Bispecific antibodies

Abstract

The present invention addresses the problem of providing a novel agent for the prevention, symptom progression suppression, recurrence suppression, or treatment of cancer. The inventors of the present invention find, as a substance capable of solving related problems, a bispecific antibody that can specifically bind to two different epitopes on the S1 domain and the S2 domain, which are extracellular domains of allergen-1, by focusing on the target molecule allergen-1 involved in the control of cancer immunity, and that can specifically bind to two different epitopes on the S1 domain and the S2 domain, which are the extracellular domains of allergen-1, as a result of in-depth studies. And it has been confirmed that the antibody can be used in the prevention, symptom progression inhibition, recurrence inhibition, or treatment of cancer.

Description

Technical Field

[0001] The present invention relates to a bispecific antibody or an antibody fragment thereof against Allergin-1, a pharmaceutical composition comprising the bispecific antibody as an effective ingredient, and medical uses thereof. Background Art

[0002] Cancer immunotherapy is different from conventional therapies such as surgery, radiotherapy, or drug therapy based on anticancer agents or molecular targeted agents. It is a therapy that acts on the inherent immune surveillance mechanism of the cancer patient to strengthen the immunity against cancer, thereby inhibiting or treating the progression of cancer. According to recent cancer immunology research, the immunosuppressive environment centered on the local cancer is involved in the progression of cancer, and the cancer itself uses a system to avoid the immune surveillance mechanism. As molecules used for such an avoidance system, so-called immune checkpoint molecules such as CTLA-4, PD-1, or PD-L1 as its ligand are known, and these inhibitors have achieved remarkable results in clinical practice.

[0003] However, there are still cancer patients for whom there is insufficient therapeutic effect even with these immune checkpoint inhibitors, and new therapies for these cancer patients or elucidation of the functions of target molecules that are indispensable for establishing such therapies are urgently needed.

[0004] However, the allergen-1 involved in the present invention is a membrane receptor having an ITIM domain in the intracellular region and an immunoglobulin-like structure outside the cell, and is a molecule that is strongly expressed in mast cells. From the analysis of gene-deficient mice using the molecule, it is known that the molecule functions as a molecule that inhibits allergic reactions, such as inhibiting anaphylaxis by inhibiting degranulation mediated by IgE receptor signals, inhibiting asthma reactions induced by mite antigens, etc. (Non-patent Documents 1, 2, and 3).

[0005] On the other hand, it has been reported that allergen-1 is involved in cancer immunity and that cancer can be treated based on its inhibition (Patent Document 1).

[0006] Prior art literature

[0007] Patent Literature

[0008] Patent Document 1: International Publication No. 2017 / 038997

[0009] Non-patent literature

[0010] Non-patent document 1: Nature Immunology, 2010, Vol. 11, No. 7, pp. 601-608

[0011] Non-patent literature 2: PLOS ONE, 2013, Vol. 8, No. 10, e76160

[0012] Non-patent document 3: Allergy and Immunity, 2011, Vol. 18, No. 4, pp. 506-514 Summary of the invention

[0013] Technical problem solved by the invention

[0014] The problem of the present invention is to provide a new drug which has a cancer immunity enhancing effect and is effective for cancer treatment.

[0015] Technical means of solving problems

[0016] As a result of intensive research, the inventors of the present invention discovered a bispecific antibody (hereinafter sometimes referred to as "bispecific antibody against allergen-1" or "anti-allergen-1 bispecific antibody") to solve the above-mentioned problem. The bispecific antibody can specifically bind to two different epitopes of the extracellular domain of allergen-1, thereby completing the present invention.

[0017] That is, the present invention mainly provides the following embodiments.

[0018] <1> A bispecific antibody or an antibody fragment thereof (hereinafter, sometimes collectively and abbreviated as "anti-allergen-1 bispecific antibody, etc.") having antigen-binding sites that specifically bind to two different epitopes of the extracellular domain of allergen-1;

[0019] <2> A pharmaceutical composition comprising a bispecific antibody against allergen-1 as an active ingredient;

[0020] <3> A pharmaceutical agent for inhibiting the progression of cancer symptoms, inhibiting recurrence and / or treating cancer, comprising a bispecific antibody against allergen-1 as an active ingredient;

[0021] <4> An antibody or an antibody fragment thereof, which specifically binds to the S1 domain of allergen-1 or specifically binds to the S2 domain of allergen-1; and

[0022] <5> polynucleotides, which respectively encode the <1> The heavy and light chains of the described bispecific antibodies.

[0023] Effects of the Invention

[0024] The present invention provides an anti-allergen-1 bispecific antibody useful as a novel agent for inhibiting symptom progression, inhibiting recurrence and / or treating cancer. BRIEF DESCRIPTION OF THE DRAWINGS

[0025] [ Figure 1 ] Figure 1 The corresponding relationship between each amino acid sequence of the heavy chain variable region (hereinafter, sometimes abbreviated as "VH") and the light chain variable region (hereinafter, sometimes abbreviated as "VL") constituting the S1-A binding site and SEQ ID NO. It should be noted that, as known to those skilled in the art, the letters in the figure represent single letters corresponding to each amino acid.

[0026] [ Figure 2 ] Figure 2 The corresponding relationship between the amino acid sequences of VH and VL constituting the S1-B binding site and SEQ ID NO. is shown.

[0027] [ Figure 3 ] Figure 3 The correspondence between the amino acid sequences of the plurality of CDRs contained in VH and VL, respectively, constituting the S1-A binding site and the SEQ ID NOs is shown.

[0028] [ Figure 4 ] Figure 4 The correspondence between the amino acid sequences of the plurality of CDRs contained in VH and VL, respectively, constituting the S1-B binding site and the SEQ ID NOs is shown.

[0029] [ Figure 5 ] Figure 5 The corresponding relationship between each amino acid sequence of VH and VL constituting the S2-C binding site and the S2-D binding site and SEQ ID NO. is shown.

[0030] [ Figure 6 ] Figure 6 The correspondence between the amino acid sequences of the plurality of CDRs contained in VH and VL, respectively constituting the S2-C binding site and the S2-D binding site, and SEQ ID NO. is shown.

[0031] [ Figure 7 ] Figure 7 The Morrison format of the anti-allergen-1 bispecific antibody of the present invention is shown.

[0032] [ Figure 8 ] Figure 8 The corresponding relationship between each amino acid sequence of the heavy chain constant region and the light chain constant region constituting the anti-allergen-1 bispecific antibody of the present invention and SEQ ID NO. is shown.

[0033] [ Fig. 9 ] Fig. 9 The correspondence between each amino acid sequence constituting the heavy chain of the anti-allergen-1 bispecific antibody of the present invention and SEQ ID NO. is shown.

[0034] [ Fig.10 ] Fig.10 The correspondence between each amino acid sequence constituting the heavy chain of the anti-allergen-1 bispecific antibody of the present invention and SEQ ID NO. is shown.

[0035] [ Fig.11 ] Fig.11 The correspondence between each amino acid sequence constituting the heavy chain of the anti-allergen-1 bispecific antibody of the present invention and SEQ ID NO. is shown.

[0036] [ Fig.12 ] Fig.12 The correspondence between each amino acid sequence constituting the heavy chain of the anti-allergen-1 bispecific antibody of the present invention and SEQ ID NO. is shown.

[0037] [ Fig.13 ] Fig.13 The correspondence between each amino acid sequence constituting the light chain of the anti-allergen-1 bispecific antibody of the present invention and SEQ ID NO. is shown.

[0038] [ Fig.14 ] Fig.14 The correspondence between each amino acid sequence constituting the light chain of the anti-allergen-1 bispecific antibody of the present invention and SEQ ID NO. is shown.

[0039] [ Fig.15 ] Fig.15 The amino acid sequence of human allergen-1L (GenBank accession number: NP_001078892.1) is shown.

[0040] [ Fig.16 ] Fig.16 Represents the result of competition test, and this result shows the blocking degree of the combination of anti-allergen-1 bispecific antibody and allergen-1 based on the present invention. A plurality of numerical values ​​in the table each represent the binding rate of anti-allergen-1 antibody and allergen-1L when anti-allergen-1 bispecific antibody of the present invention is processed relative to the binding rate of anti-allergen-1 antibody and allergen-1L when the same anti-allergen-1 bispecific antibody is not processed. The numbering of the vertical column of "Rabbit IgG ID No." (rabbit IgG ID No.) represents the clone of the anti-allergen-1 antibody evaluated respectively, "anti-allergen-1S1" represents that the anti-allergen-1 antibody is an antibody with specificity to the S1 domain, and "anti-allergen-1S2" represents an antibody with specificity to the S2 domain. The numbering of the horizontal column on the right represents each clone of the anti-allergen-1 bispecific antibody evaluated.

[0041] [ Fig.17 ] Fig.17The graph shows the evaluation results of the binding properties of the anti-allergen-1 bispecific antibody of the present invention to allergen-1 and the S1 domain and the S2 domain. 450-690nm ” (Ref. OD 450-690nm ) represents the binding amount of the anti-allergen-1 bispecific antibody against allergen-1L, and the horizontal axis represents the added concentration of the rabbit anti-allergen-1 antibody. In the figure, "rabbit IgG#50" and "rabbit IgG#85" represent the rabbit anti-allergen-1S2 IgG antibody #50 clone and the rabbit anti-allergen-1S1 IgG antibody #85 clone, respectively.

[0042] [ Fig.18 ] Fig.18 The results of Biacore analysis are shown, which relate to the inhibitory effect of the anti-allergic-1 bispecific antibody of the present invention on the binding of TLR9 ligand ODN M362 to allergic-1. The vertical axis "Response (RU)" (response value) shows the amount of ODN M362 binding to allergic-1L.

[0043] [ Fig.19 ] Fig.19 The results of the anti-tumor effects of the anti-allergen-1 bispecific antibody of the present invention and the anti-mouse PD-1 antibody 4H2 in a tumor-bearing model (mouse colorectal cancer cell line MC38) of human allergen-1L knock-in C57BL / 6 mice are shown. The vertical axis represents the tumor volume, and the horizontal axis represents the number of days after the tumor cell line was transplanted.

[0044] [ Fig. 20 ] Fig. 20 The results show the anti-tumor effect of the combination of the anti-allergen-1 bispecific antibody of the present invention and the anti-mouse PD-1 antibody 4H2 in a tumor-bearing model (mouse lung cancer cell line 3LL) of human allergen-1L knock-in C57BL / 6 mice. The vertical axis represents tumor volume, and the horizontal axis represents the number of days after the tumor cell line was transplanted.

[0045] [ Fig.21 ] Fig.21 The results show the anti-tumor effect of the anti-allergic-1 bispecific antibody of the present invention administered alone in a tumor-bearing model of human allergic-1L knock-in C57BL / 6 mice (human PD-L1 forced expression mouse colorectal cancer cell line MC38). The vertical axis represents tumor volume, and the horizontal axis represents the number of days after tumor cell line transplantation.

[0046] [ Fig. 22 ] Fig. 22 The results of evaluation of the effects of the anti-allergen-1 bispecific antibody of the present invention on cytokines released from human peripheral blood mononuclear cells are shown. DETAILED DESCRIPTION

[0047] Allergen-1 is also called MILR1, and in humans, it contains at least three splice variants, allergen-1L, allergen-1S1 and allergen-1S2 (refer to Nature Immunology (2010), Vol 11, No. 7, p.601-608), which are membrane-type proteins composed of amino acid sequences represented by GenBank accession numbers NP_001078892.1 (SEQ ID NO.115), BAJ08252.1 and BAJ08253.1, respectively. In addition, its mouse homologue is called MCA32, and has an amino acid sequence represented by GenBank accession number BAJ08254.1. Here, allergen-1L has an S1 domain and an S2 domain in its extracellular domain, and allergen-1S1 and allergen-1S2 each have only an S1 domain and only an S2 domain in their extracellular domains. The S1 domain of allergen-1L is located in the region of 37 to 121 positions from its N-terminus, and the S2 domain is located in the region of 128 to 200 positions from its N-terminus. On the other hand, the S1 domain of allergen-1S1 is similarly located in the region of 37 to 121 positions from its N-terminus, and the S2 domain of allergen-1S2 is located in the region of 38 to 110 positions from its N-terminus. In the case of being recorded as "allergen-1" in this specification, as long as there is no particular limitation, there is a case where it is used as an allergen-1 containing all its splice variants or subtypes. In the present invention, as allergen-1, human allergen-1 is selected.

[0048] The term "isolate" as used herein means to identify, separate and / or purify a substance extracted from host cells containing a plurality of or numerous components to obtain a substantially single pure component.

[0049] The term "monoclonal antibody" as used herein refers to an antibody obtained from a substantially uniform group of antibodies that bind to the same specific antigen.

[0050] The term "bispecific antibody" as used herein refers to an antibody having binding specificities for two different antigen molecules or epitopes in one molecule.

[0051] In this specification, "antigen molecule" or "antigen" refers to a chemical substance, peptide or protein that induces an immune response in an organism and is recognized by an antibody generated as a part of the immune response. The antigen in the present invention corresponds to the extracellular domain of allergen-1 or a part thereof.

[0052] In this specification, "epitope" refers to a part of the antigen that is recognized as the binding site of an antibody when the antibody binds to the antigen. The epitope in the present invention is a part of the extracellular domain of allergen-1 that specifically binds to each antigen binding site in the bispecific antibody or antibody fragment thereof of the present invention.

[0053] In this specification, "antigen binding site" refers to the smallest unit of a part of an antibody that can bind to its antigen or epitope, and is usually formed by the association of the heavy chain and light chain of an antibody, each of which has VH and VL of the antibody constituting the antigen binding site. VH and VL are each composed of the following (1) and (2):

[0054] (1) each of three complementarity determining regions (hereinafter, sometimes abbreviated as “CDRs”) (complementarity determining region 1 of VH (hereinafter, sometimes abbreviated as “VH-CDR1”), complementarity determining region 2 of VH (hereinafter, sometimes abbreviated as “VH-CDR2”), and complementarity determining region 3 of VH (hereinafter, sometimes abbreviated as “VH-CDR3”), and complementarity determining region 1 of VL (hereinafter, sometimes abbreviated as “VL-CDR1”), complementarity determining region 2 of VL (hereinafter, sometimes abbreviated as “VL-CDR2”), and complementarity determining region 3 of VL (hereinafter, sometimes abbreviated as “VL-CDR3”)); and

[0055] (2) The framework region of CDR (hereinafter sometimes abbreviated as "FW") is arranged so that the target antigen or epitope can be recognized by the combination of these CDRs.

[0056] In the present specification, "heavy chain / light chain complex" refers to a complex comprising an antibody heavy chain and its corresponding light chain, and "correspondence" here refers to the correspondence between the heavy chain and the light chain in the relationship in which the heavy chain VH and the light chain VL form an antigen binding site.

[0057] In this specification, "scFv" is the abbreviation of single chain Fv, which is a low molecular weight antibody produced in a single chain form after modification so that VH and VL can form an antigen binding site.

[0058] In this specification, "cross-competition" refers to mutual hindrance or inhibition of binding to an epitope common to multiple antibodies and recognized, regardless of the degree of binding. Whether cross-competition can be evaluated by competitive binding tests, for example, there are evaluation methods using Biacore analysis, ELISA test, flow cytometry, enzyme-linked immunosorbent assay (ELISA), fluorescence energy transfer assay (FRET) or fluorescence microassay technology (FMAT (registered trademark)).

[0059] [Antigen binding site of anti-allergen-1 bispecific antibody]

[0060] The anti-allergen-1 bispecific antibody of the present invention is a bispecific antibody having two antigen-binding sites that specifically bind to different epitopes of the extracellular domain of allergen-1. Here, the two antigen-binding sites do not compete with each other for allergen-1 and are different, optionally selected from the following four types (a) to (d):

[0061] (a) an antigen binding site that specifically binds to a specific epitope on the S1 domain of allergen-1 (sometimes referred to herein as "S1-A binding site");

[0062] (b) an antigen binding site that specifically binds to another epitope on the S1 domain of allergen-1 that is different from the epitope on the S1 domain described in (a) above (hereinafter referred to as "S1-B binding site");

[0063] (c) an antigen binding site that specifically binds to a specific epitope on the S2 domain of allergen-1 (sometimes referred to herein as "S2-C binding site"); and

[0064] (d) an antigen binding site that specifically binds to another epitope on the S2 domain of allergen-1 that is different from the epitope on the S2 domain described in (c) (sometimes referred to as "S2-D binding site" in this specification). That is, any of the S1-A binding site, S1-B binding site, S2-C binding site, and S2-D binding site are antigen binding sites that do not compete with each other for allergen-1.

[0065] Here, the epitope to which the S1-A binding site specifically binds (hereinafter, sometimes referred to as "S1-A epitope") consists of at least a sequence comprising SEQ ID The amino acid sequence represented by NO.115 is composed of any one or more or all of phenylalanine at position 70, arginine at position 71, arginine at position 72, lysine at position 73, histidine at position 75, leucine at position 76, histidine at position 96, glutamic acid at position 97, lysine at position 102, lysine at position 104 and tyrosine at position 113 of allergen-1, and the epitope to which the S2-D binding site specifically binds (hereinafter sometimes referred to as "S2-D epitope") is composed of at least any one or more or all of isoleucine at position 132, methionine at position 133, valine at position 134, isoleucine at position 135, glutamine at position 136, threonine at position 137, glutamic acid at position 138, histidine at position 146 and proline at position 215 of the allergen-1. Here, the epitope to which the S1-B binding site specifically binds (hereinafter, sometimes referred to as "S1-B epitope") is at least an epitope different from the S1-A epitope represented by the amino acids, and the epitope to which the S2-C binding site specifically binds (hereinafter, sometimes referred to as "S2-C epitope") is at least an epitope different from the S2-D epitope represented by the amino acids. In addition, "specific binding" means having a specific binding affinity of at least 1×10 -5 M, preferably 1×10 -7 M, more preferably 1×10 -9 M higher affinity (dissociation constant (Kd value)) and can directly bind to the S1 domain or S2 domain of allergen-1, at least not substantially binding to other domains of allergen-1 and other proteins, and "do not compete with each other" means, for example, the S1-B binding site does not substantially hinder the binding of the S1-A binding site to the epitope, or the S1-A binding site does not substantially hinder the binding of the S1-B binding site to the epitope, or the S2-D binding site does not substantially hinder the binding of the S2-C binding site to the epitope, or the S2-C binding site does not substantially hinder the binding of the S2-D binding site to the epitope.

[0066] [S1-A binding site and S1-B binding site]

[0067] As one embodiment of each of the "S1-A binding site" and the "S1-B binding site" in the present invention, for example, the S1-A binding site includes:

[0068] (A1) an antigen binding site comprising:

[0069] VH, which has

[0070] (a) VH-CDR1 comprising the amino acid sequence of SEQ ID NO.25;

[0071] (b) VH-CDR2 comprising the amino acid sequence of SEQ ID NO.26; and

[0072] (c) a VH-CDR3 comprising the amino acid sequence of SEQ ID NO. 27, and

[0073] VL, which has

[0074] (d) a VL-CDR1 comprising the amino acid sequence of SEQ ID NO.49;

[0075] (e) a VL-CDR2 comprising the amino acid sequence of SEQ ID NO.50; and

[0076] (f) a VL-CDR3 comprising the amino acid sequence of SEQ ID NO.51,

[0077] (A2) an antigen binding site comprising:

[0078] VH, which has

[0079] (a) VH-CDR1 comprising the amino acid sequence of SEQ ID NO.28;

[0080] (b) VH-CDR2 comprising the amino acid sequence of SEQ ID NO.29; and

[0081] (c) a VH-CDR3 comprising the amino acid sequence of SEQ ID NO. 30, and

[0082] VL, which has

[0083] (d) a VL-CDR1 comprising the amino acid sequence of SEQ ID NO.52;

[0084] (e) a VL-CDR2 comprising the amino acid sequence of SEQ ID NO.53; and

[0085] (f) a VL-CDR3 comprising the amino acid sequence of SEQ ID NO.54,

[0086] (A3) an antigen binding site comprising:

[0087] VH, which has

[0088] (a) VH-CDR1 comprising the amino acid sequence of SEQ ID NO.31;

[0089] (b) VH-CDR2 comprising the amino acid sequence of SEQ ID NO.32; and

[0090] (c) a VH-CDR3 comprising the amino acid sequence of SEQ ID NO. 33, and

[0091] VL, which has

[0092] (d) a VL-CDR1 comprising the amino acid sequence of SEQ ID NO.55;

[0093] (e) a VL-CDR2 comprising the amino acid sequence of SEQ ID NO.56; and

[0094] (f) a VL-CDR3 comprising the amino acid sequence of SEQ ID NO.57, and

[0095] (A4) an antigen binding site comprising:

[0096] VH, which has

[0097] (a) VH-CDR1 comprising the amino acid sequence of SEQ ID NO.34;

[0098] (b) VH-CDR2 comprising the amino acid sequence of SEQ ID NO.35; and

[0099] (c) a VH-CDR3 comprising the amino acid sequence of SEQ ID NO. 36, and

[0100] VL, which has

[0101] (d) a VL-CDR1 comprising the amino acid sequence of SEQ ID NO.58;

[0102] (e) a VL-CDR2 comprising the amino acid sequence of SEQ ID NO.59; and

[0103] (f) VL-CDR3 comprising the amino acid sequence of SEQ ID NO.60.

[0104] On the other hand, the S1-B binding site can be listed as follows:

[0105] (B1) an antigen binding site comprising:

[0106] VH, which has

[0107] (a) VH-CDR1 comprising the amino acid sequence of SEQ ID NO.37;

[0108] (b) VH-CDR2 comprising the amino acid sequence of SEQ ID NO.38; and

[0109] (c) a VH-CDR3 comprising the amino acid sequence of SEQ ID NO. 39, and

[0110] VL, which has

[0111] (d) a VL-CDR1 comprising the amino acid sequence of SEQ ID NO.61;

[0112] (e) a VL-CDR2 comprising the amino acid sequence of SEQ ID NO.62; and

[0113] (f) a VL-CDR3 comprising the amino acid sequence of SEQ ID NO. 63, and

[0114] (B2) an antigen binding site comprising:

[0115] VH, which has

[0116] (a) VH-CDR1 comprising the amino acid sequence of SEQ ID NO.40,

[0117] (b) VH-CDR2 comprising the amino acid sequence of SEQ ID NO.41; and

[0118] (c) a VH-CDR3 comprising the amino acid sequence of SEQ ID NO. 42, and

[0119] VL, which has

[0120] (d) a VL-CDR1 comprising the amino acid sequence of SEQ ID NO.64;

[0121] (e) a VL-CDR2 comprising the amino acid sequence of SEQ ID NO.65; and

[0122] (f) VL-CDR3 comprising the amino acid sequence of SEQ ID NO.66.

[0123] In addition, the "S1-A binding site" and "S1-B binding site" in the present invention each include: in each CDR constituting each VH and VL in (A1) to (A4) and (B1) and (B2), any 1 to 5 amino acid residues thereof are substituted with other amino acids (preferably conservative amino acids thereof), and the binding site has substantially the same binding activity to each epitope on the S1 domain as the original antigen binding site not substituted with the amino acids. For example, in the case of VH-CDR1 of the S1-A binding site, one amino acid residue may be substituted with its conservative amino acid, and in the case of VH-CDR2 or VH-CDR3, one or two amino acid residues may be substituted with its conservative amino acid. Here, substitution based on "conservative amino acids" refers to the interchangeability of residues having similar side chains, for example, glycine, alanine, valine, leucine and isoleucine in the group of amino acids having aliphatic side chains, serine and threonine in the group of amino acids having aliphatic hydroxyl side chains, asparagine and glutamine in the group of amino acids having amide-containing side chains, phenylalanine, tyrosine and tryptophan in the group of amino acids having aromatic side chains, lysine, arginine and histidine in the group of amino acids having basic side chains, and cysteine ​​and methionine in the group of amino acids having sulfur-containing side chains. Examples of substitution based on preferred conservative amino acids include substitution between valine, leucine and isoleucine, substitution between phenylalanine and tyrosine, substitution between lysine and arginine, substitution between alanine and valine, and substitution between asparagine and glutamine. In addition, here, the phrase “having substantially the same binding activity as the original antigen-binding sites that have not been substituted with the amino acids for the respective epitopes on the S1 domain” means that the binding activity of the S1-A binding site or the S1-B binding site substituted with the amino acids for the respective epitopes on the S1 domain is 95% or more, preferably 98% or more, and more preferably 99% or more of the binding activity of the original S1-A binding site or the S1-B binding site that has not been substituted with the amino acids.

[0124] In addition, the "S1-A binding site" and "S1-B binding site" in the present invention include: each CDR having the specific amino acid sequence is included in each of the VH and VL constituting these, and its FW is humanized so that it is encoded by a specific germline gene of a human or the gene in which one or more somatic mutations and / or back mutations have occurred. For example, for each CDR of the VH and VL shown in (A1) to (A4) and (B1) and (B2), the FW encoded by each of the human germline VH gene IGHV3-66 and VL gene IGKV1-39 or the genes in which one or more somatic mutations and / or back mutations have occurred can be applied. Here, "somatic mutation" refers to a mutation in an antibody gene based on the action of AID (activation-induced cytidine deaminase), and "back mutation" refers to replacing one or more amino acid residues of the FW of a humanized antibody with corresponding amino acid residues in an original non-human (e.g., rabbit, mouse, etc.) antibody. Examples of S1-A binding sites each having such humanized VH and VL include antigen binding sites composed of VH and VL each comprising an amino acid sequence selected from any one of the following sequence groups:

[0125] (a) SEQ ID NO. 1 and SEQ ID NO. 12 or 104;

[0126] (b) SEQ ID NO. 2 and SEQ ID NO. 13 or 105;

[0127] (c) SEQ ID NO. 3 and SEQ ID NO. 14 or 106;

[0128] (d) SEQ ID NO. 4 and SEQ ID NO. 15 or 107;

[0129] (e) SEQ ID NO. 5 and SEQ ID NO. 16 or 108; and

[0130] (f) SEQ ID NO. 6 and SEQ ID NO. 17 or 109,

[0131] As an example of the S1-B binding site, there can be mentioned an antigen binding site composed of VH and VL, wherein VH and VL contain the following set of amino acid sequences:

[0132] (a) SEQ ID NO. 7 and SEQ ID NO. 18 or 110; or

[0133] (b) SEQ ID NO. 8 and SEQ ID NO. 19 or 111.

[0134] In addition, the “S1-A binding site” in the present invention also includes, for example: VH and VL each having an amino acid sequence that is independently at least 80%, preferably at least 90%, further preferably at least 95%, further preferably at least 98%, and more preferably at least 99% identical to any one of the following sequence groups (excluding each of the three CDRs), and the difference from each of the original VH and VL amino acid sequences does not substantially affect the binding activity to the same epitope on the S1 domain (hereinafter, sometimes referred to as “the same S1-A binding site”), wherein the sequence group is:

[0135] (a) SEQ ID NO. 1 and SEQ ID NO. 12 or 104;

[0136] (b) SEQ ID NO. 2 and SEQ ID NO. 13 or 105;

[0137] (c) SEQ ID NO. 3 and SEQ ID NO. 14 or 106;

[0138] (d) SEQ ID NO. 4 and SEQ ID NO. 15 or 107;

[0139] (e) SEQ ID NO. 5 and SEQ ID NO. 16 or 108; and

[0140] (f) SEQ ID NO. 6 and SEQ ID NO. 17 or 109.

[0141] For example, the same S1-A binding site includes: a S1-A binding site of a VH having an amino acid sequence comprising SEQ ID NO. 1 or 5, in which cysteine ​​at position 45 or 44 (corresponding to position 44 based on the Kabat numbering system) is substituted with glycine; and a S1-A binding site of a VH having an amino acid sequence selected from SEQ ID NO. 2, 3, 4 and 6, in which glycine at position 44 (corresponding to position 44 based on the Kabat numbering system) is substituted with cysteine. Here, "% identity" used in comparison of amino acid sequence identity is defined as the percentage of amino acid sequence identical to a reference amino acid sequence (wherein, when the maximum percentage of identity needs to be achieved, the reference amino acid sequence after a gap is introduced) when two sequences are aligned. In addition, here, "the difference from each amino acid sequence of the original VH and VL has substantially no effect on the binding activity to the same epitope on the S1 domain" means that the binding activity to the same epitope on the S1 domain of the same S1-A binding site is 95% or more, preferably 98% or more, and more preferably 99% or more of the binding activity of the S1-A binding site containing the original VH and VL.

[0142] Similarly, the “S1-B binding site” in the present invention also includes, for example, a VH and a VL comprising amino acid sequences that are each independently at least 80%, preferably at least 90%, more preferably at least 95%, further preferably at least 98%, further preferably at least 99% identical to the following set of amino acid sequences (excluding each of the three CDRs), and the difference from each of the original VH and VL amino acid sequences does not substantially affect the binding activity to the same epitope on the S1 domain (hereinafter, sometimes simply referred to as “the same S1-B binding site”),

[0143] (a) SEQ ID NO. 7 and SEQ ID NO. 18 or 110; or

[0144] (b) SEQ ID NO. 8 and SEQ ID NO. 19 or 111.

[0145] For example, the same S1-B binding site includes: an S1-B binding site of a VH having an amino acid sequence comprising SEQ ID NO.7 in which the cysteine ​​at position 44 (corresponding to position 44 based on the Kabat numbering system) is substituted with glycine; and an S1-B binding site of a VH having an amino acid sequence comprising SEQ ID NO.8 in which the glycine at position 44 (corresponding to position 44 based on the Kabat numbering system) is substituted with cysteine.

[0146] It should be noted that, in the present invention, VH comprising the amino acid sequence of SEQ ID NO.1 or 5 and VL comprising the amino acid sequence selected from SEQ ID NO.12 to 17 preferably constitute each scFv, and on the other hand, VH comprising the amino acid sequence selected from SEQ ID NO.2, 3, 4 and 6 and VL comprising the amino acid sequence selected from SEQ ID NO.104 to 109 preferably constitute a part of each heavy chain / light chain complex. In addition, in the present invention, VH comprising the amino acid sequence of SEQ ID NO.7 and VL comprising the amino acid sequence of SEQ ID NO.18 or 19 preferably constitute each scFv, and on the other hand, VH comprising the amino acid sequence of SEQ ID NO.8 and VL comprising the amino acid sequence of SEQ ID NO.110 or 111 preferably constitute a part of each heavy chain / light chain complex.

[0147] In another embodiment, the "S1-A binding site" of the present invention also includes:

[0148] An antigen binding site that cross-competes for binding to an epitope on the S1 domain with an antibody or its antigen binding site having VH and VL, wherein the VH and VL comprise any one of the amino acid sequences selected from the following sequence groups:

[0149] (a) SEQ ID NO.1 and SEQ ID NO.104;

[0150] (b) SEQ ID NO.2 and SEQ ID NO.105;

[0151] (c) SEQ ID NO. 3 and SEQ ID NO. 106;

[0152] (d) SEQ ID NO.4 and SEQ ID NO.107;

[0153] (e) SEQ ID NO. 5 and SEQ ID NO. 108; and

[0154] (f) SEQ ID NO. 6 and SEQ ID NO. 109, and

[0155] An antigen binding site, whose binding to the epitope on the S1 domain is cross-competed by an antibody or its antigen binding site having VH and VL, wherein the VH and VL comprise any one of the amino acid sequences selected from the following sequence groups:

[0156] (a) SEQ ID NO.1 and SEQ ID NO.104;

[0157] (b) SEQ ID NO.2 and SEQ ID NO.105;

[0158] (c) SEQ ID NO. 3 and SEQ ID NO. 106;

[0159] (d) SEQ ID NO.4 and SEQ ID NO.107;

[0160] (e) SEQ ID NO. 5 and SEQ ID NO. 108; and

[0161] (f) SEQ ID NO.6 and SEQ ID NO.109.

[0162] Similarly, the "S1-B binding site" in the present invention also includes:

[0163] An antigen binding site that cross-competes for binding to an epitope on the S1 domain with an antibody or its antigen binding site having VH and VL comprising the following set of amino acid sequences:

[0164] (a) SEQ ID NO. 7 and SEQ ID NO. 110; or

[0165] (b) SEQ ID NO. 8 and SEQ ID NO. 111, and

[0166] An antigen binding site, whose binding to said epitope on the S1 domain is cross-competed by an antibody or its antigen binding site having VH and VL, said VH and VL comprising the following set of amino acid sequences:

[0167] (a) SEQ ID NO. 7 and SEQ ID NO. 110; or

[0168] (b) SEQ ID NO.8 and SEQ ID NO.111.

[0169] For example, as a binding site that cross-competes with the S1-A binding site composed of VH and VL each comprising the amino acid sequence of SEQ ID NO.1 and SEQ ID NO.12 or 104 for binding to the epitope on the S1 domain, for example, an antigen binding site composed of VH and VL comprising any one of the following sequence groups:

[0170] (a) SEQ ID NO. 2 and SEQ ID NO. 13 or 105;

[0171] (b) SEQ ID NO. 3 and SEQ ID NO. 14 or 106;

[0172] (c) SEQ ID NO. 4 and SEQ ID NO. 15 or 107;

[0173] (d) SEQ ID NO. 5 and SEQ ID NO. 16 or 108; and

[0174] (e) SEQ ID NO. 6 and SEQ ID NO. 17 or 109.

[0175] In addition, as a binding site that cross-competes with the S1-B binding site composed of VH and VL each comprising the amino acid sequence of SEQ ID NO.7 and SEQ ID NO.18 or 110 for binding to the epitope on the S1 domain, for example, an antigen binding site composed of VH and VL each comprising the amino acid sequence of SEQ ID NO.8 and SEQ ID NO.19 or 111 can be mentioned.

[0176] Here, the “S1-A binding site” in the present invention is preferably an antigen binding site composed of VH and VL comprising any one of the amino acid sequences selected from the following sequence groups:

[0177] (a) SEQ ID NOs. 1 and 12;

[0178] (b) SEQ ID NOs. 2 and 13;

[0179] (c) SEQ ID NO. 3 and SEQ ID NO. 14 or 106;

[0180] (d) SEQ ID NO. 4 and SEQ ID NO. 15 or 107;

[0181] (e) SEQ ID NOs. 5 and 16; and

[0182] (f) SEQ ID NO. 6 and SEQ ID NO. 17 or 109,

[0183] More preferably, the antigen binding site is composed of VH and VL comprising any one of the amino acid sequences selected from the following sequence groups:

[0184] (a) SEQ ID NO. 3 and SEQ ID NO. 14 or 106;

[0185] (b) SEQ ID NO. 4 and SEQ ID NO. 15 or 107;

[0186] (c) SEQ ID NOs. 5 and 16; and

[0187] (d) SEQ ID NO. 6 and SEQ ID NO. 17 or 109,

[0188] More preferably, the antigen-binding site is composed of VH and VL comprising any one of the amino acid sequences selected from the following sequence groups:

[0189] (a) SEQ ID NO. 3 and SEQ ID NO. 14 or 106;

[0190] (b) SEQ ID NO. 4 and SEQ ID NO. 15 or 107; and

[0191] (c) SEQ ID NOs. 5 and 16,

[0192] The “S1-B binding site” in the present invention is preferably an antigen binding site composed of VH and VL comprising any of the following groups of amino acid sequences:

[0193] (a) SEQ ID NO. 7 and SEQ ID NO. 18 or 110; or

[0194] (b) SEQ ID NO. 8 and SEQ ID NO. 19 or 111.

[0195] Here, the corresponding relationship between each amino acid sequence of VH and VL constituting the S1-A binding site and the S1-B binding site and SEQ ID NO. is as follows: Figure 1 and 2 In addition, the corresponding relationships between the amino acid sequences of the multiple CDRs contained in each of these VH and VL and SEQ ID NO. are shown as follows: Figure 3 and 4 shown.

[0196] [S2-C binding site and S2-D binding site]

[0197] As one embodiment of each of the "S2-C binding site" and the "S2-D binding site" in the present invention, for example, the S2-C binding site includes the (C1) antigen binding site,

[0198] (C1) an antigen binding site comprising:

[0199] VH, which has

[0200] (a) VH-CDR1 comprising the amino acid sequence of SEQ ID NO.43;

[0201] (b) VH-CDR2 comprising the amino acid sequence of SEQ ID NO.44; and

[0202] (c) a VH-CDR3 comprising the amino acid sequence of SEQ ID NO. 45, and

[0203] VL, which has

[0204] (d) a VL-CDR1 comprising the amino acid sequence of SEQ ID NO.67;

[0205] (e) a VL-CDR2 comprising the amino acid sequence of SEQ ID NO.68; and

[0206] (f) a VL-CDR3 comprising the amino acid sequence of SEQ ID NO.69,

[0207] On the other hand, the S2-D binding site includes the (D1) antigen binding site,

[0208] (D1) an antigen binding site comprising:

[0209] VH, which has

[0210] (a) VH-CDR1 comprising the amino acid sequence of SEQ ID NO.46,

[0211] (b) VH-CDR2 comprising the amino acid sequence of SEQ ID NO.47; and

[0212] (c) a VH-CDR3 comprising the amino acid sequence of SEQ ID NO. 48, and

[0213] VL, which has

[0214] (d) VL-CDR1 comprising the amino acid sequence of SEQ ID NO.70;

[0215] (e) a VL-CDR2 comprising the amino acid sequence of SEQ ID NO. 71; and

[0216] (f) VL-CDR3 comprising the amino acid sequence of SEQ ID NO.72.

[0217] In addition, the "S2-C binding site" and "S2-D binding site" in the present invention each include: in each CDR constituting each VH and VL in (C1) and (D1), 1 to 5 amino acid residues are substituted by other amino acids (preferably conservative amino acids), and the binding site has substantially the same binding activity to each epitope on the S2 domain as the original antigen binding site that is not substituted with the amino acids. For example, in the case of VH-CDR1 of the S2-C binding site, one amino acid residue can be substituted with its conservative amino acid, and in the case of VH-CDR2 or VH-CDR3, one or two amino acid residues can be substituted with its conservative amino acid. Here, the substitution based on "conservative amino acids" can be cited as an example of amino acid substitution in the "S1-A binding site" or "S1-B binding site". In addition, "having substantially the same binding activity as the original antigen-binding sites that have not been substituted with the amino acids for each epitope on the S2 domain" means that, similar to the above, the binding activity of the S2-C binding site or S2-D binding site substituted with the amino acids for each epitope on the S2 domain is more than 95% of the binding activity of the original S2-C binding site or S2-D binding site that has not been substituted with the amino acids, preferably more than 98%, and more preferably more than 99%.

[0218] In addition, the "S2-C binding site" and "S2-D binding site" in the present invention also include: each CDR having the specific amino acid sequence is included in each of the VH and VL constituting these, and its FW is humanized so that it is encoded by a specific human germline gene or the gene that has undergone one or more somatic mutations and / or back mutations. For example, as described above, for each CDR of the VH and VL shown in (C1) and (D1), respectively, the FW encoded by the human germline VH gene IGHV3-66 and the VL gene IGKV1-39 or the genes that have undergone one or more somatic mutations and / or back mutations can be applied. As an S2-C binding site each having such a humanized VH and VL, for example, an antigen binding site composed of a VH and VL having a set of amino acid sequences including SEQ ID NO.9 and SEQ ID NO.20 or 112 can be cited,

[0219] Examples of the S2-D binding site include an antigen binding site composed of VH and VL comprising the following amino acid sequence:

[0220] (a) SEQ ID NO. 10 and SEQ ID NO. 21 or 113; or

[0221] (b) SEQ ID NO.11 and SEQ ID NO.22 or 114.

[0222] In addition, the "S2-C binding site" in the present invention also includes, for example: VH and VL having amino acid sequences each independently having at least 80%, preferably at least 90%, more preferably at least 95%, further preferably at least 98%, further more preferably at least 99% identity with a set of amino acid sequences of SEQ ID NO. 9 and SEQ ID NO. 20 or 112 (excluding each of the three CDRs), and the difference from each amino acid sequence of the original VH and VL substantially has no effect on the binding activity to the same epitope on the S2 domain (hereinafter, sometimes referred to as "the same S2-C binding site"). For example, the same S2-C binding site includes: the S2-C binding site of VH having the amino acid sequence of SEQ ID NO. 9 in which the glycine at position 44 (corresponding to position 44 based on the Kabat numbering system) is substituted with cysteine.

[0223] Similarly, the "S2-D binding site" in the present invention includes, for example, VH and VL comprising amino acid sequences that are each independently at least 80%, preferably at least 90%, more preferably at least 95%, further preferably at least 98%, and further preferably at least 99% identical to the following set of amino acid sequences (excluding each of the three CDRs), and the difference from each of the original VH and VL amino acid sequences does not substantially affect the binding activity to the same epitope on the S2 domain (hereinafter, sometimes referred to as "the same S2-D binding site").

[0224] (a) SEQ ID NO. 10 and SEQ ID NO. 21 or 113; or

[0225] (b) SEQ ID NO.11 and SEQ ID NO.22 or 114.

[0226] For example, the same S2-D binding site includes: an S2-D binding site of a VH having an amino acid sequence comprising SEQ ID NO.11 in which the cysteine ​​at position 44 (corresponding to position 44 based on the Kabat numbering system) is substituted with glycine; and an S2-D binding site of a VH having an amino acid sequence comprising SEQ ID NO.10 in which the glycine at position 44 (corresponding to position 44 based on the Kabat numbering system) is substituted with cysteine.

[0227] It should be noted that, in the present invention, VL comprising the amino acid sequence of SEQ ID NO.20 preferably constitutes scFv, and on the other hand, VH comprising the amino acid sequence of SEQ ID NO.9 and VL comprising the amino acid sequence of SEQ ID NO.112 preferably constitute a part of each heavy chain / light chain complex. In addition, in the present invention, VH comprising the amino acid sequence of SEQ ID NO.11 and VL comprising the amino acid sequence of SEQ ID NO.21 or 22 preferably constitute each scFv, and on the other hand, VH comprising the amino acid sequence of SEQ ID NO.10 and VL comprising the amino acid sequence of SEQ ID NO.113 or 114 preferably constitute a part of each heavy chain / light chain complex.

[0228] In addition, in another embodiment, the "S2-C binding site" in the present invention also includes: an antigen binding site, which cross-competes with an antibody or its antigen binding site having VH and VL, each of which contains an amino acid sequence of SEQ ID NO.9 and SEQ ID NO.112, for binding to an epitope on the S2 domain; and an antigen binding site, which cross-competes with an antibody or its antigen binding site having VH and VL, each of which contains an amino acid sequence of SEQ ID NO.9 and SEQ ID NO.112, for binding to the epitope on the S2 domain.

[0229] Similarly, the "S2-D binding site" in the present invention also includes:

[0230] An antigen binding site that cross-competes for binding to an epitope on the S2 domain with an antibody or its antigen binding site having VH and VL comprising the following set of amino acid sequences:

[0231] (a) SEQ ID NO. 10 and SEQ ID NO. 113; or

[0232] (b) SEQ ID NO. 11 and SEQ ID NO. 114, and

[0233] An antigen binding site, whose binding to said epitope on the S2 domain is cross-competed by an antibody or its antigen binding site having VH and VL, said VH and VL comprising the following set of amino acid sequences:

[0234] (a) SEQ ID NO. 10 and SEQ ID NO. 113; or

[0235] (b) SEQ ID NO. 11 and SEQ ID NO. 114.

[0236] For example, as a binding site that cross-competes with the S2-D binding site composed of VH and VL each comprising the amino acid sequence of SEQ ID NO.10 and SEQ ID NO.21 or 113 for binding to the epitope on the S2 domain, for example, an antigen binding site composed of VH and VL each comprising the amino acid sequence of SEQ ID NO.11 and SEQ ID NO.22 or 114 can be cited.

[0237] Here, the "S2-C binding site" in the present invention is preferably an antigen binding site composed of VH and VL comprising a set of amino acid sequences of SEQ ID NO. 9 and SEQ ID NO. 20 or 112,

[0238] The “S2-D binding site” in the present invention is preferably an antigen binding site composed of VH and VL comprising the following set of amino acid sequences:

[0239] (a) SEQ ID NO. 10 and SEQ ID NO. 21 or 113; or

[0240] (b) SEQ ID NOs. 11 and 22.

[0241] Here, the corresponding relationship between each amino acid sequence of VH and VL constituting the S2-C binding site and the S2-D binding site and SEQ ID NO. is as follows Figure 5 In addition, the corresponding relationship between the amino acid sequences of the multiple CDRs contained in each of these VH and VL and SEQ ID NO. is as shown in Figure 6 shown.

