Target tissue-specific antigen-binding molecule

Abstract

The present inventors discovered that the above-mentioned problems can be solved by producing antigen-binding molecules that contain an antigen-binding domain whose antigen-binding activity varies depending on the concentration of a target tissue-specific compound. Use of antigen-binding molecules of the present invention enables various diseases that originate from a target tissue to be treated in a manner specific to the target tissue.

1 . An antigen-binding molecule comprising an antigen-binding domain whose antigen-binding activity varies depending on the concentration of a target tissue-specific compound. 
     
     
         2 . The antigen-binding molecule of  claim 1 , wherein the target tissue is a cancer tissue. 
     
     
         3 . The antigen-binding molecule of  claim 2 , wherein the compound specific to a cancer tissue is a metabolite specific to a cancer cell, a metabolite specific to an immune cell that has infiltrated into a cancer tissue, or a metabolite specific to a stromal cell in a cancer tissue. 
     
     
         4 . The antigen-binding molecule of  claim 1 , wherein the target tissue is an inflamed tissue. 
     
     
         5 . The antigen-binding molecule of  claim 4 , wherein the compound specific to an inflamed tissue is a metabolite specific to an immune cell that has infiltrated into an inflamed tissue or a metabolite specific to a normal cell that has been damaged in an inflamed tissue. 
     
     
         6 . The antigen-binding molecule of  claim 1 , wherein the compound is at least one compound selected from a nucleoside having a purine ring structure, an amino acid and its metabolite, a lipid and its metabolite, a primary metabolite of glycometabolism, and nicotinamide and its metabolite. 
     
     
         7 . The antigen-binding molecule of  claim 6 , wherein the compound is at least one compound selected from adenosine, adenosine triphosphate, inosine, alanine, glutamic acid, aspartic acid, kynurenine, prostaglandin E2, succinic acid, citric acid, and 1-methylnicotinamide. 
     
     
         8 . The antigen-binding molecule of any one of  claims 1  to  7 , wherein the antigen is a membrane-type molecule. 
     
     
         9 . The antigen-binding molecule of any one of  claims 1  to  8 , which is an antigen-binding molecule that has a neutralizing activity. 
     
     
         10 . The antigen-binding molecule of any one of  claims 1  to  9 , which is an antigen-binding molecule that has a cytotoxic activity. 
     
     
         11 . The antigen-binding molecule of any one of  claims 1  to  10 , which comprises an Fc region. 
     
     
         12 . The antigen-binding molecule of  claim 11 , wherein the Fc region is an Fc region contained in the constant region of SEQ ID NOs: 5, 6, 7, or 8. 
     
     
         13 . The antigen-binding molecule of  claim 11 , wherein the Fc region comprises an altered FcγR-binding Fc region that has a higher Fcγ receptor-binding activity than the Fcγ receptor-binding activity of a native human IgG Fc region. 
     
     
         14 . The antigen-binding molecule of  claim 13 , wherein at least one or more amino acids selected from the group consisting of amino acids at 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, 254, 255, 256, 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, 311, 313, 315, 317, 318, 320, 322, 323, 324, 325, 326, 327, 328, 329, 330, 331, 332, 333, 334, 335, 336, 337, 339, 376, 377, 378, 379, 380, 382, 385, 392, 396, 421, 427, 428, 429, 434, 436, and 440 according to EU numbering, in the amino acid sequence of the altered FcγR-binding Fc region are different from the amino acids of the native human IgG Fc region. 
     
