Antigen-binding molecule promoting disappearance of antigens having plurality of biological activities

Abstract

The present inventors newly discovered that even if an antigen-binding molecule inhibits in vitro some of the physiological activities of an antigen having two or more physiological activities without inhibiting the remaining physiological activities, the molecule can promote elimination of the antigen from blood (from serum or plasma) and as a result reduce the physiological activities in vivo, when the antigen-binding molecule is conferred with the properties: (i) of binding to human FcRn under an acidic pH range condition; (ii) of binding under a neutral pH range condition to human Fc receptor stronger than native human IgG, and (iii) that its antigen-binding activity alters according to the ion concentration.

1 .- 53 . (canceled) 
     
     
         54 . An antigen-binding molecule comprising an antigen-binding domain and at least one receptor-binding domain, wherein
 at a pH in the range of 4.0 to 6.5, the receptor-binding domain has human neonatal Fc Receptor (FcRn)-binding activity;   at a pH in the range of 7.0 to 9.0, the ability of the receptor-binding domain to bind to a human Fc receptor is greater than the ability of a native human IgG to bind to the human Fc receptor;   the antigen-binding domain binds to an antigen;   the ability of the antigen-binding domain to bind to the antigen varies with an ion concentration;   the antigen has two or more physiological activities;   binding of the antigen-binding molecule to the antigen inhibits a first physiological activity of the antigen and does not inhibit a second physiological activity of the antigen; and   introduction of the antigen-binding molecule into an individual whose plasma comprises the antigen reduces the plasma concentration of the antigen.   
     
     
         55 . The antigen-binding molecule of  claim 54 , wherein the first physiological activity of the antigen is mediated by the antigen's binding to a first target molecule; the second physiological activity of the antigen is mediated by the antigen's binding to a second target molecule that is different from the first target molecule; and the antigen-binding molecule inhibits binding of the antigen to the first target molecule but not to the second target molecule. 
     
     
         56 . The antigen-binding molecule of  claim 54 , wherein the reduction of plasma antigen concentration is due to the promotion of antigen uptake into cells by the antigen-binding molecule. 
     
     
         57 . The antigen-binding molecule of  claim 54 , wherein the reduction of the antigen's plasma concentration results in a decrease of the antigen's physiological activities in the individual. 
     
     
         58 . The antigen-binding molecule of  claim 54 , wherein the antigen is high mobility group box 1 (HMGB1). 
     
     
         59 . The antigen-binding molecule of  claim 58 , wherein the antigen-binding molecule inhibits the binding of HMGB1 to Receptor for Advanced Glycation Endproducts (RAGE). 
     
     
         60 . The antigen-binding molecule of  claim 58 , wherein the antigen-binding molecule inhibits the binding of HMGB1 to Toll-like receptor 4 (TLR4). 
     
     
         61 . The antigen-binding molecule of  claim 54 , wherein the antigen is connective tissue growth factor (CTGF). 
     
     
         62 . The antigen-binding molecule of  claim 54 , wherein the human Fc receptor is human FcRn. 
     
     
         63 . The antigen-binding molecule of  claim 62 , wherein the receptor-binding domain comprises an Fc region that differs from the Fc region of the native IgG by amino acid substitution, insertion, or deletion at one or more positions. 
     
     
         64 . The antigen-binding molecule of  claim 63 , wherein the one or more positions are selected from the following positions:
 234, 235, 236, 237, 238, 239, 244, 245, 248, 249, 250, 251, 252, 253, 254, 255, 256, 257, 258, 260, 262, 265, 267, 270, 272, 274, 279, 280, 282, 283, 284, 285, 286, 288, 289, 293, 295, 297, 298, 303, 305, 307, 308, 309, 311, 312, 313, 314, 315, 316, 317, 318, 325, 326, 327, 328, 329, 330, 332, 334, 338, 339, 340, 341, 343, 345, 360, 361, 362, 375, 376, 377, 378, 380, 382, 384, 385, 386, 387, 389, 390, 391, 413, 422, 423, 424, 427, 428, 430, 431, 433, 434, 435, 436, 437, 438, 440, and 442 (EU numbering).   
     