[0242] [Format of anti-allergen-1 bispecific antibody]

[0243] Examples of the anti-allergen-1 bispecific antibody of the present invention include bispecific antibodies (see Proc. Natl. Acad. Sci. USA (1993), Vol. 90, No. 14: p. 6444-6448), bispecific sc(Fv) 2 (See J. Biological Chemistry (1994), Vol. 269: p.199-206), bispecific F(ab') 2(Refer to Invest. Ophthalmol. Visual Sci. (2015), Vol. 56: p.5390-5400), bispecific minibody (Refer to Biochemistry (1992), Vol. 31, No. 6, p. 1579-1584), bispecific hybrid antibody, covalently linked bispecific antibody (bispecific DART) (Refer to Blood (2011), Vol. 117, No. 17, p. 4542-4551), bispecific (FvCys) 2 (See J. Immunol. (1992), Vol. 149: p.120-126), bispecific F (ab'-zipper) 2 (See J. Immunol. (1992), Vol. 148, No. 5: p.1547-1553), bispecific (Fv-zipper) 2 (Biochemistry (1992), Vol.31, No. 6: p.1579-1584), bispecific triavalent antibody (Proc. Natl. Acad. Sci. USA (1993), Vol. 90, No. 14: p.6444-6448), bispecific mAb 2 (www.f-star.com / technology_mab.html) and Morrison format antibodies, etc.

[0244] Bispecific hybrid antibodies refer to complete antibodies formed by covalently bonding the heavy and light chains of antibodies that recognize two different antigens. For example, bispecific hybrid antibodies can be produced by hybridomas prepared by the hybridoma method (refer to US4474893). In addition, a total of 4 cDNAs encoding the heavy and light chains of antibodies that recognize different antigens can be co-expressed and secreted in mammalian cells.

[0245] Morrison format antibodies refer to bispecific antibodies in which a scFv that binds to an epitope different from that of the antibody is linked to the C-terminus of the heavy chain or the C-terminus of the light chain of the antibody (see Nat. Biotechnol. (1997), Vol. 15, No. 2: p.159-63 and Protein Eng. Des. Sel. (2010), Vol. 23, No. 4: p.221-228).

[0246] Among the anti-allergen-1 bispecific antibodies of the present invention, Morrison format antibodies are preferred.

[0247] When the anti-allergen-1 bispecific antibody of the present invention is a Morrison-type antibody, one antigen-binding site constituting the bispecific antibody is formed as a part of the heavy chain / light chain complex constituting the bispecific antibody, and the other antigen-binding site is in the form of a scFv comprising VH and VL constituting the antigen-binding site. For example, the heavy chain / light chain complex can be formed by any one selected from the following combinations:

[0248] (a) a combination of a heavy chain comprising the VH constituting the S1-A binding site and a light chain comprising the VL constituting the binding site;

[0249] (b) a combination of a heavy chain having the VH constituting the S1-B binding site and a light chain having the VL constituting the binding site;

[0250] (c) a combination of a heavy chain having the VH constituting the S2-C binding site and a light chain having the VL constituting the binding site; and

[0251] (d) A combination of a heavy chain comprising the VH constituting the S2-D binding site and a light chain comprising the VL constituting the binding site.

[0252] Here, the heavy chain and the light chain can be used together with an IgG antibody, in which case the heavy chain has a heavy chain constant region 1 (hereinafter, sometimes referred to as “CH1”), a heavy chain constant region 2 (hereinafter, sometimes referred to as “CH2”), and a heavy chain constant region 3 (hereinafter, sometimes referred to as “CH3”) of an IgG antibody, and the light chain has a light chain constant region (hereinafter, sometimes referred to as “CL”) of an IgG antibody.

[0253] On the other hand, the scFv is different from the antigen binding site constituting a part of the heavy chain / light chain complex (hereinafter, sometimes referred to as "the antigen binding site in the heavy chain / light chain complex") and is selected from antigen binding sites that do not compete with each other, for example,

[0254] (a) when the antigen binding site in the heavy chain / light chain complex is the S1-A binding site, it may be selected from any one of the S1-B binding site, the S2-C binding site and the S2-D binding site,

[0255] (b) when the antigen binding site in the heavy chain / light chain complex is the S1-B binding site, it can be selected from any one of the S1-A binding site, the S2-C binding site and the S2-D binding site,

[0256] (c) When the antigen binding site in the heavy chain / light chain complex is the S2-C binding site, it can be selected from any one of the S1-A binding site, the S1-B binding site and the S2-D binding site, or

[0257] (d) When the antigen binding site in the heavy chain / light chain complex is the S2-D binding site, it can be selected from any one of the S1-A binding site, the S1-B binding site and the S2-C binding site.

[0258] Here, the combination of the antigen binding site in the heavy chain / light chain complex and the antigen binding site constituting the scFv is preferably a combination of antigen binding sites that bind to the S1 domain and S2 domain of allergen-1, respectively. For example, when the antigen binding site in the heavy chain / light chain complex is the S1-A binding site or the S1-B binding site, the antigen binding site of the scFv is the S2-C binding site or the S2-D binding site; and when the antigen binding site in the heavy chain / light chain complex is the S2-C binding site or the S2-D binding site, the antigen binding site of the scFv is the S1-A binding site or the S1-B binding site. In addition, when the antigen binding site in the heavy chain / light chain complex is the S1-A binding site, it is more preferred that the antigen binding site of the scFv is a combination of the S2-C binding site or the S2-D binding site, and when the antigen binding site in the heavy chain / light chain complex is the S2-C binding site or the S2-D binding site, it is more preferred that the antigen binding site of the scFv is a combination of the S1-A binding site.

[0259] In addition, the scFv is connected to the C-terminus of any one of the heavy chain or light chain. For example, the N-terminus of the scFv can be connected to the C-terminus of any one of the heavy chain or light chain by a direct amide bond, or can be connected thereto by a peptide linker. The scFv is preferably connected to the C-terminus of the heavy chain, and more preferably connected to its C-terminus by a peptide linker. Here, "connected by a peptide linker" means that the N-terminus of the peptide linker is connected to the C-terminus of any one of the heavy chain or light chain by an amide bond, and in addition, its C-terminus is connected to the N-terminus of the scFv by an amide bond. It should be noted that, with respect to the heavy chain or light chain connected to the scFv constituting the anti-allergic-1 bispecific antibody of the present invention, in one embodiment, as these integrated proteins, they are produced by host cells expressing them.

[0260] As for VH and VL constituting the scFv, they can be linked to each other through a direct amide bond or a peptide linker in the order of VH and VL from the N-terminal side. Conversely, they can also be linked to each other through a direct amide bond or a peptide linker in the order of VL and VH from the N-terminal side. Preferably, they are linked to each other through a peptide linker in the order of VL and VH from the N-terminal side of the scFv.

[0261] As for the peptide linker connecting the scFv to the C-terminus of any one of the heavy chain or light chain, as long as the expected activity of the bispecific antibody of the present invention can be exerted, it can be an optional peptide linker, and as such a peptide linker, it is preferably an amino acid sequence comprising Gly-Gly-Gly-Gly-Gly-Ser-Gly-Gly-Gly-Gly-Ser (SEQ ID NO.73). On the other hand, as for the peptide linker connecting the VH and VL forming the scFv to each other, as long as the antigen binding of the scFv is not impaired, it can be an optional peptide linker, and as such a peptide linker, it is preferably an amino acid sequence comprising Gly-Gly-Gly-Gly-Gly-Ser-Gly-Gly-Gly-Gly-Ser-Gly-Gly-Gly-Gly-Ser (SEQ ID NO.74). Here, in this specification, "Gly" represents glycine, and "Ser" represents serine.

[0262] When the anti-allergen-1 bispecific antibody of the present invention is a Morrison format antibody, as an embodiment thereof, it is preferably an embodiment having the same two heavy chain / light chain complexes consisting of the heavy chain and the light chain linked to the C-terminus of either of the scFv by the above-mentioned manner, for example, associated by a disulfide bond, wherein the embodiment is as follows: Figure 7 As shown in (A) and (B).

[0263] The anti-allergen-1 bispecific antibody of the present invention may be derived from any of a chimeric antibody, a humanized antibody and a human antibody.

[0264] Chimeric antibodies can be prepared, for example, by linking a gene encoding an antibody variable region isolated from an antibody-producing hybridoma isolated by a known method (see Nature (1975), Vol. 256: p.495-97, Hongo, Hybridoma (1995), Vol. 14, No. 3, p.253-260, Antibodies: A Laboratory Manual, (Cold Spring Harbor Laboratory Press (1988), Vol. 2) or Monoclonal Antibodies and T-Cell Hybridomas, p.563-681 (Elsevier, NY, 1981)) with a gene encoding a human-derived antibody constant region using a known method (see US Pat. No. 4,816,567).

[0265] In addition, in the case of humanized antibodies, genes encoding the CDRs of antibodies isolated by known methods from antibody-producing hybridomas isolated by the above methods (for example, refer to US5225539, US5530101, US5585089 or US6180370) can be connected to genes encoding human-derived antibody framework regions using known methods.

[0266] On the other hand, a human antibody refers to an antibody whose entire structure is derived from human germline immunoglobulin sequences, and can be prepared by using mice transformed in a manner to produce human antibodies, for example, Humab mice (see US5545806, US5569825, US5625126, US5633425, US5789650, US5877397, US5661016, US5814318, US5874299 or US5770429), KM mice (see WO2002 / 43478), Xeno mice (for example, see US5939598, US6075181, US6114598, US6150584 or US6162963) or Tc mice (see Proc. Natl. Acad. Sci. USA (2000), p.722-727). In addition, it is also possible to use SCID mice (with reference to US5476996 or US5698767) that have reconstructed human immune cells in a manner that causes human antibody response by immunity. In addition, it is possible to prepare by phage display method (with reference to US5223409, US5403484, US5571698, US5427908, US5580717, US5969108, US6172197, US5885793, US6521404, US6544731, US6555313, US6582915 or US6593081).

[0267] The anti-allergen-1 bispecific antibody of the present invention may be an antibody of any isotype, and a preferred isotype is IgG, and more preferably IgG 1 or IgG 4 .

[0268] Here, IgG is preferably 1 , for example, IgG whose binding to Fc receptors is lost or weakened 1 , which can be obtained by replacing, deleting or adding any amino acid in the heavy chain constant region. For example, an antibody in which the leucine at position 235 based on the EU numbering system is replaced with glycine and / or the glycine at position 236 is replaced with arginine in the two heavy chain constant regions or hinge regions of the bispecific antibody can be mentioned. In addition, in order to reduce the heterogeneity of the antibody, an IgG in which the C-terminal amino acid, such as lysine at position 447 based on the EU numbering system, is deleted is more preferred. 1 .

[0269] The anti-allergen-1 bispecific antibody of the present invention is IgG 4In the case of an isotype, in order to suppress the exchange within the antibody molecule, it is more preferred that the optional amino acid in its heavy chain constant region is replaced, deleted or added to obtain a modified body. For example, it is preferably an antibody in which the serine at position 228 located in the hinge region based on the EU numbering system is replaced with proline. It should be noted that in this specification, the CDR of the variable region of the antibody and the amino acid position assigned as the skeleton can be specified according to Kabat (refer to Sequences of Proteins of Immunological Interest (National Institute of Health, Bethesda, Md.), (1987) and (1991)), and the amino acids in the constant region can be represented according to the EU numbering system based on the amino acid position of Kabat (refer to Sequences of proteins of immunological interest, NIH Publication No. 91-3242).

[0270] The preferred isotype of the anti-allergen-1 bispecific antibody of the present invention is IgG 1 .

[0271] The isotype of the anti-allergen-1 bispecific antibody of the present invention is IgG 1 In the case of, as one embodiment, for example, an antibody having a heavy chain constant region comprising the amino acid sequence of SEQ ID NO. 23 or 99 (the arginine at position 97 (corresponding to position 214 in the heavy chain constant region based on the EU numbering system) in the amino acid sequence of SEQ ID NO. 23 or 99 can be substituted with lysine) and a light chain constant region comprising the amino acid sequence of SEQ ID NO. 24. The amino acid sequences are respectively as follows Figure 8 shown.

[0272] The "antibody fragment" of the anti-allergen-1 bispecific antibody of the present invention is a part of the bispecific antibody, and is an antibody portion that specifically binds to allergen-1 and has at least one optional antigen binding site. One form of the antibody fragment is an antibody portion that contains VH and VL that constitute any one of the S1-A binding site, S1-B binding site, S2-C binding site, and S2-D binding site. For example, the antibody portions of VH and VL listed in the items of "S1-A binding site and S1-B binding site" and "S2-C binding site and S2-D binding site" can be cited. As antibody portions containing these VH and VL, Fab, Fab', Fv and F(ab') can be cited. 2In addition, there can be mentioned a heavy chain / light chain complex comprising these VH and VL, and a complex formed by linking an scFv comprising VH and VL constituting another antigen binding site to the C-terminus of either the heavy chain or the light chain of the heavy chain / light chain complex. In addition, the scFv itself is included in the antibody fragment.

[0273] As one embodiment of the anti-allergen-1 bispecific antibody of the present invention being a Morrison-type antibody, for example, a bispecific antibody comprising two different antigen-binding sites, wherein the antigen-binding sites are selected from the group consisting of an S1-A binding site, an S1-B binding site, an S2-C binding site, and an S2-D binding site that specifically bind to two different epitopes in the extracellular domain of allergen-1 and do not compete with each other for allergen-1, wherein:

[0274] (I) the S1-A binding site is any one of the following antigen binding sites (i) to (iv),

[0275] (i) an antigen binding site comprising:

[0276] VH, which has

[0277] (a) VH-CDR1 comprising the amino acid sequence of SEQ ID NO.25;

[0278] (b) VH-CDR2 comprising the amino acid sequence of SEQ ID NO.26; and

[0279] (c) a VH-CDR3 comprising the amino acid sequence of SEQ ID NO. 27, and

[0280] VL, which has

[0281] (d) a VL-CDR1 comprising the amino acid sequence of SEQ ID NO.49;

[0282] (e) a VL-CDR2 comprising the amino acid sequence of SEQ ID NO.50; and

[0283] (f) a VL-CDR3 comprising the amino acid sequence of SEQ ID NO.51,

[0284] (ii) an antigen binding site comprising:

[0285] VH, which has

[0286] (a) VH-CDR1 comprising the amino acid sequence of SEQ ID NO.28;

[0287] (b) VH-CDR2 comprising the amino acid sequence of SEQ ID NO.29; and

[0288] (c) a VH-CDR3 comprising the amino acid sequence of SEQ ID NO. 30, and

[0289] VL, which has

[0290] (d) a VL-CDR1 comprising the amino acid sequence of SEQ ID NO.52;

[0291] (e) a VL-CDR2 comprising the amino acid sequence of SEQ ID NO.53; and

[0292] (f) a VL-CDR3 comprising the amino acid sequence of SEQ ID NO.54,

[0293] (iii) an antigen binding site comprising:

[0294] VH, which has

[0295] (a) VH-CDR1 comprising the amino acid sequence of SEQ ID NO.31;

[0296] (b) VH-CDR2 comprising the amino acid sequence of SEQ ID NO.32; and

[0297] (c) a VH-CDR3 comprising the amino acid sequence of SEQ ID NO. 33, and

[0298] VL, which has

[0299] (d) a VL-CDR1 comprising the amino acid sequence of SEQ ID NO.55;

[0300] (e) a VL-CDR2 comprising the amino acid sequence of SEQ ID NO.56; and

[0301] (f) a VL-CDR3 comprising the amino acid sequence of SEQ ID NO.57,

[0302] (iv) an antigen binding site comprising:

[0303] VH, which has

[0304] (a) VH-CDR1 comprising the amino acid sequence of SEQ ID NO.34;

[0305] (b) a VH-CDR2 comprising the amino acid sequence of SEQ ID NO. 35; and

[0306] (c) a VH-CDR3 comprising the amino acid sequence of SEQ ID NO. 36, and

[0307] VL, which has

[0308] (d) a VL-CDR1 comprising the amino acid sequence of SEQ ID NO.58;

[0309] (e) a VL-CDR2 comprising the amino acid sequence of SEQ ID NO.59; and

[0310] (f) a VL-CDR3 comprising the amino acid sequence of SEQ ID NO.60,

[0311] The S1-B binding site is the following (v) or (vi) antigen binding site,

[0312] (v) an antigen binding site comprising:

[0313] VH, which has

[0314] (a) VH-CDR1 comprising the amino acid sequence of SEQ ID NO.37;

[0315] (b) VH-CDR2 comprising the amino acid sequence of SEQ ID NO.38; and

[0316] (c) a VH-CDR3 comprising the amino acid sequence of SEQ ID NO. 39, and

[0317] VL, which has

[0318] (d) a VL-CDR1 comprising the amino acid sequence of SEQ ID NO.61;

[0319] (e) a VL-CDR2 comprising the amino acid sequence of SEQ ID NO.62; and

[0320] (f) a VL-CDR3 comprising the amino acid sequence of SEQ ID NO.63,

[0321] (vi) an antigen binding site comprising:

[0322] VH, which has

[0323] (a) VH-CDR1 comprising the amino acid sequence of SEQ ID NO.40,

[0324] (b) VH-CDR2 comprising the amino acid sequence of SEQ ID NO.41; and

[0325] (c) a VH-CDR3 comprising the amino acid sequence of SEQ ID NO. 42, and

[0326] VL, which has

[0327] (d) a VL-CDR1 comprising the amino acid sequence of SEQ ID NO.64;

[0328] (e) a VL-CDR2 comprising the amino acid sequence of SEQ ID NO.65; and

[0329] (f) VL-CDR3 comprising the amino acid sequence of SEQ ID NO.66

[0330] The S2-C binding site is an antigen binding site comprising the following VH and VL,

[0331] VH, which has

[0332] (a) VH-CDR1 comprising the amino acid sequence of SEQ ID NO.43;

[0333] (b) VH-CDR2 comprising the amino acid sequence of SEQ ID NO.44; and

[0334] (c) a VH-CDR3 comprising the amino acid sequence of SEQ ID NO.45,

[0335] VL, which has

[0336] (d) a VL-CDR1 comprising the amino acid sequence of SEQ ID NO.67;

[0337] (e) a VL-CDR2 comprising the amino acid sequence of SEQ ID NO.68; and

[0338] (f) a VL-CDR3 comprising the amino acid sequence of SEQ ID NO.69,

[0339] The S2-D binding site is an antigen binding site comprising the following VH and VL,

[0340] VH, which has

[0341] (a) VH-CDR1 comprising the amino acid sequence of SEQ ID NO.46;

[0342] (b) VH-CDR2 comprising the amino acid sequence of SEQ ID NO.47; and

[0343] (c) a VH-CDR3 comprising the amino acid sequence of SEQ ID NO.48,

[0344] VL, which has

[0345] (d) VL-CDR1 comprising the amino acid sequence of SEQ ID NO.70;

[0346] (e) a VL-CDR2 comprising the amino acid sequence of SEQ ID NO. 71; and

[0347] (f) a VL-CDR3 comprising the amino acid sequence of SEQ ID NO.72,

[0348] (II) one of the two different antigen-binding sites is an antigen-binding site in the heavy chain / light chain complex constituting the bispecific antibody, and the other is an antigen-binding site in the form of scFv, wherein:

[0349] (i) the antigen binding site in the heavy chain / light chain complex constituting the bispecific antibody is the S1-A binding site, and the antigen binding site in the form of the scFv is any one of the antigen binding sites selected from the group consisting of the S1-B binding site, the S2-C binding site, and the S2-D binding site;

[0350] (ii) the antigen binding site in the heavy chain / light chain complex is the S1-B binding site, and the antigen binding site in the form of the scFv is any one of the antigen binding sites selected from the group consisting of the S1-A binding site, the S2-C binding site, and the S2-D binding site;

[0351] (iii) the antigen binding site in the heavy chain / light chain complex is the S2-C binding site, and the antigen binding site in the form of the scFv is any one of the antigen binding sites selected from the group consisting of the S1-A binding site, the S1-B binding site and the S2-D binding site; or

[0352] (iv) the antigen binding site in the heavy chain / light chain complex is the S2-D binding site, and the antigen binding site in the form of the scFv is any one of the antigen binding sites selected from the group consisting of the S1-A binding site, the S1-B binding site and the S2-C binding site,

[0353] (III) the N-terminus of VH or VL constituting the scFv is connected to the C-terminus of either the heavy chain or the light chain via a peptide linker, and

[0354] (IV) satisfies (i) or (ii),

[0355] (i) having a heavy chain and a light chain, wherein the heavy chain and the light chain have the structures described in items (I) to (III),

[0356] (ii) comprising two identical heavy chain / light chain complexes consisting of a heavy chain and a light chain having the structures described in items (I) to (III) above.

[0357] Here, as a combination of two different antigen binding sites constituting the anti-allergen-1 bispecific antibody of the present invention, preferably, there can be mentioned a combination of any two binding sites selected from (i) to (iv),

[0358] (i) an S1-A binding site, which is composed of VH and VL, wherein VH and VL comprise any one of the following groups of amino acid sequences:

[0359] (a) SEQ ID NOs. 1 and 12;

[0360] (b) SEQ ID NOs. 2 and 13;

[0361] (c) SEQ ID NO. 3 and SEQ ID NO. 14 or 106;

[0362] (d) SEQ ID NO. 4 and SEQ ID NO. 15 or 107;

[0363] (e) SEQ ID NOs. 5 and 16; and

[0364] (f) SEQ ID NO. 6 and SEQ ID NO. 17 or 109,

[0365] (ii) an S1-B binding site, which is composed of VH and VL, wherein VH and VL comprise the following set of amino acid sequences:

[0366] (a) SEQ ID NOs. 7 and 18; or

[0367] (b) SEQ ID NOs. 8 and 19,

[0368] (iii) an S2-C binding site, which is composed of VH and VL, wherein VH and VL comprise a set of amino acid sequences of SEQ ID NO. 9 and SEQ ID NO. 20 or 112,

[0369] (iv) an S2-D binding site, which is composed of VH and VL, wherein VH and VL comprise the following set of amino acid sequences:

[0370] (a) SEQ ID NO. 10 and SEQ ID NO. 21 or 113; or

[0371] (b) SEQ ID NOs. 11 and 22,

[0372] More preferably, a combination of any two of the binding sites selected from (i) to (iii) is mentioned.

[0373] (i) an S1-A binding site, which is composed of VH and VL, wherein VH and VL comprise any one of the following groups of amino acid sequences:

[0374] (a) SEQ ID NO. 3 and SEQ ID NO. 14 or 106;

[0375] (b) SEQ ID NO. 4 and SEQ ID NO. 15 or 107;

[0376] (c) SEQ ID NOs. 5 and 16; and

[0377] (d) SEQ ID NO. 6 and SEQ ID NO. 17 or 109,

[0378] (ii) an S2-C binding site, which is composed of VH and VL, wherein VH and VL comprise a set of amino acid sequences of SEQ ID NO. 9 and SEQ ID NO. 20 or 112,

[0379] (iii) an S2-D binding site, which is composed of VH and VL, wherein VH and VL comprise the following set of amino acid sequences:

[0380] (a) SEQ ID NO. 10 and SEQ ID NO. 21 or 113; or

[0381] (b) A set of amino acid sequences of SEQ ID NOs. 11 and 22.

[0382] In addition, as a combination of two different antigen-binding sites constituting the anti-allergen-1 bispecific antibody of the present invention, preferably, the following combinations (i) to (iii) are mentioned:

[0383] (i) a combination of the S1-A binding site and the S2-C binding site,

[0384] (a) an S1-A binding site, which is composed of VH and VL, wherein VH and VL comprise a set of amino acid sequences of SEQ ID NO. 3 and SEQ ID NO. 14 or 106; and

[0385] (b) an S2-C binding site, which is composed of VH and VL, wherein VH and VL comprise a set of amino acid sequences of SEQ ID NO. 9 and SEQ ID NO. 20 or 112,

[0386] (ii) a combination of the S1-A binding site and the S2-D binding site,

[0387] (a) an S1-A binding site, which is composed of VH and VL, wherein VH and VL comprise a set of amino acid sequences of SEQ ID NO. 6 and SEQ ID NO. 17 or 109; and

[0388] (b) an S2-D binding site, which is composed of VH and VL, wherein VH and VL comprise a set of amino acid sequences of SEQ ID NO. 10 and SEQ ID NO. 21 or 113,

[0389] (iii) a combination of the S1-A binding site and the S2-D binding site,

[0390] (a) an S1-A binding site, which is composed of VH and VL, wherein VH and VL comprise any one of the following groups of amino acid sequences:

[0391] (a1) SEQ ID NO. 3 and SEQ ID NO. 14 or 106;

[0392] (a2) SEQ ID NO. 4 and SEQ ID NO. 15 or 107; and

[0393] (a3) SEQ ID NOs. 5 and 16,

[0394] (b) S2-D binding site, which is composed of VH and VL, wherein VH and VL comprise the following set of amino acid sequences:

[0395] (b1) SEQ ID NO. 10 and SEQ ID NO. 21 or 113; or

[0396] (b2) SEQ ID NOs. 11 and 22,

[0397] More preferably, the following combinations (i) to (ix) are mentioned:

[0398] (i) a combination of the S1-A binding site and the S2-C binding site,

[0399] (a) an S1-A binding site, which is composed of VH and VL, wherein VH and VL comprise a set of amino acid sequences of SEQ ID NOs. 3 and 14; and

[0400] (b) an S2-C binding site, which is composed of VH and VL, wherein VH and VL comprise a set of amino acid sequences of SEQ ID NOs. 9 and 112,

[0401] (ii) a combination of the S1-A binding site and the S2-C binding site,

[0402] (a) an S1-A binding site, which is composed of VH and VL, wherein VH and VL comprise a set of amino acid sequences of SEQ ID NOs. 3 and 106; and

[0403] (b) an S2-C binding site, which is composed of VH and VL, wherein VH and VL comprise a set of amino acid sequences of SEQ ID NOs. 9 and 20,

[0404] (iii) a combination of the S1-A binding site and the S2-D binding site,

[0405] (a) an S1-A binding site, which is composed of VH and VL, wherein VH and VL comprise a set of amino acid sequences of SEQ ID NOs. 6 and 17; and

[0406] (b) an S2-D binding site, which is composed of VH and VL, wherein VH and VL comprise a set of amino acid sequences of SEQ ID NOs. 10 and 113,

[0407] (iv) a combination of the S1-A binding site and the S2-D binding site,

[0408] (a) an S1-A binding site, which is composed of VH and VL, wherein VH and VL comprise a set of amino acid sequences of SEQ ID NOs. 6 and 109; and

[0409] (b) an S2-D binding site, which is composed of VH and VL, wherein VH and VL comprise a set of amino acid sequences of SEQ ID NOs. 10 and 21,

[0410] (v) a combination of an S1-A binding site and an S2-D binding site,

[0411] (a) an S1-A binding site, which is composed of VH and VL, wherein VH and VL comprise a set of amino acid sequences of SEQ ID NOs. 3 and 14; and

[0412] (b) an S2-D binding site, which is composed of VH and VL, wherein VH and VL comprise a set of amino acid sequences of SEQ ID NOs. 10 and 113,

[0413] (vi) a combination of an S1-A binding site and an S2-D binding site,

[0414] (a) an S1-A binding site, which is composed of VH and VL, wherein VH and VL comprise a set of amino acid sequences of SEQ ID NOs. 4 and 15; and

[0415] (b) an S2-D binding site, which is composed of VH and VL, wherein VH and VL comprise a set of amino acid sequences of SEQ ID NOs. 10 and 113,

[0416] (vii) a combination of an S1-A binding site and an S2-D binding site,

[0417] (a) an S1-A binding site, which is composed of VH and VL, wherein VH and VL comprise any one of the amino acid sequences selected from SEQ ID NO. 5 and 16; and

[0418] (b) an S2-D binding site, which is composed of VH and VL, wherein VH and VL comprise a set of amino acid sequences of SEQ ID NOs. 10 and 113,

[0419] (viii) a combination of an S1-A binding site and an S2-D binding site,

[0420] (a) an S1-A binding site, which is composed of VH and VL, wherein VH and VL comprise a set of amino acid sequences of SEQ ID NOs. 3 and 106; and

[0421] (b) an S2-D binding site, which is composed of VH and VL, wherein VH and VL comprise a combination of the amino acid sequences of SEQ ID NOs. 10 and 21,

[0422] (ix) a combination of the S1-A binding site and the S2-D binding site,

[0423] (a) an S1-A binding site, which is composed of VH and VL, wherein VH and VL comprise a set of amino acid sequences of SEQ ID NOs. 4 and 107; and

[0424] (b) The S2-D binding site is composed of VH and VL, wherein VH and VL comprise a set of amino acid sequences of SEQ ID NOs. 11 and 22.

[0425] In addition, here, the VH and VL constituting the scFv are preferably connected in the order of VL and VH from the N-terminal side thereof by a peptide linker comprising the amino acid sequence of SEQ ID NO.74. In addition, as a peptide linker connecting the scFv and the C-terminus of the heavy chain or light chain, it is preferably a peptide linker comprising the amino acid sequence of SEQ ID NO.73.

[0426] As the anti-allergen-1 bispecific antibody of the present invention having a format in which scFv is linked to the C-terminus of the heavy chain, for example, preferably, there can be mentioned antibodies satisfying (i) or (ii),

[0427] (i) having a heavy chain and a light chain comprising an amino acid sequence selected from any one of the following sequence groups:

[0428] (a) SEQ ID NOs. 75 and 76;

[0429] (b) SEQ ID NOs. 77 and 78;

[0430] (c) SEQ ID NOs. 79 and 78;

[0431] (d) SEQ ID NOs. 80 and 78;

[0432] (e) SEQ ID NOs. 81 and 82;

[0433] (f) SEQ ID NOs. 83 and 82;

[0434] (g) SEQ ID NOs. 84 and 85;

[0435] (h) SEQ ID NOs. 86 and 87;

[0436] (i) SEQ ID NOs. 98 and 78;

[0437] (j) SEQ ID NOs. 100 and 78;

[0438] (k) SEQ ID NOs. 101 and 78;

[0439] (l) SEQ ID NOs. 102 and 78; and

[0440] (m) SEQ ID NOs. 103 and 85,

[0441] (ii) comprising two identical heavy chain / light chain complexes consisting of the heavy chain and light chain described in item (i),

[0442] On the other hand, as the anti-allergen-1 bispecific antibody of the present invention having a form in which scFv is linked to the C-terminus of the light chain, for example, preferably, an antibody that satisfies (i) or (ii) is mentioned.

[0443] (i) having a heavy chain and a light chain comprising an amino acid sequence selected from any one of the following sequence groups:

[0444] (a) SEQ ID NOs. 88 and 89;

[0445] (b) SEQ ID NOs. 90 and 91;

[0446] (c) SEQ ID NOs. 90 and 92;

[0447] (d) SEQ ID NOs. 93 and 94;

[0448] (e) SEQ ID NOs. 93 and 95; and

[0449] (f) SEQ ID NOs. 96 and 97,

[0450] (ii) comprising two identical heavy chain / light chain complexes consisting of the heavy chain and light chain described in item (i). Here, the arginine at position 214 based on the EU numbering system in the heavy chain constant region of these anti-allergen-1 bispecific antibodies can be substituted with lysine, and / or the alanine at position 299 in SEQ ID NOs. 75, 81, 83, 86, 88, 93 and 96 and at position 301 in SEQ ID NOs. 80 and 90 (corresponding to position 297 based on the EU numbering system in the heavy chain constant region) can be substituted with asparagine independently.

[0451] The anti-allergen-1 bispecific antibody of the present invention is more preferably an antibody satisfying (i) or (ii).

[0452] (i) having a heavy chain and a light chain comprising an amino acid sequence selected from any one of the following sequence groups:

[0453] (a) SEQ ID NOs. 77 and 78;

[0454] (b) SEQ ID NOs. 79 and 78;

[0455] (c) SEQ ID NOs. 83 and 82;

[0456] (d) SEQ ID NOs. 84 and 85;

[0457] (e) SEQ ID NOs. 98 and 78;

[0458] (f) SEQ ID NOs. 100 and 78;

[0459] (g) SEQ ID NOs. 101 and 78;

[0460] (h) SEQ ID NOs. 102 and 78; and

[0461] (j) SEQ ID NOs. 103 and 85,

[0462] (ii) comprising two identical heavy chain / light chain complexes consisting of the heavy chain and light chain described in item (i).

[0463] As a preferred feature of the anti-allergen-1 bispecific antibody of the present invention, there can be mentioned the feature that the production of cytokines is sufficiently reduced during administration or within 24 hours after administration. Here, "sufficiently reducing the production of cytokines" means, for example, that during intravenous administration of the anti-allergen-1 bispecific antibody of the present invention by drip infusion or within 24 hours after administration, the concentration of at least one cytokine selected from IL-2, IL-4, IL-6, IL-10, IFN-γ and TNF-α in the blood or tissue does not increase or increases only to the extent that it can be suppressed by steroid administration.

[0464] One aspect of the characteristics of the anti-allergen-1 bispecific antibody of the present invention is the characteristic of inhibiting the binding between TLR9 ligand (e.g., oligodeoxynucleotide (ODN), in one embodiment, CpG ODN, preferably ODN M362, ODN 1668, ODN 1826, etc.) and allergen-1.

[0465] [Method for producing and purifying anti-allergen-1 bispecific antibodies]

[0466] The anti-allergen-1 bispecific antibody and its antibody fragment of the present invention can be produced by secretion from host cells based on known methods. For example, expression vectors to which the following nucleotides (1) and (2) are added are introduced into mammalian cells and transformed, and the heavy chain and light chain are co-expressed and secreted to produce them. The polynucleotides are (1) a polynucleotide encoding a heavy chain with scFv linked to its C-terminus and (2) a polynucleotide encoding a light chain.

[0467] Here, as host cells for expressing the anti-allergen-1 bispecific antibody of the present invention, there can be mentioned: preferably insect cells such as SF-9 cells and SF-21 cells, more preferably (i) mouse cells including CHO cells, BHK cells, SP2 / 0 cells and NS-0 myeloma cells, (ii) primate cells such as COS cells and Vero cells, and (iii) mammalian cells such as MDCK cells, BRL 3A cells, hybridomas, tumor cells, immortalized primary cells, W138 cells, HepG2 cells, Hela cells, HEK293 cells, HT1080 cells or embryonic retinal cells such as PER.C6 cells. It should be noted that mammalian cells and expression vectors therefor are sometimes used in the selection of expression systems so that the antibody is appropriately glycosylated. PER.C6 cells are preferably human cells, which are conducive to obtaining antibodies that match the glycosylation pattern of humans.

[0468] For the production of proteins in host cells transformed by gene introduction of expression vectors, for example, reference can be made to Current Protocols in Protein Science (1995), Coligan JE, Dunn BM, Ploegh HL, Speicher DW, Wingfield PT, ISBN 0-471-11184-8, Bendig, 1988, and in addition, general principles, steps and practical methods for maximizing the productivity of host cell culture can be referred to Mammalian Cell Biotechnology: a Practical Approach (M. Butler, ed., IRL Press, 1991). The expression of antibodies in host cells is described in, for example, EP0120694, EP0314161, EP0481790, EP0523949, US4816567 and WO2000 / 63403.

[0469] Here, the culture conditions of the host cell can be optimized by known methods, and the production of the protein can be optimized. For example, in culture dishes, roller bottles or reaction tanks, batch culture, fed-batch culture, continuous culture, and hollow fiber culture can be implemented. In order to produce recombinant proteins on a large scale and continuously by cell culture, it is preferred that cells are propagated in a suspension. In addition, it is preferred to culture cells without animal or human serum or its serum components.

[0470] For antibodies expressed in host cells and recovered from their cells or cell culture media by known methods, known methods can be used for purification. Purification methods include: immunoprecipitation, centrifugation, filtration, size exclusion chromatography, affinity chromatography, cation and / or anion exchange chromatography, hydrophobic interaction chromatography. In addition, protein A or protein G affinity chromatography is sometimes preferably used (for example, with reference to US4801687 and US5151504).

[0471] [Anti-allergen-1 antibody]

[0472] The present invention includes: an antibody that specifically binds to the S1 domain of allergen-1 (hereinafter referred to as "anti-S1 domain antibody") and an antibody that specifically binds to the S2 domain of allergen-1 (hereinafter referred to as "anti-S2 domain antibody") (sometimes collectively referred to as "anti-allergen-1 antibody") and antibody fragments thereof, which are used to construct the anti-allergen-1 bispecific antibody of the present invention.

[0473] As for the anti-S1 domain antibody of the present invention, any antibody that can specifically bind to the S1 domain of allergen-1 and can be used to construct the anti-allergen-1 bispecific antibody of the present invention can be selected, and can be used with a specificity ratio of at least 1×10 - 5 M, preferably 1×10 -7 M, more preferably 1×10 -9 The antibody is an antibody that directly binds to the S1 domain of allergen-1 and has a higher affinity (Kd value) than M, and does not substantially bind to at least the S2 domain of allergen-1 and other proteins. It should be noted that the anti-S1 domain antibody includes an antibody that specifically binds to the S1-A epitope (the epitope that the S1-A binding site specifically binds to) or the S1-B epitope (the epitope that the S1-B binding site specifically binds to).

[0474] On the other hand, as for the anti-S2 domain antibody of the present invention, any one of them can be used to construct the anti-allergen-1 bispecific antibody of the present invention as long as it can specifically bind to the S2 domain of allergen-1. Similarly, it can be used with a specificity ratio of at least 1×10 -5 M, preferably 1×10 -7 M, more preferably 1×10 -9 M is an antibody that directly binds to the S2 domain of allergen-1 and does not substantially bind to at least the S1 domain of allergen-1 and other proteins. It should be noted that anti-S2 domain antibodies include antibodies that specifically bind to the S2-C epitope (an epitope that specifically binds to the S2-C binding site) or the S2-D epitope (an epitope that specifically binds to the S2-D binding site). Here, the "antibody" in "anti-allergen-1 antibody", "anti-S1 domain antibody" and "anti-S2 domain antibody" refers to a full-length antibody, that is, a full-length antibody comprising two heavy chains and two light chains, and the "antibody fragment" therein refers to a part of the full-length antibody, which is an antibody part that at least comprises an antigen binding site, for example, Fab, Fab', Fv and F(ab') can be cited. 2 wait.

[0475] As for the anti-allergen-1 antibody of the present invention, when constructing the anti-allergen-1 bispecific antibody of the present invention, it is preferably a chimeric antibody, a humanized antibody or a human antibody, and also includes non-human antibodies (e.g., mouse antibodies, rat antibodies and rabbit antibodies) used in the preparation of chimeric antibodies or humanized antibodies.

[0476] As one embodiment of the anti-S1 domain antibody of the present invention, for example, antibodies (E1) to (E6) can be mentioned.

[0477] (E1) an antibody comprising:

[0478] VH, which has

[0479] (a) VH-CDR1 comprising the amino acid sequence of SEQ ID NO.25;

[0480] (b) VH-CDR2 comprising the amino acid sequence of SEQ ID NO.26; and

[0481] (c) a VH-CDR3 comprising the amino acid sequence of SEQ ID NO. 27, and

[0482] VL, which has

[0483] (d) a VL-CDR1 comprising the amino acid sequence of SEQ ID NO.49;

[0484] (e) a VL-CDR2 comprising the amino acid sequence of SEQ ID NO.50; and

[0485] (f) a VL-CDR3 comprising the amino acid sequence of SEQ ID NO.51,

[0486] (E2) an antibody comprising:

[0487] VH, which has

[0488] (a) VH-CDR1 comprising the amino acid sequence of SEQ ID NO.28;

[0489] (b) VH-CDR2 comprising the amino acid sequence of SEQ ID NO.29; and

[0490] (c) a VH-CDR3 comprising the amino acid sequence of SEQ ID NO. 30, and

[0491] VL, which has

[0492] (d) a VL-CDR1 comprising the amino acid sequence of SEQ ID NO.52;

[0493] (e) a VL-CDR2 comprising the amino acid sequence of SEQ ID NO.53; and

[0494] (f) a VL-CDR3 comprising the amino acid sequence of SEQ ID NO.54,

[0495] (E3) an antibody comprising:

[0496] VH, which has

[0497] (a) VH-CDR1 comprising the amino acid sequence of SEQ ID NO.31;

[0498] (b) VH-CDR2 comprising the amino acid sequence of SEQ ID NO.32; and

[0499] (c) a VH-CDR3 comprising the amino acid sequence of SEQ ID NO. 33, and

[0500] VL, which has

[0501] (d) a VL-CDR1 comprising the amino acid sequence of SEQ ID NO.55;

[0502] (e) a VL-CDR2 comprising the amino acid sequence of SEQ ID NO.56; and

[0503] (f) a VL-CDR3 comprising the amino acid sequence of SEQ ID NO.57,

[0504] (E4) an antibody comprising:

[0505] VH, which has

[0506] (a) VH-CDR1 comprising the amino acid sequence of SEQ ID NO.34;

[0507] (b) a VH-CDR2 comprising the amino acid sequence of SEQ ID NO. 35; and

[0508] (c) a VH-CDR3 comprising the amino acid sequence of SEQ ID NO. 36, and

[0509] VL, which has

[0510] (d) a VL-CDR1 comprising the amino acid sequence of SEQ ID NO.58;

[0511] (e) a VL-CDR2 comprising the amino acid sequence of SEQ ID NO.59; and

[0512] (f) a VL-CDR3 comprising the amino acid sequence of SEQ ID NO.60,

[0513] (E5) an antibody comprising:

[0514] VH, which has

[0515] (a) VH-CDR1 comprising the amino acid sequence of SEQ ID NO.37;

[0516] (b) VH-CDR2 comprising the amino acid sequence of SEQ ID NO.38; and

[0517] (c) a VH-CDR3 comprising the amino acid sequence of SEQ ID NO. 39, and

[0518] VL, which has

[0519] (d) a VL-CDR1 comprising the amino acid sequence of SEQ ID NO.61;

[0520] (e) a VL-CDR2 comprising the amino acid sequence of SEQ ID NO.62; and

[0521] (f) a VL-CDR3 comprising the amino acid sequence of SEQ ID NO.63,

[0522] (E6) an antibody comprising:

[0523] VH, which has

[0524] (a) VH-CDR1 comprising the amino acid sequence of SEQ ID NO.40,

[0525] (b) VH-CDR2 comprising the amino acid sequence of SEQ ID NO.41; and

[0526] (c) a VH-CDR3 comprising the amino acid sequence of SEQ ID NO. 42, and

[0527] VL, which has

[0528] (d) a VL-CDR1 comprising the amino acid sequence of SEQ ID NO.64;

[0529] (e) a VL-CDR2 comprising the amino acid sequence of SEQ ID NO.65; and

[0530] (f) VL-CDR3 comprising the amino acid sequence of SEQ ID NO.66.

[0531] On the other hand, as one embodiment of the anti-S2 domain antibody, for example, antibodies (F1) and (F2) can be mentioned.

[0532] (F1) an antibody comprising:

[0533] VH, which has

[0534] (a) VH-CDR1 comprising the amino acid sequence of SEQ ID NO.43;

[0535] (b) VH-CDR2 comprising the amino acid sequence of SEQ ID NO.44; and

[0536] (c) a VH-CDR3 comprising the amino acid sequence of SEQ ID NO. 45, and

[0537] VL, which has

[0538] (d) a VL-CDR1 comprising the amino acid sequence of SEQ ID NO.67;

[0539] (e) a VL-CDR2 comprising the amino acid sequence of SEQ ID NO.68; and

[0540] (f) a VL-CDR3 comprising the amino acid sequence of SEQ ID NO.69,

[0541] (F2) an antibody comprising:

[0542] VH, which has

[0543] (a) VH-CDR1 comprising the amino acid sequence of SEQ ID NO.46,

[0544] (b) VH-CDR2 comprising the amino acid sequence of SEQ ID NO.47; and

[0545] (c) a VH-CDR3 comprising the amino acid sequence of SEQ ID NO. 48, and

[0546] VL, which has

[0547] (d) VL-CDR1 comprising the amino acid sequence of SEQ ID NO.70;

[0548] (e) a VL-CDR2 comprising the amino acid sequence of SEQ ID NO. 71; and

[0549] (f) VL-CDR3 comprising the amino acid sequence of SEQ ID NO.72.

[0550] In addition, the anti-allergen-1 antibody of the present invention also includes antibodies in which 1 to 5 amino acid residues in each CDR are substituted with other amino acids (preferably conservative amino acids) and have substantially the same binding activity to the same epitope as the original antibody without the amino acid substitution. For example, in the case of the CDR1, one amino acid residue is substituted with a conservative amino acid, and in the case of CDR2 or CDR3, one or two amino acid residues are substituted with conservative amino acids.

[0551] In addition, the anti-allergen-1 antibodies of the present invention also include: antibodies having CDRs containing the specific amino acid sequence in their VH and VL, and the amino acid sequence of their skeleton region is encoded by a specific germline gene or the gene that has undergone one or more somatic mutations and / or back mutations, for example, the germline VH gene IGHV3-66 and the VL gene IGKV1-39 or the VH and VL respectively encoded by the genes that have undergone one or more somatic mutations and / or back mutations.