     
         15 . The antigen-binding molecule of  claim 14 , which comprises at least one or more amino acids selected from the group consisting of:
 Lys or Tyr for the amino acid at position 221;   Phe, Trp, Glu, or Tyr for the amino acid at position 222;   Phe, Trp, Glu, or Lys for the amino acid at position 223;   Phe, Trp, Glu, or Tyr for the amino acid at position 224;   Glu, Lys, or Trp for the amino acid at position 225;   Glu, Gly, Lys, or Tyr for the amino acid at position 227;   Glu, Gly, Lys, or Tyr for the amino acid at position 228;   Ala, Glu, Gly, or Tyr for the amino acid at position 230;   Glu, Gly, Lys, Pro, or Tyr for the amino acid at position 231;   Glu, Gly, Lys, or Tyr for the amino acid at position 232;   Ala, Asp, Phe, Gly, His, Ile, Lys, Leu, Met, Asn, Gln, Arg, Ser, Thr, Val, Trp, or Tyr for the amino acid at position 233;   Ala, Asp, Glu, Phe, Gly, His, Ile, Lys, Met, Asn, Pro, Gln, Arg, Ser, Thr, Val, Trp, or Tyr for the amino acid at position 234;   Ala, Asp, Glu, Phe, Gly, His, Ile, Lys, Met, Asn, Pro, Gln, Arg, Ser, Thr, Val, Trp, or Tyr for the amino acid at position 235;   Ala, Asp, Glu, Phe, His, Ile, Lys, Leu, Met, Asn, Pro, Gln, Arg, Ser, Thr, Val, Trp, or Tyr for the amino acid at position 236;   Asp, Glu, Phe, His, Ile, Lys, Leu, Met, Asn, Pro, Gln, Arg, Ser, Thr, Val, Trp, or Tyr for the amino acid at position 237;   Asp, Glu, Phe, Gly, His, Ile, Lys, Leu, Met, Asn, Gln, Arg, Ser, Thr, Val, Trp, or Tyr for the amino acid at position 238;   Asp, Glu, Phe, Gly, His, Ile, Lys, Leu, Met, Asn, Pro, Gln, Arg, Thr, Val, Trp, or Tyr for the amino acid at position 239;   Ala, Ile, Met, or Thr for the amino acid at position 240;   Asp, Glu, Leu, Arg, Trp, or Tyr for the amino acid at position 241;   Leu, Glu, Leu, Gln, Arg, Trp, or Tyr for the amino acid at position 243;   His for the amino acid at position 244;   Ala for the amino acid at position 245;   Asp, Glu, His, or Tyr for the amino acid at position 246;   Ala, Phe, Gly, His, Ile, Leu, Met, Thr, Val, or Tyr for the amino acid at position 247;   Glu, His, Gln, or Tyr for the amino acid at position 249;   Glu or Gln for the amino acid at position 250;   Phe for the amino acid at position 251;   Phe, Met, or Tyr for the amino acid at position 254;   Glu, Leu, or Tyr for the amino acid at position 255;   Ala, Met, or Pro for the amino acid at position 256;   Asp, Glu, His, Ser, or Tyr for the amino acid at position 258;   Asp, Glu, His, or Tyr for the amino acid at position 260;   Ala, Glu, Phe, Ile, or Thr for the amino acid at position 262;   Ala, Ile, Met, or Thr for the amino acid at position 263;   Asp, Glu, Phe, Gly, His, Ile, Lys, Leu, Met, Asn, Pro, Gln, Arg, Ser, Thr, Trp, or Tyr for the amino acid at position 264;   Ala, Leu, Phe, Gly, His, Ile, Lys, Leu, Met, Asn, Pro, Gln, Arg, Ser, Thr, Val, Trp, or Tyr for the amino acid at position 265;   Ala, Ile, Met, or Thr for the amino acid at position 266;   Asp, Glu, Phe, His, Ile, Lys, Leu, Met, Asn, Pro, Gln, Arg, Thr, Val, Trp, or Tyr for the amino