     
         65 . The antigen-binding molecule of  claim 63  wherein the one or more positions include at least one from the following group of positions (EU numbering), substituted with the indicated amino acid:
 the amino acid at position 234 is Arg; 
 the amino acid at position 235 is Gly, Lys, or Arg; 
 the amino acid at position 236 is Ala, Asp, Lys, or Arg; 
 the amino acid at position 237 is Lys, Met, or Arg; 
 the amino acid at position 238 is Ala, Asp, Lys, Leu, or Arg; 
 the amino acid at position 239 is Asp or Lys; 
 the amino acid at position 244 is Leu; 
 the amino acid at position 245 is Arg; 
 the amino acid at position 248 is Ile or Tyr; 
 the amino acid at position 249 is Pro; 
 the amino acid at position 250 is Ala, Glu, Phe, Ile, Met, Gln, Ser, Val, Tip, Gly, His, Leu, Asn, or Tyr; 
 the amino acid at position 251 is Arg, Asp, Glu, or Leu; 
 the amino acid at position 252 is Phe, Ser, Thr, Trp, or Tyr; 
 the amino acid at position 253 is Val; 
 the amino acid at position 254 is Ala, Gly, His, Ile, Gln, Ser, Val, or Thr; 
 the amino acid at position 255 is Ala, Asp, Phe, His, Ile, Lys, Leu, Met, Asn, Gln, Arg, Gly, Ser, Tip, Tyr, or Glu; 
 the amino acid at position 256 is Ala, Asp, Glu, Arg, Asn, Pro, Thr, Ser, or Gln; 
 the amino acid at position 257 is Ala, Gly, Ile, Leu, Met, Asn, Ser, Thr, or Val; 
 the amino acid at position 258 is Asp or His; 
 the amino acid at position 260 is Ser; 
 the amino acid at position 262 is Leu; 
 the amino acid at position 265 is Ala; 
 the amino acid at position 267 is Met or Leu; 
 the amino acid at position 270 is Lys or Phe; 
 the amino acid at position 272 is Ala, Leu, or Arg; 
 the amino acid at position 274 is Ala; 
 the amino acid at position 279 is Leu, Ala, Asp, Gly, His, Met, Asn, Gln, Arg, Ser, Thr, Trp, or Tyr; 
 the amino acid at position 280 is Ala, Gly, His, Lys, Asn, Gln, Arg, Ser, Thr, or Glu; 
 the amino acid at position 282 is Ala or Asp; 
 the amino acid at position 283 is Ala, Asp, Phe, Gly, His, Ile, Lys, Leu, Asn, Pro, Gln, Arg, Ser, Thr, Trp, or Tyr; 
 the amino acid at position 284 is Lys; 
 the amino acid at position 285 is Asn; 
 the amino acid at position 286 is Ala, Asp, Phe, Gly, His, Ile, Lys, Leu, Met, Pro, Gln, Arg, Ser, Thr, Val, Trp, Tyr, or Glu; 
 the amino acid at position 288 is Ala, Asp, Glu, Phe, Gly, His, Ile, Leu, Met, Asn, Pro, Gln, Arg, Val, Trp, Tyr, or Ser; 
 the amino acid at position 289 is His; 
 the amino acid at position 293 is Val; 
 the amino acid at position 295 is Met; 
 the amino acid at position 297 is Ala; 
 the amino acid at position 298 is Gly; 
 the amino acid at position 303 is Ala; 
 the amino acid at position 305 is Ala or Thr; 
 the amino acid at position 307 is Ala, Asp, Glu, Phe, Gly, His, Ile, Lys, Leu, Met, Asn, Pro, Gln, Arg, Ser, Val, Trp, or Tyr; 
 the amino acid at position 308 is Ala, Phe, Ile, Leu, Met, Pro, Gln, or Thr; 
 the amino acid at position 309 is Ala, Asp, Glu, Pro, His, or Arg; 
 the amino acid at position 311 is Ala, His, Glu, Lys, Leu, Met, Ser, Val, Trp, or Ile; 
 the amino acid at position 312 is Ala, Asp, Pro, or His; 
 the amino acid at position 313 is Tyr or Phe; 
 the amino acid at position 314 is Ala, Leu, Lys, or Arg; 
 the amino acid at position 315 is Ala, Asp, Glu, Phe, Gly, Ile, Lys, Leu, Met, Gln, Arg, Ser, Thr, Val, Trp, Tyr, or His; 
 the amino acid at position 316 is Ala, Glu, Phe, His, Ile, Lys, Leu, Met, Asn, Pro, Gln, Arg, Ser, Thr, Val, Trp, or Asp; 
 the amino acid at position 317 is Ala or Pro; 
 the amino acid at position 318 is Asn or Thr; 
 the amino acid at position 325 is Ala, Gly, Met, Leu, Ile, or Ser; 
 the amino acid at position 326 is Asp; 
 the amino acid at position 327 is Gly; 
 the amino acid at position 328 is Arg, Asp, Glu, or Tyr; 
 the amino acid at position 329 is Lys or Arg; 
 the amino acid at position 330 is Leu; 
 the amino acid at position 332 is Glu, Phe, His, Lys, Leu, Met, Arg, Ser, Trp, or Val; 
 the amino acid at position 334 is Leu; 
 the amino acid at position 338 is Ala; 
 the amino acid at position 339 is Asn, Thr, or Trp; 
 the amino acid at position 340 is Ala; 
 the amino acid at position 341 is Pro; 
 the amino acid at position 343 is Glu, His, Lys, Gln, Arg, Thr, or Tyr; 
 the amino acid at position 345 is Ala; 
 the amino acid at position 360 is His; 
 the amino acid at position 361 is Ala; 
 the amino acid at position 362 is Ala; 
 the amino acid at position 375 is Ala or Arg; 
 the amino acid at position 376 is Ala, Gly, Ile, Met, Pro, Thr, or Val; 
 the amino acid at position 377 is Lys; 
 the amino acid at position 378 is Asp, Asn, or Val; 
 the amino acid at position 380 is Ala, Asn, Thr, or Ser; 
 the amino acid at position 382 is Ala, Phe, His, Ile, Lys, Leu, Met, Asn, Gln, Arg, Ser, Thr, Trp, Tyr, or Val; 
 the amino acid at position 384 is Ala; 
 the amino acid at position 385 is Ala, Gly, Lys, Ser, Thr, Asp, His, or Arg; 
 the amino acid at position 386 is Arg, Asp, Ile, Met, Ser, Thr, Lys, or Pro; 
 the amino acid at position 387 is Ala, Arg, His, Pro, Ser, Thr, or Glu; 
 the amino acid at position 389 is Ala, Asn, Pro, or Ser; 
 the amino acid at position 390 is Ala; 
 the amino acid at position 391 is Ala; 
 the amino acid at position 413 is Ala; 
 the amino acid at position 423 is Asn; 
 the amino acid at position 424 is Ala or Glu; 
 the amino acid at position 427 is Asn; 
 the amino acid at position 428 is Ala, Asp, Phe, Gly, His, Ile, Lys, Leu, Met, Asn, Pro, Gln, Ser, Thr, Val, Trp, or Tyr; 
 the amino acid at position 430 is Ala, Phe, Gly, His, Ile, Lys, Leu, Met, Asn, Gln, Arg, Ser, Thr, Val, or Tyr; 
 the amino acid at position 431 is His or Asn; 
 the amino acid at position 433 is Arg, Gln, His, Ile, Pro, Ser, or Lys; 
 the amino acid at position 434 is Ala, Phe, Gly, Met, His, Ser, Trp, or Tyr; 
 the amino acid at position 435 is Lys, Arg, or Asn; 
 the amino acid at position 436 is Ala, His, Ile, Leu, Glu, Phe, Gly, Lys, Met, Asn, Arg, Ser, Thr, Trp, or Val; 
 the amino acid at position 437 is Arg; 
 the amino acid at position 438 is Lys, Leu, Thr, or Trp; 
 the amino acid at position 440 is Lys; and 
 the amino acid at position 442 is Lys. 
 
