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 . A method of treatment comprising
 identifying a patient in need of treatment for a condition that is treatable by reducing the level of an antigen in blood, wherein the antigen has two or more physiological activities;   administering to the patient a therapeutically effective amount of an antibody that has an antigen-binding domain as described in (a) below and an Fc region as described in (b) below:   (a) the antigen-binding domain binds to the antigen and thereby inhibits a first physiological activity of the antigen but not a second physiological activity of the antigen, wherein the antigen-binding domain's antigen-binding activity varies with pH as described in (i) below, or with calcium ion concentration as described in (ii) below, or with both:
 (i) the antigen-binding activity is lower at a first pH in the range of 4.0 to 6.5 than at a second pH in the range of 7.0 to 9.0, wherein the ratio of (A) the KD value for antigen binding by the selected antigen-binding domain at the first pH, to (B) the KD value for antigen binding by the selected antigen-binding domain at the second pH (KD (first pH)/KD (second pH)) is 2 or more, 
 (ii) the antigen-binding activity is lower at a first calcium ion concentration in the range of 0.1 uM to 30 uM than at a second calcium ion concentration in the range of 100 uM to 10 mM, wherein the ratio of (A) the KD value for antigen binding by the selected antigen-binding domain at the first calcium ion concentration, to (B) the KD value for antigen binding by the selected antigen-binding domain at the second calcium ion concentration (KD (first calcium ion concentration)/KD (second calcium ion concentration)) is 2 or more; and 
   (b) the Fc region:
 (1) has an amino acid sequence that is not identical to the sequence of an Fc region of any native human IgG, 
 (2) binds a neonatal Fc Receptor (FcRn) at a pH in the range of 4.0 to 6.5, and 
 (3) at a pH in the range of 7.0 to 9.0, binds to a human Fc receptor with affinity greater than the affinity with which any native human IgG binds to the human Fc receptor. 
   
     
     
         55 . The method 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 antibody inhibits binding of the antigen to the first target molecule but not to the second target molecule. 
     
     
         56 . The method of  claim 54 , wherein the human Fc receptor is human FcRn or human Fcγ receptor. 
     
     
         57 . The method of  claim 54 , wherein administration of the antibody to the patient reduces the concentration of the antigen in plasma of the patient. 
     
     
         58 . The method of  claim 54 , wherein the antigen-binding domain of the antibody comprises at least one histidine residue. 
     
     
         59 . The method of  claim 56 , wherein the human Fc receptor is human FcRn, and wherein the Fc region of the antibody differs from a naturally occurring Fc region of a native human IgG at one or more positions selected from the following positions (all positions by EU numbering): 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. 
     
     
         60 . The method of  claim 59 , wherein the one or more positions include at least one from the following positions (all positions by 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, Trp, 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, Trp, 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.   
     
     
         61 . The method claim of  56 , wherein the human Fc receptor is human Fcγ receptor, and wherein the one or more positions are selected from the following positions (all positions by EU numbering): 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. 
     
     
         62 . The method claim of  61 , wherein the one or more positions include at least one of the following positions (all positions by 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;   the amino acid at position 440 is Gly, His, Ile, Leu, or Tyr.   
     
     
         63 . The method of  claim 56 , wherein the human Fc receptor is a human Fcγ receptor selected from FcγRIa, FcγRIIa, FcγRIIb, and FcγRIIIa. 
     
     
         64 . The method of  claim 61 , wherein the one or more positions include position 238 substituted with Asp and position 271 substituted with Gly (all positions by EU numbering). 
     
     
         65 . The method of  claim 64 , wherein the one or more positions also include at least one position from the following group of positions (all positions by 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. 
     
     
         66 . The method of  65 , wherein at least one position from the following positions (all positions by 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;   the amino acid at position 396 is Asp, Glu, Phe, Ile, Lys, Leu, Met, Gln, Arg, or Tyr.   
     
     
         67 . The method of  claim 64 , wherein the one or more positions also include at least one from the following group of positions (all positions by 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. 
     
     
         68 . The method of  claim 67 , wherein at least one position from the following positions (all positions by 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;   the amino acid at position 442 is Lys.   
     
     
         69 . The method of  claim 54 , wherein the antigen is High Mobility Group Box 1 (HMGB1). 
     
     
         70 . The method of  claim 69 , wherein the antibody blocks the binding of HMGB1 to Receptor for Advanced Glycation Endproducts (RAGE) or Toll-like receptor 4 (TLR4). 
     
     
         71 . The method of  claim 69 , wherein the condition is sepsis. 
     
     
         72 . The method of  claim 54 , wherein the antigen is Connective Tissue Growth Factor (CTGF). 
     
     
         73 . The method of  claim 72 , wherein the condition is fibrosis. 
     
     
         74 . A method of reducing the concentration of an antigen in the plasma of an individual, the method comprising identifying an individual whose plasma comprises the antigen and administering an antibody that binds to the antigen, wherein the antigen has two or more physiological activities, and wherein the antibody comprises an antigen-binding domain as described in (a) below and an Fc region as described in (b) below:
 (a) the antigen-binding domain binds to the antigen and thereby inhibits a first physiological activity of the antigen but not a second physiological activity of the antigen, wherein the antigen-binding domain's antigen-binding activity varies with pH as described in (i) below, or with calcium ion concentration as described in (ii) below, or with both:
 (i) the antigen-binding activity is lower at a first pH in the range of 4.0 to 6.5 than at a second pH in the range of 7.0 to 9.0, wherein the ratio of (A) the KD value for antigen binding by the selected antigen-binding domain at the first pH, to (B) the KD value for antigen binding by the selected antigen-binding domain at the second pH (KD (first pH)/KD (second pH)) is 2 or more, 
 (ii) the antigen-binding activity is lower at a first calcium ion concentration in the range of 0.1 uM to 30 uM than at a second calcium ion concentration in the range of 100 uM to 10 mM, wherein the ratio of (A) the KD value for antigen binding by the selected antigen-binding domain at the first calcium ion concentration, to (B) the KD value for antigen binding by the selected antigen-binding domain at the second calcium ion concentration (KD (first calcium ion concentration)/KD (second calcium ion concentration)) is 2 or more; and 
   (b) the Fc region:
 (1) has an amino acid sequence that is not identical to the sequence of an Fc region of any native human IgG, 
 (2) binds a FcRn at a pH in the range of 4.0 to 6.5, and 
 (3) at a pH in the range of 7.0 to 9.0, binds to a human Fc receptor with affinity greater than the affinity with which any native human IgG binds to the human Fc receptor.