Anti-hla-dq2.5 antibody and its use for the treatment of celiac disease

Abstract

The present invention relates to anti-HLA-DQ2.5 antibodies and its use for the treatment of celiac disease. The present invention provides anti-HLA-DQ2.5 antibodies that have been modified. The anti-HLA-DQ2.5 antibodies of the invention have binding activity to complexes formed by HLA-DQ2.5 and a gluten peptide, but have substantially no binding activity to complexes formed by HLA-DQ2.5 and an irrelevant peptide. Furthermore, the antibodies of the invention are shown to have inhibitory effects on T cell activation by gluten peptides.

1 . A multispecific antigen-binding molecule comprising:
 (i) a first antigen-binding moiety that has binding activity to HLA-DQ2.5 in the form of a complex with a gluten peptide; and   (ii) a second antigen-binding moiety that has binding activity to HLA-DQ2.5 in the form of a complex with a gluten peptide;   wherein the antigen-binding molecule binds to two or more complexes of HLA-DQ2.5 and gluten peptides,   wherein at least one of the gluten peptides in the complexes bound by the first antigen-binding moiety is different from at least one of the gluten peptides in the complexes bound by the second antigen-binding moiety; and   wherein the antigen-binding molecule has substantially no binding activity to either or both of a HLA-DQ2.5 positive PBMC B cell and a Ba/F3 cell that expresses HLA-DQ2.5,   wherein the antigen-binding molecule is humanized, and   wherein one or more amino acids in a heavy chain and/or a light chain of the first antigen-binding moiety and/or second antigen-binding moiety in the multispecific antigen-binding molecule are altered.   
     
     
         2 . The multispecific antigen-binding molecule of  claim 1 , wherein the antigen-binding molecule has substantially no binding activity to a Ba/F3 cell that expresses HLA-DQ2.2. 
     
     
         3 . The multispecific antigen-binding molecule of  claim 1  or  2 , wherein the gluten peptide is an immune dominant peptide related to celiac disease. 
     
     
         4 . The multispecific antigen-binding molecule of any one of  claims 1  to  3 , wherein the gluten peptide is selected from the group consisting of: 33mer gliadin peptide, alpha 1 gliadin peptide, alpha 2 gliadin peptide, gamma 1 gliadin peptide, gamma 2 gliadin peptide, omega 1 gliadin peptide, omega 2 gliadin peptide, BC Hordein peptide, alpha 3 gliadin peptide, alpha 1b gliadin peptide, gamma 4a gliadin peptide, gamma 4b gliadin peptide, avenin 1 peptide, avenin 2 peptide, avenin 3 peptide, hordein 1 peptide, hordein 2 peptide, secalin 1 peptide, secalin 2 peptide, and 26mer gliadin peptide. 
     
     
         5 . The multispecific antigen-binding molecule of any one of  claims 1  to  4 , which has substantially no binding activity to HLA-DQ2.5 in the form of a complex with an irrelevant peptide, wherein the irrelevant peptide is at least one peptide selected from the group consisting of: CLIP peptide, Hepatitis B virus 1 peptide, Salmonella peptide, Mycobacterium bovis peptide, and thyroperoxidase peptide. 
     
     
         6 . The multispecific antigen-binding molecule of any one of  claims 1  to  5 , which has substantially no binding activity to HLA-DP, HLA-DR, HLA-DQ5.1, HLA-DQ6.3, HLA-DQ7.3, HLA-DQ7.5, and HLA-DQ8. 
     
     
         7 . The multispecific antigen-binding molecule of any one of  claims 1  to  6 , which blocks (i) the interaction between HLA-DQ2.5/gluten peptide complex and HLA-DQ2.5/gluten peptide-restricted CD4+ T cell; and/or (ii) the interaction between HLA-DQ2.2/gluten peptide complex and HLA-DQ2.2/gluten peptide-restricted CD4+ T cell. 
     
     
         8 . The multispecific antigen-binding molecule of  claim 7 , wherein the gluten peptide is selected from the group consisting of: alpha 1 gliadin peptide, alpha 1b gliadin peptide, alpha 2 gliadin peptide, omega 1 gliadin peptide, omega 2 gliadin peptide, gamma 1 gliadin peptide, gamma 2 gliadin peptide, gamma 3 gliadin peptide, gamma 4a gliadin peptide, gamma 4d gliadin peptide, and BC Hordein peptide. 
     
     
         9 . The multispecific antigen-binding molecule of any one of  claims 1  to  8 , wherein the antigen-binding molecule has enhanced binding activity to the complex formed by HLA-DQ2.5 and the gluten peptide, compared to before said humanization and alteration. 
     
     
         10 . The multispecific antigen-binding molecule of any one of  claims 1  to  9 , wherein the antigen-binding molecule has enhanced cross reactivity towards gluten peptides, compared to before said humanization and alteration. 
     
     
         11 . The multispecific antigen-binding molecule of any one of  claims 1  to  10 , wherein one, two, three or all sets of amino acid residues selected from the group consisting of the sets of amino acid residues shown in (a) to (d) below in the heavy chain and the light chain of the antigen-binding molecule are amino acid residues which electrostatically repel each other:
 (a) an amino acid residue in a heavy chain constant region (CH1) which is at position 175 according to EU numbering, and an amino acid residue in a light chain constant region (CL) which is at position 131 according to Kabat numbering, 
 (b) an amino acid residue in CH1 which is at position 175 according to EU numbering, and an amino acid residue in CL which is at position 160 according to Kabat numbering, 
 (c) amino acid residue in CH1 which is at position 175 according to EU numbering, and amino acid residues in CL which are at positions 131 and 160 according to Kabat numbering, 
 (d) amino acid residues in CH1 which are at positions 147 and 175 according to EU numbering, and amino acid residues in CL which are at positions 131 and 160 according to Kabat numbering. 
 
     
     
         12 . The multispecific antigen-binding molecule of  claim 11 , further wherein two or more amino acid residues that form an interface between a heavy chain variable region and a light chain variable region are amino acid residues which electrostatically repel each other. 
     
     
         13 . The multispecific antigen-binding molecule of  claim 12 , wherein the amino acid residues which electrostatically repel each other are one or two sets of amino acid residues selected from the group consisting of the sets of amino acid residues of (a) and (b) below:
 (a) an amino acid residue in the heavy chain variable region which is at position 39 according to Kabat numbering, and an amino acid residue in the light chain variable region which is at position 38 according to Kabat numbering,   (b) an amino acid residue in the heavy chain variable region which is at position 45 according to Kabat numbering, and an amino acid residue in the light chain variable region which is at position 44 according to Kabat numbering.   
     
     
         14 . The multispecific antigen-binding molecule of any one of  claims 11  to  13 , wherein the amino acid residues which electrostatically repel each other are selected from the amino acid residues included in either set of (X) or (Y) below:
 (X) glutamic acid (E), aspartic acid (D), 
 (Y) lysine (K), arginine (R), histidine (H). 
 
