 132, a second antibody heavy chain comprising the amino acid sequence of SEQ ID NO: 142, and a second antibody light chain comprising the amino acid sequence of SEQ ID NO: 153 (QH04/QL28//JH05/JL05); (l) a bispecific antibody which comprises a first antibody heavy chain comprising the amino acid sequence of SEQ ID NO: 123, a first antibody light chain comprising the amino acid sequence of SEQ ID NO: 132, a second antibody heavy chain comprising the amino acid sequence of SEQ ID NO: 143, and a second antibody light chain comprising the amino acid sequence of SEQ ID NO: 154 (QH04/QL28//JH06/JL06); (m) a bispecific antibody which comprises a first antibody heavy chain comprising the amino acid sequence of SEQ ID NO: 123, a first antibody light chain comprising the amino acid sequence of SEQ ID NO: 133, a second antibody heavy chain comprising the amino acid sequence of SEQ ID NO: 142, and a second antibody light chain comprising the amino acid sequence of SEQ ID NO: 153 (QH04/QL29//JH05/JL05); (n) a bispecific antibody which comprises a first antibody heavy chain comprising the amino acid sequence of SEQ ID NO: 123, a first antibody light chain comprising the amino acid sequence of SEQ ID NO: 133, a second antibody heavy chain comprising the amino acid sequence of SEQ ID NO: 143, and a second antibody light chain comprising the amino acid sequence of SEQ ID NO: 154 (QH04/QL29//JH06/JL06); (o) a bispecific antibody which comprises a first antibody heavy chain comprising the amino acid sequence of SEQ ID NO: 124, a first antibody light chain comprising the amino acid sequence of SEQ ID NO: 134, a second antibody heavy chain comprising the amino acid sequence of SEQ ID NO: 144, and a second antibody light chain comprising the amino acid sequence of SEQ ID NO: 155 (QH06/QL30//JH07/JL07); (p) a bispecific antibody which comprises a first antibody heavy chain comprising the amino acid sequence of SEQ ID NO: 123, a first antibody light chain comprising the amino acid sequence of SEQ ID NO: 135, a second antibody heavy chain comprising the amino acid sequence of SEQ ID NO: 145, and a second antibody light chain comprising the amino acid sequence of SEQ ID NO: 156 (QH04/QL31//JH08/JL08); (q) a bispecific antibody which comprises a first antibody heavy chain comprising the amino acid sequence of SEQ ID NO: 124, a first antibody light chain comprising the amino acid sequence of SEQ ID NO: 136, a second antibody heavy chain comprising the amino acid sequence of SEQ ID NO: 144, and a second antibody light chain comprising the amino acid sequence of SEQ ID NO: 155 (QH06/QL32//JH07/JL07); (r) a bispecific antibody which comprises a first antibody heavy chain comprising the amino acid sequence of SEQ ID NO: 124, a first antibody light chain comprising the amino acid sequence of SEQ ID NO: 136, a second antibody heavy chain comprising the amino acid sequence of SEQ ID NO: 146, and a second antibody light chain comprising the amino acid sequence of SEQ ID NO: 157 (QH06/QL32//JH09/JL09); (s) a bispecific antibody which comprises a first antibody heavy chain comprising the amino acid sequence of SEQ ID NO: 124, a first antibody light chain comprising the amino acid sequence of SEQ ID NO: 134, a second antibody heavy chain comprising the amino acid sequence of SEQ ID NO: 147, and a second antibody light chain comprising the amino acid sequence of SEQ ID NO: 158 (QH06/QL30//JH10/JL10); (t) a bispecific antibody which comprises a first antibody heavy chain comprising the amino acid sequence of SEQ ID NO: 125, a first antibody light chain comprising the amino acid sequence of SEQ ID NO: 137, a second antibody heavy chain comprising the amino acid sequence of SEQ ID NO: 148, and a second antibody light chain comprising the amino acid sequence of SEQ ID NO: 159 (QH07/QL33//JH11/JL11); (u) a bispecific antibody which binds to epitopes identical with both an epitope in blood coagulation factor IX and/or activated blood coagulation factor IX and an epitope in blood coagulation factor X which are recognized by any of the antibodies of (a) to (t); (v) a bispecific antibody which competes for binding to both an epitope in blood coagulation factor IX and/or activated blood coagulation factor IX and an epitope in blood coagulation factor X which are recognized by any of the antibodies of (a) to (t). 