acid at position 267;   Asp, Glu, Phe, Gly, Ile, Lys, Leu, Met, Pro, Gln, Arg, Thr, Val, or Trp for the amino acid at position 268;   Phe, Gly, His, Ile, Lys, Leu, Met, Asn, Pro, Arg, Ser, Thr, Val, Trp, or Tyr for the amino acid at position 269;   Glu, Phe, Gly, His, Ile, Leu, Met, Pro, Gln, Arg, Ser, Thr, Trp, or Tyr for the amino acid at position 270;   Ala, Asp, Glu, Phe, Gly, His, Ile, Lys, Leu, Met, Asn, Gln, Arg, Ser, Thr, Val, Trp, or Tyr for the amino acid at position 271;   Asp, Phe, Gly, His, Ile, Lys, Leu, Met, Pro, Arg, Ser, Thr, Val, Trp, or Tyr for the amino acid at position 272;   Phe or Ile for the amino acid at position 273;   Asp, Glu, Phe, Gly, His, Ile, Leu, Met, Asn, Pro, Arg, Ser, Thr, Val, Trp, or Tyr for the amino acid at position 274;   Leu or Trp for the amino acid at position 275;   Asp, Glu, Phe, Gly, His, Ile, Leu, Met, Pro, Arg, Ser, Thr, Val, Trp, or Tyr for the amino acid at position 276;   Asp, Glu, Gly, His, Ile, Lys, Leu, Met, Asn, Pro, Gln, Arg, Ser, Thr, Val, or Trp for the amino acid at position 278;   Ala for the amino acid at position 279;   Ala, Gly, His, Lys, Leu, Pro, Gln, Trp, or Tyr for the amino acid at position 280;   Asp, Lys, Pro, or Tyr for the amino acid at position 281;   Glu, Gly, Lys, Pro, or Tyr for the amino acid at position 282;   Ala, Gly, His, Ile, Lys, Leu, Met, Pro, Arg, or Tyr for the amino acid at position 283;   Asp, Glu, Leu, Asn, Thr, or Tyr for the amino acid at position 284;   Asp, Glu, Lys, Gln, Trp, or Tyr for the amino acid at position 285;   Glu, Gly, Pro, or Tyr for the amino acid at position 286;   Asn, Asp, Glu, or Tyr for the amino acid at position 288;   Asp, Gly, His, Leu, Asn, Ser, Thr, Trp, or Tyr for the amino acid at position 290;   Asp, Glu, Gly, His, Ile, Gln, or Thr for the amino acid at position 291;   Ala, Asp, Glu, Pro, Thr, or Tyr for the amino acid at position 292;   Phe, Gly, His, Ile, Leu, Met, Asn, Pro, Arg, Ser, Thr, Val, Trp, or Tyr for the amino acid at position 293;   Phe, Gly, His, Ile, Lys, Leu, Met, Asn, Pro, Arg, Ser, Thr, Val, Trp, or Tyr for the amino acid at position 294;   Asp, Glu, Phe, Gly, His, Ile, Lys, Met, Asn, Pro, Arg, Ser, Thr, Val, Trp, or Tyr for the amino acid at position 295;   Ala, Asp, Glu, Gly, His, Ile, Lys, Leu, Met, Asn, Gln, Arg, Ser, Thr, or Val for the amino acid at position 296;   Asp, Glu, Phe, Gly, His, Ile, Lys, Leu, Met, Pro, Gln, Arg, Ser, Thr, Val, Trp, or Tyr for the amino acid at position 297;   Ala, Asp, Glu, Phe, His, Ile, Lys, Met, Asn, Gln, Arg, Thr, Val, Trp, or Tyr for the amino acid at position 298;   Ala, Asp, Glu, Phe, Gly, His, Ile, Lys, Leu, Met, Asn, Pro, Gln, Arg, Ser, Val, Trp, or Tyr for the amino acid at position 299;   Ala, Asp, Glu, Gly, His, Ile, Lys, Leu, Met, Asn, Pro, Gln, Arg, Ser, Thr, Val, or Trp for the amino acid at position 300;   Asp, Glu, His, or Tyr for the amino acid at position 301;   Ile for the amino acid at position 302;   Asp, Gly, or Tyr for the amino acid at position 303;   Asp, His, Leu, Asn, or Thr for the amino