[0552] In addition, as another embodiment of the anti-S1 domain antibody of the present invention, for example, an antibody having VH and VL, wherein VH and VL comprise any one of the amino acid sequences selected from the following sequence groups:

[0553] (G1) SEQ ID NOs. 1 and 104;

[0554] (G2) SEQ ID NOs. 2 and 105;

[0555] (G3) SEQ ID NOs. 3 and 106;

[0556] (G4) SEQ ID NOs. 4 and 107;

[0557] (G5) SEQ ID NOs. 5 and 108;

[0558] (G6) SEQ ID NOs. 6 and 109;

[0559] (G7) SEQ ID NOs. 7 and 110; and

[0560] (G8) SEQ ID NO. 8 and 111,

[0561] On the other hand, as another embodiment of the anti-S2 domain antibody, for example, an antibody having VH and VL comprising any one of the amino acid sequences selected from the following sequence groups can be mentioned:

[0562] (H1) SEQ ID NOs. 9 and 112;

[0563] (H2) SEQ ID NOs. 10 and 113; and

[0564] (H3) SEQ ID NOs. 11 and 114.

[0565] In addition, the anti-allergen-1 antibody in such another embodiment also includes, for example: an antibody having VH and VL, wherein the VH and VL comprise amino acid sequences that are each independently at least 80%, preferably at least 90%, more preferably at least 95%, further preferably at least 98%, and further more preferably at least 99% identical to any one of the amino acid sequences selected from (G1) to (G8) (excluding each of the three CDRs) or any one of the amino acid sequences selected from (H1) to (H3) (excluding each of the three CDRs), and the difference from each of the amino acid sequences of the original VH and VL has substantially no effect on the binding activity to the same epitope.

[0566] In another embodiment of the anti-S1 domain antibody of the present invention, for example, further comprises:

[0567] An antibody that cross-competes with an antibody or its antigen-binding site having VH and VL for binding to an epitope on the S1 domain, wherein the VH and VL comprise any one of the amino acid sequences selected from (G1) to (G8); and

[0568] An antibody, whose binding to the epitope on the S1 domain is cross-competed by an antibody or its antigen-binding site having VH and VL, wherein the VH and VL comprise any group of amino acid sequences selected from (G1) to (G8).

[0569] In another embodiment of the anti-S2 domain antibody of the present invention, for example, further comprises:

[0570] An antibody that cross-competes with an antibody or its antigen-binding site having VH and VL for binding to an epitope on the S2 domain, wherein the VH and VL comprise an amino acid sequence selected from any one of the groups (H1) to (H3), and

[0571] An antibody, whose binding to the epitope on the S2 domain is cross-competed by an antibody or its antigen-binding site having VH and VL, wherein the VH and VL comprise an amino acid sequence selected from any one of the groups (H1) to (H3).

[0572] A preferred embodiment of the anti-allergen-1 antibody of the present invention is a monoclonal antibody. Monoclonal antibodies can be obtained by various known methods other than the above-mentioned hybridoma method.

[0573] The preferred isotype of the anti-allergen-1 antibody of the present invention is IgG 1 .

[0574] The isotype of the anti-allergen-1 antibody of the present invention is IgG 1In the case of, as one embodiment, for example, an antibody having a heavy chain constant region comprising the amino acid sequence of SEQ ID NO. 23 or 99 (the arginine at position 97 (corresponding to position 214 in the heavy chain constant region based on the EU numbering system) in the amino acid sequence of SEQ ID NO. 23 or 99 can be replaced with lysine) and a light chain constant region comprising the amino acid sequence of SEQ ID NO. 24.

[0575] [Polynucleotide encoding anti-allergen-1 bispecific antibody]

[0576] The present invention also includes: polynucleotides encoding each part of the bispecific antibody used in the production of the anti-allergen-1 bispecific antibody of the present invention, that is, VH and VL each constituting any two of the S1-A binding site, S1-B binding site, S2-C binding site and S2-D binding site, and the heavy chain constant region and the light chain constant region.

[0577] Examples of polynucleotides encoding VH and VL constituting the S1-A binding site include polynucleotides encoding VH and VL comprising an amino acid sequence selected from any one of the following sequence groups:

[0578] (a) SEQ ID NO. 1 and SEQ ID NO. 12 or 104;

[0579] (b) SEQ ID NO. 2 and SEQ ID NO. 13 or 105;

[0580] (c) SEQ ID NO. 3 and SEQ ID NO. 14 or 106;

[0581] (d) SEQ ID NO. 4 and SEQ ID NO. 15 or 107;

[0582] (e) SEQ ID NO. 5 and SEQ ID NO. 16 or 108; and

[0583] (f) SEQ ID NO. 6 and SEQ ID NO. 17 or 109,

[0584] Examples of polynucleotides encoding VH and VL constituting the S1-B binding site include polynucleotides encoding VH and VL comprising the following amino acid sequences:

[0585] (a) SEQ ID NO. 7 and SEQ ID NO. 18 or 110; or

[0586] (b) SEQ ID NO. 8 and SEQ ID NO. 19 or 111.

[0587] On the other hand, as polynucleotides encoding VH and VL constituting the S2-C binding site, for example, polynucleotides encoding VH and VL each comprising a set of amino acid sequences of SEQ ID NO. 9 and SEQ ID NO. 20 or 112 can be cited,

[0588] Examples of polynucleotides encoding each of VH and VL constituting the S2-D binding site include polynucleotides encoding each of VH and VL comprising the following set of amino acid sequences:

[0589] (a) SEQ ID NO. 10 and SEQ ID NO. 21 or 113; or

[0590] (b) SEQ ID NO.11 and SEQ ID NO.22 or 114.

[0591] Examples of the polynucleotides encoding each of the heavy chain constant region and the light chain constant region include polynucleotides encoding the amino acid sequences of SEQ ID NO. 23 or 99 and SEQ ID NO. 24, respectively.

[0592] When the C-terminus of the heavy chain or light chain and the scFv, and the VH and VL constituting the scFv are respectively connected by a peptide linker, the polynucleotides encoding each of these peptide linkers are respectively added between the polynucleotides encoding the heavy chain or light chain and the scFv, or the VH and VL constituting the scFv. As the polynucleotide encoding the former peptide linker, for example, a polynucleotide encoding the amino acid sequence of SEQ ID NO.73 can be mentioned, and as the polynucleotide encoding the latter peptide linker, for example, a polynucleotide encoding the amino acid sequence of SEQ ID NO.74 can be mentioned.

[0593] As a polynucleotide encoding the anti-allergen-1 bispecific antibody of the present invention having a format in which scFv is linked to the C-terminus of the heavy chain, for example, preferably there can be mentioned a polynucleotide encoding each of the heavy chain and the light chain, wherein the heavy chain and the light chain comprise any one of the amino acid sequences selected from the following sequence groups:

[0594] (a) SEQ ID NOs. 75 and 76;

[0595] (b) SEQ ID NOs. 77 and 78;

[0596] (c) SEQ ID NOs. 79 and 78;

[0597] (d) SEQ ID NOs. 80 and 78;

[0598] (e) SEQ ID NOs. 81 and 82;

[0599] (f) SEQ ID NOs. 83 and 82;

[0600] (g) SEQ ID NOs. 84 and 85;

[0601] (h) SEQ ID NOs. 86 and 87;

[0602] (i) SEQ ID NOs. 98 and 78;

[0603] (j) SEQ ID NOs. 100 and 78;

[0604] (k) SEQ ID NOs. 101 and 78;

[0605] (l) SEQ ID NOs. 102 and 78; and

[0606] (m) SEQ ID NOs. 103 and 85,

[0607] On the other hand, as a polynucleotide encoding the anti-allergen-1 bispecific antibody of the present invention having a form in which an scFv is linked to the C-terminus of the light chain, for example, preferably, there can be mentioned a polynucleotide encoding each of the heavy chain and the light chain, wherein the heavy chain and the light chain each comprise an amino acid sequence selected from any one of the following sequence groups:

[0608] (a) SEQ ID NOs. 88 and 89;

[0609] (b) SEQ ID NOs. 90 and 91;

[0610] (c) SEQ ID NOs. 90 and 92;

[0611] (d) SEQ ID NOs. 93 and 94;

[0612] (e) SEQ ID NOs. 93 and 95; and

[0613] (f) SEQ ID NOs. 96 and 97.

[0614] It should be noted that, as described above, the arginine at position 214 based on the EU numbering system in the heavy chain constant region of the anti-allergen-1 bispecific antibody of the present invention can be replaced with lysine, and / or the alanine at position 299 in SEQ ID NOs. 75, 81, 83, 86, 88, 93 and 96 and at position 301 in SEQ ID NOs. 80 and 90 (corresponding to position 297 based on the EU numbering system in the heavy chain constant region) can each independently be replaced with asparagine.

[0615] Here, 1 to 6 codons are known to encode one amino acid, for example, Phe corresponds to TTT or TTC, Leu corresponds to TTA, TTG, CTT, CTC, CTA or CTG, Ile corresponds to ATT, ATC or ATA, Met corresponds to ATG, Val corresponds to GTT, GTC, GTA or GTG, Ser corresponds to TCT, TCC, TCA or TCG, Pro corresponds to CCT, CCC, CCA or CCG, Thr corresponds to ACT, ACC, ACA or ACG, Ala corresponds to GCT, GCC, GCA or GCG, Tyr corresponds to TAT or TAC, His corresponds to In the embodiment of the present invention, the codons corresponding to CAT or CAC, Gln corresponds to CAA or CAG, Asn corresponds to AAT or AAC, Lys corresponds to AAA or AAG, Asp corresponds to GAT or GAC, Glu corresponds to GAA or GAG, Cys corresponds to TGT or TGC, Trp corresponds to TGG, Arg corresponds to CGT, CGC, CGA or CGG, Ser corresponds to AGT or AGC, Arg corresponds to AGA or AGG, and Gly corresponds to GGT, GGC, GGA or GGG, so that the polynucleotides encoding the various parts of the anti-allergic-1 bispecific antibody include: polynucleotides in which the codons corresponding to the amino acids are arbitrarily combined.

[0616] Furthermore, these polynucleotides also include both DNA and RNA.

[0617] [Medical Uses]

[0618] The anti-allergen-1 bispecific antibody of the present invention is not particularly limited to cancers to which it can be applied, and includes any solid cancer and hematological cancer. Here, examples of solid cancers include malignant melanoma (e.g., malignant melanoma in the skin, oral mucosal epithelium, or orbital epithelium), non-small cell lung cancer (e.g., squamous non-small cell lung cancer and non-squamous non-small cell lung cancer), small cell lung cancer, head and neck cancer (e.g., oral cancer, nasopharynx cancer, oropharyngeal cancer, hypopharyngeal cancer, laryngeal cancer, salivary gland cancer, and tongue cancer), renal cell cancer (e.g., clear cell renal cell cancer), breast cancer, ovarian cancer (e.g., serous ovarian cancer), and nasopharyngeal cancer. cancer and ovarian clear cell adenocarcinoma), uterine cancer (e.g., cervical cancer and endometrial cancer), anal cancer (e.g., anal canal cancer), colorectal cancer (e.g., high-frequency microsatellite instability (MSI-H) (hereinafter, sometimes referred to as "MSI-H") and / or mismatch repair defect (hereinafter,The following are some of the cancers that are considered to be tumours: ovarian cancer (e.g., bladder cancer, upper urinary tract cancer, ureteral cancer, renal pelvis cancer, and urethral cancer): ovarian cancer (e.g., prostate cancer, fallopian tube cancer, primary peritoneal cancer, and urethral cancer): cancer), malignant pleural mesothelium tumor, gallbladder cancer, bile duct cancer, biliary tract cancer, skin cancer (e.g.uveal melanoma and Merkel cell carcinoma), testicular cancer (germ cell tumor), vaginal cancer, vulvar cancer, penile cancer, small intestine cancer, endocrine system cancer, thyroid cancer, parathyroid cancer, adrenal cancer, spinal tumor, neuroblastoma, medulloblastoma, retinoblastoma, neuroendocrine tumor, brain tumor (e.g., gliomas) (e.g., glioblastoma and gliosarcoma) and meningioma), and squamous cell carcinomas.

[0619] Among solid cancers, examples of sarcomas include bone and soft tissue sarcomas (e.g., Ewing sarcoma, childhood rhabdomyosarcoma, uterine leiomyosarcoma, chondrosarcoma, lung sarcoma, osteosarcoma, and congenital fibrosarcoma) and Kaposi's sarcoma.

[0620] In addition, examples of blood cancer include multiple myeloma, malignant lymphoma (e.g., non-Hodgkin's lymphoma, B-cell non-Hodgkin's lymphoma, precursor B-cell acute lymphoblastic leukemia, chronic B-lymphoid leukemia, B-cell precursor leukemia, B-cell prolymphocytic leukemia, lymphoplasmacytic lymphoma, nodal marginal zone B-cell lymphoma, and lymphoplasmacytic lymphoma. lymphoma, extranodal marginal zone B-cell lymphoma (MALT lymphoma), primary splenic marginal zone B-cell lymphoma, hairy cell leukemia, hairy cell leukemia-variant, follicular lymphoma, pediatric type follicular lymphoma, diffuse large B cell lymphoma, diffuse large B cell lymphoma, not otherwise specified, splenic diffuse red pulp small B-cell lymphoma, primary mediastinal large B-cell lymphoma, primary effusion lymphomaeffusion lymphoma, Burkitt's lymphoma, mantle cell lymphoma, monoclonal B-cell lymphocytosis, splenic B-cell lymphoma / leukemia, unclassifiable, IgM monoclonal gammopathy of undetermined significance, μ heavy chain disease, λ heavy chain disease, α heavy chain disease, plasma cell myeloma, solitary plasmacytoma of bone, extraosseous plasmacytoma, monoclonal immunoglobulin deposition disease, large B-cell lymphoma with IRF4 rearrangement rearrangement), primary cutaneous follicle center lymphoma, T-cell / histiocyte-rich large B-cell lymphoma, primary diffuse large B-cell lymphoma of the central nervous system, primary cutaneous diffuse large B-cell lymphoma, leg type, EBV positive diffuse large B-cell lymphoma, not otherwise specified, EBV positive mucocutaneous ulcer,ulcer, diffuse large B-cell lymphoma associated with chronic inflammation, lymphomatoid granulomatosis, intravascular large B-cell lymphoma, ALK positive large B-cell lymphoma, plasmablastic lymphoma, HHV8 positive diffuse large B-cell lymphoma, not otherwise specified, Burkitt-like lymphoma with 11q aberration, high-grade B-cell lymphoma, with MYC and BCL2and / or BCL6 rearrangement, high-grade B-cell lymphoma, not otherwise specified B-cell lymphoma, not otherwise specified), B-cell lymphoma, unclassifiable, with intermediate features between diffuse large B-cell lymphoma and classical Hodgkin lymphoma), T / NK-cell non-Hodgkin's lymphoma (e.g., precursor T-cell lymphoblastic lymphoma, chronic T-cell lymphocytic leukemia, T-cell acute lymphocytic leukemia, T-cell large granular lymphoblastic lymphoma,lymphoblastic lymphoma, NK-cell large granular leukemia, aggressive NK-cell leukemia, peripheral T-cell lymphoma, peripheral T-cell lymphoma, not otherwise specified, unclassifiable peripheral T-cell lymphoma, angioimmunoblastic T-cell lymphoma, anaplastic large cell (CD30-positive) lymphoma, angiocentric lymphoma, intestinal T-cell lymphoma, enteropathy-type T-cell lymphoma, hepatosplenic gamma-delta T cell lymphoma lymphoma, subcutaneous panniculitis-like T-cell lymphoma, mycosis fungoides, Sezary syndrome, Hodgkin-like / Hodgkin-related anaplastic large cell lymphoma, extranodal NK / T-cell lymphoma, adult T cell leukemia, T-cell prolymphocytic leukemia, chronic lymphoproliferative disorder of NK-cells, systemic EBV positive T-cell lymphoma of childhood,childhood), hydroa vacciniforme-like lymphoproliferative disorder, extranodal NK / T-cell lymphoma, nasal type, enteropathy-associated T-cell lymphoma, monomorphic epitheliotropic intestinal T-cell lymphoma, indolent T-cell lymphoproliferative disorder of the GI tract, hepatosplenic T-cell lymphoma, primary cutaneous CD30positive T-cell lymphoproliferative disorders, lymphomatoid papulosis, primary cutaneous anaplastic large cell lymphoma cutaneous T-cell lymphoma, primary cutaneous gamma-delta T-cell lymphoma, primary cutaneous CD8 positive aggressive epidermotropic cytotoxic T-cell lymphoma, primary cutaneous acral CD8 positive T-cell lymphoma, primary cutaneous CD4 positive small / medium T-cell lymphoproliferative disorder, follicular T-cell lymphomalymphoma, nodal peripheral T-cell lymphoma with T follicular helper phenotype, anaplastic large cell lymphoma, ALK positive, anaplastic large cell lymphoma, ALK negative and breast implant-associated anaplastic large cell lymphoma, and Hodgkin's lymphoma (e.g., classical Hodgkin's lymphoma (e.g., nodular sclerosis, mixed cellularity, lymphocyte-rich, and lymphopenic), as well as nodular lymphocyte predominant Hodgkin's lymphoma (e.g., nodular sclerosis, mixed cellularity, lymphocyte-rich, and lymphopenic), Hodgkin's lymphoma), leukemia (e.g., acute myelogenous leukemia, acute promyelocytic leukemia, acute lymphoblastic leukemia (lymphoblastic lymphoma), chronic lymphocytic leukemia (chronic lymphocytic lymphoma), myelodysplastic syndrome and chronic myelogenous leukemia), primary central nervous system lymphoma, myeloproliferative syndrome, etc.

[0621] Furthermore, cancers for which the anti-allergen-1 bispecific antibody of the present invention is applicable also include childhood cancers and cancers of unknown primary origin.

[0622] In addition, the anti-allergic-1 bispecific antibody of the present invention can be applied to the following cancer patients: (a) cancer patients whose treatment effects based on other anti-malignant tumor agents are insufficient or inadequate or whose cancer has worsened after treatment with other anti-malignant tumor agents; (b) patients with cancer that cannot be cured or removed, metastatic, recurrent, refractory and / or distant metastatic; (c) cancer patients whose proportion of tumor cells expressing PD-L1 (hereinafter, sometimes referred to as "TPS") or the value obtained by dividing the number of PD-L1-positive cells (tumor cells, lymphocytes and macrophages) by the total number of tumor cells and multiplying by 100 (hereinafter, sometimes referred to as "CPS") is 50% or more, 25% or more, 10% or more, 5% or more or 1% or more; (d) patients with cancer having MSI-H or dMMR; (e) patients with BRAF as a (f) patients with cancer that is positive for EGFR gene mutation or positive for ALK fusion gene; or (g) patients with cancer that has a high tumor mutation burden (hereinafter, sometimes referred to as "TMB") (more than 10% of the tumor mutation burden) (less ... 6 Patients with cancers in which the number of base mutations is 10 or more.

[0623] Here, as "other anti-malignant tumor agents", the anti-malignant tumor agents involved in the present invention can be cited, that is, alkylating agents, platinum preparations, metabolic antagonists (for example, folic acid metabolic antagonists, pyridine metabolic inhibitors and purine metabolic inhibitors), ribonucleotide reductase inhibitors, nucleotide analogs, topoisomerase inhibitors, microtubule polymerization inhibitors, microtubule depolymerization inhibitors, anti-tumor antibiotics, cytokine preparations, anti-hormonal drugs, molecular targeted drugs, tumor immunosuppressants and other antibody drugs. In addition, "the therapeutic effect based on other anti-malignant tumor agents is insufficient or insufficient" means, for example, that in the determination of the tumor shrinkage effect RECIST, it can be cited that the case is judged as "stable (SD)" or "progression (PD)" by treatment based on existing anti-cancer drugs.

[0624] In addition, the anti-allergen-1 bispecific antibody of the present invention may sometimes be suitable for the following cancer patients: (h) cancer patients with no history of treatment based on other anti-tumor agents; (i) cancer patients with TPS or CPS less than 50%, less than 25%, less than 10%, less than 5% or less than 1%; (j) patients with cancer without MSI-H and / or dMMR, or with MSI-L; (k) patients with BRAF V600 wild-type malignant melanoma or non-small cell lung cancer; (l) patients with EGFR gene mutation-negative and / or ALK fusion gene-negative non-small cell lung cancer; or (m) patients with low TMB frequency (per 10 6 Patients with cancers with less than 10 base mutations.

[0625] Furthermore, the anti-allergen-1 bispecific antibody of the present invention can be used suitably as a postoperative adjuvant therapy for preventively suppressing recurrence or metastasis of cancer after surgical resection or as a preoperative adjuvant therapy before surgical resection.

[0626] It should be noted that, in this specification, "cancer treatment" includes, for example, the following treatments (a) to (e): (a) for reducing the proliferation of cancer cells; (b) for reducing the symptoms caused by cancer; (c) for improving the quality of life of cancer patients; (d) for reducing the dosage of other anti-cancer agents or cancer treatment adjuvants that have been administered; and / or (e) for prolonging the survival period of cancer patients. In addition, "cancer progression inhibition" means delaying the progression of cancer, stabilizing cancer-related symptoms and retarding the progression of symptoms. "Recurrence inhibition" means preventively inhibiting the recurrence of cancer in patients whose cancer lesions have been completely or substantially eliminated or removed by cancer treatment or cancer surgical resection.

[0627] The anti-allergen-1 bispecific antibody of the present invention is usually administered systemically or locally in a parenteral form. As the method of administration, specifically, injection, nasal administration, pulmonary administration, transdermal administration, etc. can be mentioned. As injection, for example, intravenous injection, intramuscular injection, intraperitoneal injection, etc. can be mentioned. In the case of intravenous injection, drip administration is preferred. Its dosage varies according to age, body weight, symptoms, therapeutic effect, administration method, treatment time, etc., usually in the range of 0.1 μg / kg to 300mg / kg per person per time for adults, particularly preferably in the range of 0.1mg / kg to 10mg / kg, once a day to several times parenterally, or continuously administered intravenously in the range of 30 minutes to 24 hours a day. Of course, as mentioned above, the dosage varies according to various conditions, so there is also a situation where the amount less than the dosage is sufficient, and there is also a situation where the administration needs to exceed the range.

[0628] [Combination use and compounding agents]

[0629] The anti-Allergin-1 bispecific antibody of the present invention can be used for: (a) inhibiting the progression, recurrence and / or enhancing the therapeutic effect of cancer; (b) reducing the dosage of the anti-malignant tumor drug prescribed in combination; (c) alleviating the side effects of the anti-malignant tumor drug prescribed in combination; and / or (d) improving the immunopotentiating effect of the anti-malignant tumor drug prescribed in combination, that is, as an adjuvant, and co-prescribing with one or more anti-malignant tumor drugs. In the present invention, the administration method when co-prescribing with the anti-malignant tumor drug can be a method of combining two components in one preparation, and can also be an administration method as different preparations. Through the above-mentioned combined use, the anti-malignant tumor drug can be supplemented for the inhibition of progression, recurrence and / or therapeutic effect of cancer, or the dosage or number of administration can be maintained or reduced. In the case where the anti-allergin-1 bispecific antibody of the present invention and the anti-malignant tumor drug are prescribed separately, they can be administered simultaneously for a certain period of time, and then only the anti-allergin-1 bispecific antibody of the present invention or only the anti-malignant tumor drug can be administered. In addition, the anti-allergen-1 bispecific antibody of the present invention can be administered first, and the anti-malignant tumor agent can be administered after the administration. The anti-malignant tumor agent can also be administered first, and then the antibody of the present invention can be administered. In addition, in the above-mentioned administration, there can be a period of time during which the two agents are administered simultaneously. In addition, the administration methods of the two agents can be the same or different. Depending on the properties of the agent, it can be provided as a kit of preparations containing the antibody of the present invention and the anti-malignant tumor agent. Here, the dosage of the anti-malignant tumor agent can be appropriately selected based on the dosage used clinically. In addition, the anti-malignant tumor agent can also be administered in an appropriate ratio of two or more optional combinations. In addition, the anti-malignant tumor agent not only includes drugs discovered so far, but also includes drugs discovered in the future.

[0630] Examples of other anti-tumor drugs include alkylating agents (e.g., dacarbazine, nimustine, temozolomide, fotemustine, bendamustine, cyclophosphamide, ifosfamide, carmustine, chlorambucil, and procarbazine). bazine, etc.), platinum preparations (e.g., cisplatin, carboplatin, nedaplatin, and oxaliplatin, etc.), metabolic antagonists (e.g., folate metabolic antagonists (e.g., pemetrexed, leucovorin, and methotrexate, etc.), pyridine metabolic inhibitors (e.g., TS-1 (registered trademark), 5-fluorouracil , UFT, Carmofur, Doxifluridine, FdUrd, Cytarabine and Capecitabine, etc.), purine metabolism inhibitors (e.g., Fludarabine, Cladribine and Nelarabine, etc.), ribonucleotide reductase inhibitors, nucleotide analogs (e.g., Gemcitabine, etc.), topoisomerase inhibitors (e.g., I The invention relates to the treatment of leukemia and leukemia with the help of the following drugs: irinotecan, nogitecan and etoposide, etc.), microtubule polymerization inhibitors (e.g., vinblastine, vincristine, vindesine, vinorelbine and eribulin, etc.), microtubule depolymerization inhibitors (e.g., docetaxel and paclitaxel, etc.), antitumor antibiotics (e.g.,Bleomycin, Mitomycin C, Doxorubicin, Daunorubicin, Idarubicin, Etoposide, Mitoxantrone, Vinblastine, Vincristine, Peplomycin, Amrubicin, Aclarubicin, and Epirubicin, etc.), cytokine preparations (e.g., IF N-α2a, IFN-α2b, PEG-IFN-α2b, natural IFN-β and interleukin-2, etc.), antihormonal drugs (for example, tamoxifen, fulvestrant, goserelin, leuprorelin, anastrozole, letrozole and exemestane, etc.), molecular target drugs, tumor immunotherapy drugs and other antibody drugs. Here, as the anti-malignant tumor agent of the present invention, it is preferred that the anti-malignant tumor agent not be accompanied by the occurrence of cytokine release syndrome by its own single administration. ,

[0631] Here, as molecular targeted drugs, for example, there can be mentioned: ALK inhibitors (for example, Crizotinib, Ceritinib, Ensartinib, Alectinib, and Lorlatinib), BCR-ABL inhibitors (for example, Imatinib and Dasatinib), EGFR inhibitors (for example, Erlotinib, EGF816, Afatinib, Osimertinib, etc.), mesilate, Gefitinib and Rociletinib, etc.), B-RAF inhibitors (e.g., Sorafenib, Vemurafenib, TAK-580, Dabrafenib, Encorafenib, LXH254, Emurafenib and Zanubrutinib, etc.), VEGFR inhibitors (e.g., Bevacizumab, Apatinib, Lenvatinib, Aflibercept and Axitinib, etc.), FGFR inhibitors (e.g., AZD4547, Vofatmab, Roblitinib and Pemigatinib, etc.), c-MET inhibitors (e.g., Savolitinib, Merestinib, Capmatinib, Capmatinib and Glesatinib, etc.), A XL inhibitors (e.g., ONO-7475 and Bemcentinib, etc.), MEK inhibitors (e.g., Cobimetinib, Binimetinib, Selumetinib and Trametinib, etc.), CDK inhibitors (e.g., Dinaciclib, Abemaciclib, Palbociclib and Trilaciclib, etc.), BTK inhibitors (e.g., Ibrutinib and Acalabrutinib, etc.), BCL-2 inhibitors (e.g., Navitoclax and Venetoclax, etc.), PI3K-δ / γ inhibitors (e.g., Umbralisib, Parsaclisib and IPI-549, etc.), JAK-1 / 2 inhibitors (e.g., Itacitinib and Ruxolitinib, etc.), ERK inhibitors (e.g., SCH 900353, etc.), TGFbR1 inhibitors (e.g., Galunisertib, etc.), cancer cell stemness kinase inhibitors (e.g., Amcasertib), FAK inhibitors (e.g., Defactinib), SYK / FLT3 dual inhibitors (e.g., Mivavotinib, etc.), ATR inhibitors (e.g., Ceralasertib, etc.), WEE1 kinase inhibitors (e.g.,Adavosertib, etc.), multi-tyrosine kinase inhibitors (e.g., Sunitinib, Pazopanib, Cabozantinib, Regorafenib, Nintedanib, Sitravatinib, and Midostaurin, etc.), mTOR inhibitors (e.g., Temsirolimus, Everolimus, Vistusertib, and Irinotecan, etc.), HDAC inhibitors (e.g., Vorinostat, Romidepsin, Entinostat, Chidamide, Mocetinostat, Citarinostat, Panobinostat, and Valproate, etc.) , PARP inhibitors (e.g., Niraparib, Olaparib, Veliparib, Rucaparib and Beigene-290, etc.), aromatase inhibitors (e.g., Exemestane and Letrozole, etc.), EZH2 inhibitors (e.g., Tazemetostat, etc.), galectin-3 inhibitors (e.g., Belapectin, etc.), STAT3 inhibitors (e.g., Napabucasin, etc.), DNMT inhibitors (e.g., Azacitidine, etc.), SMO inhibitors (e.g., Vismodegib, etc.), HSP90 inhibitors (e.g., XL888, etc.), γ-tubulin specific inhibitors (e.g., Glaziovianin, etc.), A and Plinabulin, etc.), HIF2α inhibitors (e.g., PT2385, etc.), glutaminase inhibitors (e.g., Telaglenastat, etc.), E3 ligase inhibitors (e.g., Avadomide, etc.), NRF2 activators (e.g., Omaveloxolone, etc.), arginase inhibitors (e.g., CB-1158, etc.), cell cycle inhibitors (e.g., Trabectedin, etc.), Ephrin B4 inhibitors (e.g., sEphB4-HAS, etc.), IAP antagonists (e.g., Birinapant, etc.), anti-HER2 antibodies (e.g., Pertuzumab, Margetuximab, Disitamab, Disitamabvedotin, Gancotamab, Timigutuzumab, Zanidatamab, Zenocutuzumab, Trastuzumab, Trastuzumab beta, Trastuzumab deruxtecan, Trastuzumab duocarmazine, Trastuzumabemtansine, R48, and ZW33), anti-HER1 antibodies (e.g.,Cetuximab, Cetuximab sarotalocan, Panitumumab, Necitumumab, Nimotuzumab, Depatuxizumab, Depatuxizumab mafodotin, Futuximab, Laprituximab, Laprituximab emtansine, Matuzumab, Modotuximab, Petosemtamab, Tomuzotuximab, Losatuxizumab, Losatuxizumab vedotin, Serclutamab, Serclutamab talirine, Imgatuzumab and Zalutumumab, etc.), anti-HER3 antibodies (e.g., Duligotuzumab, Elgemtumab, Istiratumab, Lumretuzumab, Zenocutuzumab, Patritumab, Patritumab deruxtecan and seribantumab, etc.), anti-CD40 antibodies (e.g., Bleselumab, Dacetuzumab, Iscalimab, Lucatumumab, Mitazalimab, Ravagalimab, Selicrelumab, Teneliximab, ABBV-428 and APX005M, etc.), anti-CD70 antibodies (e.g., Cusatuzumab, Vorsetuzumab, Vorsetuzumab mafodotin and ARGX-110, etc.), anti-VEGF antibodies (e.g., Bevacizumab, Bevacizumabbeta, Ranibizumab, Abicipar pegol, Aflibercept, Brolucizumab, Conbercept, Dilpacimab, Faricimab, Navicixizumab, Varisacumab and IMC-1C11, etc.), anti-VEGFR1 antibodies (e.g., Icrucumab, etc.), anti-VEGFR2 antibodies (e.g., Ramucirumab, Alacizumab, Alacizumab pegol, Olinvacimab, Pegdinetanib and AMG596, etc.), anti-CD20 antibodies (e.g., Rituximab, Blontuvetmab, Epitumomab, Ibritumomab tiuxetan, Ocaratuzumab, Ocrelizumab, Technetium (, 99mTc) nofetumomab merpentan, Tositumomab, Veltuzumab, Ofatumumab, Ublituximab, Obinutuzumab and Nofetumomab, etc.), anti-CD30 antibodies (e.g., Brentuximab Vedotin and Iratumumab, etc.), anti-CD38 antibodies (e.g., Daratumumab, Isatuximab, Mezagitamab, AT13 / 5 and MOR202, etc.), anti-TNFRSF10B antibodies (e.g., Benufutamab, Conatumumab, Drozitumab, Lexatumumab, Tigatuzumab, Eftozanermin alfa and DS-8273a, etc.), anti-TNFRSF10A antibodies (e.g., Mapatumumab, etc.), anti-MUC1 antibodies (e.g., Cantuzumab, Cantuzumab ravtansine, Clivatuzumab, Clivatuzumab tetraxetan, Yttrium ( 90Y) clivatuzumab tetraxetan, Epitumomab, Epitumomab cituxetan, Sontuzumab, Gatipotuzumab, Nacolomab, Nacolomab tafenatox, 7F11C7, BrE-3, CMB-401, CTM01 and HMFG1, etc.), anti-MUC5AC antibodies (e.g., Ensituximab, etc.), anti-MUC16 antibodies (e.g., Oregovomab, Abagovomab, Igovomab and Sofituzumab vedotin, etc.), anti-DLL4 antibodies (e.g., Demcizumab, Dilpacimab, Navicixizumab and Enoticumab, etc.), anti-fucosyl GM1 antibodies (e.g., BMS-986012, etc.), anti-gpNMB antibodies (e.g., Glembatumumab vedotin, etc.), anti-mesothelin antibodies (e.g., Amatuximab, Anetumab ravtansine, Anetumab corixetan, RG7784 and BMS-986148, etc.), anti-MMP9 antibodies (e.g., Andecaliximab, etc.), anti-GD2 antibodies (e.g., Dinutuximab, Dinutuximab beta, Lorukafusp alfa, Naxitamab, 14G2a, MORAb-028, Surek, TRBs07 and ME361, etc.), anti-MET antibodies (e.g., Emibetuzumab, Onartuzumab, Telisotuzumab and Telisotuzumab vedotin, etc.), anti-FOLR1 antibodies (e.g., Farletuzumab, Mirvetuximab and Mirvetuximab soravtansine, etc.), anti-CD79b antibodies (e.g., Iladatuzumab, Iladatuzumab vedotin and Polatuzumab vedotin, etc.), anti-DLL3 antibodies (e.g., Rovalpituzumab and Rovalpituzumab Tesirine, etc.), anti-CD51 antibodies (e.g., Abituzumab, Etaracizumab, and Intetumumab, etc.), anti-EPCAM antibodies (e.g.,Adecatumumab, Catumaxomab, Edrecolomab, Oportuzumab monatox, Citatuzumab bogatox, and Tucotuzumab celmoleukin, etc.), anti-CEACAM5 antibodies (e.g., Altumomab, Arcitumomab, Cergutuzumab amunaleukin, Labetuzumab, Labetuzumab govitecan, etc.) 90 Y-cT84.66, AMG211, BW431 / 26, CE25 / B7, COL-1 and T84.66 M5A, etc.), anti-CEACAM6 antibodies (e.g., Tinurilimab, etc.), anti-FGFR2 antibodies (e.g., Aprutumab, Aprutumabixadotin and Bemarituzumab, etc.), anti-CD44 antibodies (e.g., Bivatuzumab mertansine, etc.), anti-PSMA antibodies (e.g., Indium ( 111 In) capromab pendetide, 177 Lu-J591 and ES414, etc.), anti-endoglin antibodies (e.g., Carotuximab, etc.), anti-IGF1R antibodies (e.g., Cixutumumab, Figitumumab, Ganitumab, Dalotuzumab, Teprotumumab and Robatumumab, etc.), anti-TNFSF11 antibodies (e.g., Denosumab), anti-GUCY2C antibodies (e.g., Indusatumab vedotin, etc.), anti-SLC39A6 antibodies (e.g., Ladiratuzumab vedotin, etc.), anti-SLC34A2 antibodies (e.g., Lifastuzumab vedotin, etc.), anti-NCAM1 antibodies (e.g., Lorvotuzumab, etc.), mertansine and N901, etc.), anti-ganglioside GD3 antibodies (e.g., Ecomeximab and Mitumomab, etc.), anti-AMHR2 antibodies (e.g., Murlentamab, etc.), anti-CD37 antibodies (e.g., Lilotomab, Lutetium ( 177Lu) lilotomab satetraxetan, Naratuximab, Naratuximabemtansine and Otlertuzumab, etc.), anti-IL1RAP antibodies (e.g., Nidanilimab, etc.), anti-PDGFR2 antibodies (e.g., Olaratumab and Tovetumab, etc.), anti-CD200 antibodies (e.g., Samalizumab, etc.), anti-TAG-72 antibodies (e.g., Anatumomab mafenatox, Minretumomab, Indium ( 111 In) satumomab pendetide, CC49, HCC49 and M4, etc.), anti-SLITRK6 antibodies (e.g., Sirtratumab vedotin, etc.), anti-DPEP3 antibodies (e.g., Tamrintamab pamozirine, etc.), anti-CD19 antibodies (e.g., Axicabtagene ciloleucel, Coltuximabravtansine, Denintuzumab mafodotin, Inebilizumab, Loncastuximab, Loncastuximabtesirine, Obexelimab, Tafasitamab, Taplitumomab paptox and huAnti-B4, etc.), anti-NOTCH2 / 3 antibodies (e.g., Tarextumab, etc.), anti-tenascin C antibodies (e.g., Tenatumomab, etc.), anti-AXL antibodies (e.g., Enapotamab, Enapotamab vedotin and Tilvestamab, etc.), anti-STEAP1 antibodies (e.g., Vandortuzumabvedotin, etc.), anti-CTAA16 antibodies (e.g., technetium ( 99mTc) votumumab, etc.), anti-CLDN18 antibodies (e.g., Zolbetuximab, etc.), anti-GM3 antibodies (e.g., Racotumomab, FCGR1, and H22, etc.), anti-PSCA antibodies (e.g., MK-4721, etc.), anti-fibronectin extra domain B (FN extra domain B) antibodies (e.g., AS1409, etc.), anti-HAVCR1 antibodies (e.g., CDX-014, etc.), anti-TNFRSF4 antibodies (e.g., MEDI6383, etc.), anti-HER1-MET bispecific antibodies (e.g., Amivantamab), anti-EPCAM-CD3 bispecific antibodies (e.g., Solitomab and Catumaxomab, etc.), anti-Ang2-VEGF bispecific antibodies (e.g., Vanucizumab, etc.), anti-HER2-CD3 bispecific antibodies (e.g., Ertumaxomab, etc.), Mab, etc.), anti-HER3-IGF1R bispecific antibodies (e.g., Istiratumab, etc.), anti-PMSA-CD3 bispecific antibodies (e.g., Pasotuxizumab, etc.), anti-HER1-LGR5 bispecific antibodies (e.g., Petosemtamab, etc.), anti-SSTR2-CD3 bispecific antibodies (e.g., Tidutamab, etc.), anti-CD30-CD16A bispecific antibodies (e.g., AFM13, etc.), anti-CEA-CD3 bispecific antibodies (e.g., Cibisatamab and R O6958688), anti-CD3-CD19 bispecific antibodies (e.g., Duvortuxizumab and Blinatumomab, etc.), anti-IL3RA-CD3 bispecific antibodies (e.g., Flotetuzumab and Vibecotamab, etc.), anti-GPRC5D-CD3 bispecific antibodies (e.g., Talquetamab, etc.), anti-CD20-CD3 bispecific antibodies (e.g., Plamotamab, Odronextamab, Mosunetuzumab, Glofitamab, Epcoritamab and REGN1979, etc.), anti-TNFRSF17-CD3 bispecific antibodies (e.g., Teclistamab, etc.), anti-CLEC12A-CD3 bispecific antibodies (e.g., Tepoditamab, etc.), anti-HER2-HER3 bispecific antibodies (e.g., Zenocutuzumab, etc.), anti-FAP antibody / IL-2 fusion protein (e.g., RO6874281, etc.) and anti-CEA antibody / IL-2 fusion protein (e.g., Cergutuzumab, etc.), amunaleukin, etc.

[0632] In addition, examples of tumor immunotherapy drugs include anti-PD-1 antibodies (e.g., Nivolumab, Cemiplimab, Pembrolizumab, Spartalizumab, Tislelizumab, Dostarlimab, Toripalimab, Camrelizumab, Genolizumab, Sintilimab, etc.) limab), Lodapolimab, Retifanlimab, Balstilimab, Serplulimab, Budigalimab, Prolgolimab, Sasanlimab, Cetrelimab, Zimberelimab, Geptanolimab, AMP-514, STI-A1110, ENUM 388D4, ENUM244C8, Zimberelimab, CS1003, BAT-1306, Penpulimab, AK103, Ezabenlimab, LZM009, CMAB819, Sym021, SSI-361, JY034, Pucotenlimab, ISU106 and CX-188, etc.), anti-PD-L1 antibodies (e.g., Atezolizumab, Avelumab, Durvalimumab, etc.), umab), manelimab, pacmilimab, envafolimab, cosibelimab, sugemalimab, BMS-936559, STI-1014, HLX20, adebrelimab, MSB2311, BGB-A333, KL-A167, AK106, socazolimab, FAZ053, CBT-502, and JS003), PD-1 antagonists (e.g.,AUNP-12, each compound of BMS-M1 to BMS-M10 (refer to WO2014 / 151634, WO2016 / 039749, WO2016 / 057624, WO2016 / 077518, WO2016 / 100285, WO2016 / 100608, WO2016 / 126646, WO2016 / 149351, WO2017 / 151 830 and WO2017 / 176608), BMS-1, BMS-2, BMS-3, BMS-8, BMS-37, BMS-200, BMS-202, BMS-230, BM S-242, BMS-1001 and BMS-1166 (WO2015 / 034820, WO2015 / 160641, WO2017 / 066227 and Oncotarget. 2017 Sep 22; 8(42): 72167-72181.), Incyte-1 to Incyte-6 compounds (refer to WO2017 / 070089, WO2017 / 087777, WO2017 / 106634, WO2017 / 112730, WO2017 / 192961 and WO2017 / 205464), CAMC-1 to CAMC-4 (refer to WO2017 / 202273, WO2017 / 202274, WO2017 / 202275 and WO2017 / 202276), RG_1 (refer to WO2017 / 118762) and DPPA-1 (refer to Angew. Chem. Int. Ed. 2015,54,11760-11764), PD-L1 / VISTA antagonists (e.g., CA-170, etc.), PD-L1 / TIM3 antagonists (e.g., CA-327, etc.), anti-PD-L2 antibodies, PD-L1 fusion proteins, PD-L2 fusion proteins (e.g., AMP-224, etc.), anti-CTLA-4 antibodies (e.g., Ipilimumab, Zalivrelimab, Nurulimab, etc.), limab and tremelimumab, etc.), anti-LAG-3 antibodies (e.g., Relatlimab, Ieramilimab, Fianlimab, Encelimab and Mavezelimab, etc.), anti-TIM3 antibodies (e.g., MBG453 and Cobolimab, etc.), anti-KIR antibodies (e.g.,(e.g., Lirilumab, IPH2101, LY3321367, and MK-4280, etc.), anti-BTLA antibodies, anti-TIGIT antibodies (e.g., Tiragolumab, Etigilimab, Vibostolimab, and BMS-986207, etc.), anti-VISTA antibodies (e.g., Onvatilimab, etc.), anti-CD137 antibodies (e.g., Urecitumomab, Urelumab and Utomilumab, etc.), anti-CSF-1R antibodies, CSF-1R inhibitors (e.g., Cabiralizumab, Emactuzumab, LY3022855, Axatilimab, MCS-110, IMC-CS4, AMG820, Pexidartinib, BLZ945, and ARRY-38 2, etc.), anti-OX40 antibodies (e.g., MEDI6469, Ivuxolimab, MEDI0562, MEDI6383, Efizonerimod, GSK3174998, BMS-986178, and MOXR0916, etc.), anti-HVEM antibodies, anti-CD27 antibodies (e.g., Varlilumab, etc.), anti-GITR antibodies·GITR fusion proteins (e.g., Efapriner min) alfa, Efgivanermin alfa, MK-4166, INCAGN01876, GWN323 and TRX-518, etc.), anti-CD28 antibodies, anti-CCR4 antibodies (e.g., Mogamulizumab, etc.), anti-B7-H3 antibodies (e.g., Enoblituzumab, Mirzotamab, Mirzotamab The invention relates to antibodies for the treatment of leukemia and the related art. The antibodies include, for example, clezutoclax and omburtamab, etc.), anti-ICOS agonist antibodies (e.g., Vopratelimab and GSK3359609, etc.), anti-CD4 antibodies (e.g., Zanolimumab and IT1208, etc.), anti-DEC-205 antibodies / NY-ESO-1 fusion proteins (e.g., CDX-1401, etc.), anti-SLAMF7 antibodies (e.g., Azintuxizumab, Azintuxizumab vedotin and Elotuzumab, etc.), anti-CD73 antibodies (e.g.,Oleclumab and BMS-986179, etc.), PEGylated IL-2 (Bempegaldesleukin), IDO inhibitors (e.g., Epacadostat, Indoximod, and Linrodostat, etc.), TLR agonists (e.g., Motolimod, CMP-001, G100, Tilsotolimod, SD-101, and MEDI9197, etc.), adenosine A 2A receptor antagonists (e.g., Preladenant, AZD4635, Taminadenant and Ciforadenant, etc.), anti-NKG2A antibodies (e.g., Monalizumab, etc.), anti-CSF-1 antibodies (e.g., PD0360324, etc.), immunopotentiators (e.g., PV-10, etc.), IL-15SUPER agonists (e.g., ALT-803, etc.), soluble LAG3 (e.g., Eftilagimod alpha, etc.), anti-CD47 antibodies·CD47 antagonists (e.g., ALX148, etc.) and IL-12 antagonists (e.g., M9241, etc.), etc. It should be noted that nivolumab can be produced based on the method described in WO2006 / 121168, pembrolizumab can be produced based on the method described in WO2008 / 156712, BMS-936559 can be produced based on the method described in WO2007 / 005874, and ipilimumab can be produced based on the method described in WO2001 / 014424.