12. An antigen-binding molecule in which association between a heavy chain and a light chain is regulated, wherein one set or two or more sets of amino acid residues selected from the group consisting of the sets of amino acid residues shown in (a) to (c) below in the heavy chain and the light chain of the antigen-binding molecule are amino acid residues which electrostatically repel each other: (a) an amino acid residue in a heavy chain constant region (CH1) which is at position 175 according to EU numbering, and an amino acid residue in a light chain constant region (CL) which is at position 180 according to Kabat numbering, (b) an amino acid residue in CH1 which is at position 175 according to EU numbering, and an amino acid residue in CL which is at position 131 according to Kabat numbering, (c) amino acid residues in CH1 which are at positions 147 and 175 according to EU numbering, and amino acid residues in CL which are at positions 131 and 180 according to Kabat numbering. 13. The antigen-binding molecule of claim 12, wherein further two or more amino acid residues that form an interface between a heavy chain variable region and a light chain variable region are amino acid residues which electrostatically repel each other. 14. The antigen-binding molecule of claim 13, wherein the amino acid residues which electrostatically repel each other are one or two sets of amino acid residues selected from the group consisting of the sets of amino acid residues shown in (a) or (b) below: (a) an amino acid residue in the heavy chain variable region which is at position 39 according to Kabat numbering, and an amino acid residue in the light chain variable region which is at position 38 according to Kabat numbering, (b) an amino acid residue in the heavy chain variable region which is at position 45 according to Kabat numbering, and an amino acid residue in the light chain variable region which is at position 44 according to Kabat numbering. 15. The antigen-binding molecule of any one of claims 12-14, wherein the amino acid residues which electrostatically repel each other are selected from the amino acid residues included in either set of (X) or (Y) below: (X) glutamic acid (E), aspartic acid (D), (Y) lysine (K), arginine (R), histidine (H). 16. The antigen-binding molecule of any one of claims 12-15, which is a bispecific antibody. 17. A method for producing an antigen-binding molecule in which association between a heavy chain and a light chain is regulated, wherein the method comprises the steps of (1) to (3) below: (1) modifying a nucleic acid(s) encoding a heavy chain constant region (CH1) and a light chain constant region (CL) such that one set or two or more sets of amino acid residues selected from the group consisting of the sets of amino acid residues shown in (a) to (c) below electrostatically repel each other: (a) an amino acid residue in CH1 which is at position 175 according to EU numbering, and an amino acid residue in CL which is at position 180 according to Kabat numbering, (b) an amino acid residue in CH1 which is at position 175 according to EU numbering, and an amino acid residue in CL which is at position 131 according to Kabat numbering, (c) amino acid residues in CH1 which are at positions 147 and 175 according to EU numbering, and amino acid residues in CL which are at positions 131 and 180 according to Kabat numbering; (2) introducing the modified nucleic acid(s) into a host cell and culturing the host cell such that the nucleic acid(s) are expressed; (3) collecting an antigen-binding molecule from the culture of the host cell. 18. A method for regulating association between a heavy chain and a light chain in an antigen-binding molecule, wherein the method comprises modifying a nucleic acid such that one set or two or more sets of amino acid residues selected from the group consisting of the sets of amino acid residues shown in (a) to (c) below are amino acid residues that electrostatically repel each other: (a) an amino acid residue in CH1 which is at position 175 according to EU numbering, and an amino acid residue in CL which is at position 180 according to Kabat numbering, (b) an amino acid residue in CH1 which is at position 175 according to EU numbering, and an amino acid residue in CL which is at position 131 according to Kabat numbering, (c) amino acid residues in CH1 which are at positions 147 and 175 according to EU numbering, and amino acid residues in CL which are at positions 131 and 180 according to Kabat numbering. 