acid at position 304;   Glu, Ile, Thr, or Tyr for the amino acid at position 305;   Ala, Asp, Asn, Thr, Val, or Tyr for the amino acid at position 311;   Phe for the amino acid at position 313;   Leu for the amino acid at position 315;   Glu, or Gln for the amino acid at position 317;   His, Leu, Asn, Pro, Gln, Arg, Thr, Val, or Tyr for the amino acid at position 318;   Asp, Phe, Gly, His, Ile, Leu, Asn, Pro, Ser, Thr, Val, Trp, or Tyr for the amino acid at position 320;   Ala, Asp, Phe, Gly, His, Ile, Pro, Ser, Thr, Val, Trp, or Tyr for the amino acid at position 322;   Ile for the amino acid at position 323;   Asp, Phe, Gly, His, Ile, Leu, Met, Pro, Arg, Thr, Val, Trp, or Tyr for the amino acid at position 324;   Ala, Asp, Glu, Phe, Gly, His, Ile, Lys, Leu, Met, Pro, Gln, Arg, Ser, Thr, Val, Trp, or Tyr for the amino acid at position 325;   Ala, Asp, Glu, Gly, Ile, Leu, Met, Asn, Pro, Gln, Ser, Thr, Val, Trp, or Tyr for the amino acid at position 326;   Ala, Asp, Glu, Phe, Gly, His, Ile, Lys, Leu, Met, Asn, Pro, Arg, Thr, Val, Trp, or Tyr for the amino acid at position 327;   Ala, Asp, Glu, Phe, Gly, His, Ile, Lys, Met, Asn, Pro, Gln, Arg, Ser, Thr, Val, Trp, or Tyr for the amino acid at position 328;   Asp, Glu, Phe, Gly, His, Ile, Lys, Leu, Met, Asn, Gln, Arg, Ser, Thr, Val, Trp, or Tyr for the amino acid at position 329;   Cys, Glu, Phe, Gly, His, Ile, Lys, Leu, Met, Asn, Pro, Arg, Ser, Thr, Val, Trp, or Tyr for the amino acid at position 330;   Asp, Phe, His, Ile, Leu, Met, Gln, Arg, Thr, Val, Trp, or Tyr for the amino acid at position 331;   Ala, Asp, Glu, Phe, Gly, His, Lys, Leu, Met, Asn, Pro, Gln, Arg, Ser, Thr, Val, Trp, or Tyr for the amino acid at position 332;   Ala, Asp, Glu, Phe, Gly, His, Ile, Leu, Met, Pro, Ser, Thr, Val, or Tyr for the amino acid at position 333;   Ala, Glu, Phe, Ile, Leu, Pro, or Thr for the amino acid at position 334;   Asp, Phe, Gly, His, Ile, Leu, Met, Asn, Pro, Arg, Ser, Val, Trp, or Tyr for the amino acid at position 335;   Glu, Lys, or Tyr for the amino acid at position 336;   Glu, His, or Asn for the amino acid at position 337;   Asp, Phe, Gly, Ile, Lys, Met, Asn, Gln, Arg, Ser, or Thr for the amino acid at position 339;   Ala or Val for the amino acid at position 376;   Gly or Lys for the amino acid at position 377;   Asp for the amino acid at position 378;   Asn for the amino acid at position 379;   Ala, Asn, or Ser for the amino acid at position 380;   Ala, or Ile for the amino acid at position 382;   Glu for the amino acid at position 385;   Thr for the amino acid at position 392;   Leu for the amino acid at position 396;   Lys for the amino acid at position 421;   Asn for the amino acid at position 427;   Phe, or Leu for the amino acid at position 428;   Met for the amino acid at position 429;   Trp for the amino acid at position 434;   Ile for the amino acid at position 436; and   Gly, His, Ile, Leu, or Tyr for the amino acid at position 440   according to EU numbering in the amino acid sequence of the altered FcγR-binding Fc region.   
     