[0633] In addition, examples of other antibody drugs include anti-IL-1β antibodies (eg, canakinumab, etc.) and anti-CCR2 antibodies (eg, lozalizumab, etc.).

[0634] When the tumor immunotherapy agent of the present invention is used in combination with the anti-allergen-1 bispecific antibody of the present invention, for example, they can be administered in the following manner and dosage. That is, as the active ingredient of each tumor immunotherapy agent, about 1 to about 21 mg / kg (body weight) once or about 80 to about 1680 mg once is intravenously administered (for example, intravenous drip) at intervals of 1 to 8 weeks over about 30 minutes or about 60 minutes or more. Here, examples of the dosage per administration in terms of body weight include 1 mg / kg, 2 mg / kg, 3 mg / kg, 4 mg / kg, 5 mg / kg, 6 mg / kg, 7 mg / kg, 8 mg / kg, 9 mg / kg, 10 mg / kg, 12 mg / kg, 14 mg / kg, 15 mg / kg, 20 mg / kg and 21 mg / kg. On the other hand, examples of the dosage per administration include 200 mg, 240 mg, 250 mg, 280 mg, 300 mg, 320 mg, 350 mg, 360 mg, 400 mg, 420 mg, 450 mg, 480 mg, 500 mg, 540 mg, 560 mg, 600 mg, 640 mg, 700 mg, 720 mg, 750 mg, 800 mg, 840 mg, 900 mg, 960 mg, 1000 mg, In addition, examples of the dosing interval include 1 week, 2 weeks, 3 weeks, 4 weeks, 6 weeks, and 8 weeks, and examples of the single dosing time include about 30 minutes, about 60 minutes, or more than about 60 minutes.

[0635] Here, when the active ingredient of the tumor immunotherapy drug is nivolumab, which is an anti-PD-1 antibody, and when used in combination with the anti-allergic-1 bispecific antibody of the present invention, for adults, nivolumab can be administered by intravenous drip in the following manner: (a) 1 mg / kg (body weight) once at 3-week intervals; (b) 3 mg / kg (body weight) once at 2-week intervals; (c) 2 mg / kg (body weight) once at 3-week intervals; (d) 80 mg once at 3-week intervals; (e) 240 mg once at 2-week intervals; (f) 360 mg once at 3-week intervals; or (g) 480 mg once at 4-week intervals (preferably 240 mg once at 2-week intervals, 360 mg once at 3-week intervals, or 480 mg once at 4-week intervals).

[0636] When the active ingredient of the tumor immunotherapy drug is the anti-PD-1 antibody pembrolizumab, when used in combination with the anti-allergic-1 bispecific antibody of the present invention, for adults, pembrolizumab can be administered by intravenous drip in the following manner: (a) 200 mg once at 3-week intervals; (b) 400 mg once at 6-week intervals; or (c) 2 mg / kg (body weight) once (the upper limit of a single dose is 200 mg) at 3-week intervals.

[0637] When the active ingredient of the tumor immunotherapy drug is the anti-PD-1 antibody cimiprilimumab-rwlc, when used in combination with the anti-allergic-1 bispecific antibody of the present invention, for adults, cimiprilimumab-rwlc can be administered by intravenous drip at intervals of 3 weeks at a time of 350 mg. In particular, for patients with squamous cell carcinoma, the same dosage can be administered.

[0638] When the active ingredient of the tumor immunotherapy drug is dotalizumab, an anti-PD-1 antibody, and when used in combination with the anti-allergic-1 bispecific antibody of the present invention, for adults, 500 mg of dotalizumab can be administered once by intravenous drip four times at intervals of 3 weeks, and 1000 mg can be administered once by intravenous drip at intervals of 6 weeks from the fifth time 3 weeks later. In particular, for dMMR-positive endometrial cancer or solid cancer, the same dosage can be administered.

[0639] When the active ingredient of the tumor immunotherapy drug is the anti-PD-L1 antibody avelumab, when used in combination with the anti-allergic-1 bispecific antibody of the present invention, avelumab can be administered to adults by intravenous drip at a dose of 10 mg / kg (body weight) once at intervals of 2 weeks.

[0640] When the active ingredient of the tumor immunotherapy drug is atezolizumab, an anti-PD-L1 antibody, and when used in combination with the anti-allergic-1 bispecific antibody of the present invention, for adults, atezolizumab can be administered by intravenous drip in the following manner: (a) 840 mg once at 2-week intervals; (b) 1200 mg once at 3-week intervals; or (c) 1680 mg once at 4-week intervals.

[0641] When the active ingredient of the tumor immunotherapy drug is the PD-L1 antibody durvalumab, when used in combination with the anti-allergic-1 bispecific antibody of the present invention, durvalumab can be administered to adults at a dose of 10 mg / kg (body weight) once by intravenous drip at intervals of 2 weeks.

[0642] When the active ingredient of the tumor immunotherapy drug is ipilimumab, an anti-CTLA-4 antibody, and when it is used in combination with the anti-allergic-1 bispecific antibody of the present invention, for adults, ipilimumab can be administered by intravenous drip four times at intervals of three weeks at (a) 3 mg / kg (body weight) once a day or (b) 1 mg / kg (body weight) once a day.

[0643] [preparation]

[0644] When the anti-allergen-1 bispecific antibody of the present invention is formulated for use as an injection or an infusion for drip, the injection or infusion may be in the form of an aqueous solution, a suspension or an emulsion, and may also be formulated as a solid preparation together with a pharmaceutically acceptable carrier in a manner of dissolving, suspending or emulsifying by adding a solvent when used. As solvents used in the infusion for injection or drip, for example, distilled water for injection, physiological saline, glucose solution and isotonic solution (for example, solutions such as sodium chloride, potassium chloride, glycerol, mannitol, sorbitol, boric acid, borax, propylene glycol, etc.) can be used.

[0645] Here, as pharmaceutically acceptable carriers, for example, stabilizers, solubilizers, suspending agents, emulsifiers, analgesics, buffers, preservatives, preservatives, pH regulators and antioxidants can be cited. As stabilizers, for example, various amino acids, albumin, globulin, gelatin, mannitol, glucose, dextran, ethylene glycol, propylene glycol, polyethylene glycol, ascorbic acid, sodium bisulfite, sodium thiosulfate, sodium edetate, sodium citrate, butylated hydroxytoluene, etc. can be used. As solubilizers, for example, alcohols (for example, ethanol, etc.), polyols (for example, propylene glycol, polyethylene glycol, etc.), nonionic surfactants (for example, polysorbate 20 (registered trademark), polysorbate 80 (registered trademark), HCO-50, etc.) can be used. As suspending agents, for example, glycerol monostearate, aluminum monostearate, methylcellulose, carboxymethylcellulose, hydroxymethylcellulose, sodium lauryl sulfate, etc. can be used. As an emulsifier, for example, gum arabic, sodium alginate, tragacanth gum, etc. can be used. As a painless agent, for example, benzyl alcohol, chlorobutanol, sorbitol, etc. can be used. As a buffer, for example, a phosphate buffer, an acetate buffer, a boric acid buffer, a carbonate buffer, a citric acid buffer, a Tris buffer, a glutamic acid buffer, an epsilon aminocaproic acid buffer, etc. can be used. As a preservative, for example, methyl parahydroxybenzoate, ethyl parahydroxybenzoate, propyl parahydroxybenzoate, butyl parahydroxybenzoate, chlorobutanol, benzyl alcohol, benzalkonium chloride, sodium dehydroacetate, sodium edetate, boric acid, borax, etc. can be used. As a preservative, for example, benzalkonium chloride, parahydroxybenzoic acid, chlorobutanol, etc. can be used. As a pH adjuster, for example, hydrochloric acid, sodium hydroxide, phosphoric acid, acetic acid, etc. can be used. As antioxidants, for example, (1) water-soluble antioxidants such as ascorbic acid, cysteine ​​hydrochloride, sodium hydrogen sulfate monohydrate, sodium metabisulfite, sodium sulfite, etc., (2) oil-soluble antioxidants such as ascorbyl palmitate, butylated hydroxyanisole, butylated hydroxytoluene, lecithin, propyl gallate, α-tocopherol, etc., and (3) metal chelating agents such as citric acid, ethylenediaminetetraacetic acid, sorbitol, tartaric acid, phosphoric acid, etc. can be used.

[0646] In the case of an infusion for injection or drip, it can be manufactured by sterilization or aseptic operation in the final process, for example, by sterilization by filtering with a filter, etc., and then filling into a sterile container. In addition, in the case of an infusion for injection or drip, a sterile powder (which may contain a pharmaceutically acceptable carrier) based on vacuum drying and freeze drying can be dissolved in an appropriate solvent before use.

[0647] The present invention provides the embodiments described in, for example, the following [1] to

[150] , [1-1] and [1-2], [2-1] to [2-32], [3-1] to [3-3], [4-1], [5-1], [6-1], [7-1] to [7-20], and [8-1] to [8-3].

[0648] [1] A bispecific antibody or an antibody fragment thereof, comprising two antigen-binding sites that specifically bind to different epitopes in the extracellular domain of allergen-1, wherein:

[0649] The antigen binding sites do not compete with each other for allergen-1 and are two different optional antigen binding sites selected from the following (i) to (iv):

[0650] (i) an antigen binding site that specifically binds to a specific epitope on the S1 domain of allergen-1 (S1-A binding site);

[0651] (ii) an antigen binding site that specifically binds to another epitope on the S1 domain of allergen-1 that is different from the epitope described in (i) above (S1-B binding site);

[0652] (iii) an antigen binding site that specifically binds to a specific epitope on the S2 domain of allergen-1 (S2-C binding site);

[0653] (iv) an antigen binding site (S2-D binding site) that specifically binds to another epitope on the S2 domain of allergen-1 that is different from the epitope described in (iii) above,

[0654] The S1-A binding site is any one of the following antigen binding sites (A) to (D),

[0655] (A) an antigen binding site comprising:

[0656] VH, which has

[0657] (a) VH-CDR1 comprising the amino acid sequence of SEQ ID NO.25;

[0658] (b) VH-CDR2 comprising the amino acid sequence of SEQ ID NO.26; and

[0659] (c) a VH-CDR3 comprising the amino acid sequence of SEQ ID NO. 27, and

[0660] VL, which has

[0661] (d) a VL-CDR1 comprising the amino acid sequence of SEQ ID NO.49;

[0662] (e) a VL-CDR2 comprising the amino acid sequence of SEQ ID NO.50; and

[0663] (f) a VL-CDR3 comprising the amino acid sequence of SEQ ID NO.51,

[0664] (B) an antigen binding site comprising:

[0665] VH, which has

[0666] (a) VH-CDR1 comprising the amino acid sequence of SEQ ID NO.28;

[0667] (b) VH-CDR2 comprising the amino acid sequence of SEQ ID NO.29; and

[0668] (c) a VH-CDR3 comprising the amino acid sequence of SEQ ID NO. 30, and

[0669] VL, which has

[0670] (d) a VL-CDR1 comprising the amino acid sequence of SEQ ID NO.52;

[0671] (e) a VL-CDR2 comprising the amino acid sequence of SEQ ID NO.53; and

[0672] (f) a VL-CDR3 comprising the amino acid sequence of SEQ ID NO.54,

[0673] (C) an antigen binding site comprising:

[0674] VH, which has

[0675] (a) VH-CDR1 comprising the amino acid sequence of SEQ ID NO.31;

[0676] (b) VH-CDR2 comprising the amino acid sequence of SEQ ID NO.32; and

[0677] (c) a VH-CDR3 comprising the amino acid sequence of SEQ ID NO. 33, and

[0678] VL, which has

[0679] (d) a VL-CDR1 comprising the amino acid sequence of SEQ ID NO.55;

[0680] (e) a VL-CDR2 comprising the amino acid sequence of SEQ ID NO.56; and

[0681] (f) a VL-CDR3 comprising the amino acid sequence of SEQ ID NO.57,

[0682] (D) an antigen binding site comprising:

[0683] VH, which has

[0684] (a) VH-CDR1 comprising the amino acid sequence of SEQ ID NO.34;

[0685] (b) a VH-CDR2 comprising the amino acid sequence of SEQ ID NO. 35; and

[0686] (c) a VH-CDR3 comprising the amino acid sequence of SEQ ID NO. 36, and

[0687] VL, which has

[0688] (d) a VL-CDR1 comprising the amino acid sequence of SEQ ID NO.58;

[0689] (e) a VL-CDR2 comprising the amino acid sequence of SEQ ID NO.59; and

[0690] (f) a VL-CDR3 comprising the amino acid sequence of SEQ ID NO.60,

[0691] The S1-B binding site is any one of the following antigen binding sites (E) to (F),

[0692] (E) an antigen binding site comprising:

[0693] VH, which has

[0694] (a) VH-CDR1 comprising the amino acid sequence of SEQ ID NO.37;

[0695] (b) VH-CDR2 comprising the amino acid sequence of SEQ ID NO.38; and

[0696] (c) a VH-CDR3 comprising the amino acid sequence of SEQ ID NO. 39, and

[0697] VL, which has

[0698] (d) a VL-CDR1 comprising the amino acid sequence of SEQ ID NO.61;

[0699] (e) a VL-CDR2 comprising the amino acid sequence of SEQ ID NO.62; and

[0700] (f) a VL-CDR3 comprising the amino acid sequence of SEQ ID NO.63,

[0701] (F) an antigen binding site comprising:

[0702] VH, which has

[0703] (a) VH-CDR1 comprising the amino acid sequence of SEQ ID NO.40,

[0704] (b) VH-CDR2 comprising the amino acid sequence of SEQ ID NO.41; and

[0705] (c) a VH-CDR3 comprising the amino acid sequence of SEQ ID NO. 42, and

[0706] VL, which has

[0707] (d) a VL-CDR1 comprising the amino acid sequence of SEQ ID NO.64;

[0708] (e) a VL-CDR2 comprising the amino acid sequence of SEQ ID NO.65; and

[0709] (f) a VL-CDR3 comprising the amino acid sequence of SEQ ID NO.66,

[0710] The S2-C binding site is an antigen binding site comprising the following VH and VL,

[0711] VH, which has

[0712] (a) VH-CDR1 comprising the amino acid sequence of SEQ ID NO.43;

[0713] (b) VH-CDR2 comprising the amino acid sequence of SEQ ID NO.44; and

[0714] (c) a VH-CDR3 comprising the amino acid sequence of SEQ ID NO.45,

[0715] VL, which has

[0716] (d) a VL-CDR1 comprising the amino acid sequence of SEQ ID NO.67;

[0717] (e) a VL-CDR2 comprising the amino acid sequence of SEQ ID NO.68; and

[0718] (f) a VL-CDR3 comprising the amino acid sequence of SEQ ID NO.69,

[0719] The S2-D binding site is an antigen binding site comprising the following VH and VL,

[0720] VH, which has

[0721] (a) VH-CDR1 comprising the amino acid sequence of SEQ ID NO.46;

[0722] (b) VH-CDR2 comprising the amino acid sequence of SEQ ID NO.47; and

[0723] (c) a VH-CDR3 comprising the amino acid sequence of SEQ ID NO.48,

[0724] VL, which has

[0725] (d) VL-CDR1 comprising the amino acid sequence of SEQ ID NO.70;

[0726] (e) a VL-CDR2 comprising the amino acid sequence of SEQ ID NO. 71; and

[0727] (f) VL-CDR3 comprising the amino acid sequence of SEQ ID NO.72.

[0728] [2] A bispecific antibody or antibody fragment thereof against allergen-1, comprising two different antigen binding sites selected from the group consisting of a S1-A binding site, a S1-B binding site, a S2-C binding site, and a S2-D binding site, wherein:

[0729] The S1-A binding site is any one of the following antigen binding sites (A) to (D),

[0730] (A) an antigen binding site comprising:

[0731] VH, which has

[0732] (a) VH-CDR1 comprising the amino acid sequence of SEQ ID NO.25;

[0733] (b) VH-CDR2 comprising the amino acid sequence of SEQ ID NO.26; and

[0734] (c) a VH-CDR3 comprising the amino acid sequence of SEQ ID NO. 27, and

[0735] VL, which has

[0736] (d) a VL-CDR1 comprising the amino acid sequence of SEQ ID NO.49;

[0737] (e) a VL-CDR2 comprising the amino acid sequence of SEQ ID NO.50; and

[0738] (f) a VL-CDR3 comprising the amino acid sequence of SEQ ID NO.51,

[0739] (B) an antigen binding site comprising:

[0740] VH, which has

[0741] (a) VH-CDR1 comprising the amino acid sequence of SEQ ID NO.28;

[0742] (b) VH-CDR2 comprising the amino acid sequence of SEQ ID NO.29; and

[0743] (c) a VH-CDR3 comprising the amino acid sequence of SEQ ID NO. 30, and

[0744] VL, which has

[0745] (d) a VL-CDR1 comprising the amino acid sequence of SEQ ID NO.52;

[0746] (e) a VL-CDR2 comprising the amino acid sequence of SEQ ID NO.53; and

[0747] (f) a VL-CDR3 comprising the amino acid sequence of SEQ ID NO.54,

[0748] (C) an antigen binding site comprising:

[0749] VH, which has

[0750] (a) VH-CDR1 comprising the amino acid sequence of SEQ ID NO.31;

[0751] (b) VH-CDR2 comprising the amino acid sequence of SEQ ID NO.32; and

[0752] (c) a VH-CDR3 comprising the amino acid sequence of SEQ ID NO. 33, and

[0753] VL, which has

[0754] (d) a VL-CDR1 comprising the amino acid sequence of SEQ ID NO.55;

[0755] (e) a VL-CDR2 comprising the amino acid sequence of SEQ ID NO.56; and

[0756] (f) a VL-CDR3 comprising the amino acid sequence of SEQ ID NO.57,

[0757] (D) an antigen binding site comprising:

[0758] VH, which has

[0759] (a) VH-CDR1 comprising the amino acid sequence of SEQ ID NO.34;

[0760] (b) VH-CDR2 comprising the amino acid sequence of SEQ ID NO.35; and

[0761] (c) a VH-CDR3 comprising the amino acid sequence of SEQ ID NO. 36, and

[0762] VL, which has

[0763] (d) a VL-CDR1 comprising the amino acid sequence of SEQ ID NO.58;

[0764] (e) a VL-CDR2 comprising the amino acid sequence of SEQ ID NO.59; and

[0765] (f) a VL-CDR3 comprising the amino acid sequence of SEQ ID NO.60,

[0766] The S1-B binding site is the following (E) or (F) antigen binding site:

[0767] (E) an antigen binding site comprising:

[0768] VH, which has

[0769] (a) VH-CDR1 comprising the amino acid sequence of SEQ ID NO.37;

[0770] (b) VH-CDR2 comprising the amino acid sequence of SEQ ID NO.38; and

[0771] (c) a VH-CDR3 comprising the amino acid sequence of SEQ ID NO. 39, and

[0772] VL, which has

[0773] (d) a VL-CDR1 comprising the amino acid sequence of SEQ ID NO.61;

[0774] (e) a VL-CDR2 comprising the amino acid sequence of SEQ ID NO.62; and

[0775] (f) a VL-CDR3 comprising the amino acid sequence of SEQ ID NO.63,

[0776] (F) an antigen binding site comprising:

[0777] VH, which has

[0778] (a) VH-CDR1 comprising the amino acid sequence of SEQ ID NO.40;

[0779] (b) VH-CDR2 comprising the amino acid sequence of SEQ ID NO.41; and

[0780] (c) a VH-CDR3 comprising the amino acid sequence of SEQ ID NO. 42, and

[0781] VL, which has

[0782] (d) a VL-CDR1 comprising the amino acid sequence of SEQ ID NO.64;

[0783] (e) a VL-CDR2 comprising the amino acid sequence of SEQ ID NO.65; and

[0784] (f) a VL-CDR3 comprising the amino acid sequence of SEQ ID NO.66,

[0785] The S2-C binding site is an antigen binding site comprising the following VH and VL,

[0786] VH, which has

[0787] (a) VH-CDR1 comprising the amino acid sequence of SEQ ID NO.43;

[0788] (b) VH-CDR2 comprising the amino acid sequence of SEQ ID NO.44; and

[0789] (c) a VH-CDR3 comprising the amino acid sequence of SEQ ID NO.45,

[0790] VL, which has

[0791] (d) a VL-CDR1 comprising the amino acid sequence of SEQ ID NO.67;

[0792] (e) a VL-CDR2 comprising the amino acid sequence of SEQ ID NO.68; and

[0793] (f) a VL-CDR3 comprising the amino acid sequence of SEQ ID NO.69,

[0794] The S2-D binding site is an antigen binding site comprising the following VH and VL,

[0795] VH, which has

[0796] (a) VH-CDR1 comprising the amino acid sequence of SEQ ID NO.46;

[0797] (b) VH-CDR2 comprising the amino acid sequence of SEQ ID NO.47; and

[0798] (c) a VH-CDR3 comprising the amino acid sequence of SEQ ID NO.48,

[0799] VL, which has

[0800] (d) VL-CDR1 comprising the amino acid sequence of SEQ ID NO.70;

[0801] (e) a VL-CDR2 comprising the amino acid sequence of SEQ ID NO. 71; and

[0802] (f) VL-CDR3 comprising the amino acid sequence of SEQ ID NO.72.

[0803] [3] The bispecific antibody or antibody fragment thereof according to item [1] or [2], wherein:

[0804] In any one or more CDRs of VH-CDR1, VH-CDR2, VH-CDR3, VL-CDR1, VL-CDR2 and VL-CDR3 constituting the antigen-binding site, any 1 to 5 amino acid residues in each are optionally replaced by other amino acids, wherein the antigen-binding site is any two different antigen-binding sites selected from the group consisting of the S1-A binding site, the S1-B binding site, the S2-C binding site and the S2-D binding site.

[0805] [4] The bispecific antibody or antibody fragment thereof according to item [1] or [2], wherein:

[0806] The two different antigen binding sites are the S1-A binding site and the S1-B binding site.

[0807] (i) The S1-A binding site is an antigen binding site comprising the following VH and VL,

[0808] VH, which has

[0809] (a) VH-CDR1 comprising the amino acid sequence of SEQ ID NO.25;

[0810] (b) VH-CDR2 comprising the amino acid sequence of SEQ ID NO.26; and

[0811] (c) a VH-CDR3 comprising the amino acid sequence of SEQ ID NO.27,

[0812] VL, which has

[0813] (d) a VL-CDR1 comprising the amino acid sequence of SEQ ID NO.49;

[0814] (e) a VL-CDR2 comprising the amino acid sequence of SEQ ID NO.50; and

[0815] (f) a VL-CDR3 comprising the amino acid sequence of SEQ ID NO.51,

[0816] (ii) The S1-B binding site is an antigen binding site comprising the following VH and VL,

[0817] VH, which has

[0818] (a) VH-CDR1 comprising the amino acid sequence of SEQ ID NO.37;

[0819] (b) VH-CDR2 comprising the amino acid sequence of SEQ ID NO.38; and

[0820] (c) a VH-CDR3 comprising the amino acid sequence of SEQ ID NO. 39,

[0821] VL, which has

[0822] (d) a VL-CDR1 comprising the amino acid sequence of SEQ ID NO.61;

[0823] (e) a VL-CDR2 comprising the amino acid sequence of SEQ ID NO.62; and

[0824] (f) VL-CDR3 comprising the amino acid sequence of SEQ ID NO.63.

[0825] [5] The bispecific antibody or antibody fragment thereof according to item [1] or [2], wherein:

[0826] The two different antigen binding sites are the S1-A binding site and the S1-B binding site.

[0827] (i) The S1-A binding site is an antigen binding site comprising the following VH and VL,

[0828] VH, which has

[0829] (a) VH-CDR1 comprising the amino acid sequence of SEQ ID NO.25;

[0830] (b) VH-CDR2 comprising the amino acid sequence of SEQ ID NO.26; and

[0831] (c) a VH-CDR3 comprising the amino acid sequence of SEQ ID NO.27,

[0832] VL, which has

[0833] (d) a VL-CDR1 comprising the amino acid sequence of SEQ ID NO.49;

[0834] (e) a VL-CDR2 comprising the amino acid sequence of SEQ ID NO.50; and

[0835] (f) a VL-CDR3 comprising the amino acid sequence of SEQ ID NO.51,

[0836] (ii) The S1-B binding site is an antigen binding site comprising the following VH and VL,

[0837] VH, which has

[0838] (a) VH-CDR1 comprising the amino acid sequence of SEQ ID NO.40;

[0839] (b) VH-CDR2 comprising the amino acid sequence of SEQ ID NO.41; and

[0840] (c) a VH-CDR3 comprising the amino acid sequence of SEQ ID NO.42,

[0841] VL, which has

[0842] (d) a VL-CDR1 comprising the amino acid sequence of SEQ ID NO.64;

[0843] (e) a VL-CDR2 comprising the amino acid sequence of SEQ ID NO.65; and

[0844] (f) VL-CDR3 comprising the amino acid sequence of SEQ ID NO.66.

[0845] [6] The bispecific antibody or antibody fragment thereof according to item [1] or [2], wherein:

[0846] The two different antigen binding sites are the S1-A binding site and the S1-B binding site.

[0847] (i) The S1-A binding site is an antigen binding site comprising the following VH and VL,

[0848] VH, which has

[0849] (a) VH-CDR1 comprising the amino acid sequence of SEQ ID NO.28;

[0850] (b) VH-CDR2 comprising the amino acid sequence of SEQ ID NO.29; and

[0851] (c) a VH-CDR3 comprising the amino acid sequence of SEQ ID NO.30,

[0852] VL, which has

[0853] (d) a VL-CDR1 comprising the amino acid sequence of SEQ ID NO.52;

[0854] (e) a VL-CDR2 comprising the amino acid sequence of SEQ ID NO.53; and

[0855] (f) a VL-CDR3 comprising the amino acid sequence of SEQ ID NO.54,

[0856] (ii) The S1-B binding site is an antigen binding site comprising the following VH and VL,

[0857] VH, which has

[0858] (a) VH-CDR1 comprising the amino acid sequence of SEQ ID NO.37;

[0859] (b) VH-CDR2 comprising the amino acid sequence of SEQ ID NO.38; and

[0860] (c) a VH-CDR3 comprising the amino acid sequence of SEQ ID NO. 39,

[0861] VL, which has

[0862] (d) a VL-CDR1 comprising the amino acid sequence of SEQ ID NO.61;

[0863] (e) a VL-CDR2 comprising the amino acid sequence of SEQ ID NO.62; and

[0864] (f) VL-CDR3 comprising the amino acid sequence of SEQ ID NO.63.

[0865] [7] The bispecific antibody or antibody fragment thereof according to item [1] or [2], wherein:

[0866] The two different antigen binding sites are the S1-A binding site and the S1-B binding site.

[0867] (i) The S1-A binding site is an antigen binding site comprising the following VH and VL,

[0868] VH, which has

[0869] (a) VH-CDR1 comprising the amino acid sequence of SEQ ID NO.28;

[0870] (b) VH-CDR2 comprising the amino acid sequence of SEQ ID NO.29; and

[0871] (c) a VH-CDR3 comprising the amino acid sequence of SEQ ID NO.30,

[0872] VL, which has

[0873] (d) a VL-CDR1 comprising the amino acid sequence of SEQ ID NO.52;

[0874] (e) a VL-CDR2 comprising the amino acid sequence of SEQ ID NO.53; and

[0875] (f) a VL-CDR3 comprising the amino acid sequence of SEQ ID NO.54,

[0876] (ii) The S1-B binding site is an antigen binding site comprising the following VH and VL,

[0877] VH, which has

[0878] (a) VH-CDR1 comprising the amino acid sequence of SEQ ID NO.40;

[0879] (b) VH-CDR2 comprising the amino acid sequence of SEQ ID NO.41; and

[0880] (c) a VH-CDR3 comprising the amino acid sequence of SEQ ID NO.42,

[0881] VL, which has

[0882] (d) a VL-CDR1 comprising the amino acid sequence of SEQ ID NO.64;

[0883] (e) a VL-CDR2 comprising the amino acid sequence of SEQ ID NO.65; and

[0884] (f) VL-CDR3 comprising the amino acid sequence of SEQ ID NO.66.

[0885] [8] The bispecific antibody or antibody fragment thereof according to item [1] or [2], wherein:

[0886] The two different antigen binding sites are the S1-A binding site and the S1-B binding site.

[0887] (i) The S1-A binding site is an antigen binding site comprising the following VH and VL,

[0888] VH, which has

[0889] (a) VH-CDR1 comprising the amino acid sequence of SEQ ID NO.31;

[0890] (b) VH-CDR2 comprising the amino acid sequence of SEQ ID NO.32; and

[0891] (c) a VH-CDR3 comprising the amino acid sequence of SEQ ID NO. 33,

[0892] VL, which has

[0893] (d) a VL-CDR1 comprising the amino acid sequence of SEQ ID NO.55;

[0894] (e) a VL-CDR2 comprising the amino acid sequence of SEQ ID NO.56; and

[0895] (f) a VL-CDR3 comprising the amino acid sequence of SEQ ID NO.57,

[0896] (ii) The S1-B binding site is an antigen binding site comprising the following VH and VL,

[0897] VH, which has

[0898] (a) VH-CDR1 comprising the amino acid sequence of SEQ ID NO.37;

[0899] (b) VH-CDR2 comprising the amino acid sequence of SEQ ID NO.38; and

[0900] (c) a VH-CDR3 comprising the amino acid sequence of SEQ ID NO. 39,

[0901] VL, which has

[0902] (d) a VL-CDR1 comprising the amino acid sequence of SEQ ID NO.61;

[0903] (e) a VL-CDR2 comprising the amino acid sequence of SEQ ID NO.62; and

[0904] (f) VL-CDR3 comprising the amino acid sequence of SEQ ID NO.63.

[0905] [9] The bispecific antibody or antibody fragment thereof according to item [1] or [2], wherein:

[0906] The two different antigen binding sites are the S1-A binding site and the S1-B binding site.

[0907] (i) The S1-A binding site is an antigen binding site comprising the following VH and VL,

[0908] VH, which has

[0909] (a) VH-CDR1 comprising the amino acid sequence of SEQ ID NO.31;

[0910] (b) VH-CDR2 comprising the amino acid sequence of SEQ ID NO.32; and

[0911] (c) a VH-CDR3 comprising the amino acid sequence of SEQ ID NO. 33,

[0912] VL, which has

[0913] (d) a VL-CDR1 comprising the amino acid sequence of SEQ ID NO.55;

[0914] (e) a VL-CDR2 comprising the amino acid sequence of SEQ ID NO.56; and

[0915] (f) a VL-CDR3 comprising the amino acid sequence of SEQ ID NO.57,

[0916] (ii) The S1-B binding site is an antigen binding site comprising the following VH and VL,

[0917] VH, which has

[0918] (a) VH-CDR1 comprising the amino acid sequence of SEQ ID NO.40;

[0919] (b) VH-CDR2 comprising the amino acid sequence of SEQ ID NO.41; and

[0920] (c) a VH-CDR3 comprising the amino acid sequence of SEQ ID NO.42,

[0921] VL, which has

[0922] (d) a VL-CDR1 comprising the amino acid sequence of SEQ ID NO.64;

[0923] (e) a VL-CDR2 comprising the amino acid sequence of SEQ ID NO.65; and

[0924] (f) VL-CDR3 comprising the amino acid sequence of SEQ ID NO.66.

[0925]

[10] The bispecific antibody or antibody fragment thereof according to item [1] or [2], wherein:

[0926] The two different antigen binding sites are the S1-A binding site and the S1-B binding site.

[0927] (i) The S1-A binding site is an antigen binding site comprising the following VH and VL,

[0928] VH, which has

[0929] (a) VH-CDR1 comprising the amino acid sequence of SEQ ID NO.34;

[0930] (b) VH-CDR2 comprising the amino acid sequence of SEQ ID NO.35; and

[0931] (c) a VH-CDR3 comprising the amino acid sequence of SEQ ID NO.36,

[0932] VL, which has

[0933] (d) a VL-CDR1 comprising the amino acid sequence of SEQ ID NO.58;

[0934] (e) a VL-CDR2 comprising the amino acid sequence of SEQ ID NO.59; and

[0935] (f) a VL-CDR3 comprising the amino acid sequence of SEQ ID NO.60,

[0936] (ii) The S1-B binding site is an antigen binding site comprising the following VH and VL,

[0937] VH, which has

[0938] (a) VH-CDR1 comprising the amino acid sequence of SEQ ID NO.37;

[0939] (b) VH-CDR2 comprising the amino acid sequence of SEQ ID NO.38; and

[0940] (c) a VH-CDR3 comprising the amino acid sequence of SEQ ID NO. 39,

[0941] VL, which has

[0942] (d) a VL-CDR1 comprising the amino acid sequence of SEQ ID NO.61;

[0943] (e) a VL-CDR2 comprising the amino acid sequence of SEQ ID NO.62; and

[0944] (f) VL-CDR3 comprising the amino acid sequence of SEQ ID NO.63.

[0945]

[11] The bispecific antibody or antibody fragment thereof according to item [1] or [2], wherein:

[0946] The two different antigen binding sites are the S1-A binding site and the S1-B binding site.

[0947] (i) The S1-A binding site is an antigen binding site comprising the following VH and VL,

[0948] VH, which has

[0949] (a) VH-CDR1 comprising the amino acid sequence of SEQ ID NO.34;

[0950] (b) a VH-CDR2 comprising the amino acid sequence of SEQ ID NO. 35; and

[0951] (c) a VH-CDR3 comprising the amino acid sequence of SEQ ID NO.36,

[0952] VL, which has

[0953] (d) a VL-CDR1 comprising the amino acid sequence of SEQ ID NO.58;

[0954] (e) a VL-CDR2 comprising the amino acid sequence of SEQ ID NO.59; and

[0955] (f) a VL-CDR3 comprising the amino acid sequence of SEQ ID NO.60,

[0956] (ii) The S1-B binding site is an antigen binding site comprising the following VH and VL,

[0957] VH, which has

[0958] (a) VH-CDR1 comprising the amino acid sequence of SEQ ID NO.40;

[0959] (b) VH-CDR2 comprising the amino acid sequence of SEQ ID NO.41; and

[0960] (c) a VH-CDR3 comprising the amino acid sequence of SEQ ID NO.42,

[0961] VL, which has

[0962] (d) a VL-CDR1 comprising the amino acid sequence of SEQ ID NO.64;

[0963] (e) a VL-CDR2 comprising the amino acid sequence of SEQ ID NO.65; and

[0964] (f) VL-CDR3 comprising the amino acid sequence of SEQ ID NO.66.

[0965]

[12] The bispecific antibody or antibody fragment thereof according to item [1] or [2], wherein:

[0966] The two different antigen binding sites are the S1-A binding site and the S2-C binding site.

[0967] (i) The S1-A binding site is an antigen binding site comprising the following VH and VL,

[0968] VH, which has

[0969] (a) VH-CDR1 comprising the amino acid sequence of SEQ ID NO.25;

[0970] (b) VH-CDR2 comprising the amino acid sequence of SEQ ID NO.26; and

[0971] (c) a VH-CDR3 comprising the amino acid sequence of SEQ ID NO.27,

[0972] VL, which has

[0973] (d) a VL-CDR1 comprising the amino acid sequence of SEQ ID NO.49;

[0974] (e) a VL-CDR2 comprising the amino acid sequence of SEQ ID NO.50; and

[0975] (f) a VL-CDR3 comprising the amino acid sequence of SEQ ID NO.51,

[0976] (ii) The S2-C binding site is an antigen binding site comprising the following VH and VL,

[0977] VH, which has

[0978] (a) VH-CDR1 comprising the amino acid sequence of SEQ ID NO.43;

[0979] (b) VH-CDR2 comprising the amino acid sequence of SEQ ID NO.44; and

[0980] (c) a VH-CDR3 comprising the amino acid sequence of SEQ ID NO.45,

[0981] VL, which has

[0982] (d) a VL-CDR1 comprising the amino acid sequence of SEQ ID NO.67;

[0983] (e) a VL-CDR2 comprising the amino acid sequence of SEQ ID NO.68; and

[0984] (f) VL-CDR3 comprising the amino acid sequence of SEQ ID NO.69.

[0985]

[13] The bispecific antibody or antibody fragment thereof according to item [1] or [2], wherein:

[0986] The two different antigen binding sites are the S1-A binding site and the S2-C binding site.

[0987] (i) The S1-A binding site is an antigen binding site comprising the following VH and VL,

[0988] VH, which has

[0989] (a) VH-CDR1 comprising the amino acid sequence of SEQ ID NO.28;

[0990] (b) VH-CDR2 comprising the amino acid sequence of SEQ ID NO.29; and

[0991] (c) a VH-CDR3 comprising the amino acid sequence of SEQ ID NO.30,

[0992] VL, which has

[0993] (d) a VL-CDR1 comprising the amino acid sequence of SEQ ID NO.52;

[0994] (e) a VL-CDR2 comprising the amino acid sequence of SEQ ID NO.53; and

[0995] (f) a VL-CDR3 comprising the amino acid sequence of SEQ ID NO.54,

[0996] (ii) The S2-C binding site is an antigen binding site comprising the following VH and VL,

[0997] VH, which has

[0998] (a) VH-CDR1 comprising the amino acid sequence of SEQ ID NO.43;

[0999] (b) VH-CDR2 comprising the amino acid sequence of SEQ ID NO.44; and

[1000] (c) a VH-CDR3 comprising the amino acid sequence of SEQ ID NO.45,

[1001] VL, which has

[1002] (d) a VL-CDR1 comprising the amino acid sequence of SEQ ID NO.67;

[1003] (e) a VL-CDR2 comprising the amino acid sequence of SEQ ID NO.68; and

[1004] (f) VL-CDR3 comprising the amino acid sequence of SEQ ID NO.69.

[1005]

[14] The bispecific antibody or antibody fragment thereof according to item [1] or [2], wherein:

[1006] The two different antigen binding sites are the S1-A binding site and the S2-C binding site.

[1007] (i) The S1-A binding site is an antigen binding site comprising the following VH and VL,

[1008] VH, which has

[1009] (a) VH-CDR1 comprising the amino acid sequence of SEQ ID NO.31;

[1010] (b) VH-CDR2 comprising the amino acid sequence of SEQ ID NO.32; and

[1011] (c) a VH-CDR3 comprising the amino acid sequence of SEQ ID NO. 33,

[1012] VL, which has

[1013] (d) a VL-CDR1 comprising the amino acid sequence of SEQ ID NO.55;

[1014] (e) a VL-CDR2 comprising the amino acid sequence of SEQ ID NO.56; and

[1015] (f) a VL-CDR3 comprising the amino acid sequence of SEQ ID NO.57,

[1016] (ii) The S2-C binding site is an antigen binding site comprising the following VH and VL,

[1017] VH, which has

[1018] (a) VH-CDR1 comprising the amino acid sequence of SEQ ID NO.43;

[1019] (b) VH-CDR2 comprising the amino acid sequence of SEQ ID NO.44; and

[1020] (c) a VH-CDR3 comprising the amino acid sequence of SEQ ID NO.45,

[1021] VL, which has

[1022] (d) a VL-CDR1 comprising the amino acid sequence of SEQ ID NO.67;

[1023] (e) a VL-CDR2 comprising the amino acid sequence of SEQ ID NO.68; and

[1024] (f) VL-CDR3 comprising the amino acid sequence of SEQ ID NO.69.

[1025]

[15] The bispecific antibody or antibody fragment thereof according to item [1] or [2], wherein:

[1026] The two different antigen binding sites are the S1-A binding site and the S2-C binding site.

[1027] (i) The S1-A binding site is an antigen binding site comprising the following VH and VL,

[1028] VH, which has

[1029] (a) VH-CDR1 comprising the amino acid sequence of SEQ ID NO.34;

[1030] (b) a VH-CDR2 comprising the amino acid sequence of SEQ ID NO. 35; and

[1031] (c) a VH-CDR3 comprising the amino acid sequence of SEQ ID NO.36,

[1032] VL, which has

[1033] (d) a VL-CDR1 comprising the amino acid sequence of SEQ ID NO.58;

[1034] (e) a VL-CDR2 comprising the amino acid sequence of SEQ ID NO.59; and

[1035] (f) a VL-CDR3 comprising the amino acid sequence of SEQ ID NO.60,

[1036] (ii) The S2-C binding site is an antigen binding site comprising the following VH and VL,

[1037] VH, which has

[1038] (a) VH-CDR1 comprising the amino acid sequence of SEQ ID NO.43;

[1039] (b) VH-CDR2 comprising the amino acid sequence of SEQ ID NO.44; and

[1040] (c) a VH-CDR3 comprising the amino acid sequence of SEQ ID NO.45,

[1041] VL, which has

[1042] (d) a VL-CDR1 comprising the amino acid sequence of SEQ ID NO.67;

[1043] (e) a VL-CDR2 comprising the amino acid sequence of SEQ ID NO.68; and

[1044] (f) VL-CDR3 comprising the amino acid sequence of SEQ ID NO.69.

[1045]

[16] The bispecific antibody or antibody fragment thereof according to item [1] or [2], wherein:

[1046] The two different antigen binding sites are the S1-A binding site and the S2-D binding site.

[1047] (i) The S1-A binding site is an antigen binding site comprising the following VH and VL,

[1048] VH, which has

[1049] (a) VH-CDR1 comprising the amino acid sequence of SEQ ID NO.25;

[1050] (b) VH-CDR2 comprising the amino acid sequence of SEQ ID NO.26; and

[1051] (c) a VH-CDR3 comprising the amino acid sequence of SEQ ID NO.27,

[1052] VL, which has

[1053] (d) a VL-CDR1 comprising the amino acid sequence of SEQ ID NO.49;

[1054] (e) a VL-CDR2 comprising the amino acid sequence of SEQ ID NO.50; and

[1055] (f) a VL-CDR3 comprising the amino acid sequence of SEQ ID NO.51,

[1056] (ii) The S2-D binding site is an antigen binding site comprising the following VH and VL,

[1057] VH, which has

[1058] (a) VH-CDR1 comprising the amino acid sequence of SEQ ID NO.46;

[1059] (b) VH-CDR2 comprising the amino acid sequence of SEQ ID NO.47; and

[1060] (c) a VH-CDR3 comprising the amino acid sequence of SEQ ID NO.48,

[1061] VL, which has

[1062] (d) VL-CDR1 comprising the amino acid sequence of SEQ ID NO.70;

[1063] (e) a VL-CDR2 comprising the amino acid sequence of SEQ ID NO. 71; and

[1064] (f) VL-CDR3 comprising the amino acid sequence of SEQ ID NO.72.

[1065]

[17] The bispecific antibody or antibody fragment thereof according to item [1] or [2], wherein:

[1066] The two different antigen binding sites are the S1-A binding site and the S2-D binding site.

