Antigen-Binding Molecule for Promoting Disappearance of Antigen via Fc gamma RIIB

Abstract

The present invention provides antigen-binding molecules containing (i) an antigen-binding domain whose antigen-binding activity varies depending on ion concentration conditions, (ii) an FcγR-binding domain having Fcγ RIIb-selective binding activity, and (iii) an FcRn-binding domain having FcRn-binding activity under an acidic pH range condition, and methods of decreasing plasma antigen concentration as compared to before administering the molecule, which include the step of administering the molecule.

1 .- 22 . (canceled) 
     
     
         23 . A method of removing an antigen from plasma, the method comprising:
 (a) identifying a subject in need of having an antigen removed from the subject's plasma;   (b) providing an antigen-binding molecule that specifically binds to the antigen, wherein the antigen-binding molecule comprises:
 (i) an antigen-binding domain that binds to the antigen in an ion concentration-dependent manner; and 
 (ii) an Fc region in which the amino acids at positions 238 and 271 (EU numbering) are aspartic acid and glycine, respectively, and 
   (c) administering the antigen-binding molecule to the subject.   
     
     
         24 . The method of  claim 23 , wherein the Fc region is a modified Fc region that differs from the amino acid sequence of a native Fc region at sites including one or more of the following positions (EU numbering): 233, 234, 237, 264, 265, 266, 267, 268, 269, 272, 274, 296, 326, 327, 330, 331, 332, 333, 355, 356, 358, 396, 409, and 419. 
     
     
         25 . The method of  claim 24 , wherein at least one of the following positions in the modified Fc region is occupied by the indicated amino acid (all positions indicated by EU numbering):
 aspartic acid at position 233;   tyrosine at position 234;   aspartic acid at position 237;   isoleucine at position 264;   glutamic acid at position 265;   any one of phenylalanine, methionine, and leucine at position 266;   any one of alanine, glutamic acid, glycine, and glutamine at position 267;   any one of aspartic acid, glutamic acid, and glutamine at position 268;   aspartic acid at position 269;   any one of aspartic acid, phenylalanine, isoleucine, methionine, asparagine, proline, or glutamine at position 272;   glutamine at position 274;   aspartic acid or phenylalanine at position 296;   alanine or aspartic acid at position 326;   glycine at position 327;   lysine or arginine at position 330;   serine at position 331;   threonine at position 332;   any one of threonine, lysine, and arginine at position 333;   glutamine at position 355;   glutamine at position 356;   methionine at position 358;   any one of aspartic acid, glutamic acid, phenylalanine, isoleucine, lysine, leucine, methionine, glutamine, arginine, and tyrosine at position 396;   arginine at amino acid position 409; and   glutamic acid at amino acid position 419.   
     
     
         26 . The method of  claim 23 , wherein the antigen-binding domain binds the antigen in a calcium ion concentration-dependent manner. 
     
     
         27 . The method of  claim 26 , wherein the antigen-binding domain has decreased binding to the antigen at a calcium ion concentration between 0.1 μM and 30 μM compared to at a calcium ion concentration between 100 μM and 10 mM. 
     
     
         28 . The method of  claim 23 , wherein the antigen-binding domain binds the antigen in a pH-dependent manner. 
     
     
         29 . The method of  claim 28 , wherein the antigen-binding domain has decreased binding to the antigen at a pH of 4.0 to 6.5 compared to at a pH of 6.7 to 10. 
     
     
         30 . The method of  claim 23 , wherein the antigen-binding domain is an antibody variable region. 
     
     
         31 . The method of  claim 23 , wherein the Fc region is an Fc region of any one of SEQ ID NOs: 14, 15, 16, or 17 with at least the following two changes: the amino acids at positions 238 and 271 (EU numbering) are substituted with aspartic acid and glycine, respectively. 
     
     
         32 . The method of  claim 23 , wherein, at a pH of 4.0 to 6.5, the FcRn-binding activity of the Fc region is greater than the FcRn-binding activity of an Fc region selected from the group of Fc regions consisting of SEQ ID NOs: 14, 15, 16, and 17. 
     
     
         33 . The method of  claim 32 , wherein the Fc region in which the amino acids at positions 238 and 271 (EU numbering) are aspartic acid and glycine is an Fc region having an amino acid substitution at at least one or more of the following positions (indicated by EU numbering): 244, 245, 249, 250, 251, 252, 253, 254, 255, 256, 257, 258, 260, 262, 265, 270, 272, 279, 283, 285, 286, 288, 293, 303, 305, 307, 308, 309, 311, 312, 314, 316, 317, 318, 332, 339, 340, 341, 343, 356, 360, 362, 375, 376, 377, 378, 380, 382, 385, 386, 387, 388, 389, 400, 413, 415, 423, 424, 427, 428, 430, 431, 433, 434, 435, 436, 438, 439, 440, 442, and 447 in the amino acid sequence of the Fc region of any one of SEQ ID NOs: 14, 15, 16, or 17. 
     