19. An isolated nucleic acid which encodes the multispecific antigen-binding molecule of any one of claims 1-9, the multispecific antibody of claim 10, the bispecific antibody of claim 10, 11, or 16, or the antigen-binding molecule of any one of claims 12-15. 20. A host cell which comprises the nucleic acid of claim 19. 21. A method for producing a multispecific antigen-binding molecule, a multispecific antibody, a bispecific antibody, or an antigen-binding molecule, wherein the method comprises culturing the host cell of claim 20 such that a multispecific antigen-binding molecule, a multispecific antibody, a bispecific antibody, or an antigen-binding molecule is produced. 22. A pharmaceutical formulation which comprises the multispecific antigen-binding molecule of any one of claims 1-9, the multispecific antibody of claim 10, the bispecific antibody of claim 10, 11, or 16, or the antigen-binding molecule of any one of claims 12-15, and a pharmaceutically acceptable carrier. 23. The pharmaceutical formulation of claim 22, which is for use in prevention and/or treatment of bleeding, a disease involving bleeding, or a disease caused by bleeding. 24. The pharmaceutical formulation of claim 23, wherein the bleeding, the disease involving bleeding, or the disease caused by bleeding is a disease which develops and/or progresses due to a decrease or deficiency in the activity of blood coagulation factor VIII and/or activated blood coagulation factor VIII. 25. The pharmaceutical formulation of claim 24, wherein the disease which develops and/or progresses due to a decrease or deficiency in the activity of blood coagulation factor VIII and/or activated blood coagulation factor VIII is hemophilia A, a disease with emergence of an inhibitor against blood coagulation factor VIII and/or activated blood coagulation factor VIII, acquired hemophilia, or von Willebrand disease."
  ],
  "description_excerpt": "The present invention relates to multispecific antigen-binding molecules having an activity of substituting for the cofactor function of blood coagulation factor VIII (FVIII) and pharmaceutical formulations thereof. The invention also relates to antigen-binding molecules in which association between a heavy chain and a light chain is regulated, methods for producing an antigen-binding molecule in which association between a heavy chain and a light chain is regulated, and methods for regulating association between a heavy chain and a light chain of an antigen-binding molecule.\n\nHemophilia A is a bleeding abnormality caused by a hereditary decrease or deficiency of blood coagulation factor VIII (FVIII) function. Hemophilia A patients are generally administered with an FVIII formulation for the bleeding (on-demand administration). In recent years, FVIII formulations are also administered prophylactically to prevent bleeding events (preventive administration; Non-patent Documents 1 and 2). The half-life of FVIII formulations in blood is approximately 12 to 16 hours. Therefore, for continuous prevention, FVIII formulations are administered to patients three times a week (Non-patent Documents 3 and 4). In on-demand administrations, FVIII formulations are also additionally administered when necessary at regular intervals to prevent rebleeding. In addition, the administration of FVIII formulations is done intravenously. Therefore, there has been a strong need for pharmaceutical agents with a lesser burden than FVIII formulations.",
  "cpc": [
    "C07K 16/36",
    "C07K 2317/24",
    "C07K 2317/31",
    "C07K 2317/92"
  ],
  "ipc": [
    "C07K 16/36"
  ],
  "assignees": [
    "Chugai Pharmaceutical Co Ltd"
  ],
  "inventors": [
    "Yuri TERANISHI",
    "Kazuki Kato",
    "Hikaru Koga",
    "Tomoyuki Igawa",
    "Kazuki Yamaguchi",
    "Tetsuhiro Soeda"
  ],
  "filing_date": "2025-12-08",
  "publication_date": "2026-04-16",
  "priority_date": "2017-09-29",
  "application_number": "US-202519411948-A",
  "family_id": "65902289",
  "cited_by_count": 0
}