[1067] (i) The S1-A binding site is an antigen binding site comprising the following VH and VL,

[1068] VH, which has

[1069] (a) VH-CDR1 comprising the amino acid sequence of SEQ ID NO.28;

[1070] (b) VH-CDR2 comprising the amino acid sequence of SEQ ID NO.29; and

[1071] (c) a VH-CDR3 comprising the amino acid sequence of SEQ ID NO.30,

[1072] VL, which has

[1073] (d) a VL-CDR1 comprising the amino acid sequence of SEQ ID NO.52;

[1074] (e) a VL-CDR2 comprising the amino acid sequence of SEQ ID NO.53; and

[1075] (f) a VL-CDR3 comprising the amino acid sequence of SEQ ID NO.54,

[1076] (ii) The S2-D binding site is an antigen binding site comprising the following VH and VL,

[1077] VH, which has

[1078] (a) VH-CDR1 comprising the amino acid sequence of SEQ ID NO.46;

[1079] (b) VH-CDR2 comprising the amino acid sequence of SEQ ID NO.47; and

[1080] (c) a VH-CDR3 comprising the amino acid sequence of SEQ ID NO.48,

[1081] VL, which has

[1082] (d) VL-CDR1 comprising the amino acid sequence of SEQ ID NO.70;

[1083] (e) a VL-CDR2 comprising the amino acid sequence of SEQ ID NO. 71; and

[1084] (f) VL-CDR3 comprising the amino acid sequence of SEQ ID NO.72.

[1085]

[18] The bispecific antibody or antibody fragment thereof according to item [1] or [2], wherein:

[1086] The two different antigen binding sites are the S1-A binding site and the S2-D binding site.

[1087] (i) The S1-A binding site is an antigen binding site comprising the following VH and VL,

[1088] VH, which has

[1089] (a) VH-CDR1 comprising the amino acid sequence of SEQ ID NO.31;

[1090] (b) VH-CDR2 comprising the amino acid sequence of SEQ ID NO.32; and

[1091] (c) a VH-CDR3 comprising the amino acid sequence of SEQ ID NO. 33,

[1092] VL, which has

[1093] (d) a VL-CDR1 comprising the amino acid sequence of SEQ ID NO.55;

[1094] (e) a VL-CDR2 comprising the amino acid sequence of SEQ ID NO.56; and

[1095] (f) a VL-CDR3 comprising the amino acid sequence of SEQ ID NO.57,

[1096] (ii) The S2-D binding site is an antigen binding site comprising the following VH and VL,

[1097] VH, which has

[1098] (a) VH-CDR1 comprising the amino acid sequence of SEQ ID NO.46;

[1099] (b) VH-CDR2 comprising the amino acid sequence of SEQ ID NO.47; and

[1100] (c) a VH-CDR3 comprising the amino acid sequence of SEQ ID NO.48,

[1101] VL, which has

[1102] (d) VL-CDR1 comprising the amino acid sequence of SEQ ID NO.70;

[1103] (e) a VL-CDR2 comprising the amino acid sequence of SEQ ID NO. 71; and

[1104] (f) VL-CDR3 comprising the amino acid sequence of SEQ ID NO.72.

[1105]

[19] The bispecific antibody or antibody fragment thereof according to item [1] or [2], wherein:

[1106] The two different antigen binding sites are the S1-A binding site and the S2-D binding site.

[1107] (i) The S1-A binding site is an antigen binding site comprising the following VH and VL,

[1108] VH, which has

[1109] (a) VH-CDR1 comprising the amino acid sequence of SEQ ID NO.34;

[1110] (b) VH-CDR2 comprising the amino acid sequence of SEQ ID NO.35; and

[1111] (c) a VH-CDR3 comprising the amino acid sequence of SEQ ID NO.36,

[1112] VL, which has

[1113] (d) a VL-CDR1 comprising the amino acid sequence of SEQ ID NO.58;

[1114] (e) a VL-CDR2 comprising the amino acid sequence of SEQ ID NO.59; and

[1115] (f) a VL-CDR3 comprising the amino acid sequence of SEQ ID NO.60,

[1116] (ii) The S2-D binding site is an antigen binding site comprising the following VH and VL,

[1117] VH, which has

[1118] (a) VH-CDR1 comprising the amino acid sequence of SEQ ID NO.46;

[1119] (b) VH-CDR2 comprising the amino acid sequence of SEQ ID NO.47; and

[1120] (c) a VH-CDR3 comprising the amino acid sequence of SEQ ID NO.48,

[1121] VL, which has

[1122] (d) VL-CDR1 comprising the amino acid sequence of SEQ ID NO.70;

[1123] (e) a VL-CDR2 comprising the amino acid sequence of SEQ ID NO. 71; and

[1124] (f) VL-CDR3 comprising the amino acid sequence of SEQ ID NO.72.

[1125]

[20] The bispecific antibody or antibody fragment thereof according to item [1] or [2], wherein:

[1126] The two different antigen binding sites are the S1-B binding site and the S2-C binding site.

[1127] (i) The S1-B binding site is an antigen binding site comprising the following VH and VL,

[1128] VH, which has

[1129] (a) VH-CDR1 comprising the amino acid sequence of SEQ ID NO.37;

[1130] (b) VH-CDR2 comprising the amino acid sequence of SEQ ID NO.38; and

[1131] (c) a VH-CDR3 comprising the amino acid sequence of SEQ ID NO. 39,

[1132] VL, which has

[1133] (d) a VL-CDR1 comprising the amino acid sequence of SEQ ID NO.61;

[1134] (e) a VL-CDR2 comprising the amino acid sequence of SEQ ID NO.62; and

[1135] (f) a VL-CDR3 comprising the amino acid sequence of SEQ ID NO.63,

[1136] (ii) The S2-C binding site is an antigen binding site comprising the following VH and VL,

[1137] VH, which has

[1138] (a) VH-CDR1 comprising the amino acid sequence of SEQ ID NO.43;

[1139] (b) VH-CDR2 comprising the amino acid sequence of SEQ ID NO.44; and

[1140] (c) a VH-CDR3 comprising the amino acid sequence of SEQ ID NO.45,

[1141] VL, which has

[1142] (d) a VL-CDR1 comprising the amino acid sequence of SEQ ID NO.67;

[1143] (e) a VL-CDR2 comprising the amino acid sequence of SEQ ID NO.68; and

[1144] (f) VL-CDR3 comprising the amino acid sequence of SEQ ID NO.69.

[1145]

[21] The bispecific antibody or antibody fragment thereof according to item [1] or [2], wherein:

[1146] The two different antigen binding sites are the S1-B binding site and the S2-C binding site.

[1147] (i) The S1-B binding site is an antigen binding site comprising the following VH and VL,

[1148] VH, which has

[1149] (a) VH-CDR1 comprising the amino acid sequence of SEQ ID NO.40,

[1150] (b) VH-CDR2 comprising the amino acid sequence of SEQ ID NO.41; and

[1151] (c) a VH-CDR3 comprising the amino acid sequence of SEQ ID NO.42,

[1152] VL, which has

[1153] (d) a VL-CDR1 comprising the amino acid sequence of SEQ ID NO.64;

[1154] (e) a VL-CDR2 comprising the amino acid sequence of SEQ ID NO.65; and

[1155] (f) a VL-CDR3 comprising the amino acid sequence of SEQ ID NO.66,

[1156] (ii) The S2-C binding site is an antigen binding site comprising the following VH and VL,

[1157] VH, which has

[1158] (a) VH-CDR1 comprising the amino acid sequence of SEQ ID NO.43;

[1159] (b) VH-CDR2 comprising the amino acid sequence of SEQ ID NO.44; and

[1160] (c) a VH-CDR3 comprising the amino acid sequence of SEQ ID NO.45,

[1161] VL, which has

[1162] (d) a VL-CDR1 comprising the amino acid sequence of SEQ ID NO.67;

[1163] (e) a VL-CDR2 comprising the amino acid sequence of SEQ ID NO.68; and

[1164] (f) VL-CDR3 comprising the amino acid sequence of SEQ ID NO.69.

[1165]

[22] The bispecific antibody or antibody fragment thereof according to item [1] or [2], wherein:

[1166] The two different antigen binding sites are the S1-B binding site and the S2-D binding site.

[1167] (i) The S1-B binding site is an antigen binding site comprising the following VH and VL,

[1168] VH, which has

[1169] (a) VH-CDR1 comprising the amino acid sequence of SEQ ID NO.37;

[1170] (b) VH-CDR2 comprising the amino acid sequence of SEQ ID NO.38; and

[1171] (c) a VH-CDR3 comprising the amino acid sequence of SEQ ID NO. 39,

[1172] VL, which has

[1173] (d) a VL-CDR1 comprising the amino acid sequence of SEQ ID NO.61;

[1174] (e) a VL-CDR2 comprising the amino acid sequence of SEQ ID NO.62; and

[1175] (f) a VL-CDR3 comprising the amino acid sequence of SEQ ID NO.63,

[1176] (ii) The S2-D binding site is an antigen binding site comprising the following VH and VL,

[1177] VH, which has

[1178] (a) VH-CDR1 comprising the amino acid sequence of SEQ ID NO.46;

[1179] (b) VH-CDR2 comprising the amino acid sequence of SEQ ID NO.47; and

[1180] (c) a VH-CDR3 comprising the amino acid sequence of SEQ ID NO.48,

[1181] VL, which has

[1182] (d) VL-CDR1 comprising the amino acid sequence of SEQ ID NO.70;

[1183] (e) a VL-CDR2 comprising the amino acid sequence of SEQ ID NO. 71; and

[1184] (f) VL-CDR3 comprising the amino acid sequence of SEQ ID NO.72.

[1185]

[23] The bispecific antibody or antibody fragment thereof according to item [1] or [2], wherein:

[1186] The two different antigen binding sites are the S1-B binding site and the S2-D binding site.

[1187] (i) The S1-B binding site is an antigen binding site comprising the following VH and VL,

[1188] VH, which has

[1189] (a) VH-CDR1 comprising the amino acid sequence of SEQ ID NO.40,

[1190] (b) VH-CDR2 comprising the amino acid sequence of SEQ ID NO.41; and

[1191] (c) a VH-CDR3 comprising the amino acid sequence of SEQ ID NO.42,

[1192] VL, which has

[1193] (d) a VL-CDR1 comprising the amino acid sequence of SEQ ID NO.64;

[1194] (e) a VL-CDR2 comprising the amino acid sequence of SEQ ID NO.65; and

[1195] (f) a VL-CDR3 comprising the amino acid sequence of SEQ ID NO.66,

[1196] (ii) The S2-D binding site is an antigen binding site comprising the following VH and VL,

[1197] VH, which has

[1198] (a) VH-CDR1 comprising the amino acid sequence of SEQ ID NO.46;

[1199] (b) VH-CDR2 comprising the amino acid sequence of SEQ ID NO.47; and

[1200] (c) a VH-CDR3 comprising the amino acid sequence of SEQ ID NO.48,

[1201] VL, which has

[1202] (d) VL-CDR1 comprising the amino acid sequence of SEQ ID NO.70;

[1203] (e) a VL-CDR2 comprising the amino acid sequence of SEQ ID NO. 71; and

[1204] (f) VL-CDR3 comprising the amino acid sequence of SEQ ID NO.72.

[1205]

[24] The bispecific antibody or antibody fragment thereof according to item [1] or [2], wherein:

[1206] The two different antigen binding sites are the S2-C binding site and the S2-D binding site.

[1207] (i) The S2-C binding site is an antigen binding site comprising the following VH and VL,

[1208] VH, which has

[1209] (a) VH-CDR1 comprising the amino acid sequence of SEQ ID NO.43;

[1210] (b) VH-CDR2 comprising the amino acid sequence of SEQ ID NO.44; and

[1211] (c) a VH-CDR3 comprising the amino acid sequence of SEQ ID NO.45,

[1212] VL, which has

[1213] (d) a VL-CDR1 comprising the amino acid sequence of SEQ ID NO.67;

[1214] (e) a VL-CDR2 comprising the amino acid sequence of SEQ ID NO.68; and

[1215] (f) a VL-CDR3 comprising the amino acid sequence of SEQ ID NO.69,

[1216] (ii) The S2-D binding site is an antigen binding site comprising the following VH and VL,

[1217] VH, which has

[1218] (a) VH-CDR1 comprising the amino acid sequence of SEQ ID NO.46;

[1219] (b) VH-CDR2 comprising the amino acid sequence of SEQ ID NO.47; and

[1220] (c) a VH-CDR3 comprising the amino acid sequence of SEQ ID NO.48,

[1221] VL, which has

[1222] (d) VL-CDR1 comprising the amino acid sequence of SEQ ID NO.70;

[1223] (e) a VL-CDR2 comprising the amino acid sequence of SEQ ID NO. 71; and

[1224] (f) VL-CDR3 comprising the amino acid sequence of SEQ ID NO.72.

[1225]

[25] The bispecific antibody or antibody fragment thereof according to any one of items [1] to

[24] , wherein:

[1226] The FW of each VH constituting an antigen-binding site comprises an amino acid sequence encoded by the germline VH gene IGHV3-66 or said gene in which one or more somatic mutations and / or back mutations have occurred, wherein the antigen-binding site is two different antigen-binding sites selected from the group consisting of an S1-A binding site, an S1-B binding site, an S2-C binding site, and an S2-D binding site, and / or

[1227] The FW of each VL constituting each of the antigen-binding sites comprises an amino acid sequence encoded by the germline VL gene IGKV1-39 or the gene in which one or more somatic mutations and / or back mutations have occurred.

[1228]

[26] The bispecific antibody or antibody fragment thereof according to any one of items [1] to

[25] , wherein:

[1229] The S1-A binding site is composed of VH and VL, wherein VH and VL comprise: any one of the following groups of amino acid sequences, or a group of amino acid sequences that are each independently at least 80%, 90%, 95%, 98% or 99% identical to each of the above amino acid sequences (excluding each of the three CDRs),

[1230] (a) SEQ ID NO. 1 and SEQ ID NO. 12 or 104;

[1231] (b) SEQ ID NO. 2 and SEQ ID NO. 13 or 105;

[1232] (c) SEQ ID NO. 3 and SEQ ID NO. 14 or 106;

[1233] (d) SEQ ID NO. 4 and SEQ ID NO. 15 or 107;

[1234] (e) SEQ ID NO. 5 and SEQ ID NO. 16 or 108; and

[1235] (f) SEQ ID NO. 6 and SEQ ID NO. 17 or 109.

[1236]

[27] The bispecific antibody or antibody fragment thereof according to any one of items [1] to

[26] , wherein:

[1237] The S1-B binding site is composed of VH and VL, and the VH and VL comprise: the following set of amino acid sequences, or a set of amino acid sequences that are each independently at least 80%, 90%, 95%, 98% or 99% identical to each of the amino acid sequences (excluding each of the three CDRs),

[1238] (a) SEQ ID NO. 7 and SEQ ID NO. 18 or 110; or

[1239] (b) SEQ ID NO. 8 and SEQ ID NO. 19 or 111.

[1240]

[28] The bispecific antibody or antibody fragment thereof according to any one of items [1] to

[27] , wherein:

[1241] The S2-C binding site is composed of VH and VL, and the VH and VL comprise: a group of amino acid sequences of SEQ ID NO.9 and SEQ ID NO.20 or 112, or a group of amino acid sequences that are independently at least 80%, 90%, 95%, 98% or 99% identical to each of the amino acid sequences (excluding each of the three CDRs).

[1242]

[29] The bispecific antibody or antibody fragment thereof according to any one of items [1] to

[28] , wherein:

[1243] The S2-D binding site is composed of VH and VL, and the VH and VL comprise: the following set of amino acid sequences, or a set of amino acid sequences that are each independently at least 80%, 90%, 95%, 98% or 99% identical to each of the amino acid sequences (excluding each of the three CDRs),

[1244] (a) SEQ ID NO. 10 and SEQ ID NO. 21 or 113; or

[1245] (b) SEQ ID NO.11 and SEQ ID NO.22 or 114.

[1246]

[30] The bispecific antibody or antibody fragment thereof according to any one of items [1] to

[26] , wherein:

[1247] The S1-A binding site is composed of VH and VL, and the VH and VL contain any one of the amino acid sequences selected from the following sequence groups:

[1248] (a) SEQ ID NO. 1 and SEQ ID NO. 12 or 104;

[1249] (b) SEQ ID NO. 2 and SEQ ID NO. 13 or 105;

[1250] (c) SEQ ID NO. 3 and SEQ ID NO. 14 or 106;

[1251] (d) SEQ ID NO. 4 and SEQ ID NO. 15 or 107;

[1252] (e) SEQ ID NO. 5 and SEQ ID NO. 16 or 108; and

[1253] (f) SEQ ID NO. 6 and SEQ ID NO. 17 or 109.

[1254]

[31] The bispecific antibody or antibody fragment thereof according to any one of items [1] to

[25] ,

[27] and

[30] , wherein:

[1255] The S1-B binding site is composed of VH and VL, and the VH and VL contain the following set of amino acid sequences:

[1256] (a) SEQ ID NO. 7 and SEQ ID NO. 18 or 110; or

[1257] (b) SEQ ID NO. 8 and SEQ ID NO. 19 or 111.

[1258]

[32] The bispecific antibody or antibody fragment thereof according to any one of items [1] to

[25] ,

[28] ,

[30] and

[31] , wherein:

[1259] The S2-C binding site is composed of VH and VL comprising a set of amino acid sequences of SEQ ID NO.9 and SEQ ID NO.20 or 112.

[1260]

[33] The bispecific antibody or antibody fragment thereof according to any one of items [1] to

[25] and

[29] to

[32] , wherein:

[1261] The S2-D binding site is composed of VH and VL, and the VH and VL contain the following set of amino acid sequences:

[1262] (a) SEQ ID NO. 10 and SEQ ID NO. 21 or 113; or

[1263] (b) SEQ ID NO.11 and SEQ ID NO.22 or 114.

[1264]

[34] A bispecific antibody or an antibody fragment thereof, which has two antigen-binding sites that specifically bind to different epitopes in the extracellular domain of allergen-1, wherein:

[1265] The antigen binding sites do not compete with each other for allergen-1, and are two different optional antigen binding sites selected from the group consisting of the S1-A binding site, the S1-B binding site, the S2-C binding site, and the S2-D binding site.

[1266] (i) the S1-A binding site is composed of VH and VL, wherein VH and VL comprise: an amino acid sequence selected from any one of the following sequence groups, or a group of amino acid sequences that are each independently at least 80%, 90%, 95%, 98% or 99% identical to each of the above amino acid sequences (excluding each of the three CDRs),

[1267] (a) SEQ ID NO. 1 and SEQ ID NO. 12 or 104;

[1268] (b) SEQ ID NO. 2 and SEQ ID NO. 13 or 105;

[1269] (c) SEQ ID NO. 3 and SEQ ID NO. 14 or 106;

[1270] (d) SEQ ID NO. 4 and SEQ ID NO. 15 or 107;

[1271] (e) SEQ ID NO. 5 and SEQ ID NO. 16 or 108; and

[1272] (f) SEQ ID NO. 6 and SEQ ID NO. 17 or 109,

[1273] (ii) the S1-B binding site is composed of VH and VL, wherein VH and VL comprise: the following set of amino acid sequences, or a set of amino acid sequences that are each independently at least 80%, 90%, 95%, 98% or 99% identical to each of the above amino acid sequences (excluding each of the three CDRs),

[1274] (a) SEQ ID NO. 7 and SEQ ID NO. 18 or 110; or

[1275] (b) SEQ ID NO. 8 and SEQ ID NO. 19 or 111,

[1276] (iii) the S2-C binding site is composed of VH and VL, wherein VH and VL comprise: a group of amino acid sequences of SEQ ID NO. 9 and SEQ ID NO. 20 or 112, or a group of amino acid sequences that are independently at least 80%, 90%, 95%, 98% or 99% identical to each of the amino acid sequences (excluding each of the three CDRs),

[1277] (iv) the S2-D binding site is composed of VH and VL, wherein VH and VL comprise: the following set of amino acid sequences, or a set of amino acid sequences that are each independently at least 80%, 90%, 95%, 98% or 99% identical to each of the above amino acid sequences (excluding each of the three CDRs),

[1278] (a) SEQ ID NO. 10 and SEQ ID NO. 21 or 113; or

[1279] (b) SEQ ID NO.11 and SEQ ID NO.22 or 114.

[1280]

[35] A bispecific antibody or antibody fragment thereof against allergen-1, comprising two different antigen binding sites selected from the group consisting of a S1-A binding site, a S1-B binding site, a S2-C binding site, and a S2-D binding site, wherein:

[1281] (i) the S1-A binding site is composed of VH and VL, wherein VH and VL comprise: an amino acid sequence selected from any one of the following sequence groups, or a group of amino acid sequences that are each independently at least 80%, 90%, 95%, 98% or 99% identical to each of the above amino acid sequences (excluding each of the three CDRs),

[1282] (a) SEQ ID NO. 1 and SEQ ID NO. 12 or 104;

[1283] (b) SEQ ID NO. 2 and SEQ ID NO. 13 or 105;

[1284] (c) SEQ ID NO. 3 and SEQ ID NO. 14 or 106;

[1285] (d) SEQ ID NO. 4 and SEQ ID NO. 15 or 107;

[1286] (e) SEQ ID NO. 5 and SEQ ID NO. 16 or 108; and

[1287] (f) SEQ ID NO. 6 and SEQ ID NO. 17 or 109,

[1288] (ii) the S1-B binding site is composed of VH and VL, wherein VH and VL comprise: the following set of amino acid sequences, or a set of amino acid sequences that are each independently at least 80%, 90%, 95%, 98% or 99% identical to each of the above amino acid sequences (excluding each of the three CDRs),

[1289] (a) SEQ ID NO. 7 and SEQ ID NO. 18 or 110; or

[1290] (b) SEQ ID NO. 8 and SEQ ID NO. 19 or 111,

[1291] (iii) the S2-C binding site is composed of VH and VL, wherein VH and VL comprise: a group of amino acid sequences of SEQ ID NO. 9 and SEQ ID NO. 20 or 112, or a group of amino acid sequences that are independently at least 80%, 90%, 95%, 98% or 99% identical to each of the amino acid sequences (excluding each of the three CDRs),

[1292] (iv) the S2-D binding site is composed of VH and VL, wherein VH and VL comprise: the following set of amino acid sequences, or a set of amino acid sequences that are each independently at least 80%, 90%, 95%, 98% or 99% identical to each of the above amino acid sequences (excluding each of the three CDRs),

[1293] (a) SEQ ID NO. 10 and SEQ ID NO. 21 or 113; or

[1294] (b) SEQ ID NO.11 and SEQ ID NO.22 or 114.

[1295]

[36] The bispecific antibody or antibody fragment thereof according to item

[34] or

[35] , wherein:

[1296] (i) The S1-A binding site is composed of VH and VL, wherein VH and VL comprise any one of the following amino acid sequences:

[1297] (a) SEQ ID NO. 1 and SEQ ID NO. 12 or 104;

[1298] (b) SEQ ID NO. 2 and SEQ ID NO. 13 or 105;

[1299] (c) SEQ ID NO. 3 and SEQ ID NO. 14 or 106;

[1300] (d) SEQ ID NO. 4 and SEQ ID NO. 15 or 107;

[1301] (e) SEQ ID NO. 5 and SEQ ID NO. 16 or 108; and

[1302] (f) SEQ ID NO. 6 and SEQ ID NO. 17 or 109,

[1303] (ii) The S1-B binding site is composed of VH and VL, and the VH and VL comprise the following set of amino acid sequences:

[1304] (a) SEQ ID NO. 7 and SEQ ID NO. 18 or 110; or

[1305] (b) SEQ ID NO. 8 and SEQ ID NO. 19 or 111,

[1306] (iii) VH and VL constituting the S2-C binding site are composed of VH and VL comprising a set of amino acid sequences of SEQ ID NO. 9 and SEQ ID NO. 20 or 112,

[1307] (iv) The S2-D binding site is composed of VH and VL, and the VH and VL contain the following set of amino acid sequences:

[1308] (a) SEQ ID NO. 10 and SEQ ID NO. 21 or 113; or

[1309] (b) SEQ ID NO.11 and SEQ ID NO.22 or 114.

[1310]

[37] The bispecific antibody or antibody fragment thereof according to any one of items [1], [2],

[25] and

[34] to

[36] , wherein:

[1311] The two different antigen binding sites are the S1-A binding site and the S1-B binding site. The S1-A binding site is composed of VH and VL of a group of amino acid sequences including SEQ ID NO.1 and SEQ ID NO.12 or 104, and the S1-B binding site is composed of VH and VL of a group of amino acid sequences including SEQ ID NO.7 and SEQ ID NO.18 or 110.

[1312]

[38] The bispecific antibody or antibody fragment thereof according to any one of items [1], [2],

[25] and

[34] to

[36] , wherein:

[1313] The two different antigen binding sites are the S1-A binding site and the S1-B binding site. The S1-A binding site is composed of VH and VL of a group of amino acid sequences including SEQ ID NO.2 and SEQ ID NO.13 or 105, and the S1-B binding site is composed of VH and VL of a group of amino acid sequences including SEQ ID NO.7 and SEQ ID NO.18 or 110.

[1314]

[39] The bispecific antibody or antibody fragment thereof according to any one of items [1], [2],

[25] and

[34] to

[36] , wherein:

[1315] The two different antigen binding sites are the S1-A binding site and the S1-B binding site. The S1-A binding site is composed of VH and VL of a group of amino acid sequences including SEQ ID NO.3 and SEQ ID NO.14 or 106, and the S1-B binding site is composed of VH and VL of a group of amino acid sequences including SEQ ID NO.7 and SEQ ID NO.18 or 110.

[1316]

[40] The bispecific antibody or antibody fragment thereof according to any one of items [1], [2],

[25] and

[34] to

[36] , wherein:

[1317] The two different antigen binding sites are the S1-A binding site and the S1-B binding site. The S1-A binding site is composed of VH and VL of a group of amino acid sequences including SEQ ID NO.4 and SEQ ID NO.15 or 107, and the S1-B binding site is composed of VH and VL of a group of amino acid sequences including SEQ ID NO.7 and SEQ ID NO.18 or 110.

[1318]

[41] The bispecific antibody or antibody fragment thereof according to any one of items [1], [2],

[25] and

[34] to

[36] , wherein:

[1319] The two different antigen binding sites are the S1-A binding site and the S1-B binding site. The S1-A binding site is composed of VH and VL of a group of amino acid sequences comprising SEQ ID NO.5 and SEQ ID NO.16 or 108, and the S1-B binding site is composed of VH and VL of a group of amino acid sequences comprising SEQ ID NO.7 and SEQ ID NO.18 or 110.

[1320]

[42] The bispecific antibody or antibody fragment thereof according to any one of items [1], [2],

[25] and

[34] to

[36] , wherein:

[1321] The two different antigen binding sites are the S1-A binding site and the S1-B binding site. The S1-A binding site is composed of VH and VL of a group of amino acid sequences including SEQ ID NO.6 and SEQ ID NO.17 or 109, and the S1-B binding site is composed of VH and VL of a group of amino acid sequences including SEQ ID NO.7 and SEQ ID NO.18 or 110.

[1322]

[43] The bispecific antibody or antibody fragment thereof according to any one of items [1], [2],

[25] and

[34] to

[36] , wherein:

[1323] The two different antigen binding sites are the S1-A binding site and the S1-B binding site. The S1-A binding site is composed of VH and VL of a group of amino acid sequences including SEQ ID NO.1 and SEQ ID NO.12 or 104, and the S1-B binding site is composed of VH and VL of a group of amino acid sequences including SEQ ID NO.8 and SEQ ID NO.19 or 111.

[1324]

[44] The bispecific antibody or antibody fragment thereof according to any one of items [1], [2],

[25] and

[34] to

[36] , wherein:

[1325] The two different antigen binding sites are the S1-A binding site and the S1-B binding site. The S1-A binding site is composed of VH and VL of a group of amino acid sequences including SEQ ID NO.2 and SEQ ID NO.13 or 105, and the S1-B binding site is composed of VH and VL of a group of amino acid sequences including SEQ ID NO.8 and SEQ ID NO.19 or 111.

[1326]

[45] The bispecific antibody or antibody fragment thereof according to any one of items [1], [2],

[25] and

[34] to

[36] , wherein:

[1327] The two different antigen binding sites are the S1-A binding site and the S1-B binding site. The S1-A binding site is composed of VH and VL of a group of amino acid sequences including SEQ ID NO.3 and SEQ ID NO.14 or 106, and the S1-B binding site is composed of VH and VL of a group of amino acid sequences including SEQ ID NO.8 and SEQ ID NO.19 or 111.

[1328]

[46] The bispecific antibody or antibody fragment thereof according to any one of items [1], [2],

[25] and

[34] to

[36] , wherein:

[1329] The two different antigen binding sites are the S1-A binding site and the S1-B binding site. The S1-A binding site is composed of VH and VL of a group of amino acid sequences including SEQ ID NO.4 and SEQ ID NO.15 or 107, and the S1-B binding site is composed of VH and VL of a group of amino acid sequences including SEQ ID NO.8 and SEQ ID NO.19 or 111.

[1330]

[47] The bispecific antibody or antibody fragment thereof according to any one of items [1], [2],

[25] and

[34] to

[36] , wherein:

[1331] The two different antigen binding sites are the S1-A binding site and the S1-B binding site. The S1-A binding site is composed of VH and VL of a group of amino acid sequences including SEQ ID NO.5 and SEQ ID NO.16 or 108, and the S1-B binding site is composed of VH and VL of a group of amino acid sequences including SEQ ID NO.8 and SEQ ID NO.19 or 111.

[1332]

[48] ​​The bispecific antibody or antibody fragment thereof according to any one of items [1], [2],

[25] and

[34] to

[36] , wherein:

[1333] The two different antigen binding sites are the S1-A binding site and the S1-B binding site. The S1-A binding site is composed of VH and VL of a group of amino acid sequences including SEQ ID NO.6 and SEQ ID NO.17 or 109, and the S1-B binding site is composed of VH and VL of a group of amino acid sequences including SEQ ID NO.8 and SEQ ID NO.19 or 111.

[1334]

[49] The bispecific antibody or antibody fragment thereof according to any one of items [1], [2],

[25] and

[34] to

[36] , wherein:

[1335] The two different antigen binding sites are the S1-A binding site and the S2-C binding site. The S1-A binding site is composed of VH and VL of a group of amino acid sequences including SEQ ID NO.1 and SEQ ID NO.12 or 104, and the S2-C binding site is composed of VH and VL of a group of amino acid sequences including SEQ ID NO.9 and SEQ ID NO.20 or 112.

[1336]

[50] The bispecific antibody or antibody fragment thereof according to any one of items [1], [2],

[25] and

[34] to

[36] , wherein:

[1337] The two different antigen binding sites are the S1-A binding site and the S2-C binding site. The S1-A binding site is composed of VH and VL of a group of amino acid sequences including SEQ ID NO.2 and SEQ ID NO.13 or 105, and the S2-C binding site is composed of VH and VL of a group of amino acid sequences including SEQ ID NO.9 and SEQ ID NO.20 or 112.

[1338]

[51] The bispecific antibody or antibody fragment thereof according to any one of items [1], [2],

[25] and

[34] to

[36] , wherein:

[1339] The two different antigen binding sites are the S1-A binding site and the S2-C binding site. The S1-A binding site is composed of VH and VL of a group of amino acid sequences including SEQ ID NO.3 and SEQ ID NO.14 or 106, and the S2-C binding site is composed of VH and VL of a group of amino acid sequences including SEQ ID NO.9 and SEQ ID NO.20 or 112.

[1340]

[52] The bispecific antibody or antibody fragment thereof according to any one of items [1], [2],

[25] and

[34] to

[36] , wherein:

[1341] The two different antigen binding sites are the S1-A binding site and the S2-C binding site. The S1-A binding site is composed of VH and VL of a group of amino acid sequences including SEQ ID NO.4 and SEQ ID NO.15 or 107, and the S2-C binding site is composed of VH and VL of a group of amino acid sequences including SEQ ID NO.9 and SEQ ID NO.20 or 112.

[1342]

[53] The bispecific antibody or antibody fragment thereof according to any one of items [1], [2],

[25] and

[34] to

[36] , wherein:

[1343] The two different antigen binding sites are the S1-A binding site and the S2-C binding site. The S1-A binding site is composed of VH and VL of a group of amino acid sequences including SEQ ID NO.5 and SEQ ID NO.16 or 108, and the S2-C binding site is composed of VH and VL of a group of amino acid sequences including SEQ ID NO.9 and SEQ ID NO.20 or 112.

[1344]

[54] The bispecific antibody or antibody fragment thereof according to any one of items [1], [2],

[25] and

[34] to

[36] , wherein:

[1345] The two different antigen binding sites are the S1-A binding site and the S2-C binding site. The S1-A binding site is composed of VH and VL of a group of amino acid sequences comprising SEQ ID NO.6 and SEQ ID NO.17 or 109, and the S2-C binding site is composed of VH and VL of a group of amino acid sequences comprising SEQ ID NO.9 and SEQ ID NO.20 or 112.

[1346]

[55] The bispecific antibody or antibody fragment thereof according to any one of items [1], [2],

[25] and

[34] to

[36] , wherein:

[1347] The two different antigen binding sites are the S1-A binding site and the S2-D binding site. The S1-A binding site is composed of VH and VL of a group of amino acid sequences including SEQ ID NO.1 and SEQ ID NO.12 or 104, and the S2-D binding site is composed of VH and VL of a group of amino acid sequences including SEQ ID NO.10 and SEQ ID NO.21 or 113.

[1348]

[56] The bispecific antibody or antibody fragment thereof according to any one of items [1], [2],

[25] and

[34] to

[36] , wherein:

[1349] The two different antigen binding sites are the S1-A binding site and the S2-D binding site. The S1-A binding site is composed of VH and VL of a group of amino acid sequences comprising SEQ ID NO.2 and SEQ ID NO.13 or 105, and the S2-D binding site is composed of VH and VL of a group of amino acid sequences comprising SEQ ID NO.10 and SEQ ID NO.21 or 113.

[1350]

[57] The bispecific antibody or antibody fragment thereof according to any one of items [1], [2],

[25] and

[34] to

[36] , wherein:

[1351] The two different antigen binding sites are the S1-A binding site and the S2-D binding site. The S1-A binding site is composed of VH and VL of a group of amino acid sequences including SEQ ID NO.3 and SEQ ID NO.14 or 106, and the S2-D binding site is composed of VH and VL of a group of amino acid sequences including SEQ ID NO.10 and SEQ ID NO.21 or 113.

[1352]

[58] The bispecific antibody or antibody fragment thereof according to any one of items [1], [2],

[25] and

[34] to

[36] , wherein:

[1353] The two different antigen binding sites are the S1-A binding site and the S2-D binding site. The S1-A binding site is composed of VH and VL of a group of amino acid sequences including SEQ ID NO.4 and SEQ ID NO.15 or 107, and the S2-D binding site is composed of VH and VL of a group of amino acid sequences including SEQ ID NO.10 and SEQ ID NO.21 or 113.

[1354]

[59] The bispecific antibody or antibody fragment thereof according to any one of items [1], [2],

[25] and

[34] to

[36] , wherein:

[1355] The two different antigen binding sites are the S1-A binding site and the S2-D binding site. The S1-A binding site is composed of VH and VL of a group of amino acid sequences including SEQ ID NO.5 and SEQ ID NO.16 or 108, and the S2-D binding site is composed of VH and VL of a group of amino acid sequences including SEQ ID NO.10 and SEQ ID NO.21 or 113.

[1356]

[60] The bispecific antibody or antibody fragment thereof according to any one of items [1], [2],

[25] and

[34] to

[36] , wherein:

[1357] The two different antigen binding sites are the S1-A binding site and the S2-D binding site. The S1-A binding site is composed of VH and VL of a group of amino acid sequences including SEQ ID NO.6 and SEQ ID NO.17 or 109, and the S2-D binding site is composed of VH and VL of a group of amino acid sequences including SEQ ID NO.10 and SEQ ID NO.21 or 113.

[1358]

[61] The bispecific antibody or antibody fragment thereof according to any one of items [1], [2],

[25] and

[34] to

[36] , wherein:

[1359] The two different antigen binding sites are the S1-A binding site and the S2-D binding site. The S1-A binding site is composed of VH and VL of a group of amino acid sequences including SEQ ID NO.1 and SEQ ID NO.12 or 104, and the S2-D binding site is composed of VH and VL of a group of amino acid sequences including SEQ ID NO.11 and SEQ ID NO.22 or 114.

[1360]

[62] The bispecific antibody or antibody fragment thereof according to any one of items [1], [2],

[25] and

[34] to

[36] , wherein:

[1361] The two different antigen binding sites are the S1-A binding site and the S2-D binding site. The S1-A binding site is composed of VH and VL of a group of amino acid sequences including SEQ ID NO.2 and SEQ ID NO.13 or 105, and the S2-D binding site is composed of VH and VL of a group of amino acid sequences including SEQ ID NO.11 and SEQ ID NO.22 or 114.

[1362]

[63] The bispecific antibody or antibody fragment thereof according to any one of items [1], [2],

[25] and

[34] to

[36] , wherein:

[1363] The two different antigen binding sites are the S1-A binding site and the S2-D binding site. The S1-A binding site is composed of VH and VL of a group of amino acid sequences including SEQ ID NO.3 and SEQ ID NO.14 or 106, and the S2-D binding site is composed of VH and VL of a group of amino acid sequences including SEQ ID NO.11 and SEQ ID NO.22 or 114.

[1364]

[64] The bispecific antibody or antibody fragment thereof according to any one of items [1], [2],

[25] and

[34] to

[36] , wherein:

[1365] The two different antigen binding sites are the S1-A binding site and the S2-D binding site. The S1-A binding site is composed of VH and VL of a group of amino acid sequences including SEQ ID NO.4 and SEQ ID NO.15 or 107, and the S2-D binding site is composed of VH and VL of a group of amino acid sequences including SEQ ID NO.11 and SEQ ID NO.22 or 114.

[1366]

[65] The bispecific antibody or antibody fragment thereof according to any one of items [1], [2],

[25] and

[34] to

[36] , wherein:

[1367] The two different antigen binding sites are the S1-A binding site and the S2-D binding site. The S1-A binding site is composed of VH and VL of a group of amino acid sequences including SEQ ID NO.5 and SEQ ID NO.16 or 108, and the S2-D binding site is composed of VH and VL of a group of amino acid sequences including SEQ ID NO.11 and SEQ ID NO.22 or 114.

[1368]

[66] The bispecific antibody or antibody fragment thereof according to any one of items [1], [2],

[25] and

[34] to

[36] , wherein:

[1369] The two different antigen binding sites are the S1-A binding site and the S2-D binding site. The S1-A binding site is composed of VH and VL of a group of amino acid sequences including SEQ ID NO.6 and SEQ ID NO.17 or 109, and the S2-D binding site is composed of VH and VL of a group of amino acid sequences including SEQ ID NO.11 and SEQ ID NO.22 or 114.

[1370]

[67] The bispecific antibody or antibody fragment thereof according to any one of items [1], [2],

[25] and

[34] to

[36] , wherein:

[1371] The two different antigen binding sites are the S1-B binding site and the S2-C binding site. The S1-B binding site is composed of VH and VL of a group of amino acid sequences including SEQ ID NO.7 and SEQ ID NO.18 or 110, and the S2-C binding site is composed of VH and VL of a group of amino acid sequences including SEQ ID NO.9 and SEQ ID NO.20 or 112.

[1372]

[68] The bispecific antibody or antibody fragment thereof according to any one of items [1], [2],

[25] and

[34] to

[36] , wherein:

[1373] The two different antigen binding sites are the S1-B binding site and the S2-C binding site. The S1-B binding site is composed of VH and VL of a group of amino acid sequences including SEQ ID NO.8 and SEQ ID NO.19 or 111, and the S2-C binding site is composed of VH and VL of a group of amino acid sequences including SEQ ID NO.9 and SEQ ID NO.20 or 112.

[1374]

[69] The bispecific antibody or antibody fragment thereof according to any one of items [1], [2],

[25] and

[34] to

[36] , wherein:

[1375] The two different antigen binding sites are the S1-B binding site and the S2-D binding site. The S1-B binding site is composed of VH and VL of a group of amino acid sequences including SEQ ID NO.7 and SEQ ID NO.18 or 110, and the S2-D binding site is composed of VH and VL of a group of amino acid sequences including SEQ ID NO.10 and SEQ ID NO.21 or 113.

[1376]

[70] The bispecific antibody or antibody fragment thereof according to any one of items [1], [2],

[25] and

[34] to

[36] , wherein:

[1377] The two different antigen binding sites are the S1-B binding site and the S2-D binding site. The S1-B binding site is composed of VH and VL of a group of amino acid sequences including SEQ ID NO.7 and SEQ ID NO.18 or 110, and the S2-D binding site is composed of VH and VL of a group of amino acid sequences including SEQ ID NO.11 and SEQ ID NO.22 or 114.

[1378]

[71] The bispecific antibody or antibody fragment thereof according to any one of items [1], [2],

[25] and

[34] to

[36] , wherein:

[1379] The two different antigen binding sites are the S1-B binding site and the S2-D binding site. The S1-B binding site is composed of VH and VL of a group of amino acid sequences including SEQ ID NO.8 and SEQ ID NO.19 or 111, and the S2-D binding site is composed of VH and VL of a group of amino acid sequences including SEQ ID NO.10 and SEQ ID NO.21 or 113.

[1380]

[72] The bispecific antibody or antibody fragment thereof according to any one of items [1], [2],

[25] and

[34] to

[36] , wherein:

[1381] The two different antigen binding sites are the S1-B binding site and the S2-D binding site. The S1-B binding site is composed of VH and VL of a group of amino acid sequences including SEQ ID NO.8 and SEQ ID NO.19 or 111, and the S2-D binding site is composed of VH and VL of a group of amino acid sequences including SEQ ID NO.11 and SEQ ID NO.22 or 114.

[1382]

[73] The bispecific antibody or antibody fragment thereof according to any one of items [1], [2],

[25] and

[34] to

[36] , wherein:

[1383] The two different antigen binding sites are the S2-C binding site and the S2-D binding site. The S2-C binding site is composed of VH and VL of a group of amino acid sequences including SEQ ID NO.9 and SEQ ID NO.20 or 112, and the S2-D binding site is composed of VH and VL of a group of amino acid sequences including SEQ ID NO.10 and SEQ ID NO.21 or 113.

[1384]

[74] The bispecific antibody or antibody fragment thereof according to any one of items [1], [2],

[25] and

[34] to

[36] , wherein:

[1385] The two different antigen binding sites are the S2-C binding site and the S2-D binding site. The S2-C binding site is composed of VH and VL of a group of amino acid sequences including SEQ ID NO.9 and SEQ ID NO.20 or 112, and the S2-D binding site is composed of VH and VL of a group of amino acid sequences including SEQ ID NO.11 and SEQ ID NO.22 or 114.

[1386]

[75] A bispecific antibody or an antibody fragment thereof, which has two antigen-binding sites that specifically bind to different epitopes in the extracellular domain of allergen-1, wherein:

[1387] The antigen binding sites do not compete with each other for allergen-1, and are two different optional antigen binding sites selected from the group consisting of the S1-A binding site, the S1-B binding site, the S2-C binding site, and the S2-D binding site.

[1388] (i) The S1-A binding site is capable of cross-competing with an antibody or its antigen-binding site having VH and VL for binding to the S1 domain of allergen-1, wherein the VH and VL comprise any one of the following groups of amino acid sequences:

[1389] (a) SEQ ID NO.1 and SEQ ID NO.104;

[1390] (b) SEQ ID NO.2 and SEQ ID NO.105;

[1391] (c) SEQ ID NO. 3 and SEQ ID NO. 106;

[1392] (d) SEQ ID NO.4 and SEQ ID NO.107;

[1393] (e) SEQ ID NO. 5 and SEQ ID NO. 108; and

[1394] (f) SEQ ID NO.6 and SEQ ID NO.109,

[1395] (ii) the S1-B binding site is capable of cross-competing for binding to the S1 domain of Allergy-1 with an antibody or its antigen-binding site having VH and VL comprising the following set of amino acid sequences:

[1396] (a) SEQ ID NO. 7 and SEQ ID NO. 110; or

[1397] (b) SEQ ID NO.8 and SEQ ID NO.111,

[1398] (iii) the S2-C binding site is capable of cross-competing with an antibody or its antigen binding site having VH and VL for binding to the S2 domain of allergen-1, wherein the VH and VL comprise a set of amino acid sequences of SEQ ID NO.9 and SEQ ID NO.112,

[1399] (iv) the S2-D binding site is capable of cross-competing for binding to the S2 domain of Allergy-1 with an antibody or its antigen-binding site having VH and VL comprising the following set of amino acid sequences:

[1400] (a) SEQ ID NO. 10 and SEQ ID NO. 113; or

[1401] (b) SEQ ID NO. 11 and SEQ ID NO. 114.