     
     
         66 . The antigen-binding molecule of  claim 63 , wherein the native IgG is an IgG native to a nonhuman animal. 
     
     
         67 . The antigen-binding molecule of  claim 63 , wherein the native IgG is a native human IgG. 
     
     
         68 . The antigen-binding molecule of claim  1 , wherein the human Fc receptor is a human Fcγ receptor. 
     
     
         69 . The antigen-binding molecule of  claim 68 , wherein the receptor-binding domain comprises an Fc region that differs from the Fc region of the native IgG by amino acid substitution, insertion, or deletion at one or more positions. 
     
     
         70 . The antigen-binding molecule of  claim 69 , wherein the one or more positions are selected from the following positions:
 221, 222, 223, 224, 225, 227, 228, 230, 231, 232, 233, 234, 235, 236, 237, 238, 239, 240, 241, 243, 244, 245, 246, 247, 249, 250, 251, 252, 254, 255, 256, 257, 258, 260, 262, 263, 264, 265, 266, 267, 268, 269, 270, 271, 272, 273, 274, 275, 276, 278, 279, 280, 281, 282, 283, 284, 285, 286, 288, 290, 291, 292, 293, 294, 295, 296, 297, 298, 299, 300, 301, 302, 303, 304, 305, 307, 308, 309, 311, 312, 313, 314, 315, 316, 317, 318, 320, 322, 323, 324, 325, 326, 327, 328, 329, 330, 331, 332, 333, 334, 335, 336, 337, 339, 341, 343, 375, 376, 377, 378, 379, 380, 382, 385, 386, 387, 389, 392, 396, 421, 423, 427, 428, 429, 430, 431, 433, 434, 436, 438, 440; and 442 (EU numbering).   
     