     
         16 . The antigen-binding molecule of  claim 11 , wherein the Fc region is modified so that there is a higher proportion of Fc region bound by a fucose-deficient sugar chain in a composition of sugar chain bound at position 297, according to EU numbering, of the Fc region, or so that there is a higher proportion of Fc region with an added bisecting N-acetylglucosamine. 
     
     
         17 . The antigen-binding molecule of any one of  claims 11  and  13  to  16 , wherein the FcRn-binding activity of the Fc region under an acidic pH range condition is enhanced compared to the FcRn-binding activity of the Fc region of SEQ ID NO: 5, 6, 7, or 8. 
     
     
         18 . The antigen-binding molecule of  claim 17 , wherein the Fc region is an Fc region with substitution of at least one or more amino acids selected from the group consisting of amino acids at positions 238, 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, according to EU numbering, in the amino acid sequence of the Fc region comprised in the constant region of SEQ ID NO: 5, 6, 7, or 8. 
     
     
         19 . The antigen-binding molecule of  claim 18 , wherein the Fc region comprises at least one or more amino acids selected from the group consisting of:
 Leu for the amino acid at position 238;   Leu for the amino acid at position 244;   Arg for the amino acid at position 245;   Pro for the amino acid at position 249;   Gln or Glu for the amino acid at position 250;   Arg, Asp, Glu, or Leu for the amino acid at position 251;   Phe, Ser, Thr, or Tyr for the amino acid at position 252;   Ser or Thr for the amino acid at position 254;   Arg, Gly, Ile, or Leu for the amino acid at position 255;   Ala, Arg, Asn, Asp, Gln, Glu, Pro, or Thr for the amino acid at position 256;   Ala, Ile, Met, Asn, Ser, or Val for the amino acid at position 257;   Asp for the amino acid at position 258;   Ser for the amino acid at position 260;   Leu for the amino acid at position 262;   Lys for the amino acid at position 270;   Leu, or Arg for the amino acid at position 272;   Ala, Asp, Gly, His, Met, Asn, Gln, Arg, Ser, Thr, Trp, or Tyr for the amino acid at position 279;   Ala, Asp, Phe, Gly, His, Ile, Lys, Leu, Asn, Pro, Gln, Arg, Ser, Thr, Trp, or Tyr for the amino acid at position 283;   Asn for the amino acid at position 285;   Phe for the amino acid at position 286;   Asn or Pro for the amino acid at position 288;   Val for the amino acid at position 293,   Ala, Glu, Gln, or Met for the amino acid at position 307;   Ala, Glu, Ile, Lys, Leu, Met, Ser, Val, or Trp for the amino acid at position 311;   Pro for the amino acid at position 309;   Ala, Asp, or Pro for the amino acid at position 312;   Ala or Leu for the amino acid at position 314;   Lys for the amino acid at position 316;   Pro for the amino acid at position 317;   Asn or Thr for the amino acid at position 318;   Phe, His, Lys, Leu, Met, Arg, Ser, or Trp for the amino acid at position 332;   Asn, Thr, or Trp for the amino acid at position 339;   Pro for the amino acid at position 341;   Glu, His, Lys, Gln, Arg, Thr, or Tyr for the amino acid at position 343;   Arg for the amino acid at position 375;   Gly, Ile, Met, Pro, Thr, or Val for the amino acid at position 376;   Lys for the amino acid at position 377;   Asp, Asn, or Val for the amino acid at position 378;   Ala, Asn, Ser, or Thr for the amino acid at position 380;   Phe, His, Ile, Lys, Leu, Met, Asn, Gln, Arg, Ser, Thr, Val, Trp, or Tyr for the amino acid at position 382;   Ala, Arg, Asp, Gly, His, Lys, Ser, or Thr for the amino acid at position 385;   Arg, Asp, Ile, Lys, Met, Pro, Ser, or Thr for the amino acid at position 386;   Ala, Arg, His, Pro, Ser, or Thr for the amino acid at position 387;   Asn, Pro, or Ser for the amino acid at position 389;   Asn for the amino acid at position 423;   Asn for the amino acid at position 427;   Leu, Met, Phe, Ser, or Thr for the amino acid at position 428;   Ala, Phe, Gly, His, Ile, Lys, Leu, Met, Asn, Gln, Arg, Ser, Thr, Val, or Tyr for the amino acid at position 430;   His or Asn for the amino acid at position 431;   Arg, Gln, His, Ile, Lys, Pro, or Ser for the amino acid at position 433;   Ala, Gly, His, Phe, Ser, Trp, or Tyr for the amino acid at position 434;   Arg, Asn, His, Ile, Leu, Lys, Met, or Thr for the amino acid at position 436;   Lys, Leu, Thr, or Trp for the amino acid at position 438;   Lys for the amino acid at position 440;   Lys for the amino acid at position 442; and   Ile, Pro, or Thr for the amino acid at position 308;   as indicated by EU numbering, in the amino acid sequence of the Fc region comprised in the constant region of SEQ ID NO: 5, 6, 7, or 8.   
     
     
         20 . The antigen-binding molecule of any one of  claims 1  to  19 , wherein the antigen-binding domain is a multispecific or a multiparatopic antigen-binding domain. 
     