     
         34 . The method of  claim 33 , wherein the Fc region in which the amino acids at positions 238 and 271 (EU numbering) are aspartic acid and glycine has at least one of the following positions occupied by the indicated amino acid (all positions indicated by EU numbering):
 leucine at position 244;   arginine at position 245;   proline at position 249;   glutamine or glutamic acid at position 250;   any one of arginine, aspartic acid, glutamic acid, and leucine at position 251;   any one of phenylalanine, serine, threonine, and tyrosine at position 252;   serine or threonine at position 254;   any one of arginine, glycine, isoleucine, and leucine at position 255;   any one of alanine, arginine, asparagine, aspartic acid, glutamine, glutamic acid, proline, and threonine at position 256;   any one of alanine, isoleucine, methionine, asparagine, serine, and valine at position 257;   aspartic acid at position 258;   serine at position 260;   leucine at position 262;   lysine at position 270;   leucine or arginine at position 272;   any one of alanine, aspartic acid, glycine, histidine, methionine, asparagine, glutamine, arginine, serine, threonine, tryptophan, and tyrosine at position 279;   any one of alanine, aspartic acid, phenylalanine, glycine, histidine, isoleucine, lysine, leucine, asparagine, proline, glutamine, arginine, serine, threonine, tryptophan, and tyrosine at position 283;   asparagine at position 285;   phenylalanine at position 286;   asparagine or proline at position 288;   valine at position 293;   any one of alanine, glutamic acid, glutamine, and methionine at position 307;   any one of isoleucine, proline, and threonine at position 308;   proline at position 309;   any one of alanine, glutamic acid, isoleucine, lysine, leucine, methionine, serine, valine, and tryptophan at position 311;   any one of alanine, aspartic acid, and proline at position 312;   alanine or leucine at position 314;   lysine at position 316;   proline at position 317;   asparagine or threonine at position 318;   any one of phenylalanine, histidine, lysine, leucine, methionine, arginine, serine, and tryptophan at position 332;   any one of asparagine, threonine, and tryptophan at position 339;   proline at position 341;   any one of glutamic acid, histidine, lysine, glutamine, arginine, threonine, or tyrosine at position 343;   arginine at position 375;   any one of glycine, isoleucine, methionine, proline, threonine, and valine at position 376;   lysine at position 377;   any one of aspartic acid, asparagine, and valine at position 378;   any one of alanine, asparagine, serine, and threonine at position 380;   any one of phenylalanine, histidine, isoleucine, lysine, leucine, methionine, asparagine, glutamine, arginine, serine, threonine, valine, tryptophan, and tyrosine at position 382;   any one of alanine, arginine, aspartic acid, glycine, His, lysine, serine, and threonine at position 385;   any one of arginine, aspartic acid, isoleucine, lysine, methionine, proline, serine, and threonine at position 386;   any one of alanine, arginine, His, proline, serine, and threonine at amino acid position 387;   any one of asparagine, proline, and serine at position 389;   asparagine at position 423;   asparagine at position 427;   any one of leucine, methionine, phenylalanine, serine, and threonine at position 428;   any one of alanine, phenylalanine, glycine, histidine, isoleucine, lysine, leucine, methionine, asparagine, glutamine, arginine, serine, threonine, valine, and tyrosine at position 430;   histidine or asparagine at position 431;   any one of arginine, glutamine, histidine, isoleucine, lysine, proline, and serine at position 433;   any one of alanine, glycine, histidine, phenylalanine, serine, tryptophan, and tyrosine at position 434;   any one of arginine, asparagine, histidine, isoleucine, leucine, lysine, methionine, and threonine at position 436;   any one of lysine, leucine, threonine, and tryptophan at position 438;   lysine at position 440; and   lysine at position 442   
       in the amino acid sequence of the Fc region of any one of SEQ ID NOs: 14, 15, 16, or 17. 
     
     
         35 . The method of  claim 23 , wherein the antigen-binding molecule is an antibody. 
     
     
         36 . A pharmaceutical composition comprising an antigen-binding molecule that specifically binds to an antigen, wherein the antigen-binding molecule comprises:
 (i) an antigen-binding domain that binds to the antigen in an ion concentration-dependent manner; and   (ii) an Fc region in which the amino acids at positions 238 and 271 (EU numbering) are aspartic acid and glycine, respectively.   
     