     
         71 . The antigen-binding molecule of  claim 69 , wherein the one or more positions include at least one from the following group of positions (EU numbering), substituted with the indicated amino acid:
 the amino acid at position 221 is Lys or Tyr;   the amino acid at position 222 is Phe, Trp, Glu, or Tyr;   the amino acid at position 223 is Phe, Trp, Glu, or Lys;   the amino acid at position 224 is Phe, Trp, Glu, or Tyr;   the amino acid at position 225 is Glu, Lys, or Trp;   the amino acid at position 227 is Glu, Gly, Lys, or Tyr;   the amino acid at position 228 is Glu, Gly, Lys, or Tyr;   the amino acid at position 230 is Ala, Glu, Gly, or Tyr;   the amino acid at position 231 is Glu, Gly, Lys, Pro, or Tyr;   the amino acid at position 232 is Glu, Gly, Lys, or Tyr;   the amino acid at position 233 is Ala, Asp, Phe, Gly, His, Ile, Lys, Leu, Met, Asn, Gln, Arg, Ser, Thr, Val, Trp, or Tyr;   the amino acid at position 234 is Ala, Asp, Glu, Phe, Gly, His, Ile, Lys, Met, Asn, Pro, Gln, Arg, Ser, Thr, Val, Trp, or Tyr;   the amino acid at position 235 is Ala, Asp, Glu, Phe, Gly, His, Ile, Lys, Met, Asn, Pro, Gln, Arg, Ser, Thr, Val, Trp, or Tyr;   the amino acid at position 236 is Ala, Asp, Glu, Phe, His, Ile, Lys, Leu, Met, Asn, Pro, Gln, Arg, Ser, Thr, Val, Trp, or Tyr;   the amino acid at position 237 is Ala, Asp, Glu, Phe, His, Ile, Lys, Leu, Met, Asn, Pro, Gln, Arg, Ser, Thr, Val, Trp, or Tyr;   the amino acid at position 238 is Asp, Glu, Phe, Gly, His, Ile, Lys, Leu, Met, Asn, Gln, Arg, Ser, Thr, Val, Trp, or Tyr;   the amino acid at position 239 is Asp, Glu, Phe, Gly, His, Ile, Lys, Leu, Met, Asn, Pro, Gln, Arg, Thr, Val, Trp, or Tyr;   the amino acid at position 240 is Ala, Ile, Met, or Thr;   the amino acid at position 241 is Asp, Glu, Leu, Arg, Trp, or Tyr;   the amino acid at position 243 is Leu, Glu, Leu, Gln, Arg, Trp, or Tyr;   the amino acid at position 244 is His;   the amino acid at position 245 is Ala;   the amino acid at position 246 is Asp, Glu, His, or Tyr,   the amino acid at position 247 is Ala, Phe, Gly, His, Ile, Leu, Met, Thr, Val, or Tyr;   the amino acid at position 249 is Glu, His, Gln, or Tyr;   the amino acid at position 250 is Glu or Gln;   the amino acid at position 251 is Phe;   the amino acid at position 254 is Phe, Met, or Tyr;   the amino acid at position 255 is Glu, Leu, or Tyr;   the amino acid at position 256 is Ala, Met, or Pro;   the amino acid at position 258 is Asp, Glu, His, Ser, or Tyr;   the amino acid at position 260 is Asp, Glu, His, or Tyr;   the amino acid at position 262 is Ala, Glu, Phe, Ile, or Thr;   the amino acid at position 263 is Ala, Ile, Met, or Thr;   the amino acid at position 264 is Asp, Glu, Phe, Gly, His, Ile, Lys, Leu, Met, Asn, Pro, Gln, Arg, Ser, Thr, Trp, or Tyr;   the amino acid at position 265 is Ala, Glu, Leu, Phe, Gly, His, Ile, Lys, Leu, Met, Asn, Pro, Gln, Arg, Ser, Thr, Val, Trp, or Tyr;   the amino acid at position 266 is Ala, Phe, Ile, Leu, Met, or Thr;   the amino acid at position 267 is Ala, Asp, Glu, Phe, Gly, His, Ile, Lys, Leu, Met, Asn, Pro, Gln, Arg, Thr, Val, Trp, or Tyr;   the amino acid at position 268 is Ala, Asp, Glu, Phe, Gly, Ile, Lys, Leu, Met, Asn, Pro, Gln, Arg, Thr, Val, or Trp;   the amino acid at position 269 is Asp, Phe, Gly, His, Ile, Lys, Leu, Met, Asn, Pro, Arg, Ser, Thr, Val, Trp, or Tyr;   the amino acid at position 270 is Glu, Phe, Gly, His, Ile, Leu, Met, Pro, Gln, Arg, Ser, Thr, Trp, or Tyr;   the amino acid at position 271 is Ala, Asp, Glu, Phe, Gly, His, Ile, Lys, Leu, Met, Asn, Gln, Arg, Ser, Thr, Val, Trp, or Tyr;   the amino acid at position 272 is Asp, Phe, Gly, His, Ile, Lys, Leu, Met, Asn, Pro, Gln, Arg, Ser, Thr, Val, Trp, or Tyr;   the amino acid at position 273 is Phe or Ile;   the amino acid at position 274 is Asp, Glu, Phe, Gly, His, Ile, Leu, Met, Asn, Pro, Arg, Ser, Thr, Val, Trp, or Tyr;   the amino acid at position 275 is Leu or Trp;   the amino acid at position 276 is Asp, Glu, Phe, Gly, His, Ile, Leu, Met, Pro, Arg, Ser, Thr, Val, Trp, or Tyr;   the amino acid at position 278 is Asp, Glu, Gly, His, Ile, Lys, Leu, Met, Asn, Pro, Gln, Arg, Ser, Thr, Val, or Trp;   the amino acid at position 279 is Ala;   the amino acid at position 280 is Ala, Gly, His, Lys, Leu, Pro, Gln, Trp, or Tyr;   the amino acid at position 281 is Asp, Lys, Pro, or Tyr;   the amino acid at position 282 is Glu, Gly, Lys, Pro, or Tyr;   the amino acid at position 283 is Ala, Gly, His, Ile, Lys, Leu, Met, Pro, Arg, or Tyr;   the amino acid at position 284 is Asp, Glu, Leu, Asn, Thr, or Tyr;   the amino