     
     
         15 . The multispecific antigen-binding molecule of any one of  claims 11  to  14 , which further comprises an Fc domain that exhibits reduced binding affinity to human Fc gamma receptor, as compared to a native human IgG 1  Fc domain. 
     
     
         16 . The multispecific antigen-binding molecule of  claim 15 , wherein the Fc domain comprises Arg at position 235 and Arg at position 236,
 wherein the amino acid positions are numbered according to EU numbering.   
     
     
         17 . The multispecific antigen-binding molecule of  claim 15  or  16 , wherein the Fc domain is composed of a first Fc-region subunit and a second Fc-region subunit that are capable of stable association. 
     
     
         18 . The multispecific antigen-binding molecule of  claim 17 , wherein the Fc domain comprises (e1) or (e2) below:
 (e1) the first Fc-region subunit comprising Cys at position 349, Ser at position 366, Ala at position 368 and Val at position 407, and the second Fc-region comprising Cys at position 354 and Trp at position 366;   (e2) the first Fc-region subunit comprising Glu at position 439, and the second Fc-region comprising Lys at position 356,   wherein the amino acid positions are numbered according to EU numbering.   
     
     
         19 . The multispecific antigen-binding molecule of any one of  claims 15  to  18 , wherein the Fc domain further exhibits stronger FcRn binding affinity to human FcRn, as compared to a native human IgG 1  Fc domain. 
     
     
         20 . The multispecific antigen-binding molecule of  claim 18 , wherein the first and/or Fc-region subunit comprises Leu at position 428, Ala at position 434, Arg at position 438, and Glu at position 440,
 wherein the amino acid positions are numbered according to EU numbering.   
     
     
         21 . The multispecific antigen-binding molecule of any one of  claims 1  to  20 , wherein the multispecific antigen-binding molecule has substantially no binding activity to the gluten peptide itself. 
     
     
         22 . The multispecific antigen-binding molecule of any one of  claims 1  to  10 , wherein the multispecific antigen-binding molecule comprises one or more of the amino acid residues of (i) to (xii) below:
 (i) glutamic acid or lysine at position 175 (EU numbering) in the heavy-chain constant region; 
 (ii) glutamic acid at position 147 (EU numbering) in the heavy-chain constant region; 
 (iii) glutamic acid or lysine at position 131 (Kabat numbering) in the light-chain constant region; 
 (iv) glutamic acid or lysine at position 160 (Kabat numbering) in the light-chain constant region; 
 (v) arginine at position 235 (EU numbering) in the heavy-chain constant region; 
 (vi) arginine at position 236 (EU numbering) in the heavy-chain constant region; 
 (vii) lysine at position 356 (EU numbering) in the heavy-chain constant region; 
 (viii) leucine at position 428 (EU numbering) in the heavy-chain constant region; 
 (ix) alanine at position 434 (EU numbering) in the heavy-chain constant region; 
 (x) arginine at position 438 (EU numbering) in the heavy-chain constant region; 
 (xi) glutamic acid at position 439 (EU numbering) in the heavy-chain constant region; 
 (xii) glutamic acid at position 440 (EU numbering) in the heavy-chain constant region. 
 
     
     
         23 . A multispecific antigen-binding molecule comprising a first antigen-binding moiety and a second antigen-binding moiety;
 wherein the first antigen-binding moiety comprises any one of (a1) to (a3) below:   (a1) a first antibody variable region comprising the complementarity determining region (CDR) 1 of SEQ ID NO: 129, the CDR 2 of SEQ ID NO: 130, the CDR 3 of SEQ ID NO: 131, and a second antibody variable region comprising the CDR 1 of SEQ ID NO: 132, the CDR 2 of SEQ ID NO: 133, the CDR 3 of SEQ ID NO: 134;   (a2) a first antibody variable region comprising the complementarity determining region (CDR) 1 of SEQ ID NO: 164, the CDR 2 of SEQ ID NO: 165, the CDR 3 of SEQ ID NO: 166, and a second antibody variable region comprising the CDR 1 of SEQ ID NO: 167, the CDR 2 of SEQ ID NO: 168, the CDR 3 of SEQ ID NO: 169; and   (a3) a first amino acid sequence that has at least 70%, 75%, 80%, 85%, 90%, or 95% sequence identity to the first antibody variable region recited in (a1) or (a2), and a second amino acid sequence that has at least 70%, 75%, 80%, 85%, 90%, or 95% sequence identity to the second antibody variable region recited in (a1) or (a2).   
     
     
         24 . The multispecific antigen-binding molecule of  claim 23 ,
 wherein the second antigen-binding moiety comprises any one of (b1) to (b8) below:   (b1) a third antibody variable region comprising the complementarity determining region (CDR) 1 of SEQ ID NO: 135, the CDR 2 of SEQ ID NO: 136, the CDR 3 of SEQ ID NO: 137 and a fourth antibody variable region comprising the CDR 1 of SEQ ID NO: 138, the CDR 2 of SEQ ID NO: 139, the CDR 3 of SEQ ID NO: 140;   (b2) a third antibody variable region comprising the complementarity determining region (CDR) 1 of SEQ ID NO: 135, the CDR 2 of SEQ ID NO: 136, the CDR 3 of SEQ ID NO: 137, and a fourth antibody variable region comprising the CDR 1 of SEQ ID NO: 141, the CDR 2 of SEQ ID NO: 142, the CDR 3 of SEQ ID NO: 143;   (b3) a third antibody variable region comprising the complementarity determining region (CDR) 1 of SEQ ID NO: 144, the CDR 2 of SEQ ID NO: 145, the CDR 3 of SEQ ID NO: 146, and a fourth antibody variable region comprising the CDR 1 of SEQ ID NO: 141, the CDR 2 of SEQ ID NO: 142, the CDR 3 of SEQ ID NO: 143;   (b4) a third antibody variable region comprising the complementarity determining region (CDR) 1 of SEQ ID NO: 147, the CDR 2 of SEQ ID NO: 148, the CDR 3 of SEQ ID NO: 149, and a fourth antibody variable region comprising the CDR 1 of SEQ ID NO: 150, the CDR 2 of SEQ ID NO: 151, the CDR 3 of SEQ ID NO: 152;   (b5) a third antibody variable region comprising the complementarity determining region (CDR) 1 of SEQ ID NO: 153, the CDR 2 of SEQ ID NO: 154, the CDR 3 of SEQ ID NO: 155, and a fourth antibody variable region comprising the CDR 1 of SEQ ID NO: 150, the CDR 2 of SEQ ID NO: 151, the CDR 3 of SEQ ID NO: 152;   (b6) a third antibody variable region comprising the complementarity determining region (CDR) 1 of SEQ ID NO: 156, the CDR 2 of SEQ ID NO: 157, the CDR 3 of SEQ ID NO: 158, and a fourth antibody variable region comprising the CDR 1 of SEQ ID NO: 150, the CDR 2 of SEQ ID NO: 151, the CDR 3 of SEQ ID NO: 152;   (b7) a third antibody variable region comprising the complementarity determining region (CDR) 1 of SEQ ID NO: 159, the CDR 2 of SEQ ID NO: 160, the CDR 3 of SEQ ID NO: 161, and a fourth antibody variable region comprising the CDR 1 of SEQ ID NO: 141, the CDR 2 of SEQ ID NO: 142, the CDR 3 of SEQ ID NO: 143; and   (b8) a third amino acid sequence that has at least 70%, 75%, 80%, 85%, 90%, or 95% sequence identity to the third antibody variable region recited in any one of (b1) to (b7), and a fourth amino acid sequence that has at least 70%, 75%, 80%, 85%, 90%, or 95% sequence identity to the fourth antibody variable region recited in any one of (b1) to (b7).   
     