     
         21 . The antigen-binding molecule of  claim 20 , wherein an antigen bound by at least one of the antigen-binding domains is a membrane-type molecule expressed on a cancer cell membrane, and an antigen bound by at least one of the antigen-binding domains is a membrane-type molecule expressed on an effector cell membrane. 
     
     
         22 . The antigen-binding molecule of  claim 21 , wherein the effector cell is an NK cell, a macrophage, or a T cell. 
     
     
         23 . The antigen-binding molecule of  claim 21  or  22 , wherein the membrane-type molecule expressed on an effector cell membrane is a TCR-constituting polypeptide, CD2, CD3, CD28, CD44, CD16, CD32, CD64, or NKG2D. 
     
     
         24 . The antigen-binding molecule of  claim 20 , wherein an antigen bound by at least one of the antigen-binding domains is a membrane-type molecule expressed on a cancer cell membrane, and an antigen bound by at least one of the antigen-binding domains is a cytotoxic substance. 
     
     
         25 . The antigen-binding molecule of any one of  claims 20  to  24 , wherein the antigen-binding molecule is an antibody fragment. 
     
     
         26 . The antigen-binding molecule of any one of  claims 1  to  24 , wherein the antigen-binding molecule is an antibody. 
     
     
         27 . The antigen-binding molecule of any one of  claims 1  to  7 , wherein the antigen is a soluble molecule. 
     
     
         28 . The antigen-binding molecule of  claim 27 , which is an antigen-binding molecule having a neutralizing activity. 
     
     
         29 . The antigen-binding molecule of  claim 27  or  28 , which comprises an Fc region. 
     
     
         30 . The antigen-binding molecule of  claim 29 , wherein the Fc region is an Fc region comprised in the constant region of SEQ ID NO: 5, 6, 7, or 8. 
     
     
         31 . The antigen-binding molecule of  claim 29 , wherein the FcRn-binding activity of the Fc region under an acidic pH range condition is enhanced compared to the FcRn-binding activity of the Fc region comprised in the constant region of SEQ ID NO: 5, 6, 7, or 8. 
     
     
         32 . The antigen-binding molecule of  claim 31 , wherein the Fc region is an Fc region with substitution of at least one or more amino acids selected from the group consisting of amino acids at positions 238, 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, according to EU numbering, in the amino acid sequence of the Fc region comprised in the constant region of SEQ ID NO: 5, 6, 7, or 8. 
     