acid at position 285 is Asp, Glu, Lys, Gln, Trp, or Tyr;   the amino acid at position 286 is Glu, Gly, Pro, or Tyr;   the amino acid at position 288 is Asn, Asp, Glu, or Tyr;   the amino acid at position 290 is Asp, Gly, His, Leu, Asn, Ser, Thr, Trp, or Tyr;   the amino acid at position 291 is Asp, Glu, Gly, His, Ile, Gln, or Thr;   the amino acid at position 292 is Ala, Asp, Glu, Pro, Thr, or Tyr;   the amino acid at position 293 is Phe, Gly, His, Ile, Leu, Met, Asn, Pro, Arg, Ser, Thr, Val, Trp, or Tyr;   the amino acid at position 294 is Phe, Gly, His, Ile, Lys, Leu, Met, Asn, Pro, Arg, Ser, Thr, Val, Trp, or Tyr;   the amino acid at position 295 is Asp, Glu, Phe, Gly, His, Ile, Lys, Leu, Met, Asn, Pro, Arg, Ser, Thr, Val, Trp, or Tyr;   the amino acid at position 296 is Ala, Asp, Glu, Gly, His, Ile, Lys, Leu, Met, Asn, Gln, Arg, Ser, Thr, or Val;   the amino acid at position 297 is Asp, Glu, Phe, Gly, His, Ile, Lys, Leu, Met, Pro, Gln, Arg, Ser, Thr, Val, Trp, or Tyr;   the amino acid at position 298 is Ala, Asp, Glu, Phe, His, Ile, Lys, Met, Asn, Gln, Arg, Thr, Val, Trp, or Tyr;   the amino acid at position 299 is Ala, Asp, Glu, Phe, Gly, His, Ile, Lys, Leu, Met, Asn, Pro, Gln, Arg, Ser, Val, Trp, or Tyr;   the amino acid at position 300 is Ala, Asp, Glu, Gly, His, Ile, Lys, Leu, Met, Asn, Pro, Gln, Arg, Ser, Thr, Val, or Trp;   the amino acid at position 301 is Asp, Glu, His, or Tyr;   the amino acid at position 302 is Ile;   the amino acid at position 303 is Asp, Gly, or Tyr;   the amino acid at position 304 is Asp, His, Leu, Asn, or Thr;   the amino acid at position 305 is Glu, Ile, Thr, or Tyr;   the amino acid at position 311 is Ala, Asp, Asn, Thr, Val or Tyr;   the amino acid at position 313 is Phe;   the amino acid at position 315 is Leu;   the amino acid at position 317 is Glu or Gln;   the amino acid at position 318 is His, Leu, Asn, Pro, Gln, Arg, Thr, Val, or Tyr;   the amino acid at position 320 is Asp, Phe, Gly, His, Ile, Leu, Asn, Pro, Ser, Thr, Val, Trp, or Tyr;   the amino acid at position 322 is Ala, Asp, Phe, Gly, His, Ile, Pro, Ser, Thr, Val, Trp, or Tyr;   the amino acid at position 323 is Ile, Leu, or Met;   the amino acid at position 324 is Asp, Phe, Gly, His, Ile, Leu, Met, Pro, Arg, Thr, Val, Trp, or Tyr;   the amino acid at position 325 is Ala, Asp, Glu, Phe, Gly, His, Ile, Lys, Leu, Met, Pro, Gln, Arg, Ser, Thr, Val, Trp, or Tyr;   the amino acid at position 326 is Ala, Asp, Glu, Phe, Gly, His, Ile, Leu, Met, Asn, Pro, Gln, Ser, Thr, Val, Trp, or Tyr;   the amino acid at position 327 is Ala, Asp, Glu, Phe, Gly, His, Ile, Lys, Leu, Met, Asn, Pro, Arg, Thr, Val, Trp, or Tyr;   the amino acid at position 328 is Ala, Asp, Glu, Phe, Gly, His, Ile, Lys, Met, Asn, Pro, Gln, Arg, Ser, Thr, Val, Trp, or Tyr;   the amino acid at position 329 is Asp, Glu, Phe, Gly, His, Ile, Lys, Leu, Met, Asn, Gln, Arg, Ser, Thr, Val, Trp, or Tyr;   the amino acid at position 330 is Cys, Glu, Phe, Gly, His, Ile, Lys, Leu, Met, Asn, Pro, Arg, Ser, Thr, Val, Trp, or Tyr;   the amino acid at position 331 is Asp, Phe, His, Ile, Leu, Met, Gln, Arg, Ser, Thr, Val, Trp, or Tyr;   the amino acid at position 332 is Ala, Asp, Glu, Phe, Gly, His, Lys, Leu, Met, Asn, Pro, Gln, Arg, Ser, Thr, Val, Trp, or Tyr;   the amino acid at position 333 is Ala, Asp, Glu, Phe, Gly, His, Ile, Lys, Leu, Met, Pro, Arg, Ser, Thr, Val, or Tyr;   the amino acid at position 334 is Ala, Glu, Phe, His, Ile, Leu, Met, Asn, Pro, Gln, Arg, Ser, Thr, Val, Trp, or Tyr;   the amino acid at position 335 is Asp, Phe, Gly, His, Ile, Leu, Met, Asn, Pro, Arg, Ser, Val, Trp, or Tyr;   the amino acid at position 336 is Glu, Lys, or Tyr;   the amino acid at position 337 is Asp, Glu, His, or Asn;   the amino acid at position 339 is Asp, Phe, Gly, Ile, Lys, Met, Asn, Gln, Arg, Ser, or Thr;   the amino acid at position 376 is Ala or Val;   the amino acid at position 377 is Gly or Lys;   the amino acid at position 378 is Asp;   the amino acid at position 379 is Asn;   the amino acid at position 380 is Ala, Asn, or Ser;   the amino acid at position 382 is Ala or Ile;   the amino acid at position 385 is Glu;   the amino acid at position 392 is Thr;   the amino acid at position 396 is Asp, Glu, Phe, Ile, Lys, Leu, Met, Gln, Arg, or Tyr;   the amino acid at position 421 is Lys;   the amino acid at position 427 is Asn;   the amino acid at position 428 is Phe or Leu;   the amino acid at position 429 is Met;   the amino acid at position 434 is Trp;   the amino acid at position 436 is Ile; and   the amino acid at position 440 is Gly, His, Ile, Leu, or Tyr.   
     