     
         25 . A multispecific antigen-binding molecule comprising a first antigen-binding moiety and a second antigen-binding moiety,
 wherein the second antigen-binding moiety comprises any one of (b1) to (b8) below:   (b1) a first antibody variable region comprising the complementarity determining region (CDR) 1 of SEQ ID NO: 135, the CDR 2 of SEQ ID NO: 136, the CDR 3 of SEQ ID NO: 137 and a second antibody variable region comprising the CDR 1 of SEQ ID NO: 138, the CDR 2 of SEQ ID NO: 139, the CDR 3 of SEQ ID NO: 140;   (b2) a first antibody variable region comprising the complementarity determining region (CDR) 1 of SEQ ID NO: 135, the CDR 2 of SEQ ID NO: 136, the CDR 3 of SEQ ID NO: 137, and a second antibody variable region comprising the CDR 1 of SEQ ID NO: 141, the CDR 2 of SEQ ID NO: 142, the CDR 3 of SEQ ID NO: 143;   (b3) a first antibody variable region comprising the complementarity determining region (CDR) 1 of SEQ ID NO: 144, the CDR 2 of SEQ ID NO: 145, the CDR 3 of SEQ ID NO: 146, and a second antibody variable region comprising the CDR 1 of SEQ ID NO: 141, the CDR 2 of SEQ ID NO: 142, the CDR 3 of SEQ ID NO: 143;   (b4) a first antibody variable region comprising the complementarity determining region (CDR) 1 of SEQ ID NO: 147, the CDR 2 of SEQ ID NO: 148, the CDR 3 of SEQ ID NO: 149, and a second antibody variable region comprising the CDR 1 of SEQ ID NO: 150, the CDR 2 of SEQ ID NO: 151, the CDR 3 of SEQ ID NO: 152;   (b5) a first antibody variable region comprising the complementarity determining region (CDR) 1 of SEQ ID NO: 153, the CDR 2 of SEQ ID NO: 154, the CDR 3 of SEQ ID NO: 155, and a second antibody variable region comprising the CDR 1 of SEQ ID NO: 150, the CDR 2 of SEQ ID NO: 151, the CDR 3 of SEQ ID NO: 152;   (b6) a first antibody variable region comprising the complementarity determining region (CDR) 1 of SEQ ID NO: 156, the CDR 2 of SEQ ID NO: 157, the CDR 3 of SEQ ID NO: 158, and a second antibody variable region comprising the CDR 1 of SEQ ID NO: 150, the CDR 2 of SEQ ID NO: 151, the CDR 3 of SEQ ID NO: 152;   (b7) a first antibody variable region comprising the complementarity determining region (CDR) 1 of SEQ ID NO: 159, the CDR 2 of SEQ ID NO: 160, the CDR 3 of SEQ ID NO: 161, and a second antibody variable region comprising the CDR 1 of SEQ ID NO: 141, the CDR 2 of SEQ ID NO: 142, the CDR 3 of SEQ ID NO: 143; and   (b8) a first amino acid sequence that has at least 70%, 75%, 80%, 85%, 90%, or 95% sequence identity to the first antibody variable region recited in any one of (b1) to (b7), and a second amino acid sequence that has at least 70%, 75%, 80%, 85%, 90%, or 95% sequence identity to the second antibody variable region recited in any one of (b1) to (b7).   
     
     
         26 . A multispecific antigen-binding molecule comprising a first antigen-binding moiety and a second antigen-binding moiety;
 wherein the first antigen-binding moiety comprises any one of (c1) to (c3) below:   (c1) a first antibody variable region comprising the complementarity determining region (CDR) 1 of SEQ ID NO: 129, the CDR 2 of SEQ ID NO: 130, the CDR 3 of SEQ ID NO: 131, and a second antibody variable region comprising the CDR 1 of SEQ ID NO: 132, the CDR 2 of SEQ ID NO: 133, the CDR 3 of SEQ ID NO: 134;   (c2) a first antibody variable region comprising the complementarity determining region (CDR) 1 of SEQ ID NO: 164, the CDR 2 of SEQ ID NO: 165, the CDR 3 of SEQ ID NO: 166, and a second antibody variable region comprising the CDR 1 of SEQ ID NO: 167, the CDR 2 of SEQ ID NO: 168, the CDR 3 of SEQ ID NO: 169; and   (c3) a first amino acid sequence that has at least 70%, 75%, 80%, 85%, 90%, or 95% sequence identity to the first antibody variable region recited in (c1) or (c2), and a second amino acid sequence that has at least 70%, 75%, 80%, 85%, 90%, or 95% sequence identity to the second antibody variable region recited in (c1) or (c2),   wherein the second antigen-binding moiety comprises any one of (d1) to (d8) below:   (d1) a third antibody variable region comprising the complementarity determining region (CDR) 1 of SEQ ID NO: 135, the CDR 2 of SEQ ID NO: 136, the CDR 3 of SEQ ID NO: 137 and a fourth antibody variable region comprising the CDR 1 of SEQ ID NO: 138, the CDR 2 of SEQ ID NO: 139, the CDR 3 of SEQ ID NO: 140;   (d2) a third antibody variable region comprising the complementarity determining region (CDR) 1 of SEQ ID NO: 135, the CDR 2 of SEQ ID NO: 136, the CDR 3 of SEQ ID NO: 137, and a fourth antibody variable region comprising the CDR 1 of SEQ ID NO: 141, the CDR 2 of SEQ ID NO: 142, the CDR 3 of SEQ ID NO: 143;   (d3) a third antibody variable region comprising the complementarity determining region (CDR) 1 of SEQ ID NO: 144, the CDR 2 of SEQ ID NO: 145, the CDR 3 of SEQ ID NO: 146, and a fourth antibody variable region comprising the CDR 1 of SEQ ID NO: 141, the CDR 2 of SEQ ID NO: 142, the CDR 3 of SEQ ID NO: 143;   (d4) a third antibody variable region comprising the complementarity determining region (CDR) 1 of SEQ ID NO: 147, the CDR 2 of SEQ ID NO: 148, the CDR 3 of SEQ ID NO: 149, and a fourth antibody variable region comprising the CDR 1 of SEQ ID NO: 150, the CDR 2 of SEQ ID NO: 151, the CDR 3 of SEQ ID NO: 152;   (d5) a third antibody variable region comprising the complementarity determining region (CDR) 1 of SEQ ID NO: 153, the CDR 2 of SEQ ID NO: 154, the CDR 3 of SEQ ID NO: 155, and a fourth antibody variable region comprising the CDR 1 of SEQ ID NO: 150, the CDR 2 of SEQ ID NO: 151, the CDR 3 of SEQ ID NO: 152;   (d6) a third antibody variable region comprising the complementarity determining region (CDR) 1 of SEQ ID NO: 156, the CDR 2 of SEQ ID NO: 157, the CDR 3 of SEQ ID NO: 158, and a fourth antibody variable region comprising the CDR 1 of SEQ ID NO: 150, the CDR 2 of SEQ ID NO: 151, the CDR 3 of SEQ ID NO: 152;   (d7) a third antibody variable region comprising the complementarity determining region (CDR) 1 of SEQ ID NO: 159, the CDR 2 of SEQ ID NO: 160, the CDR 3 of SEQ ID NO: 161, and a fourth antibody variable region comprising the CDR 1 of SEQ ID NO: 141, the CDR 2 of SEQ ID NO: 142, the CDR 3 of SEQ ID NO: 143; and   (d8) a third amino acid sequence that has at least 70%, 75%, 80%, 85%, 90%, or 95% sequence identity to the third antibody variable region recited in any one of (d1) to (d7), and a fourth amino acid sequence that has at least 70%, 75%, 80%, 85%, 90%, or 95% sequence identity to the fourth antibody variable region recited in any one of (d1) to (d7).   
     