[1402]

[76] A bispecific antibody or an antibody fragment thereof, which has two antigen-binding sites that specifically bind to different epitopes in the extracellular domain of allergen-1, wherein:

[1403] The antigen binding sites do not compete with each other for allergen-1, and are two different optional antigen binding sites selected from the group consisting of the S1-A binding site, the S1-B binding site, the S2-C binding site, and the S2-D binding site.

[1404] (i) The S1-A binding site is an antigen binding site, the binding of which to the S1 domain of Allergy-1 is cross-competed by an antibody or its antigen binding site having VH and VL, wherein the VH and VL comprise any one of the following groups of amino acid sequences:

[1405] (a) SEQ ID NO.1 and SEQ ID NO.104;

[1406] (b) SEQ ID NO.2 and SEQ ID NO.105;

[1407] (c) SEQ ID NO. 3 and SEQ ID NO. 106;

[1408] (d) SEQ ID NO.4 and SEQ ID NO.107;

[1409] (e) SEQ ID NO. 5 and SEQ ID NO. 108; and

[1410] (f) SEQ ID NO.6 and SEQ ID NO.109,

[1411] (ii) The S1-B binding site is an antigen binding site, the binding of which to the S1 domain of Allergy-1 is cross-competed by an antibody or its antigen binding site having a VH and a VL comprising the following set of amino acid sequences:

[1412] (a) SEQ ID NO. 7 and SEQ ID NO. 110; or

[1413] (b) SEQ ID NO.8 and SEQ ID NO.111,

[1414] (iii) the S2-C binding site is an antigen binding site, and its binding to the S2 domain of allergen-1 is cross-competed by an antibody or its antigen binding site having VH and VL, wherein the VH and VL comprise a set of amino acid sequences of SEQ ID NO.9 and SEQ ID NO.112,

[1415] (iv) The S2-D binding site is an antigen binding site, the binding of which to the S2 domain of Allergy-1 is cross-competed by an antibody or its antigen binding site having a VH and a VL comprising the following set of amino acid sequences:

[1416] (a) SEQ ID NO. 10 and SEQ ID NO. 113; or

[1417] (b) SEQ ID NO. 11 and SEQ ID NO. 114.

[1418]

[77] The bispecific antibody or antibody fragment thereof according to any one of items [1] to

[76] , wherein:

[1419] One antigen binding site is formed as a part of the heavy chain / light chain complex constituting the anti-allergen-1 bispecific antibody.

[1420]

[78] The bispecific antibody or antibody fragment thereof according to item

[77] , wherein:

[1421] The heavy chain / light chain complex is formed by any one selected from the following combinations:

[1422] (a) a combination of a heavy chain having VH that constitutes the S1-A binding site and a light chain having VL that constitutes the S1-A binding site;

[1423] (b) a combination of a heavy chain having VH constituting the S1-B binding site and a light chain having VL constituting the S1-B binding site;

[1424] (c) a combination of a heavy chain having VH constituting the S2-C binding site and a light chain having VL constituting the S2-C binding site; and

[1425] (d) A combination of a heavy chain having VH constituting the S2-D binding site and a light chain having VL constituting the S2-D binding site.

[1426]

[79] The bispecific antibody or antibody fragment thereof according to any one of items [1] to

[78] , wherein:

[1427] Another antigen binding site has the form of scFv comprising VH and VL constituting the antigen binding site.

[1428]

[80] The bispecific antibody or antibody fragment thereof according to item

[79] , wherein:

[1429] The scFv is linked to the C-terminus of the heavy chain or light chain.

[1430]

[81] The bispecific antibody or antibody fragment thereof according to item

[79] , wherein:

[1431] The scFv is linked to the C-terminus of the heavy chain.

[1432]

[82] The bispecific antibody or antibody fragment thereof according to item

[79] , wherein:

[1433] The scFv is linked to the C-terminus of the light chain.

[1434]

[83] The bispecific antibody or antibody fragment thereof according to any one of items

[79] to

[81] , which satisfies (i) or (ii),

[1435] (i) having (a) a heavy chain, the C-terminus of which is linked to the scFv; and (b) a light chain,

[1436] (ii) comprising two identical heavy chain / light chain complexes consisting of the heavy chain and light chain described in (i).

[1437]

[84] The bispecific antibody or antibody fragment thereof according to any one of items

[79] ,

[80] and

[82] , which satisfies (i) or (ii),

[1438] (i) having (a) a heavy chain; and (b) a light chain, the C-terminus of which is connected to the scFv,

[1439] (ii) comprising two identical heavy chain / light chain complexes consisting of the heavy chain and light chain described in (i).

[1440]

[85] The bispecific antibody or antibody fragment thereof according to any one of items

[79] to

[84] , wherein:

[1441] The antigen binding site in the heavy chain / light chain complex is the S1-A binding site, and the antigen binding site in the form of the scFv is any one antigen binding site selected from the group consisting of the S1-B binding site, the S2-C binding site and the S2-D binding site.

[1442]

[86] The bispecific antibody or antibody fragment thereof according to any one of items

[79] to

[84] , wherein:

[1443] The antigen binding site in the heavy chain / light chain complex is the S1-B binding site, and the antigen binding site in the form of the scFv is any one antigen binding site selected from the S1-A binding site, the S2-C binding site and the S2-D binding site.

[1444]

[87] The bispecific antibody or antibody fragment thereof according to any one of items

[79] to

[84] , wherein:

[1445] The antigen binding site in the heavy chain / light chain complex is the S2-C binding site, and the antigen binding site in the form of the scFv is any one antigen binding site selected from the S1-A binding site, the S1-B binding site and the S2-D binding site.

[1446]

[88] The bispecific antibody or antibody fragment thereof according to any one of items

[79] to

[84] , wherein:

[1447] The antigen binding site in the heavy chain / light chain complex is the S2-D binding site, and the antigen binding site in the form of the scFv is any one antigen binding site selected from the S1-A binding site, the S1-B binding site and the S2-C binding site.

[1448]

[89] The bispecific antibody or antibody fragment thereof according to any one of items

[79] to

[84] , wherein:

[1449] The antigen binding site in the heavy chain / light chain complex is the S1-A binding site, and the antigen binding site in the form of the scFv is the S1-B binding site.

[1450]

[90] The bispecific antibody or antibody fragment thereof according to any one of items

[79] to

[84] , wherein:

[1451] The antigen binding site in the heavy chain / light chain complex is the S1-A binding site, and the antigen binding site in the form of the scFv is the S2-C binding site.

[1452]

[91] The bispecific antibody or antibody fragment thereof according to any one of items

[79] to

[84] , wherein:

[1453] The antigen binding site in the heavy chain / light chain complex is the S1-A binding site, and the antigen binding site in the form of the scFv is the S2-D binding site.

[1454]

[92] The bispecific antibody or antibody fragment thereof according to any one of items

[79] to

[84] , wherein:

[1455] The antigen binding site in the heavy chain / light chain complex is the S1-B binding site, and the antigen binding site in the form of the scFv is the S1-A binding site.

[1456]

[93] The bispecific antibody or antibody fragment thereof according to any one of items

[79] to

[84] , wherein:

[1457] The antigen binding site in the heavy chain / light chain complex is the S1-B binding site, and the antigen binding site in the form of the scFv is the S2-C binding site.

[1458]

[94] The bispecific antibody or antibody fragment thereof according to any one of items

[79] to

[84] , wherein:

[1459] The antigen binding site in the heavy chain / light chain complex is the S1-B binding site, and the antigen binding site in the form of the scFv is the S2-D binding site.

[1460]

[95] The bispecific antibody or antibody fragment thereof according to any one of items

[79] to

[84] , wherein:

[1461] The antigen binding site in the heavy chain / light chain complex is the S2-C binding site, and the antigen binding site in the form of the scFv is the S1-A binding site.

[1462]

[96] The bispecific antibody or antibody fragment thereof according to any one of items

[79] to

[84] , wherein:

[1463] The antigen binding site in the heavy chain / light chain complex is the S2-C binding site, and the antigen binding site in the form of the scFv is the S1-B binding site.

[1464]

[97] The bispecific antibody or antibody fragment thereof according to any one of items

[79] to

[84] , wherein:

[1465] The antigen binding site in the heavy chain / light chain complex is the S2-C binding site, and the antigen binding site in the form of the scFv is the S2-D binding site.

[1466]

[98] The bispecific antibody or antibody fragment thereof according to any one of items

[79] to

[84] , wherein:

[1467] The antigen binding site in the heavy chain / light chain complex is the S2-D binding site, and the antigen binding site in the form of the scFv is the S1-A binding site.

[1468]

[99] The bispecific antibody or antibody fragment thereof according to any one of items

[79] to

[84] , wherein:

[1469] The antigen binding site in the heavy chain / light chain complex is the S2-D binding site, and the antigen binding site in the form of the scFv is the S1-B binding site.

[1470]

[100] The bispecific antibody or antibody fragment thereof according to any one of items

[79] to

[84] , wherein:

[1471] The antigen binding site in the heavy chain / light chain complex is the S2-D binding site, and the antigen binding site in the form of the scFv is the S2-C binding site.

[1472]

[101] The bispecific antibody or antibody fragment thereof according to any one of items

[79] to

[100] , wherein:

[1473] The scFv is linked to the C-terminus of the heavy or light chain via (a) a direct amide bond or (b) a peptide linker.

[1474]

[102] The bispecific antibody or antibody fragment thereof according to any one of items

[79] to

[101] , wherein:

[1475] The N-terminus of the VH constituting the scFv is linked to the C-terminus of the heavy chain or light chain via (a) a direct amide bond or (b) a peptide linker.

[1476]

[103] The bispecific antibody or antibody fragment thereof according to any one of items

[79] to

[101] , wherein:

[1477] The N-terminus of the VL constituting the scFv is linked to the C-terminus of the heavy chain or light chain via (a) a direct amide bond or (b) a peptide linker.

[1478]

[104] The bispecific antibody or antibody fragment thereof according to any one of items

[79] to

[102] , wherein:

[1479] VL and VH constituting the scFv are linked to each other in the order of VL and VH from the N-terminal side thereof via (a) a direct amide bond or (b) a peptide linker.

[1480]

[105] The bispecific antibody or antibody fragment thereof according to any one of items

[79] to

[101] and

[103] , wherein:

[1481] VH and VL constituting the scFv are linked to each other in the order of VL and VH from the N-terminal side thereof via (a) a direct amide bond or (b) a peptide linker.

[1482]

[106] The bispecific antibody or antibody fragment thereof according to any one of items

[101] to

[103] , wherein:

[1483] The peptide linker connecting the scFv to the C-terminus of the heavy chain or light chain comprises the amino acid sequence of SEQ ID NO.73.

[1484]

[107] The bispecific antibody or antibody fragment thereof according to any one of item

[104] or

[105] , wherein:

[1485] The peptide linker connecting VH and VL constituting the scFv comprises the amino acid sequence of SEQ ID NO.74.

[1486]

[108] The bispecific antibody or antibody fragment thereof has two antigen-binding sites that specifically bind to two different epitopes of the extracellular domain of allergen-1, wherein:

[1487] The antigen binding sites do not compete with each other for allergen-1, and are two different optional antigen binding sites selected from the group consisting of the S1-A binding site, the S1-B binding site, the S2-C binding site, and the S2-D binding site.

[1488] (I) the S1-A binding site is any one of the following antigen binding sites (i) to (iv),

[1489] (i) an antigen binding site comprising:

[1490] VH, which has

[1491] (a) VH-CDR1 comprising the amino acid sequence of SEQ ID NO.25;

[1492] (b) VH-CDR2 comprising the amino acid sequence of SEQ ID NO.26; and

[1493] (c) a VH-CDR3 comprising the amino acid sequence of SEQ ID NO. 27, and

[1494] VL, which has

[1495] (d) a VL-CDR1 comprising the amino acid sequence of SEQ ID NO.49;

[1496] (e) a VL-CDR2 comprising the amino acid sequence of SEQ ID NO.50; and

[1497] (f) a VL-CDR3 comprising the amino acid sequence of SEQ ID NO.51,

[1498] (ii) an antigen binding site comprising:

[1499] VH, which has

[1500] (a) VH-CDR1 comprising the amino acid sequence of SEQ ID NO.28;

[1501] (b) VH-CDR2 comprising the amino acid sequence of SEQ ID NO.29; and

[1502] (c) a VH-CDR3 comprising the amino acid sequence of SEQ ID NO. 30, and

[1503] VL, which has

[1504] (d) a VL-CDR1 comprising the amino acid sequence of SEQ ID NO.52;

[1505] (e) a VL-CDR2 comprising the amino acid sequence of SEQ ID NO.53; and

[1506] (f) a VL-CDR3 comprising the amino acid sequence of SEQ ID NO.54,

[1507] (iii) an antigen binding site comprising:

[1508] VH, which has

[1509] (a) VH-CDR1 comprising the amino acid sequence of SEQ ID NO.31;

[1510] (b) VH-CDR2 comprising the amino acid sequence of SEQ ID NO.32; and

[1511] (c) a VH-CDR3 comprising the amino acid sequence of SEQ ID NO. 33, and

[1512] VL, which has

[1513] (d) a VL-CDR1 comprising the amino acid sequence of SEQ ID NO.55;

[1514] (e) a VL-CDR2 comprising the amino acid sequence of SEQ ID NO.56; and

[1515] (f) a VL-CDR3 comprising the amino acid sequence of SEQ ID NO.57,

[1516] (iv) an antigen binding site comprising:

[1517] VH, which has

[1518] (a) VH-CDR1 comprising the amino acid sequence of SEQ ID NO.34;

[1519] (b) a VH-CDR2 comprising the amino acid sequence of SEQ ID NO. 35; and

[1520] (c) a VH-CDR3 comprising the amino acid sequence of SEQ ID NO. 36, and

[1521] VL, which has

[1522] (d) a VL-CDR1 comprising the amino acid sequence of SEQ ID NO.58;

[1523] (e) a VL-CDR2 comprising the amino acid sequence of SEQ ID NO.59; and

[1524] (f) a VL-CDR3 comprising the amino acid sequence of SEQ ID NO.60,

[1525] The S1-B binding site is the following (v) or (vi) antigen binding site,

[1526] (v) an antigen binding site comprising:

[1527] VH, which has

[1528] (a) VH-CDR1 comprising the amino acid sequence of SEQ ID NO.37;

[1529] (b) VH-CDR2 comprising the amino acid sequence of SEQ ID NO.38; and

[1530] (c) a VH-CDR3 comprising the amino acid sequence of SEQ ID NO. 39, and

[1531] VL, which has

[1532] (d) a VL-CDR1 comprising the amino acid sequence of SEQ ID NO.61;

[1533] (e) a VL-CDR2 comprising the amino acid sequence of SEQ ID NO.62; and

[1534] (f) a VL-CDR3 comprising the amino acid sequence of SEQ ID NO.63,

[1535] (vi) an antigen binding site comprising:

[1536] VH, which has

[1537] (a) VH-CDR1 comprising the amino acid sequence of SEQ ID NO.40;

[1538] (b) VH-CDR2 comprising the amino acid sequence of SEQ ID NO.41; and

[1539] (c) a VH-CDR3 comprising the amino acid sequence of SEQ ID NO. 42, and

[1540] VL, which has

[1541] (d) a VL-CDR1 comprising the amino acid sequence of SEQ ID NO.64;

[1542] (e) a VL-CDR2 comprising the amino acid sequence of SEQ ID NO.65; and

[1543] (f) a VL-CDR3 comprising the amino acid sequence of SEQ ID NO.66,

[1544] The S2-C binding site is an antigen binding site comprising the following VH and VL,

[1545] VH, which has

[1546] (a) VH-CDR1 comprising the amino acid sequence of SEQ ID NO.43;

[1547] (b) VH-CDR2 comprising the amino acid sequence of SEQ ID NO.44; and

[1548] (c) a VH-CDR3 comprising the amino acid sequence of SEQ ID NO.45,

[1549] VL, which has

[1550] (d) a VL-CDR1 comprising the amino acid sequence of SEQ ID NO.67;

[1551] (e) a VL-CDR2 comprising the amino acid sequence of SEQ ID NO.68; and

[1552] (f) a VL-CDR3 comprising the amino acid sequence of SEQ ID NO.69,

[1553] The S2-D binding site is an antigen binding site comprising the following VH and VL,

[1554] VH, which has

[1555] (a) VH-CDR1 comprising the amino acid sequence of SEQ ID NO.46;

[1556] (b) VH-CDR2 comprising the amino acid sequence of SEQ ID NO.47; and

[1557] (c) a VH-CDR3 comprising the amino acid sequence of SEQ ID NO.48,

[1558] VL, which has

[1559] (d) VL-CDR1 comprising the amino acid sequence of SEQ ID NO.70;

[1560] (e) a VL-CDR2 comprising the amino acid sequence of SEQ ID NO. 71; and

[1561] (f) a VL-CDR3 comprising the amino acid sequence of SEQ ID NO.72,

[1562] (II) one of the two different antigen-binding sites is an antigen-binding site in the heavy chain / light chain complex constituting the bispecific antibody, and the other is an antigen-binding site constituting a form having an scFv,

[1563] (i) the antigen binding site in the heavy chain / light chain complex is the S1-A binding site, and the antigen binding site in the form of the scFv is any one of the antigen binding sites selected from the group consisting of the S1-B binding site, the S2-C binding site, and the S2-D binding site;

[1564] (ii) the antigen binding site in the heavy chain / light chain complex is the S1-B binding site, and the antigen binding site in the form of the scFv is any one of the antigen binding sites selected from the group consisting of the S1-A binding site, the S2-C binding site, and the S2-D binding site;

[1565] (iii) the antigen binding site in the heavy chain / light chain complex is the S2-C binding site, and the antigen binding site in the form of the scFv is any one of the antigen binding sites selected from the group consisting of the S1-A binding site, the S1-B binding site and the S2-D binding site; or

[1566] (iv) the antigen binding site in the heavy chain / light chain complex is the S2-D binding site, and the antigen binding site in the form of the scFv is any one of the antigen binding sites selected from the group consisting of the S1-A binding site, the S1-B binding site and the S2-C binding site,

[1567] (III) the N-terminus of either VH or VL constituting the scFv is linked to the C-terminus of the heavy chain or light chain via a peptide linker,

[1568] (IV) satisfies (i) or (ii),

[1569] (i) a heavy chain and a light chain having the structures described in items (I) to (III),

[1570] (ii) comprising two identical heavy chain / light chain complexes consisting of a heavy chain and a light chain having the structures described in items (I) to (III) above.

[1571]

[109] A bispecific antibody or antibody fragment thereof against Allergen-1, comprising two different antigen binding sites selected from the group consisting of a S1-A binding site, a S1-B binding site, a S2-C binding site and a S2-D binding site, wherein:

[1572] (I) the S1-A binding site is any one of the following antigen binding sites (i) to (iv),

[1573] (i) an antigen binding site comprising:

[1574] VH, which has

[1575] (a) VH-CDR1 comprising the amino acid sequence of SEQ ID NO.25;

[1576] (b) VH-CDR2 comprising the amino acid sequence of SEQ ID NO.26; and

[1577] (c) a VH-CDR3 comprising the amino acid sequence of SEQ ID NO. 27, and

[1578] VL, which has

[1579] (d) a VL-CDR1 comprising the amino acid sequence of SEQ ID NO.49;

[1580] (e) a VL-CDR2 comprising the amino acid sequence of SEQ ID NO.50; and

[1581] (f) a VL-CDR3 comprising the amino acid sequence of SEQ ID NO.51,

[1582] (ii) an antigen binding site comprising:

[1583] VH, which has

[1584] (a) VH-CDR1 comprising the amino acid sequence of SEQ ID NO.28;

[1585] (b) VH-CDR2 comprising the amino acid sequence of SEQ ID NO.29; and

[1586] (c) a VH-CDR3 comprising the amino acid sequence of SEQ ID NO. 30, and

[1587] VL, which has

[1588] (d) a VL-CDR1 comprising the amino acid sequence of SEQ ID NO.52;

[1589] (e) a VL-CDR2 comprising the amino acid sequence of SEQ ID NO.53; and

[1590] (f) a VL-CDR3 comprising the amino acid sequence of SEQ ID NO.54,

[1591] (iii) an antigen binding site comprising:

[1592] VH, which has

[1593] (a) VH-CDR1 comprising the amino acid sequence of SEQ ID NO.31;

[1594] (b) VH-CDR2 comprising the amino acid sequence of SEQ ID NO.32; and

[1595] (c) a VH-CDR3 comprising the amino acid sequence of SEQ ID NO. 33, and

[1596] VL, which has

[1597] (d) a VL-CDR1 comprising the amino acid sequence of SEQ ID NO.55;

[1598] (e) a VL-CDR2 comprising the amino acid sequence of SEQ ID NO.56; and

[1599] (f) a VL-CDR3 comprising the amino acid sequence of SEQ ID NO.57,

[1600] (iv) an antigen binding site comprising:

[1601] VH, which has

[1602] (a) VH-CDR1 comprising the amino acid sequence of SEQ ID NO.34;

[1603] (b) VH-CDR2 comprising the amino acid sequence of SEQ ID NO.35; and

[1604] (c) a VH-CDR3 comprising the amino acid sequence of SEQ ID NO. 36, and

[1605] VL, which has

[1606] (d) a VL-CDR1 comprising the amino acid sequence of SEQ ID NO.58;

[1607] (e) a VL-CDR2 comprising the amino acid sequence of SEQ ID NO.59; and

[1608] (f) a VL-CDR3 comprising the amino acid sequence of SEQ ID NO.60,

[1609] The S1-B binding site is the following (v) or (vi) antigen binding site,

[1610] (v) an antigen binding site comprising:

[1611] VH, which has

[1612] (a) VH-CDR1 comprising the amino acid sequence of SEQ ID NO.37;

[1613] (b) VH-CDR2 comprising the amino acid sequence of SEQ ID NO.38; and

[1614] (c) a VH-CDR3 comprising the amino acid sequence of SEQ ID NO. 39, and

[1615] VL, which has

[1616] (d) a VL-CDR1 comprising the amino acid sequence of SEQ ID NO.61;

[1617] (e) a VL-CDR2 comprising the amino acid sequence of SEQ ID NO.62; and

[1618] (f) a VL-CDR3 comprising the amino acid sequence of SEQ ID NO.63,

[1619] (vi) an antigen binding site comprising:

[1620] VH, which has

[1621] (a) VH-CDR1 comprising the amino acid sequence of SEQ ID NO.40;

[1622] (b) VH-CDR2 comprising the amino acid sequence of SEQ ID NO.41; and

[1623] (c) a VH-CDR3 comprising the amino acid sequence of SEQ ID NO. 42, and

[1624] VL, which has

[1625] (d) a VL-CDR1 comprising the amino acid sequence of SEQ ID NO.64;

[1626] (e) a VL-CDR2 comprising the amino acid sequence of SEQ ID NO.65; and

[1627] (f) a VL-CDR3 comprising the amino acid sequence of SEQ ID NO.66,

[1628] The S2-C binding site is an antigen binding site comprising the following VH and VL,

[1629] VH, which has

[1630] (a) VH-CDR1 comprising the amino acid sequence of SEQ ID NO.43;

[1631] (b) VH-CDR2 comprising the amino acid sequence of SEQ ID NO.44; and

[1632] (c) a VH-CDR3 comprising the amino acid sequence of SEQ ID NO.45,

[1633] VL, which has

[1634] (d) a VL-CDR1 comprising the amino acid sequence of SEQ ID NO.67;

[1635] (e) a VL-CDR2 comprising the amino acid sequence of SEQ ID NO.68; and

[1636] (f) a VL-CDR3 comprising the amino acid sequence of SEQ ID NO.69,

[1637] The S2-D binding site is an antigen binding site comprising the following VH and VL,

[1638] VH, which has

[1639] (a) VH-CDR1 comprising the amino acid sequence of SEQ ID NO.46;

[1640] (b) VH-CDR2 comprising the amino acid sequence of SEQ ID NO.47; and

[1641] (c) a VH-CDR3 comprising the amino acid sequence of SEQ ID NO.48,

[1642] VL, which has

[1643] (d) VL-CDR1 comprising the amino acid sequence of SEQ ID NO.70;

[1644] (e) a VL-CDR2 comprising the amino acid sequence of SEQ ID NO. 71; and

[1645] (f) a VL-CDR3 comprising the amino acid sequence of SEQ ID NO.72,

[1646] (II) one of the two different antigen-binding sites is an antigen-binding site in the heavy chain / light chain complex constituting the bispecific antibody, and the other is an antigen-binding site constituting a form having an scFv,

[1647] (i) the antigen binding site in the heavy chain / light chain complex is the S1-A binding site, and the antigen binding site in the form of the scFv is any one of the antigen binding sites selected from the group consisting of the S1-B binding site, the S2-C binding site, and the S2-D binding site;

[1648] (ii) the antigen binding site in the heavy chain / light chain complex is the S1-B binding site, and the antigen binding site in the form of the scFv is any one of the antigen binding sites selected from the group consisting of the S1-A binding site, the S2-C binding site, and the S2-D binding site;

[1649] (iii) the antigen binding site in the heavy chain / light chain complex is the S2-C binding site, and the antigen binding site in the form of the scFv is any one of the antigen binding sites selected from the group consisting of the S1-A binding site, the S1-B binding site and the S2-D binding site; or

[1650] (iv) the antigen binding site in the heavy chain / light chain complex is the S2-D binding site, and the antigen binding site in the form of the scFv is any one of the antigen binding sites selected from the group consisting of the S1-A binding site, the S1-B binding site and the S2-C binding site,

[1651] (III) the N-terminus of either VH or VL constituting the scFv is linked to the C-terminus of the heavy chain or light chain via a peptide linker,

[1652] (IV) satisfies (i) or (ii),

[1653] (i) a heavy chain and a light chain having the structures described in items (I) to (III),

[1654] (ii) comprising two identical heavy chain / light chain complexes consisting of the heavy chain and light chain having the structures described in items (I) to (III) above.

[1655]

[110] The bispecific antibody or antibody fragment thereof according to item

[108] or

[109] , wherein:

[1656] The two different antigen binding sites are any two selected from the following binding sites (i) to (iv),

[1657] (i) an S1-A binding site, which is composed of VH and VL, wherein VH and VL comprise any one of the following groups of amino acid sequences:

[1658] (a) SEQ ID NOs. 1 and 12;

[1659] (b) SEQ ID NOs. 2 and 13;

[1660] (c) SEQ ID NO. 3 and SEQ ID NO. 14 or 106;

[1661] (d) SEQ ID NO. 4 and SEQ ID NO. 15 or 107;

[1662] (e) SEQ ID NOs. 5 and 16; and

[1663] (f) SEQ ID NO. 6 and SEQ ID NO. 17 or 109,

[1664] (ii) an S1-B binding site, which is composed of VH and VL, wherein VH and VL comprise the following set of amino acid sequences:

[1665] (a) SEQ ID NOs. 7 and 18; or

[1666] (b) SEQ ID NOs. 8 and 19,

[1667] (iii) an S2-C binding site, which is composed of VH and VL, wherein VH and VL comprise a set of amino acid sequences of SEQ ID NO. 9 and SEQ ID NO. 20 or 112,

[1668] (iv) an S2-D binding site, which is composed of VH and VL, wherein VH and VL comprise the following set of amino acid sequences:

[1669] (a) SEQ ID NO. 10 and SEQ ID NO. 21 or 113; or

[1670] (b) SEQ ID NOs. 11 and 22.

[1671]

[111] The bispecific antibody or antibody fragment thereof according to item

[108] or

[109] , wherein:

[1672] The two different antigen binding sites are any two selected from the following binding sites (i) to (iii),

[1673] (i) an S1-A binding site, which is composed of VH and VL, wherein VH and VL comprise any one of the following groups of amino acid sequences:

[1674] (a) SEQ ID NO. 3 and SEQ ID NO. 14 or 106;

[1675] (b) SEQ ID NO. 4 and SEQ ID NO. 15 or 107;

[1676] (c) SEQ ID NOs. 5 and 16; and

[1677] (d) SEQ ID NO. 6 and SEQ ID NO. 17 or 109,

[1678] (ii) an S2-C binding site, which is composed of VH and VL, wherein VH and VL comprise a set of amino acid sequences of SEQ ID NO. 9 and SEQ ID NO. 20 or 112,

[1679] (iii) an S2-D binding site, which is composed of VH and VL, wherein VH and VL comprise the following set of amino acid sequences:

[1680] (a) SEQ ID NO. 10 and SEQ ID NO. 21 or 113; or

[1681] (b) SEQ ID NOs. 11 and 22.

[1682]

[112] The bispecific antibody or antibody fragment thereof according to item

[108] or

[109] , wherein:

[1683] The two different antigen binding sites are:

[1684] (a) an S1-A binding site, which is composed of VH and VL, wherein VH and VL comprise a set of amino acid sequences of SEQ ID NO. 3 and SEQ ID NO. 14 or 106; and

[1685] (b) The S2-C binding site is composed of VH and VL, wherein VH and VL comprise a set of amino acid sequences of SEQ ID NO. 9 and SEQ ID NO. 20 or 112.

[1686]

[113] The bispecific antibody or antibody fragment thereof according to item

[108] or

[109] , wherein:

[1687] The two different antigen binding sites are:

[1688] (a) an S1-A binding site, which is composed of VH and VL, wherein VH and VL comprise a set of amino acid sequences of SEQ ID NO. 6 and SEQ ID NO. 17 or 109; and

[1689] (b) The S2-D binding site is composed of VH and VL, wherein VH and VL comprise a set of amino acid sequences of SEQ ID NO.10 and SEQ ID NO.21 or 113.

[1690]

[114] The bispecific antibody or antibody fragment thereof according to item

[108] or

[109] , wherein:

[1691] The two different antigen binding sites are the S1-A binding site and the S2-D binding site.

[1692] The S1-A binding site is composed of VH and VL, and the VH and VL contain any one of the amino acid sequences selected from the following sequence groups:

[1693] (a) SEQ ID NO. 3 and SEQ ID NO. 14 or 106;

[1694] (b) SEQ ID NO. 4 and SEQ ID NO. 15 or 107; and

[1695] (c) SEQ ID NOs. 5 and 16,

[1696] The S2-D binding site is composed of VH and VL, and the VH and VL contain the following set of amino acid sequences:

[1697] (d) SEQ ID NO. 10 and SEQ ID NO. 21 or 113; or

[1698] (e) SEQ ID NOs. 11 and 22.

[1699]

[115] The bispecific antibody or antibody fragment thereof according to any one of items

[110] to

[114] , wherein:

[1700] (a)

[1701] (i) When the S1-A binding site constitutes an scFv, the VL constituting the scFv comprises an amino acid sequence selected from SEQ ID NOs. 12 to 17,

[1702] (ii) in the case where the S1-A binding site constitutes part of a heavy chain / light chain complex, the VL constituting the light chain comprises an amino acid sequence selected from the group consisting of SEQ ID NOs. 106, 107 and 109,

[1703] (b)

[1704] (i) When the S1-B binding site constitutes an scFv, the VL constituting the scFv comprises the amino acid sequence of SEQ ID NO. 18 or 19,

[1705] (ii) when the S1-B binding site constitutes a part of the heavy chain / light chain complex, the VL constituting the light chain comprises the amino acid sequence of SEQ ID NO. 110 or 111,

[1706] (c)

[1707] (i) When the S2-C binding site constitutes an scFv, the VL constituting the scFv comprises the amino acid sequence of SEQ ID NO. 20,

[1708] (ii) when the S2-C binding site constitutes part of the heavy chain / light chain complex, the VL constituting the light chain comprises the amino acid sequence of SEQ ID NO. 112,

[1709] (d)

[1710] (i) When the S2-D binding site constitutes an scFv, the VL constituting the scFv comprises the amino acid sequence of SEQ ID NO. 21 or 22,

[1711] (ii) When the S2-D binding site constitutes a part of the heavy chain / light chain complex, the VL constituting the light chain comprises the amino acid sequence of SEQ ID NO.113.

[1712]

[116] The bispecific antibody or antibody fragment thereof according to item

[108] or

[109] , wherein:

[1713] The two different antigen binding sites are:

[1714] (a) an S1-A binding site, which is composed of VH and VL, wherein VH and VL comprise a set of amino acid sequences of SEQ ID NOs. 3 and 14; and

[1715] (b) The S2-C binding site is composed of VH and VL, wherein VH and VL comprise a set of amino acid sequences of SEQ ID NOs. 9 and 112.

[1716]

[117] The bispecific antibody or antibody fragment thereof according to item

[108] or

[109] , wherein:

[1717] The two different antigen binding sites are:

[1718] (a) an S1-A binding site, which is composed of VH and VL, wherein VH and VL comprise a set of amino acid sequences of SEQ ID NOs. 3 and 106; and

[1719] (b) The S2-C binding site is composed of VH and VL, wherein VH and VL comprise a set of amino acid sequences of SEQ ID NOs. 9 and 20.

[1720]

[118] The bispecific antibody or antibody fragment thereof according to item

[108] or

[109] , wherein:

[1721] The two different antigen binding sites are:

[1722] (a) an S1-A binding site, which is composed of VH and VL, wherein VH and VL comprise a set of amino acid sequences of SEQ ID NOs. 6 and 17; and

[1723] (b) The S2-D binding site is composed of VH and VL, wherein VH and VL comprise a set of amino acid sequences of SEQ ID NOs. 10 and 113.

[1724]

[119] The bispecific antibody or antibody fragment thereof according to item

[108] or

[109] , wherein:

[1725] The two different antigen binding sites are:

[1726] (a) an S1-A binding site, which is composed of VH and VL, wherein VH and VL comprise a set of amino acid sequences of SEQ ID NOs. 6 and 109; and

[1727] (b) The S2-D binding site is composed of VH and VL, wherein VH and VL comprise a set of amino acid sequences of SEQ ID NOs. 10 and 21.

[1728]

[120] The bispecific antibody or antibody fragment thereof according to item

[108] or

[109] , wherein:

[1729] The two different antigen binding sites are:

[1730] (a) an S1-A binding site, which is composed of VH and VL, wherein VH and VL comprise a set of amino acid sequences of SEQ ID NOs. 3 and 14; and

[1731] (b) The S2-D binding site is composed of VH and VL, wherein VH and VL comprise a set of amino acid sequences of SEQ ID NOs. 10 and 113.

[1732]

[121] The bispecific antibody or antibody fragment thereof according to item

[108] or

[109] , wherein:

[1733] The two different antigen binding sites are:

[1734] (a) an S1-A binding site, which is composed of VH and VL, wherein VH and VL comprise a set of amino acid sequences of SEQ ID NOs. 4 and 15; and

[1735] (b) The S2-D binding site is composed of VH and VL, wherein VH and VL comprise a set of amino acid sequences of SEQ ID NOs. 10 and 113.

[1736]

[122] The bispecific antibody or antibody fragment thereof according to item

[108] or

[109] , wherein:

[1737] The two different antigen binding sites are:

[1738] (a) an S1-A binding site, which is composed of VH and VL, wherein VH and VL comprise a set of amino acid sequences of SEQ ID NOs. 5 and 16; and

[1739] (b) The S2-D binding site is composed of VH and VL, wherein VH and VL comprise a set of amino acid sequences of SEQ ID NOs. 10 and 113.

[1740]

[123] The bispecific antibody or antibody fragment thereof according to item

[108] or

[109] , wherein:

[1741] The two different antigen binding sites are:

[1742] (a) an S1-A binding site, which is composed of VH and VL, wherein VH and VL comprise a set of amino acid sequences of SEQ ID NOs. 3 and 106; and

[1743] (b) The S2-D binding site is composed of VH and VL, wherein VH and VL comprise a set of amino acid sequences of SEQ ID NOs. 10 and 21.

[1744]

[124] The bispecific antibody or antibody fragment thereof according to item

[108] or

[109] , wherein:

[1745] The two different antigen binding sites are:

[1746] (a) an S1-A binding site, which is composed of VH and VL, wherein VH and VL comprise a set of amino acid sequences of SEQ ID NOs. 4 and 107; and

[1747] (b) The S2-D binding site is composed of VH and VL, wherein VH and VL comprise a set of amino acid sequences of SEQ ID NOs. 11 and 22.

[1748]

[125] The bispecific antibody or antibody fragment thereof according to any one of items

[108] to

[124] , wherein:

[1749] VH and VL constituting the scFv are linked to each other in the order of VL and VH from the N-terminal side thereof via a peptide linker comprising the amino acid sequence of SEQ ID NO.74.

[1750]

[126] The bispecific antibody or antibody fragment thereof according to any one of items

[108] to

[125] , wherein:

[1751] The scFv is linked to the C-terminus of the heavy chain via a peptide linker comprising the amino acid sequence of SEQ ID NO.73.

[1752]

[127] The bispecific antibody or antibody fragment thereof according to any one of items [1] to

[126] , wherein:

[1753] The epitope to which the S1-A binding site specifically binds, i.e., the S1-A epitope, is composed of at least one or more of or all of phenylalanine at position 70, arginine at position 71, arginine at position 72, lysine at position 73, histidine at position 75, leucine at position 76, histidine at position 96, glutamic acid at position 97, lysine at position 102, lysine at position 104, and tyrosine at position 113 of allergen-1 comprising the amino acid sequence represented by SEQ ID NO. 115,

[1754] The epitope to which the S2-D binding site specifically binds, i.e., the S2-D epitope, is composed of at least one or more of the isoleucine at position 132, the methionine at position 133, the valine at position 134, the isoleucine at position 135, the glutamine at position 136, the threonine at position 137, the glutamic acid at position 138, the histidine at position 146, and the proline at position 215 of the allergen-1,

[1755] The epitope to which the S1-B binding site specifically binds is at least different from the S1-A epitope represented by the amino acids described above,

[1756] The epitope specifically bound by the S2-C binding site is different from the S2-D epitope represented by at least the amino acids.

[1757]

[128] A bispecific antibody or antibody fragment thereof against Allergen-1, comprising two different antigen binding sites selected from the group consisting of a S1-A binding site, a S1-B binding site, a S2-C binding site and a S2-D binding site, wherein:

[1758] (a) the epitope to which the S1-A binding site specifically binds, i.e., the S1-A epitope, is composed of at least one or more of or all of phenylalanine at position 70, arginine at position 71, arginine at position 72, lysine at position 73, histidine at position 75, leucine at position 76, histidine at position 96, glutamic acid at position 97, lysine at position 102, lysine at position 104, and tyrosine at position 113 of allergen-1 comprising the amino acid sequence represented by SEQ ID NO. 115,

[1759] (b) the epitope to which the S2-D binding site specifically binds, i.e., the S2-D epitope, is composed of at least one or more of the isoleucine at position 132, the methionine at position 133, the valine at position 134, the isoleucine at position 135, the glutamine at position 136, the threonine at position 137, the glutamic acid at position 138, the histidine at position 146, and the proline at position 215 of the allergen-1,

[1760] (c) the epitope to which the S1-B binding site specifically binds is at least different from the S1-A epitope represented by said amino acids,

[1761] (d) The epitope specifically bound by the S2-C binding site is at least different from the S2-D epitope represented by the amino acids.

[1762]

[129] The bispecific antibody or antibody fragment thereof according to any one of items

[77] to

[128] , wherein:

[1763] The heavy chain and light chain are both derived from IgG antibodies.

[1764]

[130] The bispecific antibody or antibody fragment thereof according to item

[129] , wherein:

[1765] The heavy chain has CH1, CH2, and CH3 of an IgG antibody, and the light chain has CL of the antibody.

[1766]

[131] The bispecific antibody or antibody fragment thereof according to item

[129] or

[130] , wherein:

[1767] The IgG antibody is IgG 1 Antibodies or IgG 4 .

[1768]

[132] The bispecific antibody or antibody fragment thereof according to item

[129] or

[130] , wherein:

[1769] The IgG antibody is IgG 1 Antibody.

[1770]

[133] The bispecific antibody or antibody fragment thereof according to item

[132] , wherein:

[1771] The IgG 1 The leucine at position 235 in the EU numbering system in both heavy chain constant regions of the antibody is each substituted with glycine, and / or the glycine at position 236 is each substituted with arginine.

[1772]

[134] The bispecific antibody or antibody fragment thereof according to item

[132] or

[133] , wherein:

[1773] Each lacks the IgG 1 The lysine at position 447 based on the EU numbering system in both heavy chain constant regions of the antibody.

[1774]

[135] The bispecific antibody or antibody fragment thereof according to item

[129] or

[130] , wherein:

[1775] The IgG antibody is IgG 4 Antibody.

[1776]

[136] The bispecific antibody or antibody fragment thereof according to item

[135] , wherein:

[1777] The IgG 4 The serine at position 228 based on the EU numbering system in both heavy chain constant regions of the antibody was substituted with proline.

[1778]

[137] The bispecific antibody or antibody fragment thereof according to any one of items

[77] to

[132] , wherein:

[1779] The heavy chain constant region comprises the amino acid sequence of SEQ ID NO. 23 or 99.

[1780]

[138] The bispecific antibody or antibody fragment thereof according to any one of items

[77] to

[132] and

[137] , wherein:

[1781] The light chain constant region comprises the amino acid sequence of SEQ ID NO.24.

[1782]

[139] The bispecific antibody or antibody fragment thereof according to any one of items

[77] to

[132] , wherein:

[1783] The heavy chain constant region and the light chain constant region each comprise the amino acid sequence of SEQ ID NO.23 or 99 and SEQ ID NO.24.

[1784]

[140] The bispecific antibody or antibody fragment thereof according to any one of items

[137] to

[139] , wherein:

[1785] The arginine at position 97 in the amino acid sequence of SEQ ID NO. 23 or 99 of the heavy chain constant region is substituted with lysine.

[1786]

[141] A bispecific antibody against Allergen-1, which satisfies (i) or (ii),

[1787] (i) having a heavy chain and a light chain comprising an amino acid sequence selected from any one of the following sequence groups:

[1788] (a) SEQ ID NOs. 75 and 76;

[1789] (b) SEQ ID NOs. 77 and 78;

[1790] (c) SEQ ID NOs. 79 and 78;

[1791] (d) SEQ ID NOs. 80 and 78;

[1792] (e) SEQ ID NOs. 81 and 82;

[1793] (f) SEQ ID NOs. 83 and 82;

[1794] (g) SEQ ID NOs. 84 and 85;

[1795] (h) SEQ ID NOs. 86 and 87;

[1796] (i) SEQ ID NOs. 88 and 89;

[1797] (j) SEQ ID NOs. 90 and 91;

[1798] (k) SEQ ID NOs. 90 and 92;

[1799] (l) SEQ ID NOs. 93 and 94;

[1800] (m) SEQ ID NOs. 93 and 95;

[1801] (n) SEQ ID NOs. 96 and 97;

[1802] (o) SEQ ID NOs. 98 and 78;

[1803] (p) SEQ ID NOs. 100 and 78;

[1804] (q) SEQ ID NOs. 101 and 78;

[1805] (r) SEQ ID NOs. 102 and 78; and

[1806] (s) SEQ ID NOs. 103 and 85,

[1807] (ii) comprising two identical heavy chain / light chain complexes consisting of the heavy chain and light chain described in item (i).

[1808]

[142] A bispecific antibody against Allergen-1, which satisfies (i) or (ii),

[1809] (i) having a heavy chain and a light chain comprising an amino acid sequence selected from any one of the following sequence groups:

[1810] (a) SEQ ID NOs. 77 and 78;

[1811] (b) SEQ ID NOs. 79 and 78;

[1812] (c) SEQ ID NOs. 83 and 82;

[1813] (d) SEQ ID NOs. 84 and 85;

[1814] (e) SEQ ID NOs. 98 and 78;

[1815] (f) SEQ ID NOs. 100 and 78;

[1816] (g) SEQ ID NOs. 101 and 78;

[1817] (h) SEQ ID NOs. 102 and 78; and

[1818] (i) SEQ ID NOs. 103 and 85,

[1819] (ii) comprising two identical heavy chain / light chain complexes consisting of the heavy chain and light chain described in item (i).

[1820]

[143] The bispecific antibody against Allergen-1 according to item

[141] or

[142] , wherein:

[1821] The arginine at position 214 based on the EU numbering system in the constant region of the heavy chain is replaced with lysine, and / or the alanine at position 299 in SEQ ID NOs. 75, 81, 83, 86, 88, 93 and 96 and position 301 in SEQ ID NOs. 80 and 90, i.e. corresponding to position 297 based on the EU numbering system in the constant region of the heavy chain, are each independently replaced with asparagine.

[1822]

[144] The bispecific antibody or antibody fragment thereof according to any one of items [1] to

[143] , which substantially reduces cytokine production during administration or within 24 hours of administration.

[1823]

[145] The bispecific antibody or antibody fragment thereof according to item

[144] , wherein:

[1824] The cytokine includes at least one selected from the group consisting of IL-2, IL-4, IL-6, IL-10, IFN-γ and TNF-α.