     
         72 . The antigen-binding molecule of  claim 68 , wherein the human Fcγ receptor is FcγRIa, FcγRIIa, FcγRIIb, or FcγRIIIa. 
     
     
         73 . The antigen-binding molecule of  claim 70 , wherein the one or more positions include position 238 substituted with Asp and position 271 substituted with Gly (EU numbering). 
     
     
         74 . The antigen-binding molecule of  claim 73 , wherein the one or more positions also include at least one from the following group of positions (EU numbering):
 233, 234, 237, 244, 245, 249, 250, 251, 252, 254, 255, 256, 257, 258, 260, 262, 264, 265, 266, 267, 268, 269, 270, 272, 279, 283, 285, 286, 288, 293, 296, 307, 308, 309, 311, 312, 314, 316, 317, 318, 326, 327, 330, 331, 332, 333, 339, 341, 343, 375, 376, 377, 378, 380, 382, 385, 386, 387, 389, 396, 423, 427, 428, 430, 431, 433, 434, 436, 438, 440, and 442.   
     
     
         75 . The antigen-binding molecule of  claim 74 , wherein at least one position from the following group of positions (EU numbering) is substituted with the indicated amino acid:
 the amino acid at position 233 is Asp;   the amino acid at position 234 is Tyr;   the amino acid at position 237 is Asp;   the amino acid at position 264 is Ile;   the amino acid at position 265 is Glu;   the amino acid at position 266 is Phe, Met, or Leu;   the amino acid at position 267 is Ala, Glu, Gly, or Gln;   the amino acid at position 268 is Asp or Glu;   the amino acid at position 269 is Asp;   the amino acid at position 272 is Asp, Phe, Ile, Met, Asn, or Gln;   the amino acid at position 296 is Asp;   the amino acid at position 326 is Ala or Asp;   the amino acid at position 327 is Gly;   the amino acid at position 330 is Lys or Arg;   the amino acid at position 331 is Ser;   the amino acid at position 332 is Thr,   the amino acid at position 333 is Thr, Lys, or Arg; and   the amino acid at position 396 is Asp, Glu, Phe, Ile, Lys, Leu, Met, Gln, Arg, or Tyr.   
     
     
         76 . The antigen-binding molecule of  claim 73 , wherein the one or more positions also include at least one from the following group of positions (EU numbering):
 244, 245, 249, 250, 251, 252, 254, 255, 256, 257, 258, 260, 262, 270, 272, 279, 283, 285, 286, 288, 293, 307, 308, 309, 311, 312, 314, 316, 317, 318, 332, 339, 341, 343, 375, 376, 377, 378, 380, 382, 385, 386, 387, 389, 423, 427, 428, 430, 431, 433, 434, 436, 438, 440, and 442.   
     