     
         27 . A multispecific antigen-binding molecule that comprises a first antigen-binding moiety comprising first and second antibody variable regions and a second antigen-binding moiety comprising third and fourth antibody variable regions, wherein the multispecific antigen-binding molecule comprises any one of (1) to (15) below:
 (1) a first antibody variable region comprising the complementarity determining region (CDR) 1 of SEQ ID NO: 129, the CDR 2 of SEQ ID NO: 130, the CDR 3 of SEQ ID NO: 131; a second antibody variable region comprising the CDR 1 of SEQ ID NO: 132, the CDR 2 of SEQ ID NO: 133, the CDR 3 of SEQ ID NO: 134; a third antibody variable region comprising the complementarity determining region (CDR) 1 of SEQ ID NO: 135, the CDR 2 of SEQ ID NO: 136, the CDR 3 of SEQ ID NO: 137; and a fourth antibody variable region comprising the CDR 1 of SEQ ID NO: 138, the CDR 2 of SEQ ID NO: 139, the CDR 3 of SEQ ID NO: 140;   (2) a first antibody variable region comprising the complementarity determining region (CDR) 1 of SEQ ID NO: 129, the CDR 2 of SEQ ID NO: 130, the CDR 3 of SEQ ID NO: 131; a second antibody variable region comprising the CDR 1 of SEQ ID NO: 132, the CDR 2 of SEQ ID NO: 133, the CDR 3 of SEQ ID NO: 134; a third antibody variable region comprising the complementarity determining region (CDR) 1 of SEQ ID NO: 135, the CDR 2 of SEQ ID NO: 136, the CDR 3 of SEQ ID NO: 137; and a fourth antibody variable region comprising the CDR 1 of SEQ ID NO: 141, the CDR 2 of SEQ ID NO: 142, the CDR 3 of SEQ ID NO: 143;   (3) a first antibody variable region comprising the complementarity determining region (CDR) 1 of SEQ ID NO: 129, the CDR 2 of SEQ ID NO: 130, the CDR 3 of SEQ ID NO: 131; a second antibody variable region comprising the CDR 1 of SEQ ID NO: 132, the CDR 2 of SEQ ID NO: 133, the CDR 3 of SEQ ID NO: 134; a third antibody variable region comprising the complementarity determining region (CDR) 1 of SEQ ID NO: 144, the CDR 2 of SEQ ID NO: 145, the CDR 3 of SEQ ID NO: 146; and a fourth antibody variable region comprising the CDR 1 of SEQ ID NO: 141, the CDR 2 of SEQ ID NO: 142, the CDR 3 of SEQ ID NO: 143;   (4) a first antibody variable region comprising the complementarity determining region (CDR) 1 of SEQ ID NO: 129, the CDR 2 of SEQ ID NO: 130, the CDR 3 of SEQ ID NO: 131; a second antibody variable region comprising the CDR 1 of SEQ ID NO: 132, the CDR 2 of SEQ ID NO: 133, the CDR 3 of SEQ ID NO: 134; a third antibody variable region comprising the complementarity determining region (CDR) 1 of SEQ ID NO: 147, the CDR 2 of SEQ ID NO: 148, the CDR 3 of SEQ ID NO: 149; and a fourth antibody variable region comprising the CDR 1 of SEQ ID NO: 150, the CDR 2 of SEQ ID NO: 151, the CDR 3 of SEQ ID NO: 152;   (5) a first antibody variable region comprising the complementarity determining region (CDR) 1 of SEQ ID NO: 129, the CDR 2 of SEQ ID NO: 130, the CDR 3 of SEQ ID NO: 131; a second antibody variable region comprising the CDR 1 of SEQ ID NO: 132, the CDR 2 of SEQ ID NO: 133, the CDR 3 of SEQ ID NO: 134; a third antibody variable region comprising the complementarity determining region (CDR) 1 of SEQ ID NO: 153, the CDR 2 of SEQ ID NO: 154, the CDR 3 of SEQ ID NO: 155; and a fourth antibody variable region comprising the CDR 1 of SEQ ID NO: 150, the CDR 2 of SEQ ID NO: 151, the CDR 3 of SEQ ID NO: 152;   (6) a first antibody variable region comprising the complementarity determining region (CDR) 1 of SEQ ID NO: 129, the CDR 2 of SEQ ID NO: 130, the CDR 3 of SEQ ID NO: 131; a second antibody variable region comprising the CDR 1 of SEQ ID NO: 132, the CDR 2 of SEQ ID NO: 133, the CDR 3 of SEQ ID NO: 134; a third antibody variable region comprising the complementarity determining region (CDR) 1 of SEQ ID NO: 156, the CDR 2 of SEQ ID NO: 157, the CDR 3 of SEQ ID NO: 158; and a fourth antibody variable region comprising the CDR 1 of SEQ ID NO: 150, the CDR 2 of SEQ ID NO: 151, the CDR 3 of SEQ ID NO: 152;   (7) a first antibody variable region comprising the complementarity determining region (CDR) 1 of SEQ ID NO: 129, the CDR 2 of SEQ ID NO: 130, the CDR 3 of SEQ ID NO: 131; a second antibody variable region comprising the CDR 1 of SEQ ID NO: 132, the CDR 2 of SEQ ID NO: 133, the CDR 3 of SEQ ID NO: 134; a third antibody variable region comprising the complementarity determining region (CDR) 1 of SEQ ID NO: 159, the CDR 2 of SEQ ID NO: 160, the CDR 3 of SEQ ID NO: 161; and a fourth antibody variable region comprising the CDR 1 of SEQ ID NO: 141, the CDR 2 of SEQ ID NO: 142, the CDR 3 of SEQ ID NO: 143; and   (8) a first antibody variable region comprising the complementarity determining region (CDR) 1 of SEQ ID NO: 164, the CDR 2 of SEQ ID NO: 165, the CDR 3 of SEQ ID NO: 166; a second