     
         33 . The antigen-binding molecule of  claim 32 , wherein the Fc region comprises at least one or more amino acids selected from the group consisting of:
 Leu for the amino acid at position 238;   Leu for the amino acid at position 244;   Arg for the amino acid at position 245;   Pro for the amino acid at position 249;   Gln or Glu for the amino acid at position 250;   Arg, Asp, Glu, or Leu for the amino acid at position 251;   Phe, Ser, Thr, or Tyr for the amino acid at position 252;   Ser or Thr for the amino acid at position 254;   Arg, Gly, Ile, or Leu for the amino acid at position 255;   Ala, Arg, Asn, Asp, Gln, Glu, Pro, or Thr for the amino acid at position 256;   Ala, Ile, Met, Asn, Ser, or Val for the amino acid at position 257;   Asp for the amino acid at position 258;   Ser for the amino acid at position 260;   Leu for the amino acid at position 262;   Lys for the amino acid at position 270;   Leu, or Arg for the amino acid at position 272;   Ala, Asp, Gly, His, Met, Asn, Gln, Arg, Ser, Thr, Trp, or Tyr for the amino acid at position 279;   Ala, Asp, Phe, Gly, His, Ile, Lys, Leu, Asn, Pro, Gln, Arg, Ser, Thr, Trp, or Tyr for the amino acid at position 283;   Asn for the amino acid at position 285;   Phe for the amino acid at position 286;   Asn or Pro for the amino acid at position 288;   Val for the amino acid at position 293,   Ala, Glu, Gln, or Met for the amino acid at position 307;   Ala, Glu, Ile, Lys, Leu, Met, Ser, Val, or Trp for the amino acid at position 311;   Pro for the amino acid at position 309;   Ala, Asp, or Pro for the amino acid at position 312;   Ala or Leu for the amino acid at position 314;   Lys for the amino acid at position 316;   Pro for the amino acid at position 317;   Asn or Thr for the amino acid at position 318;   Phe, His, Lys, Leu, Met, Arg, Ser, or Trp for the amino acid at position 332;   Asn, Thr, or Trp for the amino acid at position 339;   Pro for the amino acid at position 341;   Glu, His, Lys, Gln, Arg, Thr, or Tyr for the amino acid at position 343;   Arg for the amino acid at position 375;   Gly, Ile, Met, Pro, Thr, or Val for the amino acid at position 376;   Lys for the amino acid at position 377;   Asp, Asn, or Val for the amino acid at position 378;   Ala, Asn, Ser, or Thr for the amino acid at position 380;   Phe, His, Ile, Lys, Leu, Met, Asn, Gln, Arg, Ser, Thr, Val, Trp, or Tyr for the amino acid at position 382;   Ala, Arg, Asp, Gly, His, Lys, Ser, or Thr for the amino acid at position 385;   Arg, Asp, Ile, Lys, Met, Pro, Ser, or Thr for the amino acid at position 386;   Ala, Arg, His, Pro, Ser, or Thr for the amino acid at position 387;   Asn, Pro, or Ser for the amino acid at position 389;   Asn for the amino acid at position 423;   Asn for the amino acid at position 427;   Leu, Met, Phe, Ser, or Thr for the amino acid at position 428;   Ala, Phe, Gly, His, Ile, Lys, Leu, Met, Asn, Gln, Arg, Ser, Thr, Val, or Tyr for the amino acid at position 430;   His or Asn for the amino acid at position 431;   Arg, Gln, His, Ile, Lys, Pro, or Ser for the amino acid at position 433;   Ala, Gly, His, Phe, Ser, Trp, or Tyr for the amino acid at position 434;   Arg, Asn, His, Ile, Leu, Lys, Met, or Thr for the amino acid at position 436;   Lys, Leu, Thr, or Trp for the amino acid at position 438;   Lys for the amino acid at position 440;   Lys for the amino acid at position 442; and   Ile, Pro, or Thr for the amino acid at position 308;   as indicated by EU numbering, in the amino acid sequence of the Fc region comprised in the constant region of SEQ ID NO: 5, 6, 7, or 8.   
     
     
         34 . The antigen-binding molecule of  claim 29 , wherein the FcRn-binding activity of the Fc region under a neutral pH range condition is enhanced compared to the FcRn-binding activity of the Fc region comprised in the constant region of SEQ ID NO: 5, 6, 7, or 8. 
     
     
         35 . The antigen-binding molecule of  claim 34 , wherein the Fc region is an Fc region with substitution of at least one or more amino acids selected from the group consisting of amino acids at positions 237, 248, 250, 252, 254, 255, 256, 257, 258, 265, 286, 289, 297, 298, 303, 305, 307, 308, 309, 311, 312, 314, 315, 317, 332, 334, 360, 376, 380, 382, 384, 385, 386, 387, 389, 424, 428, 433, 434, and 436 according to EU numbering, in the amino acid sequence of the Fc region comprised in the constant region of SEQ ID NO: 5, 6, 7, or 8. 
     