     
         77 . The antigen-binding molecule of  claim 76 , wherein at least one position from the following group of positions (EU numbering) is substituted with the indicated amino acid:
 the amino acid at position 244 is Leu;   the amino acid at position 245 is Arg;   the amino acid at position 249 is Pro;   the amino acid at position 250 is Gln or Glu;   the amino acid at position 251 is Arg, Asp, Glu, or Leu;   the amino acid at position 252 is Phe, Ser, Thr, or Tyr;   the amino acid at position 254 is Ser or Thr;   the amino acid at position 255 is Arg, Gly, Ile, or Leu;   the amino acid at position 256 is Ala, Arg, Asn, Asp, Gln, Glu, Pro, or Thr;   the amino acid at position 257 is Ala, Ile, Met, Asn, Ser, or Val;   the amino acid at position 258 is Asp;   the amino acid at position 260 is Ser;   the amino acid at position 262 is Leu;   the amino acid at position 270 is Lys;   the amino acid at position 272 is Leu or Arg;   the amino acid at position 279 is Ala, Asp, Gly, His, Met, Asn, Gln, Arg, Ser, Thr, Trp, or Tyr;   the amino acid at position 283 is Ala, Asp, Phe, Gly, His, Ile, Lys, Leu, Asn, Pro, Gln, Arg, Ser, Thr, Trp, or Tyr;   the amino acid at position 285 is Asn;   the amino acid at position 286 is Phe;   the amino acid at position 288 is Asn or Pro;   the amino acid at position 293 is Val;   the amino acid at position 307 is Ala, Glu, Gln, or Met;   the amino acid at position 308 is Ile, Pro, or Thr;   the amino acid at position 309 is Pro,   the amino acid at position 311 is Ala, Glu, Ile, Lys, Leu, Met, Ser, Val, or Trp;   the amino acid at position 312 is Ala, Asp, or Pro;   the amino acid at position 314 is Ala or Leu;   the amino acid at position 316 is Lys;   the amino acid at position 317 is Pro;   the amino acid at position 318 is Asn or Thr;   the amino acid at position 332 is Phe, His, Lys, Leu, Met, Arg, Ser, or Trp;   the amino acid at position 339 is Asn, Thr, or Trp;   the amino acid at position 341 is Pro;   the amino acid at position 343 is Glu, His, Lys, Gln, Arg, Thr, or Tyr;   the amino acid at position 375 is Arg;   the amino acid at position 376 is Gly, Ile, Met, Pro, Thr, or Val;   the amino acid at position 377 is Lys;   the amino acid at position 378 is Asp, Asn, or Val;   the amino acid at position 380 is Ala, Asn, Ser, or Thr;   the amino acid at position 382 is Phe, His, Ile, Lys, Leu, Met, Asn, Gln, Arg, Ser, Thr, Val, Trp, or Tyr;   the amino acid at position 385 is Ala, Arg, Asp, Gly, His, Lys, Ser, or Thr;   the amino acid at position 386 is Arg, Asp, Ile, Lys, Met, Pro, Ser, or Thr;   the amino acid at position 387 is Ala, Arg, His, Pro, Ser, or Thr;   the amino acid at position 389 is Asn, Pro, or Ser;   the amino acid at position 423 is Asn;   the amino acid at position 427 is Asn;   the amino acid at position 428 is Leu, Met, Phe, Ser, or Thr;   the amino acid at position 430 is Ala, Phe, Gly, His, Ile, Lys, Leu, Met, Asn, Gln, Arg, Ser, Thr, Val, or Tyr;   the amino acid at position 431 is His or Asn;   the amino acid at position 433 is Arg, Gln, His, Ile, Lys, Pro, or Ser;   the amino acid at position 434 is Ala, Gly, His, Phe, Ser, Trp, or Tyr;   the amino acid at position 436 is Arg, Asn, His, Ile, Leu, Lys, Met, or Thr;   the amino acid at position 438 is Lys, Leu, Thr, or Trp;   the amino acid at position 440 is Lys; and   the amino acid at position 442 is Lys.   
     
     
         78 . The antigen-binding molecule of  claim 69 , wherein the native IgG is an IgG native to a nonhuman animal. 
     
     
         79 . The antigen-binding molecule of  claim 69 , wherein the native IgG is a native human IgG. 
     
     
         80 . The antigen-binding molecule of  claim 54 , wherein the ion concentration is hydrogen ion concentration (pH), and the antigen-binding activity is lower at a first pH that is in the range of 4.0 to 6.5 than at a second pH that is in the range of 7.0 to 9.0. 
     
     
         81 . The antigen-binding molecule of  claim 80 , wherein the first pH is endosomal pH. 
     
     
         82 . The antigen-binding molecule of  claim 80 , wherein the second pH is plasma pH. 
     
     
         83 . The antigen-binding molecule of  claim 80 , wherein the first pH is in the range of pH 5.5 to 6.5 and the second pH is in the range of pH 7.0 to 8.0. 
     