antibody variable region comprising the CDR 1 of SEQ ID NO: 167, the CDR 2 of SEQ ID NO: 168, the CDR 3 of SEQ ID NO: 169; a third antibody variable region comprising the complementarity determining region (CDR) 1 of SEQ ID NO: 135, the CDR 2 of SEQ ID NO: 136, the CDR 3 of SEQ ID NO: 137; and a fourth antibody variable region comprising the CDR 1 of SEQ ID NO: 138, the CDR 2 of SEQ ID NO: 139, the CDR 3 of SEQ ID NO: 140;   (9) a first antibody variable region comprising the complementarity determining region (CDR) 1 of SEQ ID NO: 164, the CDR 2 of SEQ ID NO: 165, the CDR 3 of SEQ ID NO: 166; a second antibody variable region comprising the CDR 1 of SEQ ID NO: 167, the CDR 2 of SEQ ID NO: 168, the CDR 3 of SEQ ID NO: 169; a third antibody variable region comprising the complementarity determining region (CDR) 1 of SEQ ID NO: 135, the CDR 2 of SEQ ID NO: 136, the CDR 3 of SEQ ID NO: 137; and a fourth antibody variable region comprising the CDR 1 of SEQ ID NO: 141, the CDR 2 of SEQ ID NO: 142, the CDR 3 of SEQ ID NO: 143;   (10) a first antibody variable region comprising the complementarity determining region (CDR) 1 of SEQ ID NO: 164, the CDR 2 of SEQ ID NO: 165, the CDR 3 of SEQ ID NO: 166; a second antibody variable region comprising the CDR 1 of SEQ ID NO: 167, the CDR 2 of SEQ ID NO: 168, the CDR 3 of SEQ ID NO: 169; a third antibody variable region comprising the complementarity determining region (CDR) 1 of SEQ ID NO: 144, the CDR 2 of SEQ ID NO: 145, the CDR 3 of SEQ ID NO: 146; and a fourth antibody variable region comprising the CDR 1 of SEQ ID NO: 141, the CDR 2 of SEQ ID NO: 142, the CDR 3 of SEQ ID NO: 143;   (11) a first antibody variable region comprising the complementarity determining region (CDR) 1 of SEQ ID NO: 164, the CDR 2 of SEQ ID NO: 165, the CDR 3 of SEQ ID NO: 166; a second antibody variable region comprising the CDR 1 of SEQ ID NO: 167, the CDR 2 of SEQ ID NO: 168, the CDR 3 of SEQ ID NO: 169; a third antibody variable region comprising the complementarity determining region (CDR) 1 of SEQ ID NO: 147, the CDR 2 of SEQ ID NO: 148, the CDR 3 of SEQ ID NO: 149; and a fourth antibody variable region comprising the CDR 1 of SEQ ID NO: 150, the CDR 2 of SEQ ID NO: 151, the CDR 3 of SEQ ID NO: 152;   (12) a first antibody variable region comprising the complementarity determining region (CDR) 1 of SEQ ID NO: 164, the CDR 2 of SEQ ID NO: 165, the CDR 3 of SEQ ID NO: 166; a second antibody variable region comprising the CDR 1 of SEQ ID NO: 167, the CDR 2 of SEQ ID NO: 168, the CDR 3 of SEQ ID NO: 169; a third antibody variable region comprising the complementarity determining region (CDR) 1 of SEQ ID NO: 153, the CDR 2 of SEQ ID NO: 154, the CDR 3 of SEQ ID NO: 155; and a fourth antibody variable region comprising the CDR 1 of SEQ ID NO: 150, the CDR 2 of SEQ ID NO: 151, the CDR 3 of SEQ ID NO: 152;   (13) a first antibody variable region comprising the complementarity determining region (CDR) 1 of SEQ ID NO: 164, the CDR 2 of SEQ ID NO: 165, the CDR 3 of SEQ ID NO: 166; a second antibody variable region comprising the CDR 1 of SEQ ID NO: 167, the CDR 2 of SEQ ID NO: 168, the CDR 3 of SEQ ID NO: 169; a third antibody variable region comprising the complementarity determining region (CDR) 1 of SEQ ID NO: 156, the CDR 2 of SEQ ID NO: 157, the CDR 3 of SEQ ID NO: 158; and a fourth antibody variable region comprising the CDR 1 of SEQ ID NO: 150, the CDR 2 of SEQ ID NO: 151, the CDR 3 of SEQ ID NO: 152;   (14) a first antibody variable region comprising the complementarity determining region (CDR) 1 of SEQ ID NO: 164, the CDR 2 of SEQ ID NO: 165, the CDR 3 of SEQ ID NO: 166; a second antibody variable region comprising the CDR 1 of SEQ ID NO: 167, the CDR 2 of SEQ ID NO: 168, the CDR 3 of SEQ ID NO: 169; a third antibody variable region comprising the complementarity determining region (CDR) 1 of SEQ ID NO: 159, the CDR 2 of SEQ ID NO: 160, the CDR 3 of SEQ ID NO: 161; and a fourth antibody variable region comprising the CDR 1 of SEQ ID NO: 141, the CDR 2 of SEQ ID NO: 142, the CDR 3 of SEQ ID NO: 143; and   (15) a first amino acid sequence that has at least 70%, 75%, 80%, 85%, 90%, or 95% sequence identity to the first antibody variable region recited in any one of (1) to (14); a second amino acid sequence that has at least 70%, 75%, 80%, 85%, 90%, or 95% sequence identity to the second antibody variable region recited in any one of (1) to (14); a third amino acid sequence that has at least 70%, 75%, 80%, 85%, 90%, or 95% sequence identity to the third antibody variable region recited in any one of (1) to (14); and a fourth amino acid sequence that has at least 70%, 75%, 80%, 85%, 90%, or 95% sequence identity to the fourth antibody variable region recited in any one of (1) to (14).   
     