[1825]

[146] A bispecific antibody or an antibody fragment thereof according to any one of items [1] to

[145] , which inhibits the binding of a TLR9 ligand (preferably ODN M362, ODN 1668, ODN 1826, etc.) to allergen-1.

[1826]

[147] The bispecific antibody or antibody fragment thereof according to any one of items [1] to

[146] , wherein:

[1827] Allergen-1 is human allergen-1.

[1828]

[148] The bispecific antibody or antibody fragment thereof according to item

[147] , wherein:

[1829] The human allergen-1 is any one or more human allergen-1 selected from the group consisting of human allergen-1L, human allergen-1S1 and human allergen-1S2.

[1830]

[149] The bispecific antibody or antibody fragment thereof according to any one of items [1] to

[148] , which is a monoclonal antibody.

[1831]

[150] The bispecific antibody or antibody fragment thereof according to any one of items [1] to

[149] , which is an isolated antibody.

[1832] [1-1] A pharmaceutical composition comprising the anti-allergen-1 bispecific antibody or the antibody fragment thereof according to any one of items [1] to

[150] as an active ingredient.

[1833] [1-2] The pharmaceutical composition according to item [1-1], further comprising at least one pharmaceutically acceptable carrier.

[1834] [2-1] An agent for inhibiting the progression of cancer symptoms, inhibiting recurrence and / or treating cancer, comprising an anti-allergen-1 bispecific antibody or an antibody fragment thereof selected from any one of items [1] to

[150] as an active ingredient.

[1835] [2-2] The agent according to item [2-1], wherein

[1836] The cancer is a solid cancer or a blood cancer.

[1837] [2-3] The agent according to item [2-2] for solid cancer, wherein:

[1838] The cancer is a solid cancer, which is one or more selected from the following cancers: malignant melanoma (e.g., malignant melanoma in the skin, oral mucosal epithelium, or orbital epithelium), non-small cell lung cancer (e.g., squamous non-small cell lung cancer and non-squamous non-small cell lung cancer), small cell lung cancer, head and neck cancer (e.g., oral cancer, epipharyngeal cancer, nasopharyngeal cancer, oropharyngeal cancer, laryngeal cancer, salivary gland cancer, and tongue cancer), renal cell carcinoma (e.g., clear cell renal cell carcinoma), breast cancer, ovarian cancer (e.g., serous ovarian cancer and ovarian clear cell carcinoma), uterine cancer (e.g., cervical cancer and endometrial cancer), anal cancer (e.g., anal canal cancer), colorectal cancer (e.g., MSI-H and / or dMMR) positive colorectal cancer), rectal cancer, colon cancer, hepatocellular carcinoma, esophageal cancer, gastric cancer, esophagogastric cancer Junction cancer, pancreatic cancer (e.g., pancreatic duct cancer, insulinoma, intraductal papillary mucinous neoplasm), urothelial cancer (e.g., bladder cancer, upper urinary tract cancer, ureteral cancer, renal pelvis cancer and urethral cancer), prostate cancer, fallopian tube cancer, primary peritoneal cancer, malignant pleural mesothelioma, gallbladder cancer, bile duct cancer, biliary tract cancer, skin cancer (e.g., uveal malignant melanoma and Merkel cell carcinoma), testicular cancer (germ cell tumor), vaginal cancer, vulvar cancer, penile cancer, small intestine cancer, endocrine system cancer, thyroid cancer, parathyroid cancer, adrenal cancer, spinal tumors, neuroblastoma, medulloblastoma, retinoblastoma of the eye, neuroendocrine tumors, brain tumors (e.g., gliomas (e.g., glioblastomas and gliosarcoma) and meningiomas) and squamous cell carcinoma, etc.

[1839] [2-4] The drug according to item [2-2], wherein:

[1840] The cancer is a solid cancer, which is a bone / soft tissue sarcoma (eg, Ewing sarcoma, childhood rhabdomyosarcoma, uterine leiomyosarcoma, chondrosarcoma, pulmonary sarcoma, osteosarcoma, and congenital fibrosarcoma) and Kaposi sarcoma.

[1841] [2-5] The drug according to item [2-2], wherein:

[1842] The cancer is a blood cancer, and the blood cancer is one or more selected from the following cancers: multiple myeloma, malignant lymphoma (e.g., non-Hodgkin's lymphoma (e.g., B-cell non-Hodgkin's lymphoma (e.g., precursor B-cell lymphoblastic lymphoma, precursor B-cell acute lymphoblastic leukemia, chronic B-lymphocytic leukemia, B-cell precursor leukemia, B-cell prolymphocytic leukemia, lymphoplasmacytic lymphoma, lymph node marginal zone B-cell lymphoma, extranodal marginal zone B-cell lymphoma (MALT lymphoma), primary splenic marginal zone B-cell lymphoma leukemia, hairy cell leukemia, hairy cell leukemia variant, follicular lymphoma, childhood follicular lymphoma, diffuse large B-cell lymphoma, diffuse large B-cell lymphoma / not specified, splenic diffuse red pulp small B-cell lymphoma, primary mediastinal large B-cell lymphoma, primary effusion lymphoma, Burkitt lymphoma, mantle cell lymphoma, monoclonal B-cell lymphocytosis, splenic B-cell lymphoma / leukemia / unclassifiable, IgM monoclonal gammopathy of undetermined significance, μ heavy chain disease, λ heavy chain disease, α heavy chain disease, plasma cell myeloma, solitary plasmacytoma of bone, extraosseous plasmacytoma, monoclonal immunoglobulin deposition disease, large B-cell lymphoma with IRF4 rearrangement, primary cutaneous follicle center lymphoma, T cell / histiocyte-rich large B-cell lymphoma, primary central nervous system diffuse large B-cell lymphoma, primary cutaneous diffuse large B-cell lymphoma / lower extremity type, EBV-positive diffuse large B-cell lymphoma / not specified, EBV-positive mucocutaneous ulcer, chronic inflammation-associated diffuse large B-cell lymphoma, lymphomatoid granuloma, Intravascular large B-cell lymphoma, ALK-positive large B-cell lymphoma, plasmablastic lymphoma, HHV8-positive diffuse large B-cell lymphoma / not otherwise specified, Burkitt-like lymphoma with 11q abnormality, high-grade B-cell lymphoma with rearrangement of MYC and either or both BCL2 and BCL6, high-grade B-cell lymphoma / not otherwise specified, and B-cell lymphoma with features intermediate between diffuse large B-cell lymphoma and classical Hodgkin lymphoma / unclassifiable), T / NK-cell non-Hodgkin lymphoma (e.g.,Precursor T-cell lymphoblastic lymphoma, chronic T-cell lymphocytic leukemia, T-cell acute lymphoblastic leukemia, T-cell large granular lymphoblastic lymphoma, NK-cell large granular leukemia, aggressive NK-cell leukemia, peripheral T-cell lymphoma, peripheral T-cell lymphoma / unspecified, peripheral T-cell lymphoma unclassifiable, angioimmunoblastic T-cell lymphoma, anaplastic large cell (CD30-positive) lymphoma, angiocentric lymphoma, intestinal T-cell lymphoma, enteropathy-type T-cell lymphoma, hepatosplenic gamma-delta T-cell lymphoma, subcutaneous panniculitis-like T-cell lymphoma, Mycosis fungoides, Sezary syndrome, Hodgkin-like / Hodgkin-associated anaplastic large cell lymphoma, extranodal NK / T cell lymphoma, adult T cell leukemia, T cell prolymphocytic leukemia, NK cell chronic lymphoproliferative disease, systemic EBV-positive T cell lymphoma in children, vaccinia vesicular lymphoproliferative disease, extranodal NK / T cell lymphoma / nasal type, enteropathy-associated T cell lymphoma, monomorphic epithelial-tropic intestinal T cell lymphoma, inert T cell lymphoma proliferative disease of the digestive tract, hepatosplenic T cell lymphoma, primary skin CD30-positive T-cell lymphoproliferative disorder, lymphomatoid papulosis, primary cutaneous anaplastic large cell lymphoma, cutaneous T-cell lymphoma, primary cutaneous gamma-delta T-cell lymphoma, primary cutaneous CD8-positive aggressive epidermotropic cytotoxic T-cell lymphoma, primary cutaneous acral CD8-positive T-cell lymphoma, primary cutaneous CD4-positive small / medium T-cell lymphoproliferative disorder, follicular T-cell lymphoma, nodal peripheral T-cell lymphoma with follicular helper T-cell phenotype, anaplastic large cell lymphoma, ALK-positive, anaplastic large cell lymphoma, ALK-negative, and breast Implant-associated anaplastic large cell lymphoma) and Hodgkin's lymphoma (such as classical Hodgkin's lymphoma (such as nodular sclerosis type, mixed cell type, lymphocyte-rich type and lymphocyte-penic type) and nodular lymphocyte-predominant Hodgkin's lymphoma)), leukemia (such as acute myeloid leukemia, acute promyelocytic leukemia, acute lymphoblastic leukemia (lymphoblastic lymphoma), chronic lymphocytic leukemia (small lymphocytic lymphoma), myelodysplastic syndrome and chronic myeloid leukemia), primary central nervous system lymphoma, myeloproliferative syndrome, etc. ,

[1843] [2-6] The drug according to any one of items [2-1] to [2-5], wherein

[1844] The cancer is a childhood cancer or a cancer of unknown primary origin.

[1845] [2-7] The drug according to any one of items [2-1] to [2-6], wherein

[1846] Cancer treatments based on other anti-malignant tumor agents are inadequate or insufficient.

[1847] [2-8] The drug according to any one of items [2-1] to [2-7], wherein

[1848] The cancer is a cancer that has progressed after treatment with other anti-cancer agents.

[1849] [2-9] The drug according to any one of items [2-1] to [2-6], wherein

[1850] Cancer patients Cancer patients who have no history of treatment based on other anti-malignant tumor agents.

[1851] [2-10] The drug according to any one of items [2-1] to [2-9], which is prescribed in postoperative adjuvant therapy or preoperative adjuvant therapy.

[1852] [2-11] The drug according to any one of items [2-1] to [2-10], wherein

[1853] The cancer is incurable or incurable, metastatic, recurrent, refractory, and / or has distant metastases.

[1854] [2-12] The drug according to any one of items [2-1] to [2-11], wherein

[1855] TPS or CPS is 50% or more, 25% or more, 10% or more, 5% or more, or 1% or more.

[1856] [2-13] The drug according to any one of items [2-1] to [2-11], wherein

[1857] TPS or CPS is less than 50%, less than 25%, less than 10%, less than 5% or less than 1%.

[1858] [2-14] The drug according to any one of items [2-1] to [2-13], wherein

[1859] TMB is high frequency.

[1860] [2-15] The drug according to any one of items [2-1] to [2-13], wherein

[1861] TMB is low frequency.

[1862] [2-16] The drug according to any one of items [2-1] to [2-15], which is further used in combination with other anti-tumor drugs.

[1863] [2-17] The agent according to any one of items [2-7] to [2-9] and [2-16], wherein

[1864] The other anti-malignant tumor agents are any one or more selected from the following agents (preferably agents that do not cause the onset of cytokine release syndrome): alkylating agents, platinum preparations, metabolic antagonists (such as folate metabolic antagonists, pyridine metabolic inhibitors and purine metabolic inhibitors), ribonucleotide reductase inhibitors, nucleotide analogs, topoisomerase inhibitors, microtubule polymerization inhibitors, microtubule depolymerization inhibitors, antitumor antibiotics, cytokine preparations, antihormonal drugs, molecular targeted drugs, as well as tumor immunosuppressants and other antibody drugs.

[1865] [2-18] The agent according to item [2-17], wherein

[1866] The other anti-malignant tumor agent is a molecular targeted drug, and the molecular targeted drug is any one or more selected from the following agents: ALK inhibitors, BCR-ABL inhibitors, EGFR inhibitors, B-RAF inhibitors, VEGFR inhibitors, FGFR inhibitors, c-MET inhibitors, AXL inhibitors, MEK inhibitors, CDK inhibitors, BTK inhibitors, BCL-2 inhibitors, PI3K-δ / γ inhibitors, JAK-1 / 2 inhibitors, ERK inhibitors, TGFbR1 inhibitors, cancer stem cell kinase inhibitors, FAK inhibitors, SYK / FLT3 dual inhibitors, ATR inhibitors, WEE1 kinase inhibitors, multi-tyrosine kinase inhibitors, mTOR inhibitors, HDAC inhibitors, PARP inhibitors, aromatase inhibitors, EZH2 inhibitors, galectin-3 inhibitors, STAT3 inhibitors, DNMT inhibitors, SMO inhibitors, HSP90 inhibitors, γ-tubulin specific inhibitors, HIF2α inhibitors, glutaminase inhibitors, E3 ligase inhibitors, NRF2 activators, arginase inhibitors, cell cycle inhibitors, Ephrin B4 inhibitor, IAP antagonist, anti-HER2 antibody, anti-HER1 antibody, anti-HER3 antibody, anti-CD40 antibody, anti-CD70 antibody, anti-VEGF antibody, anti-VEGFR1 antibody, anti-VEGFR2 antibody, anti-CD20 antibody, anti-CD30 antibody, anti-CD38 antibody, anti-TNFRSF10B antibody, anti-TNFRSF10A antibody, anti-MUC1 antibody, anti-MUC5AC antibody, anti-MUC16 antibody, anti-DLL4 antibody, anti-fucosyl GM1 antibody, anti-gpNMB antibody, anti-mesothelin antibody, anti-MMP9 antibody, anti-GD2 antibody, anti-MET antibody, anti-FOLR1 antibody, anti-CD79b antibody, anti-DLL3 antibody, anti-CD51 antibody, anti-E PCAM antibody, anti-CEACAM5 antibody, anti-CEACAM6 antibody, anti-FGFR2 antibody, anti-CD44 antibody, anti-PSMA antibody, anti-Endoglin antibody, anti-IGF1R antibody, anti-TNFSF11 antibody, anti-GUCY2C antibody, anti-SLC39A6 antibody, anti-SLC34A2 antibody, anti-NCAM1 antibody, anti-ganglioside GD3 antibody, anti-AMHR2 antibody, anti-CD37 antibody, anti-IL1RAP antibody, anti-PDGFR2 antibody, anti-CD200 antibody, anti-TAG-72 antibody, anti-SLITRK6 antibody, anti-DPEP3 antibody, anti-CD19 antibody, anti-NOTCH2 / 3 antibody, anti-tenascinC antibody, anti-AXL antibody, anti-STEAP1 antibody, anti-CTAA16 antibody, anti-CLDN18 antibody, anti-GM3 antibody, anti-PSCA antibody, anti-fibronectin extra domain B (FNextra domain B) antibody, anti-HAVCR1 antibody, anti-TNFRSF4 antibody, anti-HER1-MET bispecific antibody, anti-EPCAM-CD3 bispecific antibody, anti-Ang2-VEGF bispecific antibody, anti-HER2-CD3 bispecific antibody, anti-HER3-IGF1R bispecific antibody, anti-PMSA-CD3 bispecific antibody, anti-HER1-LGR5 bispecific antibody, anti-SSTR2-CD3 bispecific antibody, anti-CD30-CD16A bispecific antibody, anti-CEA-CD3 bispecific antibody, anti-CD3-CD19 bispecific antibody, anti-IL3RA-CD3 bispecific antibody, anti-GPRC5D-CD3 bispecific antibody, anti-CD20-CD3 bispecific antibody, anti-TNFRSF17-CD3 bispecific antibody, anti-CLEC12A-CD3 bispecific antibody, anti-HER2-HER3 bispecific antibody, anti-FAP antibody / IL-2 fusion protein and anti-CEA antibody / IL-2 fusion protein.

[1867] [2-19] The agent according to item [2-17], wherein

[1868] The other anti-malignant tumor agent is a tumor immunotherapy drug, and the tumor immunotherapy drug is any one or more selected from the following agents: anti-PD-1 antibody, anti-PD-L1 antibody, PD-1 antagonist, PD-L1 / VISTA antagonist, PD-L1 / TIM3 antagonist, anti-PD-L2 antibody, PD-L1 fusion protein, PD-L2 fusion protein, anti-CTLA-4 antibody, anti-LAG-3 antibody, anti-TIM3 antibody, anti-KIR antibody, anti-BTLA antibody, anti-TIGIT antibody, anti-VISTA antibody, anti-CD137 antibody, anti-CSF-1R antibody·CSF-1R inhibitor, anti-OX40 antibody body, anti-HVEM antibody, anti-CD27 antibody, anti-GITR antibody·GITR fusion protein, anti-CD28 antibody, anti-CCR4 antibody, anti-B7-H3 antibody, anti-ICOS agonist antibody, anti-CD4 antibody, anti-DEC-205 antibody / NY-ESO-1 fusion protein, anti-SLAMF7 antibody, anti-CD73 antibody, PEGylated IL-2, IDO inhibitor, TLR agonist, adenosine A2A receptor antagonist, anti-NKG2A antibody, anti-CSF-1 antibody, immune enhancer, IL-15SUPER agonist, soluble LAG3, anti-CD47 antibody / CD47 antagonist and IL-12 antagonist.

[1869] [2-20] The agent according to item [2-17], wherein

[1870] The other anti-tumor agent is a tumor immunotherapy drug, and the tumor immunotherapy drug is an anti-PD-1 antibody, an anti-PD-L1 antibody or an anti-CTLA-4 antibody.

[1871] [2-21] The agent according to item [2-20], wherein

[1872] The tumor immunotherapy drug is an anti-PD-1 antibody, and the anti-PD-1 antibody is an antibody selected from the following: nivolumab, cemiprilimab-rwlc, pembrolizumab, spartalizumab, tislelizumab, dotalimumab, toripalimab, carrelizumab, genomab, sintilimab, lodalimab, rivalimab, batilizumab, srulimab, bruglimab, palollimab, saxalizumab, silimumab, sepalizumab, gelolimab, AMP-514, STI-A1110, ENUM 388D4, ENUM 244C8, sepalizumab, CS1003, BAT-1306, penicillin, AK103, ebenalizumab, LZM009, CMAB819, Sym021, SSI-361, JY034, putalimab, ISU106, and CX-188.

[1873] [2-22] The agent according to item [2-20], wherein

[1874] The tumor immunotherapy drug is an anti-PD-L1 antibody, and the anti-PD-L1 antibody is an antibody selected from the following: atezolizumab, avelumab, durvalumab, manelizumab, pacmilimab, envolimab, coxilimab, sugemalimab, BMS-936559, STI-1014, HLX20, adebelimumab, MSB2311, BGB-A333, KL-A167, AK106, socazolimab, FAZ053, CBT-502 and JS003.

[1875] [2-23] The agent according to item [2-20], wherein

[1876] The tumor immunotherapy drug is an anti-CTLA-4 antibody, and the anti-CTLA-4 antibody is an antibody selected from the following: ipilimumab, zeflalimab, norelizumab and tremelimumab.

[1877] [2-24] The agent according to item [2-21], wherein

[1878] When the anti-PD-1 antibody is nivolumab, for adults, nivolumab is administered by intravenous drip in the following manner:

[1879] (a) 1 mg / kg (body weight) once at 3-week intervals;

[1880] (b) 3 mg / kg (body weight) once at 2-week intervals;

[1881] (c) 2 mg / kg (body weight) once at 3-week intervals;

[1882] (d) 80 mg once every 3 weeks;

[1883] (e) 240 mg once every 2 weeks;

[1884] (f) 1 dose of 360 mg at 3-week intervals; or

[1885] (g) 480 mg once at 4-week intervals.

[1886] [2-25] The agent according to item [2-21], wherein

[1887] When the anti-PD-1 antibody is pembrolizumab, for adults, pembrolizumab is administered by intravenous drip in the following manner:

[1888] (a) 200 mg once every 3 weeks;

[1889] (b) 400 mg once at 6-week intervals; or

[1890] (c) 2 mg / kg (body weight) once at 3-week intervals (up to 200 mg for a single dose).

[1891] [2-26] The agent according to item [2-21], wherein

[1892] When the anti-PD-1 antibody is Cemiplimab-rwlc, for adults, 350 mg of Cemiplimab-rwlc is administered once by intravenous drip at intervals of 3 weeks.

[1893] [2-27] The agent according to item [2-21], wherein

[1894] When the anti-PD-1 antibody is dostarlimab, for adults, 500 mg of dostarlimab is administered by intravenous drip 1 to 4 times at intervals of 3 weeks, and 1000 mg is administered by intravenous drip 1 time at intervals of 6 weeks from the fifth time 3 weeks later.

[1895] [2-28] The agent according to item [2-22], wherein

[1896] When the anti-PD-1 antibody is avelumab, avelumab is administered to adults at a dose of 10 mg / kg (body weight) once by intravenous drip at intervals of 2 weeks.

[1897] [2-29] The agent according to item [2-22], wherein

[1898] When the anti-PD-1 antibody is atezolizumab, for adults, atezolizumab is administered by intravenous drip in the following manner:

[1899] (a) 840 mg once every 2 weeks;

[1900] (b) 1200 mg once at 3-week intervals; or

[1901] (c) 1680 mg once at 4-week intervals.

[1902] [2-30] The agent according to item [2-22], wherein:

[1903] When the anti-PD-1 antibody is Durvalumab, Durvalumab is administered to adults at a dose of 10 mg / kg (body weight) once by intravenous drip at intervals of 2 weeks.

[1904] [2-31] The agent according to item [2-23], wherein

[1905] When the anti-CTLA-4 antibody is ipilimumab, for adults, ipilimumab is used as

[1906] (a) 3 mg / kg (body weight) once a day, or

[1907] (b) 1 mg / kg (body weight) once a day,

[1908] The drug was administered via 4 intravenous infusions at 3-week intervals.

[1909] [2-32] The agent according to any one of items [2-20] to [2-31], wherein

[1910] The anti-PD-1 antibody, anti-PD-L1 antibody or anti-CTLA-4 antibody is administered by intravenous drip over 30 minutes, 60 minutes, 30 to 60 minutes or more than 60 minutes.

[1911] [3-1] A preparation for intravenous injection, comprising:

[1912] An anti-allergen-1 bispecific antibody or an antibody fragment thereof selected from items [1] to

[150] , and

[1913] At least one pharmaceutically acceptable carrier.

[1914] [3-2] The preparation for intravenous injection according to [3-1], which is used for:

[1915] Inhibit the progression of cancer symptoms, inhibit recurrence and / or treat cancer.

[1916] [3-3] The preparation for intravenous injection according to item [3-1] or [3-2], which is for drip infusion.

[1917] [4-1] A method for inhibiting the progression of cancer symptoms, inhibiting recurrence and / or treating cancer, comprising:

[1918] An effective amount of the anti-allergen-1 bispecific antibody or the antibody fragment thereof selected from any one of items [1] to

[150] is administered to a patient.

[1919] [5-1] An anti-allergen-1 bispecific antibody or an antibody fragment thereof selected from any one of items [1] to

[150] , which is used for inhibiting the progression of cancer symptoms, inhibiting recurrence and / or treating cancer.

[1920] [6-1] Use of an anti-allergen-1 bispecific antibody or an antibody fragment thereof selected from any one of items [1] to

[150] in the manufacture of a drug for inhibiting symptom progression, inhibiting recurrence and / or treating cancer.

[1921] [7-1] An antibody (anti-S1 domain antibody) or an antibody fragment thereof that specifically binds to the S1 domain of allergen-1, which cross-competes with an antibody or its antigen-binding site for binding to the S1 domain of allergen-1, wherein the antibody or its antigen-binding site has VH and VL, and the VH and VL comprise any one of the following amino acid sequences:

[1922] (a) SEQ ID NOs. 1 and 104;

[1923] (b) SEQ ID NOs. 2 and 105;

[1924] (c) SEQ ID NOs. 3 and 106;

[1925] (d) SEQ ID NOs. 4 and 107;

[1926] (e) SEQ ID NOs. 5 and 108;

[1927] (f) SEQ ID NOs. 6 and 109;

[1928] (g) SEQ ID NOs. 7 and 110; and

[1929] (h) SEQ ID NOs. 8 and 111.

[1930] [7-2] An anti-S1 domain antibody or an antibody fragment thereof, wherein the binding to the S1 domain of allergen-1 is cross-competed by an antibody or an antigen-binding site thereof having VH and VL, wherein the VH and VL comprise any one of the following amino acid sequences:

[1931] (a) SEQ ID NOs. 1 and 104,

[1932] (b) SEQ ID NOs. 2 and 105,

[1933] (c) SEQ ID NOs. 3 and 106,

[1934] (d) SEQ ID NOs. 4 and 107,

[1935] (e) SEQ ID NOs. 5 and 108,

[1936] (f) SEQ ID NOs. 6 and 109,

[1937] (g) SEQ ID NOs. 7 and 110, and

[1938] (h) SEQ ID NOs. 8 and 111.

[1939] [7-3] An antibody (anti-S2 domain antibody) or an antibody fragment thereof that specifically binds to the S2 domain of allergen-1, which cross-competes with an antibody or its antigen-binding site for binding to the S2 domain of allergen-1, wherein the antibody or its antigen-binding site has VH and VL, and the VH and VL comprise any one of the following amino acid sequences:

[1940] (a) SEQ ID NOs. 9 and 112,

[1941] (b) SEQ ID NOs. 10 and 113, and

[1942] (c) SEQ ID NOs. 11 and 114.

[1943] [7-4] An anti-S2 domain antibody or an antibody fragment thereof, wherein the binding to the S2 domain of allergen-1 is cross-competed by an antibody or an antigen-binding site thereof having VH and VL, wherein the VH and VL comprise any one of the following groups of amino acid sequences:

[1944] (a) SEQ ID NOs. 9 and 112;

[1945] (b) SEQ ID NOs. 10 and 113; and

[1946] (c) SEQ ID NOs. 11 and 114.

[1947] [7-5] The antibody or antibody fragment thereof according to item [7-1] or [7-2], which has a VH and a VL selected from any one of the following groups (A) to (F):

[1948] (A)

[1949] VH, which has

[1950] (a) VH-CDR1 comprising the amino acid sequence of SEQ ID NO.25;

[1951] (b) VH-CDR2 comprising the amino acid sequence of SEQ ID NO.26; and

[1952] (c) a VH-CDR3 comprising the amino acid sequence of SEQ ID NO. 27, and

[1953] VL, which has

[1954] (d) a VL-CDR1 comprising the amino acid sequence of SEQ ID NO.49;

[1955] (e) a VL-CDR2 comprising the amino acid sequence of SEQ ID NO.50; and

[1956] (f) a VL-CDR3 comprising the amino acid sequence of SEQ ID NO.51,

[1957] (B)

[1958] VH, which has

[1959] (a) VH-CDR1 comprising the amino acid sequence of SEQ ID NO.28;

[1960] (b) VH-CDR2 comprising the amino acid sequence of SEQ ID NO.29; and

[1961] (c) a VH-CDR3 comprising the amino acid sequence of SEQ ID NO. 30, and

[1962] VL, which has

[1963] (d) a VL-CDR1 comprising the amino acid sequence of SEQ ID NO.52;

[1964] (e) a VL-CDR2 comprising the amino acid sequence of SEQ ID NO.53; and

[1965] (f) a VL-CDR3 comprising the amino acid sequence of SEQ ID NO.54,

[1966] (C)

[1967] VH, which has

[1968] (a) VH-CDR1 comprising the amino acid sequence of SEQ ID NO.31;

[1969] (b) VH-CDR2 comprising the amino acid sequence of SEQ ID NO.32; and

[1970] (c) a VH-CDR3 comprising the amino acid sequence of SEQ ID NO. 33, and

[1971] VL, which has

[1972] (d) a VL-CDR1 comprising the amino acid sequence of SEQ ID NO.55;

[1973] (e) a VL-CDR2 comprising the amino acid sequence of SEQ ID NO.56; and

[1974] (f) a VL-CDR3 comprising the amino acid sequence of SEQ ID NO.57,

[1975] (D)

[1976] VH, which has

[1977] (a) VH-CDR1 comprising the amino acid sequence of SEQ ID NO.34;

[1978] (b) a VH-CDR2 comprising the amino acid sequence of SEQ ID NO. 35; and

[1979] (c) a VH-CDR3 comprising the amino acid sequence of SEQ ID NO. 36, and

[1980] VL, which has

[1981] (d) a VL-CDR1 comprising the amino acid sequence of SEQ ID NO.58;

[1982] (e) a VL-CDR2 comprising the amino acid sequence of SEQ ID NO.59; and

[1983] (f) a VL-CDR3 comprising the amino acid sequence of SEQ ID NO.60,

[1984] (E)

[1985] VH, which has

[1986] (a) VH-CDR1 comprising the amino acid sequence of SEQ ID NO.37;

[1987] (b) VH-CDR2 comprising the amino acid sequence of SEQ ID NO.38; and

[1988] (c) a VH-CDR3 comprising the amino acid sequence of SEQ ID NO. 39, and

[1989] VL, which has

[1990] (d) a VL-CDR1 comprising the amino acid sequence of SEQ ID NO.61;

[1991] (e) a VL-CDR2 comprising the amino acid sequence of SEQ ID NO.62; and

[1992] (f) a VL-CDR3 comprising the amino acid sequence of SEQ ID NO.63,

[1993] (F)

[1994] VH, which has

[1995] (a) VH-CDR1 comprising the amino acid sequence of SEQ ID NO.40,

[1996] (b) VH-CDR2 comprising the amino acid sequence of SEQ ID NO.41; and

[1997] (c) a VH-CDR3 comprising the amino acid sequence of SEQ ID NO. 42, and

[1998] VL, which has

[1999] (d) a VL-CDR1 comprising the amino acid sequence of SEQ ID NO.64;

[2000] (e) a VL-CDR2 comprising the amino acid sequence of SEQ ID NO.65; and

[2001] (f) VL-CDR3 comprising the amino acid sequence of SEQ ID NO.66.

[2002] [7-6] The antibody or antibody fragment thereof according to item [7-3] or [7-4], which has a set of VH and VL of the following (A) or (B):

[2003] (A)

[2004] VH, which has

[2005] (a) VH-CDR1 comprising the amino acid sequence of SEQ ID NO.43;

[2006] (b) VH-CDR2 comprising the amino acid sequence of SEQ ID NO.44; and

[2007] (c) a VH-CDR3 comprising the amino acid sequence of SEQ ID NO.45,

[2008] VL, which has

[2009] (d) a VL-CDR1 comprising the amino acid sequence of SEQ ID NO.67;

[2010] (e) a VL-CDR2 comprising the amino acid sequence of SEQ ID NO.68; and

[2011] (f) a VL-CDR3 comprising the amino acid sequence of SEQ ID NO.69,

[2012] (B)

[2013] VH, which has

[2014] (a) VH-CDR1 comprising the amino acid sequence of SEQ ID NO.46;

[2015] (b) VH-CDR2 comprising the amino acid sequence of SEQ ID NO.47; and

[2016] (c) a VH-CDR3 comprising the amino acid sequence of SEQ ID NO.48,

[2017] VL, which has

[2018] (d) VL-CDR1 comprising the amino acid sequence of SEQ ID NO.70;

[2019] (e) a VL-CDR2 comprising the amino acid sequence of SEQ ID NO. 71; and

[2020] (f) VL-CDR3 comprising the amino acid sequence of SEQ ID NO.72.

[2021] [7-7] The antibody or antibody fragment thereof according to item [7-5] or [7-6], wherein

[2022] In any one or more CDRs selected from VH-CDR1, VH-CDR2, VH-CDR3, VL-CDR1, VL-CDR2 and VL-CDR3, any 1 to 5 amino acid residues in each CDR are optionally substituted with other amino acids.

[2023] [7-8] The antibody or antibody fragment thereof according to any one of items [7-1] to [7-7], wherein

[2024] The FW of VH and VL comprises the amino acid sequence encoded by the germline VH gene IGHV3-66 and the VL gene IGKV1-39, or the said genes in which one or more somatic mutations and / or back mutations have occurred.

[2025] [7-9] The antibody or antibody fragment thereof according to any one of items [7-1], [7-2], [7-5], [7-7] and [7-8], which has VH and VL, wherein each of the VH and VL comprises: an amino acid sequence selected from any one of the following sequence groups, or an amino acid sequence that is independently at least 80%, 90%, 95%, 98% or 99% identical to each of the amino acid sequences (excluding each of the three CDRs),

[2026] (a) SEQ ID NOs. 1 and 104;

[2027] (b) SEQ ID NOs. 2 and 105;

[2028] (c) SEQ ID NOs. 3 and 106;

[2029] (d) SEQ ID NOs. 4 and 107;

[2030] (e) SEQ ID NOs. 5 and 108;

[2031] (f) SEQ ID NOs. 6 and 109;

[2032] (g) SEQ ID NOs. 7 and 110; and

[2033] (h) SEQ ID NOs. 8 and 111.

[2034] [7-10] The antibody or antibody fragment thereof according to any one of items [7-3], [7-4] and [7-6] to [7-8], which has VH and VL, wherein VH and VL comprise: any one of the following groups of amino acid sequences, or a group of amino acid sequences that are each independently at least 80%, 90%, 95%, 98% or 99% identical to each of the amino acid sequences (excluding each of the three CDRs),

[2035] (a) SEQ ID NOs. 9 and 112;

[2036] (b) SEQ ID NOs. 10 and 113; and

[2037] (c) SEQ ID NOs. 11 and 114.

[2038] [7-11] An antibody or antibody fragment thereof against allergen-1, which has an antigen binding site selected from the group consisting of an S1-A binding site, an S1-B binding site, an S2-C binding site, and an S2-D binding site, wherein:

[2039] (a) the epitope to which the S1-A binding site specifically binds, i.e., the S1-A epitope, is composed of at least one or more of or all of phenylalanine at position 70, arginine at position 71, arginine at position 72, lysine at position 73, histidine at position 75, leucine at position 76, histidine at position 96, glutamic acid at position 97, lysine at position 102, lysine at position 104, and tyrosine at position 113 of allergen-1 comprising the amino acid sequence represented by SEQ ID NO. 115,

[2040] (b) the epitope to which the S2-D binding site specifically binds, i.e., the S2-D epitope, is composed of at least one or more of the isoleucine at position 132, the methionine at position 133, the valine at position 134, the isoleucine at position 135, the glutamine at position 136, the threonine at position 137, the glutamic acid at position 138, the histidine at position 146, and the proline at position 215 of the allergen-1,

[2041] (c) the epitope to which the S1-B binding site specifically binds is at least different from the S1-A epitope represented by said amino acids,

[2042] (d) The epitope specifically bound by the S2-C binding site is at least different from the S2-D epitope represented by the amino acids.

[2043] [7-12] The antibody or antibody fragment thereof according to any one of items [7-1] to [7-11], which is an IgG antibody.

[2044] [7-13] The antibody or antibody fragment thereof according to item [7-12], wherein:

[2045] The IgG antibody is IgG 1 Antibodies or IgG 4 .

[2046] [7-14] The antibody or antibody fragment thereof according to any one of items [7-1] to [7-13], wherein

[2047] Allergen-1 is human allergen-1.

[2048] [7-15] The antibody or antibody fragment thereof according to Item [7-14], wherein:

[2049] The human allergen-1 is any one or more human allergen-1 selected from the group consisting of human allergen-1L, human allergen-1S1 and human allergen-1S2.

[2050] [7-16] The antibody or antibody fragment thereof according to any one of items [7-1] to [7-7] and [7-11] to [7-15], which is a rabbit antibody.

[2051] [7-17] The antibody or antibody fragment thereof according to any one of items [7-1] to [7-7] and [7-11] to [7-16], which is a chimeric antibody.

[2052] [7-18] The antibody or antibody fragment thereof according to any one of items [7-1] to [7-16], which is a humanized antibody.

[2053] [7-19] The antibody or antibody fragment thereof according to any one of items [7-1] to [7-18], which is a monoclonal antibody.

[2054] [7-20] The antibody or antibody fragment thereof according to any one of items [7-1] to [7-19], which is an isolated antibody.

[2055] [8-1] A polynucleotide encoding an amino acid sequence selected from any one of SEQ ID NOs. 1 to 24 and SEQ ID NOs. 75 to 114.

[2056] [8-2] An expression vector comprising any one of the polynucleotides described in item [8-1].

[2057] [8-3] An animal cell into which the expression vector according to item [8-2] is introduced, or into which the animal cell is transformed by the introduction of the vector.

[2058] The contents of all patent documents, non-patent documents or reference documents explicitly cited in this specification can be incorporated herein as a part of the entire specification.

[2059] The present invention is described in more detail by the following examples, but the scope of the present invention is not limited thereto. A person skilled in the art can make various changes and modifications based on the description of the present invention, and the present invention includes these changes and modifications.

[2060] Example

[2061] Example 1: Using recombinant human allergen-1L-His fusion protein and human allergen-1L expression plasmid vector Immunization of rabbits

[2062] In order to obtain antibodies (including anti-S1 domain antibodies and anti-S2 domain antibodies) that specifically bind to human allergen-1 of the present invention, rabbits were immunized with recombinant human allergen-1L protein. In addition, rabbits were also immunized with expression vectors containing cDNAs encoding human allergen-1L, human allergen-1S1, and human allergen-1S2.

[2063] As a method for immunizing recombinant human allergen-1L protein, recombinant human allergen-1L-His fusion protein (Sino Biological, model 16083-H08H) emulsified with incomplete Freund's adjuvant and complete Freund's adjuvant was subcutaneously administered 4 times within 56 days or 5 times within 104 days to immunize rabbits (9 rabbits). Blood was collected from the immunized rabbits, and the antibody titer in the serum was evaluated by ELISA using the same recombinant human allergen-1L-His fusion protein or by Cell ELISA (CELISA) using a CHO cell line stably expressing human allergen-1L.

[2064] As a method for immunizing with an expression vector comprising a cDNA encoding human allergen-1, rabbits (11) were immunized by subcutaneously administering an expression vector comprising a cDNA encoding human allergen-1L, human allergen-1S1, and human allergen-1S2 eight times over 114 days. Blood was collected from the immunized rabbits, and the antibody titer in the serum was evaluated by CELISA using a CHO cell line stably expressing human allergen-1L, human allergen-1S1, and human allergen-1S2.

[2065] The spleen was removed from individuals whose serum antibody titers were confirmed to be increased, and the proportion of the cell population bound to the fluorescently labeled recombinant human allergen-1L-His fusion protein in the lymphocytes prepared therefrom was analyzed by flow cytometry to calculate the proportion of B cells producing antigen-specific antibodies. Screening of anti-allergen-1 antibody-producing B cells was performed using spleen lymphocytes of individuals showing high values ​​for serum antibody titers and the proportion of antigen-specific antibody-producing B cells in spleen lymphocytes.

[2066] Example 2: Screening of B cells producing anti-allergen-1 antibodies

[2067] By the spleen lymphocytes of each individual recovered separately from the rabbit selected from Example 1, the cells to which the fluorescently labeled recombinant human allergen-1L-His fusion protein is combined, that is, the B cells producing antigen-specific antibodies are separated by flow cytometry. The B cells obtained by culture separation, the antibody in its culture supernatant is analyzed by ELISA for the combination of recombinant human allergen-1L protein, or, it is analyzed by CELISA for the combination of membrane expressed human allergen-1L. In addition, for the antibody clones confirmed by optional analysis, the combination with the Chinese hamster ovary ovary celI of stably expressing human allergen-1S1, human allergen-1S2 and monkey allergen-1 is analyzed by CELISA. In the described CELISA, the clones of the signals more than 10% of the signals (OD values) obtained in the positive control wells (using the anti-human allergen-1 antibody obtained) are used as positive clones. In addition, by using the surface plasmon resonance method (SPR method) of MASS-2 SPR device (SierraSensors), the binding of the antibody in the culture supernatant to the recombinant human allergen-1L protein is analyzed and the dissociation constant (KD value) is calculated. In this analysis, the rabbit antibody in the culture supernatant is combined with the anti-rabbit IgG antibody fixed on the sensor chip (SPR-2 Affinity sensor, High Capacity Amine, Bruker LabScape), and then the recombinant human allergen-1L protein is flowed through the flow chamber as an analyte to be analyzed. According to the analysis results, multiple antibody clones containing positive clones that are combined with both human allergen-1L and monkey allergen-1 are screened out.

[2068] Example 3: DNA sequencing of candidate clones of anti-allergen-1 antibodies

[2069] RNA was extracted from each of the positive clones of the B cells isolated in Example 2, and cDNA was prepared by reverse transcription. PCR was performed on the prepared cDNA and each variable region of the immunoglobulin heavy chain and light chain using specific primers. DNA sequencing was performed on the amplified PCR products to determine the DNA sequences encoding each variable region sequence of the heavy chain and light chain of the antibody produced by the B cell clone.

[2070] Example 4: Binding evaluation of allergen-1 expressing cells using rabbit IgG and competition-based binding Test and Screen

[2071] Expression vectors encoding the heavy and light chains of the rabbit antibodies of the DNA sequences determined in Example 3 were prepared, and the expression vectors were genetically introduced into mammalian cells to produce antibodies in the culture supernatant. The culture supernatant was recovered and treated by protein A affinity chromatography to purify the rabbit IgG.

[2072] The binding of the purified rabbit IgG to CHO cells stably expressing human allergen-1L, human allergen-1S1, human allergen-1S2 and monkey allergen-1 was analyzed by CELISA. Specifically, the CHO cells stably expressing each allergen-1 were inoculated into a 96-well plate, diluted rabbit IgG was added thereto, and incubated at 37°C. After washing the CHO cells, diluted goat anti-rabbit IgG antibody labeled with HRP (Horseradish peroxidase) was added thereto, and incubated again at 37°C. After washing the CHO cells again, a colorimetric substrate...

Claims

1. A bispecific antibody or antibody fragment thereof against allergen-1, comprising two different antigen binding sites selected from the group consisting of a S1-A binding site, a S1-B binding site, a S2-C binding site and a S2-D binding site, wherein: The S1-A binding site is any one of the following antigen binding sites (A) to (D), (A) an antigen binding site comprising: VH, which has (a) VH-CDR1 comprising the amino acid sequence of SEQ ID NO.25; (b) VH-CDR2 comprising the amino acid sequence of SEQ ID NO.26; and (c) a VH-CDR3 comprising the amino acid sequence of SEQ ID NO. 27, and VL, which has (d) a VL-CDR1 comprising the amino acid sequence of SEQ ID NO.49; (e) a VL-CDR2 comprising the amino acid sequence of SEQ ID NO.50; and (f) a VL-CDR3 comprising the amino acid sequence of SEQ ID NO.51, (B) an antigen binding site comprising: VH, which has (a) VH-CDR1 comprising the amino acid sequence of SEQ ID NO.28; (b) VH-CDR2 comprising the amino acid sequence of SEQ ID NO.29; and (c) a VH-CDR3 comprising the amino acid sequence of SEQ ID NO. 30, and VL, which has (d) a VL-CDR1 comprising the amino acid sequence of SEQ ID NO.52; (e) a VL-CDR2 comprising the amino acid sequence of SEQ ID NO.53; and (f) a VL-CDR3 comprising the amino acid sequence of SEQ ID NO.54, (C) an antigen binding site comprising: VH, which has (a) VH-CDR1 comprising the amino acid sequence of SEQ ID NO.31; (b) VH-CDR2 comprising the amino acid sequence of SEQ ID NO.32; and (c) a VH-CDR3 comprising the amino acid sequence of SEQ ID NO. 33, and VL, which has (d) a VL-CDR1 comprising the amino acid sequence of SEQ ID NO.55; (e) a VL-CDR2 comprising the amino acid sequence of SEQ ID NO.56; and (f) a VL-CDR3 comprising the amino acid sequence of SEQ ID NO.57, (D) an antigen binding site comprising: VH, which has (a) VH-CDR1 comprising the amino acid sequence of SEQ ID NO.34; (b) a VH-CDR2 comprising the amino acid sequence of SEQ ID NO. 35; and (c) a VH-CDR3 comprising the amino acid sequence of SEQ ID NO. 36, and VL, which has (d) a VL-CDR1 comprising the amino acid sequence of SEQ ID NO.58; (e) a VL-CDR2 comprising the amino acid sequence of SEQ ID NO.59; and (f) a VL-CDR3 comprising the amino acid sequence of SEQ ID NO.60, The S1-B binding site is the following (E) or (F) antigen binding site: (E) an antigen binding site comprising: VH, which has (a) VH-CDR1 comprising the amino acid sequence of SEQ ID NO.37; (b) VH-CDR2 comprising the amino acid sequence of SEQ ID NO.38; and (c) a VH-CDR3 comprising the amino acid sequence of SEQ ID NO. 39, and VL, which has (d) a VL-CDR1 comprising the amino acid sequence of SEQ ID NO.61; (e) a VL-CDR2 comprising the amino acid sequence of SEQ ID NO.62; and (f) a VL-CDR3 comprising the amino acid sequence of SEQ ID NO.63, (F) an antigen binding site comprising: VH, which has (a) VH-CDR1 comprising the amino acid sequence of SEQ ID NO.40; (b) VH-CDR2 comprising the amino acid sequence of SEQ ID NO.41; and (c) a VH-CDR3 comprising the amino acid sequence of SEQ ID NO. 42, and VL, which has (d) a VL-CDR1 comprising the amino acid sequence of SEQ ID NO.64; (e) a VL-CDR2 comprising the amino acid sequence of SEQ ID NO.65; and (f) a VL-CDR3 comprising the amino acid sequence of SEQ ID NO.66, The S2-C binding site is an antigen binding site comprising the following VH and VL, VH, which has (a) VH-CDR1 comprising the amino acid sequence of SEQ ID NO.43; (b) VH-CDR2 comprising the amino acid sequence of SEQ ID NO.44; and (c) a VH-CDR3 comprising the amino acid sequence of SEQ ID NO.45, VL, which has (d) a VL-CDR1 comprising the amino acid sequence of SEQ ID NO.67; (e) a VL-CDR2 comprising the amino acid sequence of SEQ ID NO.68; and (f) a VL-CDR3 comprising the amino acid sequence of SEQ ID NO.69, The S2-D binding site is an antigen binding site comprising the following VH and VL, VH, which has (a) VH-CDR1 comprising the amino acid sequence of SEQ ID NO.46; (b) VH-CDR2 comprising the amino acid sequence of SEQ ID NO.47; and (c) a VH-CDR3 comprising the amino acid sequence of SEQ ID NO.48, VL, which has (d) VL-CDR1 comprising the amino acid sequence of SEQ ID NO.70; (e) a VL-CDR2 comprising the amino acid sequence of SEQ ID NO. 71; and (f) VL-CDR3 comprising the amino acid sequence of SEQ ID NO.