     
         84 . The antigen-binding molecule of  claim 80 , wherein the ratio of (a) the KD value for antigen binding by the antigen-binding molecule at the first pH, to (b) the KD value for antigen binding by the antigen-binding molecule at the second pH
   ( KD (first pH)/ KD (second pH))   
       is 2 or more. 
     
     
         85 . The antigen-binding molecule of  claim 80 , wherein the antigen-binding domain comprises at least one His residue. 
     
     
         86 . The antigen-binding molecule of  claim 80 , wherein the antigen-binding activity is dependent not only on pH, but also on calcium ion concentration, with antigen binding activity lower at a first calcium ion concentration in the range of 0.1 μM to 30 μM than at a second calcium ion concentration in the range of 100 μM to 10 mM. 
     
     
         87 . The antigen-binding molecule of  claim 54 , wherein the ion concentration is calcium ion concentration and the antigen-binding activity is lower at a first calcium ion concentration in the range of 0.1 μM to 30 μM than at a second calcium ion concentration in the range of 100 to 10 mM. 
     
     
         88 . The antigen-binding molecule of  claim 87 , wherein the first calcium ion concentration is an endosomal calcium ion concentration. 
     
     
         89 . The antigen-binding molecule of  claim 87 , wherein the second calcium ion concentration is a plasma calcium ion concentration. 
     
     
         90 . The antigen-binding molecule of  claim 87 , wherein the first calcium ion concentration is in the range of 1 μM to 5 μM and the second calcium ion concentration is in the range of 0.5 mM to 2.5 mM. 
     
     
         91 . The antigen-binding molecule of  claim 87 , wherein the ratio of (a) the KD value for antigen binding by the antigen-binding molecule at the first calcium ion concentration, to (b) the KD value for antigen binding by the antigen-binding molecule at the second calcium ion concentration
   ( KD (first calcium ion concentration)/ KD (second calcium ion concentration))   
       is 2 or more. 
     
     
         92 . The antigen-binding molecule of  claim 54 , wherein the antigen-binding molecule is an antibody. 
     
     
         93 . The antigen-binding molecule of  claim 92 , wherein the antibody is a chimeric antibody, a humanized antibody, or a human antibody. 
     
     
         94 . A pharmaceutical composition comprising as an active ingredient the antigen-binding molecule of  claim 54 . 
     
     
         95 . The pharmaceutical composition of  claim 94 , wherein the antigen is HMGB1. 
     
     
         96 . The pharmaceutical composition of  claim 94 , wherein the antigen is CTGF. 
     
     
         97 . A method of treatment comprising
 identifying a patient in need of treatment for a condition that is treatable by reducing the level of a particular antigen in blood; and   administering a therapeutically effective amount of the pharmaceutical composition of  claim 94  to the patient, wherein the antigen to which the antigen-binding molecule binds is the particular antigen.   
     
     
         98 . The method of  claim 97 , wherein the antigen is HMGB1. 
     
     
         99 . The method of  claim 98 , wherein the condition is sepsis. 
     
     
         100 . The method of  claim 97 , wherein the antigen is CTGF. 
     
     
         101 . The method of  claim 100 , wherein the condition is fibrosis. 
     
     
         102 . A method for producing the antigen-binding molecule of  claim 54 , the method comprising:
 (a) identifying one or more antigen-binding domains that inhibit the first physiological activity of the antigen by binding to the antigen, and do not inhibit the second physiological activity of the antigen;   (b) of the antigen-binding domain(s) identified in (a), selecting an antigen-binding domain whose ability to bind to the antigen varies with the concentration of the ion;   (c) identifying a receptor-binding domain that
 (i) has human FcRn-binding activity at a pH in the range of 4.0 to 6.5, and 
 (ii) at a pH in the range of 7.0 to 9.0, has a greater ability to bind to the human Fc receptor than does the native human IgG; 
   (d) preparing an antigen-binding molecule comprising the antigen-binding domain selected in (b) and the receptor-binding domain identified in (c); and   (e) confirming that the antigen-binding molecule prepared in (d) inhibits the first physiological activity of the antigen by binding to the antigen and does not inhibit the second physiological activity of the antigen.   
     
     
         103 . The method of  claim 102 , wherein the amino acid sequence of the receptor-binding domain is not identical to a sequence of any naturally-occurring receptor-binding domain. 
     
     
         104 . The method of  claim 102 , wherein (d) comprises producing recombinant DNA encoding the antigen-binding molecule and expressing the recombinant DNA, thereby producing the antigen-binding molecule. 
     
     
         105 . The method of  claim 102 , wherein the first physiological activity of the antigen is mediated by the antigen's binding to a first target molecule; the second physiological activity of the antigen is mediated by the antigen's binding to a second target molecule that is different from the first target molecule; and the antigen-binding molecule inhibits binding of the antigen to the first target molecule but not to the second target molecule. 
     
     
         106 . The method of  claim 102 , wherein the human Fc receptor is human FcRn or human Fcγ receptor.