     
         28 . The multispecific antigen-binding molecule of any one of  claims 23  to  27 , wherein the antibody variable region comprised in the first and/or second antigen-binding moiety comprises human antibody frameworks or humanized antibody frameworks. 
     
     
         29 . A multispecific antigen-binding molecule comprising a first antigen-binding moiety and a second antigen-binding moiety;
 wherein the first antigen-binding moiety comprises any one of (e1) to (e3) below:   (e1) a first antibody variable region comprising the amino acid sequence of SEQ ID NO: 88, and a second antibody variable region comprising the amino acid sequence of SEQ ID NO: 90;   (e2) a first antibody variable region comprising the amino acid sequence of SEQ ID NO: 89, and a second antibody variable region comprising the amino acid sequence of SEQ ID NO: 91; and   (e3) a first amino acid sequence that has at least 70%, 75%, 80%, 85%, 90%, or 95% sequence identity to the first antibody variable region recited in (e1) or (e2), and a second amino acid sequence that has at least 70%, 75%, 80%, 85%, 90%, or 95% sequence identity to the second antibody variable region recited in (e1) or (e2).   
     
     
         30 . The multispecific antigen-binding molecule of  claim 29 , wherein the second antigen-binding moiety comprises any one of (f1) to (f8) below:
 (f1) a third antibody variable region comprising the amino acid sequence of SEQ ID NO: 92, and a fourth antibody variable region comprising the amino acid sequence of SEQ ID NO: 98;   (f2) a third antibody variable region comprising the amino acid sequence of SEQ ID NO: 92, and a fourth antibody variable region comprising the amino acid sequence of SEQ ID NO: 99;   (f3) a third antibody variable region comprising the amino acid sequence of SEQ ID NO: 93, and a fourth antibody variable region comprising the amino acid sequence of SEQ ID NO: 99;   (f4) a third antibody variable region comprising the amino acid sequence of SEQ ID NO: 94, and a fourth antibody variable region comprising the amino acid sequence of SEQ ID NO: 100;   (f5) a third antibody variable region comprising the amino acid sequence of SEQ ID NO: 95, and a fourth antibody variable region comprising the amino acid sequence of SEQ ID NO: 100;   (f6) a third antibody variable region comprising the amino acid sequence of SEQ ID NO: 96, and a fourth antibody variable region comprising the amino acid sequence of SEQ ID NO: 100;   (f7) a third antibody variable region comprising the amino acid sequence of SEQ ID NO: 97, and a fourth antibody variable region comprising the amino acid sequence of SEQ ID NO: 99; and   (f8) a third amino acid sequence that has at least 70%, 75%, 80%, 85%, 90%, or 95% sequence identity to the third antibody variable region recited in any one of (f1) to (f7), and a fourth amino acid sequence that has at least 70%, 75%, 80%, 85%, 90%, or 95% sequence identity to the fourth antibody variable region recited in any one of (f1) to (f7).   
     
     
         31 . A multispecific antigen-binding molecule comprising a first antigen-binding moiety and a second antigen-binding moiety;
 wherein the first antigen-binding moiety comprises any one of (e1) to (e3) below:   (e1) a first antibody variable region comprising the amino acid sequence of SEQ ID NO: 88, and a second antibody variable region comprising the amino acid sequence of SEQ ID NO: 90;   (e2) a first antibody variable region comprising the amino acid sequence of SEQ ID NO: 89, and a second antibody variable region comprising the amino acid sequence of SEQ ID NO: 91; and   (e3) a first amino acid sequence that has at least 70%, 75%, 80%, 85%, 90%, or 95% sequence identity to the first antibody variable region recited in (e1) or (e2), and a second amino acid sequence that has at least 70%, 75%, 80%, 85%, 90%, or 95% sequence identity to the second antibody variable region recited in (e1) or (e2), and   wherein the second antigen-binding moiety comprises any one of (f1) to (f8) below:   (f1) a third antibody variable region comprising the amino acid sequence of SEQ ID NO: 92, and a fourth antibody variable region comprising the amino acid sequence of SEQ ID NO: 98;   (f2) a third antibody variable region comprising the amino acid sequence of SEQ ID NO: 92, and a fourth antibody variable region comprising the amino acid sequence of SEQ ID NO: 99;   (f3) a third antibody variable region comprising the amino acid sequence of SEQ ID NO: 93, and a fourth antibody variable region comprising the amino acid sequence of SEQ ID NO: 99;   (f4) a third antibody variable region comprising the amino acid sequence of SEQ ID NO: 94, and a fourth antibody variable region comprising the amino acid sequence of SEQ ID NO: 100;   (f5) a third antibody variable region comprising the amino acid sequence of SEQ ID NO: 95, and a fourth antibody variable region comprising the amino acid sequence of SEQ ID NO: 100;   (f6) a third antibody variable region comprising the amino acid sequence of SEQ ID NO: 96, and a fourth antibody variable region comprising the amino acid sequence of SEQ ID NO: 100;   (f7) a third antibody variable region comprising the amino acid sequence of SEQ ID NO: 97, and a fourth antibody variable region comprising the amino acid sequence of SEQ ID NO: 99; and   (f8) a third amino acid sequence that has at least 70%, 75%, 80%, 85%, 90%, or 95% sequence identity to the third antibody variable region recited in any one of (f1) to (f7), and a fourth amino acid sequence that has at least 70%, 75%, 80%, 85%, 90%, or 95% sequence identity to the fourth antibody variable region recited in any one of (f1) to (f7).   
     