     
         36 . The antigen-binding molecule of  claim 35 , wherein the Fc region comprises at least one or more amino acids selected from the group consisting of:
 Met for the amino acid at position 237;   Ile for the amino acid at position 248;   Ala, Phe, Ile, Met, Gln, Ser, Val, Trp, or Tyr for the amino acid at position 250;   Phe, Trp, or Tyr for the amino acid at position 252;   Thr for the amino acid at position 254;   Glu for the amino acid at position 255;   Asp, Asn, Glu, or Gln for the amino acid at position 256;   Ala, Gly, Ile, Leu, Met, Asn, Ser, Thr, or Val for the amino acid at position 257;   His for the amino acid at position 258;   Ala for the amino acid at position 265;   Ala or Glu for the amino acid at position 286;   His for the amino acid at position 289;   Ala for the amino acid at position 297;   Ala for the amino acid at position 303;   Ala for the amino acid at position 305;   Ala, Asp, Phe, Gly, His, Ile, Lys, Leu, Met, Asn, Pro, Gln, Arg, Ser, Val, Trp, or Tyr for the amino acid at position 307;   Ala, Phe, Ile, Leu, Met, Pro, Gln, or Thr for the amino acid at position 308;   Ala, Asp, Glu, Pro, or Arg for the amino acid at position 309;   Ala, His, or Ile for the amino acid at position 311;   Ala or His for the amino acid at position 312;   Lys or Arg for the amino acid at position 314;   Ala, Asp, or His for the amino acid at position 315;   Ala for the amino acid at position 317;   Val for the amino acid at position 332;   Leu for the amino acid at position 334;   His for the amino acid at position 360;   Ala for the amino acid at position 376;   Ala for the amino acid at position 380;   Ala for the amino acid at position 382;   Ala for the amino acid at position 384;   Asp or His for the amino acid at position 385;   Pro for the amino acid at position 386;   Glu for the amino acid at position 387;   Ala or Ser for the amino acid at position 389;   Ala for the amino acid at position 424;   Ala, Asp, Phe, Gly, His, Ile, Lys, Leu, Asn, Pro, Gln, Ser, Thr, Val, Trp, or Tyr for the amino acid at position 428;   Lys for the amino acid at position 433;   Ala, Phe, His, Ser, Trp, or Tyr for the amino acid at position 434; and   His, Ile, Leu, Phe, Thr, or Val for the amino acid at position 436 as indicated by EU numbering, in the amino acid sequence of the Fc region of SEQ ID NO: 5, 6, 7, or 8.   
     
     
         37 . The antigen-binding molecule of any one of  claims 29  and  31  to  36 , wherein the Fc region has a higher binding activity to an inhibitory Fcγ receptor than to an activating Fcγ receptor. 
     
     
         38 . The antigen-binding molecule of  claim 37 , wherein the inhibitory Fcγ receptor is human FcγRIIb. 
     
     
         39 . The antigen-binding molecule of  claim 37  or  38 , wherein the activating Fcγ receptor is human FcγRIa, human FcγRIIa (R), human FcγRIIa (H), human FcγRIIIa (V), or human FcγRIIIa (F). 
     
     
         40 . The antigen-binding molecule of any one of  claims 37  to  39 , wherein the amino acid at position 238 or 328 (EU numbering) of the Fc region includes an amino acid that is different from the amino acid of the native human IgG Fc region. 
     
     
         41 . The antigen-binding molecule of  claim 40 , wherein the amino acid at position 238 indicated by EU numbering in the Fc region is Asp or the amino acid at position 328 is Glu. 
     
     
         42 . The antigen-binding molecule of  claim 40  or  41 , which comprises at least one or more amino acids selected from the group consisting of:
 Asp for the amino acid at position 233; 
 Trp or Tyr for the amino acid at position 234; 
 Ala, Asp, Glu, Leu, Met, Phe, Trp, or Tyr for the amino acid at position 237; 
 Asp for the amino acid at position 239; 
 Ala, Gln, or Val for the amino acid at position 267; 
 Asn, Asp, or Glu for the amino acid at position 268; 
 Gly for the amino acid at position 271; 
 Ala, Asn, Asp, Gln, Glu, Leu, Met, Ser, or Thr for the amino acid at position 326; 
 Arg, Lys, or Met for the amino acid at position 330; 
 Ile, Leu, or Met for the amino acid at position 323; and 
 Asp for the amino acid at position 296 according to EU numbering, in the amino acid sequence of the Fc region. 
 
     
     
         43 . The antigen-binding molecule of any one of  claims 27  to  42 , wherein the antigen-binding molecule is an antibody. 
     
     
         44 . A method for producing the antigen-binding molecule of any one of  claims 1  to  43 , which comprises selecting an antigen-binding domain whose antigen-binding activity varies depending on the concentration of a target tissue-specific compound. 
     
     
         45 . A method of screening for the antigen-binding molecule of any one of  claims 1  to  43 , which comprises selecting an antigen-binding domain whose antigen-binding activity varies depending on the concentration of a target tissue-specific compound. 
     
     
         46 . A pharmaceutical composition comprising the antigen-binding molecule of any one of  claims 1  to  43 .