     
         37 . The pharmaceutical composition of  claim 36 , wherein the Fc region is a modified Fc region which differs from the amino acid sequence of a native Fc region at sites including one or more of the following positions (EU numbering): 233, 234, 237, 264, 265, 266, 267, 268, 269, 272, 274, 296, 326, 327, 330, 331, 332, 333, 355, 356, 358, 396, 409, and 419. 
     
     
         38 . The pharmaceutical composition of  claim 37 , wherein at least one of the following positions in the modified Fc region is occupied by the indicated amino acid (all positions indicated by EU numbering):
 aspartic acid at position 233;   tyrosine at position 234;   aspartic acid at position 237;   isoleucine at position 264;   glutamic acid at position 265;   any one of phenylalanine, methionine, and leucine at position 266;   any one of alanine, glutamic acid, glycine, and glutamine at position 267;   any one of aspartic acid, glutamic acid, and glutamine at position 268;   aspartic acid at position 269;   any one of aspartic acid, phenylalanine, isoleucine, methionine, asparagine, proline, or glutamine at position 272;   glutamine at position 274;   aspartic acid or phenylalanine at position 296;   alanine or aspartic acid at position 326;   glycine at position 327;   lysine or arginine at position 330;   serine at position 331;   threonine at position 332;   any one of threonine, lysine, and arginine at position 333;   glutamine at position 355;   glutamine at position 356;   methionine at position 358;   any one of aspartic acid, glutamic acid, phenylalanine, isoleucine, lysine, leucine, methionine, glutamine, arginine, and tyrosine at position 396;   arginine at position 409; and   glutamic acid at position 419.   
     
     
         39 . A method of producing an antigen-binding molecule that specifically binds to an antigen, the method comprising:
 (a) identifying a first coding sequence encoding an antigen-binding domain of an antibody heavy chain, wherein the heavy chain, when associated with an antibody light chain, forms an antigen-binding molecule that binds to the antigen in an ion-dependent manner;   (b) providing a host cell containing a nucleic acid or nucleic acids comprising (i) the first coding sequence linked in-frame to a second coding sequence encoding an Fc region in which the amino acids at positions 238 and 271 (indicated by EU numbering) are aspartic acid and glycine, respectively, and (ii) a third coding sequence encoding the light chain;   (c) culturing the host cell to express the nucleic acid or nucleic acids and thereby produce the antigen-binding molecule; and   (d) collecting the antigen-binding molecule.   
     
     
         40 . The method of  claim 39 , wherein the Fc region is a modified Fc region which differs from the amino acid sequence of a native Fc region at sites including one or more of the following positions (EU numbering): 233, 234, 237, 264, 265, 266, 267, 268, 269, 272, 274, 296, 326, 327, 330, 331, 332, 333, 355, 356, 358, 396, 409, and 419. 
     
     
         41 . The method of  claim 40 , wherein at least one of the following positions in the modified Fc region is occupied by the indicated amino acid (all positions indicated by EU numbering):
 aspartic acid at position 233;   tyrosine at position 234;   aspartic acid at position 237;   isoleucine at position 264;   glutamic acid at position 265;   any one of phenylalanine, methionine, and leucine at position 266;   any one of alanine, glutamic acid, glycine, and glutamine at position 267;   any one of aspartic acid, glutamic acid, and glutamine at position 268;   aspartic acid at position 269;   any one of aspartic acid, phenylalanine, isoleucine, methionine, asparagine, proline, or glutamine at position 272;   glutamine at position 274;   aspartic acid or phenylalanine at position 296;   alanine or aspartic acid at position 326;   glycine at position 327;   lysine or arginine at position 330;   serine at position 331;   threonine at position 332;   any one of threonine, lysine, and arginine at position 333;   glutamine at position 355;   glutamine at position 356;   methionine at position 358;   any one of aspartic acid, glutamic acid, phenylalanine, isoleucine, lysine, leucine, methionine, glutamine, arginine, and tyrosine at position 396;   arginine at position 409; and   glutamic acid at position 419.   
     
     
         42 . The method of  claim 39 , further comprising formulating the antigen-binding molecule as a pharmaceutical composition. 
     
     
         43 . The method of  claim 40 , further comprising formulating the antigen-binding molecule as a pharmaceutical composition. 
     
     
         44 . The method of  claim 41 , further comprising formulating the antigen-binding molecule as a pharmaceutical composition.