     
         32 . A multispecific antigen-binding molecule that comprises a first antigen-binding moiety comprising first and second antibody variable regions and a second antigen-binding moiety comprising third and fourth antibody variable regions, wherein the multispecific antigen-binding molecule comprises any one of (1) to (15) below:
 (1) a first antibody variable region comprising the amino acid sequence of SEQ ID NO: 88; a second antibody variable region comprising the amino acid sequence of SEQ ID NO: 90; a third antibody variable region comprising the amino acid sequence of SEQ ID NO: 92; and a fourth antibody variable region comprising the amino acid sequence of SEQ ID NO: 98;   (2) a first antibody variable region comprising the amino acid sequence of SEQ ID NO: 88; and a second antibody variable region comprising the amino acid sequence of SEQ ID NO: 90; a third antibody variable region comprising the amino acid sequence of SEQ ID NO: 92; and a fourth antibody variable region comprising the amino acid sequence of SEQ ID NO: 99;   (3) a first antibody variable region comprising the amino acid sequence of SEQ ID NO: 88; a second antibody variable region comprising the amino acid sequence of SEQ ID NO: 90; a third antibody variable region comprising the amino acid sequence of SEQ ID NO: 93; and a fourth antibody variable region comprising the amino acid sequence of SEQ ID NO: 99;   (4) a first antibody variable region comprising the amino acid sequence of SEQ ID NO: 88; a second antibody variable region comprising the amino acid sequence of SEQ ID NO: 90; a third antibody variable region comprising the amino acid sequence of SEQ ID NO: 94; and a fourth antibody variable region comprising the amino acid sequence of SEQ ID NO: 100;   (5) a first antibody variable region comprising the amino acid sequence of SEQ ID NO: 88; a second antibody variable region comprising the amino acid sequence of SEQ ID NO: 90; a third antibody variable region comprising the amino acid sequence of SEQ ID NO: 95; and a fourth antibody variable region comprising the amino acid sequence of SEQ ID NO: 100;   (6) a first antibody variable region comprising the amino acid sequence of SEQ ID NO: 88; a second antibody variable region comprising the amino acid sequence of SEQ ID NO: 90; a third antibody variable region comprising the amino acid sequence of SEQ ID NO: 96; a fourth antibody variable region comprising the amino acid sequence of SEQ ID NO: 100;   (7) a first antibody variable region comprising the amino acid sequence of SEQ ID NO: 88; a second antibody variable region comprising the amino acid sequence of SEQ ID NO: 90; a third antibody variable region comprising the amino acid sequence of SEQ ID NO: 97; and a fourth antibody variable region comprising the amino acid sequence of SEQ ID NO: 99;   (8) a first antibody variable region comprising the amino acid sequence of SEQ ID NO: 89; a second antibody variable region comprising the amino acid sequence of SEQ ID NO: 91; a third antibody variable region comprising the amino acid sequence of SEQ ID NO: 92; and a fourth antibody variable region comprising the amino acid sequence of SEQ ID NO: 98;   (9) a first antibody variable region comprising the amino acid sequence of SEQ ID NO: 89; and a second antibody variable region comprising the amino acid sequence of SEQ ID NO: 91; a third antibody variable region comprising the amino acid sequence of SEQ ID NO: 92; and a fourth antibody variable region comprising the amino acid sequence of SEQ ID NO: 99;   (10) a first antibody variable region comprising the amino acid sequence of SEQ ID NO: 89; a second antibody variable region comprising the amino acid sequence of SEQ ID NO: 91; a third antibody variable region comprising the amino acid sequence of SEQ ID NO: 93; and a fourth antibody variable region comprising the amino acid sequence of SEQ ID NO: 99;   (11) a first antibody variable region comprising the amino acid sequence of SEQ ID NO: 89; a second antibody variable region comprising the amino acid sequence of SEQ ID NO: 91; a third antibody variable region comprising the amino acid sequence of SEQ ID NO: 94; and a fourth antibody variable region comprising the amino acid sequence of SEQ ID NO: 100;   (12) a first antibody variable region comprising the amino acid sequence of SEQ ID NO: 89; a second antibody variable region comprising the amino acid sequence of SEQ ID NO: 91; a third antibody variable region comprising the amino acid sequence of SEQ ID NO: 95; and a fourth antibody variable region comprising the amino acid sequence of SEQ ID NO: 100;   (13) a first antibody variable region comprising the amino acid sequence of SEQ ID NO: 89; a second antibody variable region comprising the amino acid sequence of SEQ ID NO: 91; a third antibody variable region comprising the amino acid sequence of SEQ ID NO: 96; and a fourth antibody variable region comprising the amino acid sequence of SEQ ID NO: 100;   (14) a first antibody variable region comprising the amino acid sequence of SEQ ID NO: 89; a second antibody variable region comprising the amino acid sequence of SEQ ID NO: 91; a third antibody variable region comprising the amino acid sequence of SEQ ID NO: 97; and a fourth antibody variable region comprising the amino acid sequence of SEQ ID NO: 99;   (15) a first amino acid sequence that has at least 70%, 75%, 80%, 85%, 90%, or 95% sequence identity to the first antibody variable region recited in (1) or (14); a second amino acid sequence that has at least 70%, 75%, 80%, 85%, 90%, or 95% sequence identity to the second antibody variable region recited in (1) or (14); a third amino acid sequence that has at least 70%, 75%, 80%, 85%, 90%, or 95% sequence identity to the third antibody variable region recited in any one of (1) to (14); and a fourth amino acid sequence that has at least 70%, 75%, 80%, 85%, 90%, or 95% sequence identity to the fourth antibody variable region recited in any one of (1) to (14).   
     
     
         33 . A multispecific antigen-binding molecule comprising a combination of two polypeptide chains selected from the group consisting of (A1) to (A3) below:
 (A1) a first heavy chain comprising amino acid sequence of SEQ ID NO: 42 and a first light chain comprising amino acid sequence of SEQ ID NO: 43;   (A2) a first heavy chain comprising amino acid sequence of SEQ ID NO: 45 and a first light chain comprising amino acid sequence of SEQ ID NO: 46; and   (A3) a first amino acid sequence that has at least 70%, 75%, 80%, 85%, 90%, or 95% sequence identity to the first heavy chain sequence recited in (A1) or (A2), and a second amino acid sequence that has at least 70%, 75%, 80%, 85%, 90%, or 95% sequence identity to the first light chain sequence recited in (A1) or (A2).   
     
     
         34 . The multispecific antigen-binding molecule of  claim 33 , further comprising a combination of two polypeptide chains selected from the group consisting of (B1) to (B8) below:
 (B1) a second heavy chain comprising amino acid sequence of SEQ ID NO: 54 and a second light chain comprising amino acid sequence of SEQ ID NO: 55;   (B2) a second heavy chain comprising amino acid sequence of SEQ ID NO: 54 and a second light chain comprising amino acid sequence of SEQ ID NO: 56;   (B3) a second heavy chain comprising amino acid sequence of SEQ ID NO: 58 and a second light chain comprising amino acid sequence of SEQ ID NO: 56;   (B4) a second heavy chain comprising amino acid sequence of SEQ ID NO: 60 and a second light chain comprising amino acid sequence of SEQ ID NO: 61;   (B5) a second heavy chain comprising amino acid sequence of SEQ ID NO: 63 and a second light chain comprising amino acid sequence of SEQ ID NO: 61;   (B6) a second heavy chain comprising amino acid sequence of SEQ ID NO: 65 and a second light chain comprising amino acid sequence of SEQ ID NO: 61;   (B7) a second heavy chain comprising amino acid sequence of SEQ ID NO: 67 and a second light chain comprising amino acid sequence of SEQ ID NO: 56; and   (B8) a third amino acid sequence that has at least 70%, 75%, 80%, 85%, 90%, or 95% sequence identity to the second heavy chain sequence recited in any one of (B1) to (B7), and a fourth amino acid sequence that has at least 70%, 75%, 80%, 85%, 90%, or 95% sequence identity to the second light chain sequence recited in any one of (B1) to (B7).   
     
     
         35 . A multispecific antigen-binding molecule comprising a combination of four polypeptide chains selected from the group consisting of (1) to (15) below:
 (1) a first heavy chain comprising amino acid sequence of SEQ ID NO: 42 and a first light chain comprising amino acid sequence of SEQ ID NO: 43, and a second heavy chain comprising amino acid sequence of SEQ ID NO: 54 and a second light chain comprising amino acid sequence of SEQ ID NO: 55;   (2) a first heavy chain comprising amino acid sequence of SEQ ID NO: 42 and a first light chain comprising amino acid sequence of SEQ ID NO: 43, and a second heavy chain comprising amino acid sequence of SEQ ID NO: 54 and a second light chain comprising amino acid sequence of SEQ ID NO: 56;   (3) a first heavy chain comprising amino acid sequence of SEQ ID NO: 42 and a first light chain comprising amino acid sequence of SEQ ID NO: 43, and a second heavy chain comprising amino acid sequence of SEQ ID NO: 58 and a second light chain comprising amino acid sequence of SEQ ID NO: 56;   (4) a first heavy chain comprising amino acid sequence of SEQ ID NO: 42 and a first light chain comprising amino acid sequence of SEQ ID NO: 43, and a second heavy chain comprising amino acid sequence of SEQ ID NO: 60 and a second light chain comprising amino acid sequence of SEQ ID NO: 61;   (5) a first heavy chain comprising amino acid sequence of SEQ ID NO: 42 and a first light chain comprising amino acid sequence of SEQ ID NO: 43, and a second heavy chain comprising amino acid sequence of SEQ ID NO: 63 and a second light chain comprising amino acid sequence of SEQ ID NO: 61;   (6) a first heavy chain comprising amino acid sequence of SEQ ID NO: 45 and a first light chain comprising amino acid sequence of SEQ ID NO: 46, and a second heavy chain comprising amino acid sequence of SEQ ID NO: 54 and a second light chain comprising amino acid sequence of SEQ ID NO: 55;   (7) a first heavy chain comprising amino acid sequence of SEQ ID NO: 45 and a first light chain comprising amino acid sequence of SEQ ID NO: 46, and a second heavy chain comprising amino acid sequence of SEQ ID NO: 65 and a second light chain comprising amino acid sequence of SEQ ID NO: 61;   (8) a first heavy chain comprising amino acid sequence of SEQ ID NO: 45 and a first light chain comprising amino acid sequence of SEQ ID NO: 46, and a second heavy chain comprising amino acid sequence of SEQ ID NO: 54 and a second light chain comprising amino acid sequence of SEQ ID NO: 56;   (9) a first heavy chain comprising amino acid sequence of SEQ ID NO: 45 and a first light chain comprising amino acid sequence of SEQ ID NO: 46, and a second heavy chain comprising amino acid sequence of SEQ ID NO: 58 and a second light chain comprising amino acid sequence of SEQ ID NO: 56;   (10) a first heavy chain comprising amino acid sequence of SEQ ID NO: 45 and a first light chain comprising amino acid sequence of SEQ ID NO: 46, and a second heavy chain comprising amino acid sequence of SEQ ID NO: 67 and a second light chain comprising amino acid sequence of SEQ ID NO: 56;   (11) a first heavy chain comprising amino acid sequence of SEQ ID NO: 42 and a first light chain comprising amino acid sequence of SEQ ID NO: 43, and a second heavy chain comprising amino acid sequence of SEQ ID NO: 65 and a second light chain comprising amino acid sequence of SEQ ID NO: 61;   (12) a first heavy chain comprising amino acid sequence of SEQ ID NO: 42 and a first light chain comprising amino acid sequence of SEQ ID NO: 43, and a second heavy chain comprising amino acid sequence of SEQ ID NO: 67 and a second light chain comprising amino acid sequence of SEQ ID NO: 56;   (13) a first heavy chain comprising amino acid sequence of SEQ ID NO: 45 and a first light chain comprising amino acid sequence of SEQ ID NO: 46, and a second heavy chain comprising amino acid sequence of SEQ ID NO: 63 and a second light chain comprising amino acid sequence of SEQ ID NO: 61;   (14) a first heavy chain comprising amino acid sequence of SEQ ID NO: 45 and a first light chain comprising amino acid sequence of SEQ ID NO: 46, and a second heavy chain comprising amino acid sequence of SEQ ID NO: 60 and a second light chain comprising amino acid sequence of SEQ ID NO: 61; and   (15) a first amino acid sequence that has at least 70%, 75%, 80%, 85%, 90%, or 95% sequence identity to the first heavy chain sequence recited in any one of (1) to (14); a second amino acid sequence that has at least 70%, 75%, 80%, 85%, 90%, or 95% sequence identity to the first light chain sequence recited in any one of (1) to (14); a third amino acid sequence that has at least 70%, 75%, 80%, 85%, 90%, or 95% sequence identity to the second heavy chain sequence recited in any one of (1) to (14); and a fourth amino acid sequence that has at least 70%, 75%, 80%, 85%, 90%, or 95% sequence identity to the second light chain sequence recited in any one of (1) to (14).   
     
     
         36 . A combination of any one of (i) to (iii) below:
 (i) a multispecific antigen-binding molecule comprising the sequences recited in any one of (a1) to (a3) of  claim 23 , and a multispecific antigen-binding molecule comprising the sequences recited in any one of (b1) to (b8) of  claim 24 ;   (ii) a multispecific antigen-binding molecule comprising the sequences recited in any one of (e1) to (e3) of  claim 29 , and a multispecific antigen-binding molecule comprising the sequences recited in any one of (f1) to (f8) of  claim 30 ; and   (iii) a multispecific antigen-binding molecule comprising the sequences recited in any one of (A1) to (A3) of  claim 33 , and a multispecific antigen-binding molecule comprising the sequences recited in any one of (B1) to (B8) of  claim 34 .   
     
     
         37 . A nucleic acid encoding the multispecific antigen-binding molecule of any one of  claims 1  to  35 . 
     
     
         38 . A vector comprising the nucleic acid of  claim 37   
     
     
         39 . A cell comprising the nucleic acid of  claim 37  or the vector of  claim 38 . 
     
     
         40 . A method of producing a multispecific antigen-binding molecule comprising culturing the cell of  claim 39  so that the multispecific antigen-binding molecule is produced. 
     
     
         41 . The method of  claim 40 , further comprising recovering the multispecific antigen-binding molecule from the culture of the cell. 
     
     
         42 . A pharmaceutical composition comprising the multispecific antigen-binding molecule of any one of  claims 1  to  35  or the combination of  claim 36 , and a pharmaceutically acceptable carrier. 
     
     
         43 . The composition of  claim 42 , which is a pharmaceutical composition for use in the treatment and/or prevention of celiac disease. 
     
     
         44 . Use of the multispecific antigen-binding molecule of any one of  claims 1  to  35  or the combination of  claim 36  in the manufacture of a medicament. 
     
     
         45 . The use of  claim 44 , wherein the medicament is a medicament for treatment and/or prevention of celiac disease. 
     
     
         46 . A method of treating an individual having celiac disease comprising administering to the individual an effective amount of the multispecific antigen-binding molecule of any one of  claims 1  to  35  or the combination of  claim 36 . 
     
     
         47 . A kit for use in the treatment and/or prevention of celiac disease, which comprising at least the multispecific antigen-binding molecule of any one of  claims 1  to  35  or the combination of  claim 36 , and instructions for use.