72.

2. The bispecific antibody or antibody fragment thereof according to claim 1, wherein: In any one or more CDRs of VH-CDR1, VH-CDR2, VH-CDR3, VL-CDR1, VL-CDR2 and VL-CDR3 constituting the antigen-binding site, any 1 to 5 amino acid residues in each are optionally replaced by other amino acids, wherein the antigen-binding site is any two different antigen-binding sites selected from the group consisting of the S1-A binding site, the S1-B binding site, the S2-C binding site and the S2-D binding site.

3. The bispecific antibody or antibody fragment thereof according to claim 1, wherein: The two different antigen binding sites are the S1-A binding site and the S2-C binding site. (i) The S1-A binding site is an antigen binding site comprising the following VH and VL, VH, which has (a) VH-CDR1 comprising the amino acid sequence of SEQ ID NO.25; (b) VH-CDR2 comprising the amino acid sequence of SEQ ID NO.26; and (c) a VH-CDR3 comprising the amino acid sequence of SEQ ID NO.27, VL, which has (d) a VL-CDR1 comprising the amino acid sequence of SEQ ID NO.49; (e) a VL-CDR2 comprising the amino acid sequence of SEQ ID NO.50; and (f) a VL-CDR3 comprising the amino acid sequence of SEQ ID NO.51, (ii) The S2-C binding site is an antigen binding site comprising the following VH and VL, VH, which has (a) VH-CDR1 comprising the amino acid sequence of SEQ ID NO.43; (b) VH-CDR2 comprising the amino acid sequence of SEQ ID NO.44; and (c) a VH-CDR3 comprising the amino acid sequence of SEQ ID NO.45, VL, which has (d) a VL-CDR1 comprising the amino acid sequence of SEQ ID NO.67; (e) a VL-CDR2 comprising the amino acid sequence of SEQ ID NO.68; and (f) VL-CDR3 comprising the amino acid sequence of SEQ ID NO.

69.

4. The bispecific antibody or antibody fragment thereof according to claim 1, wherein: The two different antigen binding sites are the S1-A binding site and the S2-C binding site. (i) The S1-A binding site is an antigen binding site comprising the following VH and VL, VH, which has (a) VH-CDR1 comprising the amino acid sequence of SEQ ID NO.28; (b) VH-CDR2 comprising the amino acid sequence of SEQ ID NO.29; and (c) a VH-CDR3 comprising the amino acid sequence of SEQ ID NO.30, VL, which has (d) a VL-CDR1 comprising the amino acid sequence of SEQ ID NO.52; (e) a VL-CDR2 comprising the amino acid sequence of SEQ ID NO.53; and (f) a VL-CDR3 comprising the amino acid sequence of SEQ ID NO.54, (ii) The S2-C binding site is an antigen binding site comprising the following VH and VL, VH, which has (a) VH-CDR1 comprising the amino acid sequence of SEQ ID NO.43; (b) VH-CDR2 comprising the amino acid sequence of SEQ ID NO.44; and (c) a VH-CDR3 comprising the amino acid sequence of SEQ ID NO.45, VL, which has (d) a VL-CDR1 comprising the amino acid sequence of SEQ ID NO.67; (e) a VL-CDR2 comprising the amino acid sequence of SEQ ID NO.68; and (f) VL-CDR3 comprising the amino acid sequence of SEQ ID NO.

69.

5. The bispecific antibody or antibody fragment thereof according to claim 1, wherein: The two different antigen binding sites are the S1-A binding site and the S2-C binding site. (i) The S1-A binding site is an antigen binding site comprising the following VH and VL, VH, which has (a) VH-CDR1 comprising the amino acid sequence of SEQ ID NO.31; (b) VH-CDR2 comprising the amino acid sequence of SEQ ID NO.32; and (c) a VH-CDR3 comprising the amino acid sequence of SEQ ID NO. 33, VL, which has (d) a VL-CDR1 comprising the amino acid sequence of SEQ ID NO.55; (e) a VL-CDR2 comprising the amino acid sequence of SEQ ID NO.56; and (f) a VL-CDR3 comprising the amino acid sequence of SEQ ID NO.57, (ii) The S2-C binding site is an antigen binding site comprising the following VH and VL, VH, which has (a) VH-CDR1 comprising the amino acid sequence of SEQ ID NO.43; (b) VH-CDR2 comprising the amino acid sequence of SEQ ID NO.44; and (c) a VH-CDR3 comprising the amino acid sequence of SEQ ID NO.45, VL, which has (d) a VL-CDR1 comprising the amino acid sequence of SEQ ID NO.67; (e) a VL-CDR2 comprising the amino acid sequence of SEQ ID NO.68; and (f) VL-CDR3 comprising the amino acid sequence of SEQ ID NO.

69.

6. The bispecific antibody or antibody fragment thereof according to claim 1, wherein: The two different antigen binding sites are the S1-A binding site and the S2-C binding site. (i) The S1-A binding site is an antigen binding site comprising the following VH and VL, VH, which has (a) VH-CDR1 comprising the amino acid sequence of SEQ ID NO.34; (b) a VH-CDR2 comprising the amino acid sequence of SEQ ID NO. 35; and (c) a VH-CDR3 comprising the amino acid sequence of SEQ ID NO.36, VL, which has (d) a VL-CDR1 comprising the amino acid sequence of SEQ ID NO.58; (e) a VL-CDR2 comprising the amino acid sequence of SEQ ID NO.59; and (f) a VL-CDR3 comprising the amino acid sequence of SEQ ID NO.60, (ii) The S2-C binding site is an antigen binding site comprising the following VH and VL, VH, which has (a) VH-CDR1 comprising the amino acid sequence of SEQ ID NO.43; (b) VH-CDR2 comprising the amino acid sequence of SEQ ID NO.44; and (c) a VH-CDR3 comprising the amino acid sequence of SEQ ID NO.45, VL, which has (d) a VL-CDR1 comprising the amino acid sequence of SEQ ID NO.67; (e) a VL-CDR2 comprising the amino acid sequence of SEQ ID NO.68; and (f) VL-CDR3 comprising the amino acid sequence of SEQ ID NO.

69.

7. The bispecific antibody or antibody fragment thereof according to claim 1, wherein: The two different antigen binding sites are the S1-A binding site and the S2-D binding site. (i) The S1-A binding site is an antigen binding site comprising the following VH and VL, VH, which has (a) VH-CDR1 comprising the amino acid sequence of SEQ ID NO.25; (b) VH-CDR2 comprising the amino acid sequence of SEQ ID NO.26; and (c) a VH-CDR3 comprising the amino acid sequence of SEQ ID NO.27, VL, which has (d) a VL-CDR1 comprising the amino acid sequence of SEQ ID NO.49; (e) a VL-CDR2 comprising the amino acid sequence of SEQ ID NO.50; and (f) a VL-CDR3 comprising the amino acid sequence of SEQ ID NO.51, (ii) The S2-D binding site is an antigen binding site comprising the following VH and VL, VH, which has (a) VH-CDR1 comprising the amino acid sequence of SEQ ID NO.46; (b) VH-CDR2 comprising the amino acid sequence of SEQ ID NO.47; and (c) a VH-CDR3 comprising the amino acid sequence of SEQ ID NO.48, VL, which has (d) VL-CDR1 comprising the amino acid sequence of SEQ ID NO.70; (e) a VL-CDR2 comprising the amino acid sequence of SEQ ID NO. 71; and (f) VL-CDR3 comprising the amino acid sequence of SEQ ID NO.

72.

8. The bispecific antibody or antibody fragment thereof according to claim 1, wherein: The two different antigen binding sites are the S1-A binding site and the S2-D binding site. (i) The S1-A binding site is an antigen binding site comprising the following VH and VL, VH, which has (a) VH-CDR1 comprising the amino acid sequence of SEQ ID NO.28; (b) VH-CDR2 comprising the amino acid sequence of SEQ ID NO.29; and (c) a VH-CDR3 comprising the amino acid sequence of SEQ ID NO.30, VL, which has (d) a VL-CDR1 comprising the amino acid sequence of SEQ ID NO.52; (e) a VL-CDR2 comprising the amino acid sequence of SEQ ID NO.53; and (f) a VL-CDR3 comprising the amino acid sequence of SEQ ID NO.54, (ii) The S2-D binding site is an antigen binding site comprising the following VH and VL, VH, which has (a) VH-CDR1 comprising the amino acid sequence of SEQ ID NO.46; (b) VH-CDR2 comprising the amino acid sequence of SEQ ID NO.47; and (c) a VH-CDR3 comprising the amino acid sequence of SEQ ID NO.48, VL, which has (d) VL-CDR1 comprising the amino acid sequence of SEQ ID NO.70; (e) a VL-CDR2 comprising the amino acid sequence of SEQ ID NO. 71; and (f) VL-CDR3 comprising the amino acid sequence of SEQ ID NO.

72.

9. The bispecific antibody or antibody fragment thereof according to claim 1, wherein: The two different antigen binding sites are the S1-A binding site and the S2-D binding site. (i) The S1-A binding site is an antigen binding site comprising the following VH and VL, VH, which has (a) VH-CDR1 comprising the amino acid sequence of SEQ ID NO.31; (b) VH-CDR2 comprising the amino acid sequence of SEQ ID NO.32; and (c) a VH-CDR3 comprising the amino acid sequence of SEQ ID NO. 33, VL, which has (d) a VL-CDR1 comprising the amino acid sequence of SEQ ID NO.55; (e) a VL-CDR2 comprising the amino acid sequence of SEQ ID NO.56; and (f) a VL-CDR3 comprising the amino acid sequence of SEQ ID NO.57, (ii) The S2-D binding site is an antigen binding site comprising the following VH and VL, VH, which has (a) VH-CDR1 comprising the amino acid sequence of SEQ ID NO.46; (b) VH-CDR2 comprising the amino acid sequence of SEQ ID NO.47; and (c) a VH-CDR3 comprising the amino acid sequence of SEQ ID NO.48, VL, which has (d) VL-CDR1 comprising the amino acid sequence of SEQ ID NO.70; (e) a VL-CDR2 comprising the amino acid sequence of SEQ ID NO. 71; and (f) VL-CDR3 comprising the amino acid sequence of SEQ ID NO.

72.

10. The bispecific antibody or antibody fragment thereof according to claim 1, wherein: The two different antigen binding sites are the S1-A binding site and the S2-D binding site. (i) The S1-A binding site is an antigen binding site comprising the following VH and VL, VH, which has (a) VH-CDR1 comprising the amino acid sequence of SEQ ID NO.34; (b) a VH-CDR2 comprising the amino acid sequence of SEQ ID NO. 35; and (c) a VH-CDR3 comprising the amino acid sequence of SEQ ID NO.36, VL, which has (d) a VL-CDR1 comprising the amino acid sequence of SEQ ID NO.58; (e) a VL-CDR2 comprising the amino acid sequence of SEQ ID NO.59; and (f) a VL-CDR3 comprising the amino acid sequence of SEQ ID NO.60, (ii) The S2-D binding site is an antigen binding site comprising the following VH and VL, VH, which has (a) VH-CDR1 comprising the amino acid sequence of SEQ ID NO.46; (b) VH-CDR2 comprising the amino acid sequence of SEQ ID NO.47; and (c) a VH-CDR3 comprising the amino acid sequence of SEQ ID NO.48, VL, which has (d) VL-CDR1 comprising the amino acid sequence of SEQ ID NO.70; (e) a VL-CDR2 comprising the amino acid sequence of SEQ ID NO. 71; and (f) VL-CDR3 comprising the amino acid sequence of SEQ ID NO.

72.

11. The bispecific antibody or antibody fragment thereof according to any one of claims 1 to 10, wherein: The framework region of each VH constituting an antigen-binding site comprises an amino acid sequence encoded by the germline VH gene IGHV3-66 or said gene in which one or more somatic mutations and / or back mutations have occurred, wherein the antigen-binding site is any two different antigen-binding sites selected from the group consisting of the S1-A binding site, the S1-B binding site, the S2-C binding site and the S2-D binding site, and / or The framework region of each VL constituting each of the antigen-binding sites comprises an amino acid sequence encoded by the germline VL gene IGKV1-39 or the gene in which one or more somatic mutations and / or back mutations have occurred.

12. The bispecific antibody or antibody fragment thereof according to any one of claims 1, 2 and 11, wherein: The S1-A binding site is composed of VH and VL, wherein VH and VL comprise: any one of the following groups of amino acid sequences, or a group of amino acid sequences that are each independently at least 80%, 90%, 95%, 98% or 99% identical to each of the amino acid sequences (excluding each of the three CDRs), (a) SEQ ID NO. 1 and SEQ ID NO. 12 or 104; (b) SEQ ID NO. 2 and SEQ ID NO. 13 or 105; (c) SEQ ID NO. 3 and SEQ ID NO. 14 or 106; (d) SEQ ID NO. 4 and SEQ ID NO. 15 or 107; (e) SEQ ID NO. 5 and SEQ ID NO. 16 or 108; and (f) SEQ ID NO. 6 and SEQ ID NO. 17 or 109.

13. The bispecific antibody or antibody fragment thereof according to any one of claims 1, 2, 11 and 12, wherein: The S1-B binding site is composed of VH and VL, and the VH and VL comprise: the following set of amino acid sequences, or a set of amino acid sequences that are each independently at least 80%, 90%, 95%, 98% or 99% identical to each of the amino acid sequences (excluding each of the three CDRs), (a) SEQ ID NO. 7 and SEQ ID NO. 18 or 110; or (b) SEQ ID NO. 8 and SEQ ID NO. 19 or 111.

14. The bispecific antibody or antibody fragment thereof according to any one of claims 1, 2, and 11 to 13, wherein: The S2-C binding site is composed of VH and VL, and the VH and VL comprise: a group of amino acid sequences of SEQ ID NO.9 and SEQ ID NO.20 or 112, or a group of amino acid sequences that are independently at least 80%, 90%, 95%, 98% or 99% identical to each of the amino acid sequences (excluding each of the three CDRs).

15. The bispecific antibody or antibody fragment thereof according to any one of claims 1, 2, and 11 to 14, wherein: The S2-D binding site is composed of VH and VL, and the VH and VL comprise: the following set of amino acid sequences, or a set of amino acid sequences that are each independently at least 80%, 90%, 95%, 98% or 99% identical to each of the amino acid sequences (excluding each of the three CDRs), (a) SEQ ID NO. 10 and SEQ ID NO. 21 or 113; or (b) SEQ ID NO.11 and SEQ ID NO.22 or 114.

16. The bispecific antibody or antibody fragment thereof according to claim 1 or 11, wherein: The S1-A binding site is composed of VH and VL, and the VH and VL contain any one of the amino acid sequences selected from the following sequence groups: (a) SEQ ID NO. 1 and SEQ ID NO. 12 or 104; (b) SEQ ID NO. 2 and SEQ ID NO. 13 or 105; (c) SEQ ID NO. 3 and SEQ ID NO. 14 or 106; (d) SEQ ID NO. 4 and SEQ ID NO. 15 or 107; (e) SEQ ID NO. 5 and SEQ ID NO. 16 or 108; and (f) SEQ ID NO. 6 and SEQ ID NO. 17 or 109.

17. The bispecific antibody or antibody fragment thereof according to any one of claims 1, 11 and 16, wherein: The S1-B binding site is composed of VH and VL, and the VH and VL contain the following set of amino acid sequences: (a) SEQ ID NO. 7 and SEQ ID NO. 18 or 110; or (b) SEQ ID NO. 8 and SEQ ID NO. 19 or 111.

18. The bispecific antibody or antibody fragment thereof according to any one of claims 1, 11, 16 and 17, wherein: The S2-C binding site is composed of VH and VL comprising a set of amino acid sequences of SEQ ID NO.9 and SEQ ID NO.20 or 112.

19. The bispecific antibody or antibody fragment thereof according to any one of claims 1, 11, and 16 to 18, wherein: The S2-D binding site is composed of VH and VL, and the VH and VL contain the following set of amino acid sequences: (a) SEQ ID NO. 10 and SEQ ID NO. 21 or 113; or (b) SEQ ID NO.11 and SEQ ID NO.22 or 114.

20. A bispecific antibody or antibody fragment thereof against allergen-1, comprising two different antigen binding sites selected from the group consisting of a S1-A binding site, a S1-B binding site, a S2-C binding site and a S2-D binding site, wherein: (i) the S1-A binding site is composed of VH and VL, wherein VH and VL comprise: an amino acid sequence selected from any one of the following sequence groups, or a group of amino acid sequences that are each independently at least 80%, 90%, 95%, 98% or 99% identical to each of the above amino acid sequences (excluding each of the three CDRs), (a) SEQ ID NO. 1 and SEQ ID NO. 12 or 104; (b) SEQ ID NO. 2 and SEQ ID NO. 13 or 105; (c) SEQ ID NO. 3 and SEQ ID NO. 14 or 106; (d) SEQ ID NO. 4 and SEQ ID NO. 15 or 107; (e) SEQ ID NO. 5 and SEQ ID NO. 16 or 108; and (f) SEQ ID NO. 6 and SEQ ID NO. 17 or 109, (ii) the S1-B binding site is composed of VH and VL, wherein VH and VL comprise: the following set of amino acid sequences, or a set of amino acid sequences that are each independently at least 80%, 90%, 95%, 98% or 99% identical to each of the above amino acid sequences (excluding each of the three CDRs), (a) SEQ ID NO. 7 and SEQ ID NO. 18 or 110; or (b) SEQ ID NO. 8 and SEQ ID NO. 19 or 111, (iii) the S2-C binding site is composed of VH and VL, wherein VH and VL comprise: a group of amino acid sequences of SEQ ID NO. 9 and SEQ ID NO. 20 or 112, or a group of amino acid sequences that are independently at least 80%, 90%, 95%, 98% or 99% identical to each of the amino acid sequences (excluding each of the three CDRs), (iv) the S2-D binding site is composed of VH and VL, wherein VH and VL comprise: the following set of amino acid sequences, or a set of amino acid sequences that are each independently at least 80%, 90%, 95%, 98% or 99% identical to each of the above amino acid sequences (excluding each of the three CDRs), (a) SEQ ID NO. 10 and SEQ ID NO. 21 or 113; or (b) SEQ ID NO.11 and SEQ ID NO.22 or 114.

21. The bispecific antibody or antibody fragment thereof according to claim 20, wherein: (i) The S1-A binding site is composed of VH and VL, wherein VH and VL comprise any one of the following amino acid sequences: (a) SEQ ID NO. 1 and SEQ ID NO. 12 or 104; (b) SEQ ID NO. 2 and SEQ ID NO. 13 or 105; (c) SEQ ID NO. 3 and SEQ ID NO. 14 or 106; (d) SEQ ID NO. 4 and SEQ ID NO. 15 or 107; (e) SEQ ID NO. 5 and SEQ ID NO. 16 or 108; and (f) SEQ ID NO. 6 and SEQ ID NO. 17 or 109, (ii) The S1-B binding site is composed of VH and VL, and the VH and VL comprise the following set of amino acid sequences: (a) SEQ ID NO. 7 and SEQ ID NO. 18 or 110; or (b) SEQ ID NO. 8 and SEQ ID NO. 19 or 111, (iii) VH and VL constituting the S2-C binding site are composed of VH and VL comprising a set of amino acid sequences of SEQ ID NO. 9 and SEQ ID NO. 20 or 112, (iv) The S2-D binding site is composed of VH and VL, and the VH and VL contain the following set of amino acid sequences: (a) SEQ ID NO. 10 and SEQ ID NO. 21 or 113; or (b) SEQ ID NO.11 and SEQ ID NO.22 or 114.

22. The bispecific antibody or antibody fragment thereof according to any one of claims 1, 11, 20 and 21, wherein: The two different antigen binding sites are the S1-A binding site and the S2-C binding site. The S1-A binding site is composed of VH and VL of a group of amino acid sequences including SEQID NO.1 and SEQ ID NO.12 or 104, and the S2-C binding site is composed of VH and VL of a group of amino acid sequences including SEQID NO.9 and SEQ ID NO.20 or 112.

23. The bispecific antibody or antibody fragment thereof according to any one of claims 1, 11, 20 and 21, wherein: The two different antigen binding sites are the S1-A binding site and the S2-C binding site. The S1-A binding site is composed of VH and VL of a group of amino acid sequences including SEQID NO.2 and SEQ ID NO.13 or 105, and the S2-C binding site is composed of VH and VL of a group of amino acid sequences including SEQID NO.9 and SEQ ID NO.20 or 112.

24. The bispecific antibody or antibody fragment thereof according to any one of claims 1, 11, 20 and 21, wherein: The two different antigen binding sites are the S1-A binding site and the S2-C binding site. The S1-A binding site is composed of VH and VL of a group of amino acid sequences including SEQID NO.3 and SEQ ID NO.14 or 106, and the S2-C binding site is composed of VH and VL of a group of amino acid sequences including SEQID NO.9 and SEQ ID NO.20 or 112.

25. The bispecific antibody or antibody fragment thereof according to any one of claims 1, 11, 20 and 21, wherein: The two different antigen binding sites are the S1-A binding site and the S2-C binding site. The S1-A binding site is composed of VH and VL of a group of amino acid sequences including SEQID NO.4 and SEQ ID NO.15 or 107, and the S2-C binding site is composed of VH and VL of a group of amino acid sequences including SEQID NO.9 and SEQ ID NO.20 or 112.

26. The bispecific antibody or antibody fragment thereof according to any one of claims 1, 11, 20 and 21, wherein: The two different antigen binding sites are the S1-A binding site and the S2-C binding site. The S1-A binding site is composed of VH and VL of a group of amino acid sequences including SEQID NO.5 and SEQ ID NO.16 or 108, and the S2-C binding site is composed of VH and VL of a group of amino acid sequences including SEQID NO.9 and SEQ ID NO.20 or 112.

27. The bispecific antibody or antibody fragment thereof according to any one of claims 1, 11, 20 and 21, wherein: The two different antigen binding sites are the S1-A binding site and the S2-C binding site. The S1-A binding site is composed of VH and VL of a group of amino acid sequences including SEQID NO.6 and SEQ ID NO.17 or 109, and the S2-C binding site is composed of VH and VL of a group of amino acid sequences including SEQID NO.9 and SEQ ID NO.20 or 112.

28. The bispecific antibody or antibody fragment thereof according to any one of claims 1, 11, 20 and 21, wherein: The two different antigen binding sites are the S1-A binding site and the S2-D binding site. The S1-A binding site is composed of VH and VL of a group of amino acid sequences comprising SEQID NO.1 and SEQ ID NO.12 or 104, and the S2-D binding site is composed of VH and VL of a group of amino acid sequences comprising SEQID NO.10 and SEQ ID NO.21 or 113.

29. The bispecific antibody or antibody fragment thereof according to any one of claims 1, 11, 20 and 21, wherein: The two different antigen binding sites are the S1-A binding site and the S2-D binding site. The S1-A binding site is composed of VH and VL of a group of amino acid sequences comprising SEQID NO.2 and SEQ ID NO.13 or 105, and the S2-D binding site is composed of VH and VL of a group of amino acid sequences comprising SEQID NO.10 and SEQ ID NO.21 or 113.

30. The bispecific antibody or antibody fragment thereof according to any one of claims 1, 11, 20 and 21, wherein: The two different antigen binding sites are the S1-A binding site and the S2-D binding site. The S1-A binding site is composed of VH and VL of a group of amino acid sequences including SEQID NO.3 and SEQ ID NO.14 or 106, and the S2-D binding site is composed of VH and VL of a group of amino acid sequences including SEQID NO.10 and SEQ ID NO.21 or 113.

31. The bispecific antibody or antibody fragment thereof according to any one of claims 1, 11, 20 and 21, wherein: The two different antigen binding sites are the S1-A binding site and the S2-D binding site. The S1-A binding site is composed of VH and VL of a group of amino acid sequences including SEQID NO.4 and SEQ ID NO.15 or 107, and the S2-D binding site is composed of VH and VL of a group of amino acid sequences including SEQID NO.10 and SEQ ID NO.21 or 113.

32. The bispecific antibody or antibody fragment thereof according to any one of claims 1, 11, 20 and 21, wherein: The two different antigen binding sites are the S1-A binding site and the S2-D binding site. The S1-A binding site is composed of VH and VL of a group of amino acid sequences including SEQID NO.5 and SEQ ID NO.16 or 108, and the S2-D binding site is composed of VH and VL of a group of amino acid sequences including SEQID NO.10 and SEQ ID NO.21 or 113.

33. The bispecific antibody or antibody fragment thereof according to any one of claims 1, 11, 20 and 21, wherein: The two different antigen binding sites are the S1-A binding site and the S2-D binding site. The S1-A binding site is composed of VH and VL of a group of amino acid sequences including SEQID NO.6 and SEQ ID NO.17 or 109, and the S2-D binding site is composed of VH and VL of a group of amino acid sequences including SEQID NO.10 and SEQ ID NO.21 or 113.

34. The bispecific antibody or antibody fragment thereof according to any one of claims 1, 11, 20 and 21, wherein: The two different antigen binding sites are the S1-A binding site and the S2-D binding site. The S1-A binding site is composed of VH and VL of a group of amino acid sequences including SEQID NO.1 and SEQ ID NO.12 or 104, and the S2-D binding site is composed of VH and VL of a group of amino acid sequences including SEQID NO.11 and SEQ ID NO.22 or 114.

35. The bispecific antibody or antibody fragment thereof according to any one of claims 1, 2, 11, 20 and 21, wherein: The two different antigen binding sites are the S1-A binding site and the S2-D binding site. The S1-A binding site is composed of VH and VL of a group of amino acid sequences including SEQID NO.2 and SEQ ID NO.13 or 105, and the S2-D binding site is composed of VH and VL of a group of amino acid sequences including SEQID NO.11 and SEQ ID NO.22 or 114.

36. The bispecific antibody or antibody fragment thereof according to any one of claims 1, 11, 20 and 21, wherein: The two different antigen binding sites are the S1-A binding site and the S2-D binding site. The S1-A binding site is composed of VH and VL of a group of amino acid sequences including SEQID NO.3 and SEQ ID NO.14 or 106, and the S2-D binding site is composed of VH and VL of a group of amino acid sequences including SEQID NO.11 and SEQ ID NO.22 or 114.

37. The bispecific antibody or antibody fragment thereof according to any one of claims 1, 11, 20 and 21, wherein: The two different antigen binding sites are the S1-A binding site and the S2-D binding site. The S1-A binding site is composed of VH and VL of a group of amino acid sequences including SEQID NO.4 and SEQ ID NO.15 or 107, and the S2-D binding site is composed of VH and VL of a group of amino acid sequences including SEQID NO.11 and SEQ ID NO.22 or 114.

38. The bispecific antibody or antibody fragment thereof according to any one of claims 1, 11, 20 and 21, wherein: The two different antigen binding sites are the S1-A binding site and the S2-D binding site. The S1-A binding site is composed of VH and VL of a group of amino acid sequences including SEQID NO.5 and SEQ ID NO.16 or 108, and the S2-D binding site is composed of VH and VL of a group of amino acid sequences including SEQID NO.11 and SEQ ID NO.22 or 114.

39. The bispecific antibody or antibody fragment thereof according to any one of claims 1, 11, 20 and 21, wherein: The two different antigen binding sites are the S1-A binding site and the S2-D binding site. The S1-A binding site is composed of VH and VL of a group of amino acid sequences including SEQID NO.6 and SEQ ID NO.17 or 109, and the S2-D binding site is composed of VH and VL of a group of amino acid sequences including SEQID NO.11 and SEQ ID NO.22 or 114.

40. A bispecific antibody or antibody fragment thereof, which has two antigen-binding sites that specifically bind to different epitopes of the extracellular domain of allergen-1, wherein: The antigen binding sites do not compete with each other for allergen-1, and are two different optional antigen binding sites selected from the group consisting of the S1-A binding site, the S1-B binding site, the S2-C binding site, and the S2-D binding site. (i) The S1-A binding site is capable of cross-competing with an antibody or its antigen-binding site having VH and VL for binding to the S1 domain of allergen-1, wherein the VH and VL comprise any one of the following groups of amino acid sequences: (a) SEQ ID NO.1 and SEQ ID NO.104; (b) SEQ ID NO.2 and SEQ ID NO.105; (c) SEQ ID NO. 3 and SEQ ID NO. 106; (d) SEQ ID NO.4 and SEQ ID NO.107; (e) SEQ ID NO. 5 and SEQ ID NO. 108; and (f) SEQ ID NO.6 and SEQ ID NO.109, (ii) the S1-B binding site is capable of cross-competing for binding to the S1 domain of Allergy-1 with an antibody or its antigen-binding site having VH and VL comprising the following set of amino acid sequences: (a) SEQ ID NO. 7 and SEQ ID NO. 110; or (b) SEQ ID NO.8 and SEQ ID NO.111, (iii) the S2-C binding site is capable of cross-competing with an antibody or its antigen binding site having VH and VL for binding to the S2 domain of allergen-1, wherein the VH and VL comprise the amino acid sequences of SEQ ID NO.9 and SEQ ID NO.112, and (iv) the S2-D binding site is capable of cross-competing for binding to the S2 domain of Allergy-1 with an antibody or its antigen-binding site having VH and VL comprising the following set of amino acid sequences: (a) SEQ ID NO. 10 and SEQ ID NO. 113; or (b) SEQ ID NO. 11 and SEQ ID NO.

114.

41. A bispecific antibody or antibody fragment thereof, which has two antigen-binding sites that specifically bind to different epitopes of the extracellular domain of allergen-1, wherein: The antigen binding sites do not compete with each other for allergen-1, and are two different optional antigen binding sites selected from the group consisting of the S1-A binding site, the S1-B binding site, the S2-C binding site, and the S2-D binding site. (i) The S1-A binding site is an antigen binding site, the binding of which to the S1 domain of Allergy-1 is cross-competed by an antibody or its antigen binding site having VH and VL, wherein the VH and VL comprise any one of the following groups of amino acid sequences: (a) SEQ ID NO.1 and SEQ ID NO.104; (b) SEQ ID NO.2 and SEQ ID NO.105; (c) SEQ ID NO. 3 and SEQ ID NO. 106; (d) SEQ ID NO.4 and SEQ ID NO.107; (e) SEQ ID NO. 5 and SEQ ID NO. 108; and (f) SEQ ID NO.6 and SEQ ID NO.109, (ii) The S1-B binding site is an antigen binding site, the binding of which to the S1 domain of Allergy-1 is cross-competed by an antibody or its antigen binding site having a VH and a VL comprising the following set of amino acid sequences: (a) SEQ ID NO. 7 and SEQ ID NO. 110; or (b) SEQ ID NO.8 and SEQ ID NO.111, (iii) the S2-C binding site is an antigen binding site, and its binding to the S2 domain of allergen-1 is cross-competed by an antibody or its antigen binding site having VH and VL, wherein the VH and VL comprise a set of amino acid sequences of SEQ ID NO.9 and SEQ ID NO.112, (iv) The S2-D binding site is an antigen binding site, the binding of which to the S2 domain of Allergy-1 is cross-competed by an antibody or its antigen binding site having a VH and a VL comprising the following set of amino acid sequences: (a) SEQ ID NO. 10 and SEQ ID NO. 113; or (b) SEQ ID NO. 11 and SEQ ID NO.

114.

42. The bispecific antibody or antibody fragment thereof according to any one of claims 1 to 41, wherein One antigen binding site is formed as a part of the heavy chain / light chain complex constituting the anti-allergen-1 bispecific antibody.

43. The bispecific antibody or antibody fragment thereof according to claim 42, wherein: The heavy chain / light chain complex is formed by any one selected from the following combinations: (A) a combination of (a) a heavy chain having the VH that constitutes the S1-A binding site and (b) a light chain having the VL that constitutes the S1-A binding site; (B) a combination of (a) a heavy chain having the VH that constitutes the S1-B binding site and (b) a light chain having the VL that constitutes the S1-B binding site; (C) a combination of (a) a heavy chain having said VH constituting the S2-C binding site and (b) a light chain having said VL constituting the S2-C binding site; and (D) A combination of (a) a heavy chain having the VH constituting the S2-D binding site and (b) a light chain having the VL constituting the S2-D binding site.

44. The bispecific antibody or antibody fragment thereof according to any one of claims 1 to 43, wherein Another antigen binding site has the form of scFv comprising VH and VL constituting the antigen binding site.

45. The bispecific antibody or antibody fragment thereof according to claim 44, wherein: The scFv is linked to the C-terminus of the heavy chain or light chain.

46. ​​The bispecific antibody or antibody fragment thereof according to claim 44, wherein: The scFv is linked to the C-terminus of the heavy chain.

47. The bispecific antibody or antibody fragment thereof according to claim 44, wherein: The scFv is linked to the C-terminus of the light chain.

48. The bispecific antibody or antibody fragment thereof according to claim 44 or 46, which satisfies (i) or (ii), (i) having (a) a heavy chain, the C-terminus of which is linked to the scFv; and (b) a light chain, (ii) comprising two identical heavy chain / light chain complexes consisting of the heavy chain and light chain described in item (i).

49. The bispecific antibody or antibody fragment thereof according to claim 44 or 47, which satisfies (i) or (ii), (i) having (a) a heavy chain; and (b) a light chain, the C-terminus of which is connected to the scFv, (ii) comprising two identical heavy chain / light chain complexes consisting of the heavy chain and light chain described in item (i).

50. The bispecific antibody or antibody fragment thereof according to any one of claims 44 to 49, wherein The antigen binding site in the heavy chain / light chain complex is the S1-A binding site, and the antigen binding site in the form of the scFv is any one antigen binding site selected from the group consisting of the S1-B binding site, the S2-C binding site and the S2-D binding site.

51. The bispecific antibody or antibody fragment thereof according to any one of claims 44 to 49, wherein The antigen binding site in the heavy chain / light chain complex is the S2-C binding site, and the antigen binding site in the form of the scFv is any one antigen binding site selected from the S1-A binding site, the S1-B binding site and the S2-D binding site.

52. The bispecific antibody or antibody fragment thereof according to any one of claims 44 to 49, wherein The antigen binding site in the heavy chain / light chain complex is the S2-D binding site, and the antigen binding site in the form of the scFv is any one antigen binding site selected from the S1-A binding site, the S1-B binding site and the S2-C binding site.

53. The bispecific antibody or antibody fragment thereof according to any one of claims 44 to 49, wherein The antigen binding site in the heavy chain / light chain complex is the S1-A binding site, and the antigen binding site in the form of the scFv is the S2-C binding site.

54. The bispecific antibody or antibody fragment thereof according to any one of claims 44 to 49, wherein The antigen binding site in the heavy chain / light chain complex is the S1-A binding site, and the antigen binding site in the form of the scFv is the S2-D binding site.

55. The bispecific antibody or antibody fragment thereof according to any one of claims 44 to 49, wherein The antigen binding site in the heavy chain / light chain complex is the S2-C binding site, and the antigen binding site in the form of the scFv is the S1-A binding site.

56. The bispecific antibody or antibody fragment thereof according to any one of claims 44 to 49, wherein The antigen binding site in the heavy chain / light chain complex is the S2-D binding site, and the antigen binding site in the form of the scFv is the S1-A binding site.

57. The bispecific antibody or antibody fragment thereof according to any one of claims 44 to 56, wherein The scFv is linked to the C-terminus of the heavy or light chain via a direct amide bond or a peptide linker.

58. The bispecific antibody or antibody fragment thereof according to claim 57, wherein: The N-terminus of the VL constituting the scFv is linked to the C-terminus of the heavy chain or light chain via a direct amide bond or a peptide linker.

59. The bispecific antibody or antibody fragment thereof according to any one of claims 44 to 58, wherein VH and VL constituting the scFv are linked to each other in the order of VL and VH from the N-terminal side thereof via a direct amide bond or a peptide linker.

60. The bispecific antibody or antibody fragment thereof according to claim 57 or 58, wherein: The peptide linker connecting the scFv to the C-terminus of the heavy chain or light chain comprises the amino acid sequence of SEQ ID NO.

73.

61. The bispecific antibody or antibody fragment thereof according to claim 59, wherein: The peptide linker connecting VH and VL constituting the scFv comprises the amino acid sequence of SEQ ID NO.

74.

62. A bispecific antibody or antibody fragment thereof against Allergen-1, comprising two different antigen binding sites selected from the group consisting of a S1-A binding site, a S2-C binding site and a S2-D binding site, wherein: (I) the S1-A binding site is any one of the following antigen binding sites (A) to (D), (A) an antigen binding site comprising: VH, which has (a) VH-CDR1 comprising the amino acid sequence of SEQ ID NO.25; (b) VH-CDR2 comprising the amino acid sequence of SEQ ID NO.26; and (c) a VH-CDR3 comprising the amino acid sequence of SEQ ID NO. 27, and VL, which has (d) a VL-CDR1 comprising the amino acid sequence of SEQ ID NO.49; (e) a VL-CDR2 comprising the amino acid sequence of SEQ ID NO.50; and (f) a VL-CDR3 comprising the amino acid sequence of SEQ ID NO.51, (B) an antigen binding site comprising: VH, which has (a) VH-CDR1 comprising the amino acid sequence of SEQ ID NO.28; (b) VH-CDR2 comprising the amino acid sequence of SEQ ID NO.29; and (c) a VH-CDR3 comprising the amino acid sequence of SEQ ID NO. 30, and VL, which has (d) a VL-CDR1 comprising the amino acid sequence of SEQ ID NO.52; (e) a VL-CDR2 comprising the amino acid sequence of SEQ ID NO.53; and (f) a VL-CDR3 comprising the amino acid sequence of SEQ ID NO.54, (C) an antigen binding site comprising: VH, which has (a) VH-CDR1 comprising the amino acid sequence of SEQ ID NO.31; (b) VH-CDR2 comprising the amino acid sequence of SEQ ID NO.32; and (c) a VH-CDR3 comprising the amino acid sequence of SEQ ID NO. 33, and VL, which has (d) a VL-CDR1 comprising the amino acid sequence of SEQ ID NO.55; (e) a VL-CDR2 comprising the amino acid sequence of SEQ ID NO.56; and (f) a VL-CDR3 comprising the amino acid sequence of SEQ ID NO.57, (D) an antigen binding site comprising: VH, which has (a) VH-CDR1 comprising the amino acid sequence of SEQ ID NO.34; (b) a VH-CDR2 comprising the amino acid sequence of SEQ ID NO. 35; and (c) a VH-CDR3 comprising the amino acid sequence of SEQ ID NO. 36, and VL, which has (d) a VL-CDR1 comprising the amino acid sequence of SEQ ID NO.58; (e) a VL-CDR2 comprising the amino acid sequence of SEQ ID NO.59; and (f) a VL-CDR3 comprising the amino acid sequence of SEQ ID NO.60, The S2-C binding site is an antigen binding site comprising the following VH and VL, VH, which has (a) VH-CDR1 comprising the amino acid sequence of SEQ ID NO.43; (b) VH-CDR2 comprising the amino acid sequence of SEQ ID NO.44; and (c) a VH-CDR3 comprising the amino acid sequence of SEQ ID NO.45, VL, which has (d) a VL-CDR1 comprising the amino acid sequence of SEQ ID NO.67; (e) a VL-CDR2 comprising the amino acid sequence of SEQ ID NO.68; and (f) a VL-CDR3 comprising the amino acid sequence of SEQ ID NO.69, The S2-D binding site is an antigen binding site comprising the following VH and VL, VH, which has (a) VH-CDR1 comprising the amino acid sequence of SEQ ID NO.46; (b) VH-CDR2 comprising the amino acid sequence of SEQ ID NO.47; and (c) a VH-CDR3 comprising the amino acid sequence of SEQ ID NO.48, VL, which has (d) VL-CDR1 comprising the amino acid sequence of SEQ ID NO.70; (e) a VL-CDR2 comprising the amino acid sequence of SEQ ID NO. 71; and (f) a VL-CDR3 comprising the amino acid sequence of SEQ ID NO.72, (II) one of the two different antigen-binding sites constitutes a part of a heavy chain / light chain complex and the other constitutes an antigen-binding site in the form of an scFv, wherein the heavy chain / light chain complex constitutes the bispecific antibody, (i) the antigen binding site in the heavy chain / light chain complex is the S1-A binding site, and the antigen binding site in the form of the scFv is the S2-C binding site or the S2-D binding site; (ii) the antigen binding site in the heavy chain / light chain complex is the S2-C binding site, and the antigen binding site in the form of the scFv is the S1-A binding site; or (iii) the antigen binding site in the heavy chain / light chain complex is the S2-D binding site, and the antigen binding site in the form of the scFv is the S1-A binding site, (III) the N-terminus of the VL constituting the scFv is connected to the C-terminus of the heavy chain or light chain via a peptide linker, (IV) (i) having a heavy chain and a light chain, wherein the heavy chain and the light chain have the structures described in items (I) to (III); or (ii) comprising two identical heavy chain / light chain complexes composed of a heavy chain and a light chain having the structures described in items (I) to (III).

63. The bispecific antibody or antibody fragment thereof according to claim 62, wherein: The two different antigen binding sites are any two selected from the following binding sites (i) to (iii), (i) an S1-A binding site, which is composed of VH and VL, wherein VH and VL comprise any one of the following groups of amino acid sequences: (a) SEQ ID NOs. 1 and 12; (b) SEQ ID NOs. 2 and 13; (c) SEQ ID NO. 3 and SEQ ID NO. 14 or 106; (d) SEQ ID NO. 4 and SEQ ID NO. 15 or 107; (e) SEQ ID NOs. 5 and 16; and (f) SEQ ID NO. 6 and SEQ ID NO. 17 or 109, (ii) an S2-C binding site, which is composed of VH and VL, wherein VH and VL comprise a set of amino acid sequences of SEQ ID NO. 9 and SEQ ID NO. 20 or 112, (iii) an S2-D binding site, which is composed of VH and VL, wherein VH and VL comprise the following set of amino acid sequences: (a) SEQ ID NO. 10 and SEQ ID NO. 21 or 113; or (b) SEQ ID NOs. 11 and 22.

64. The bispecific antibody or antibody fragment thereof according to claim 62, wherein: The two different antigen binding sites are any two selected from the following binding sites (i) to (iii), (i) an S1-A binding site, which is composed of VH and VL, wherein VH and VL comprise any one of the following groups of amino acid sequences: (a) SEQ ID NO. 3 and SEQ ID NO. 14 or 106; (b) SEQ ID NO. 4 and SEQ ID NO. 15 or 107; (c) SEQ ID NOs. 5 and 16; and (d) SEQ ID NO. 6 and SEQ ID NO. 17 or 109, (ii) an S2-C binding site, which is composed of VH and VL, wherein VH and VL comprise a set of amino acid sequences of SEQ ID NO. 9 and SEQ ID NO. 20 or 112, (iii) an S2-D binding site, which is composed of VH and VL, wherein VH and VL comprise the following set of amino acid sequences: (a) SEQ ID NO. 10 and SEQ ID NO. 21 or 113; or (b) SEQ ID NOs. 11 and 22.

65. The bispecific antibody or antibody fragment thereof according to claim 62, wherein: The two different antigen binding sites are (a) an S1-A binding site, which is composed of VH and VL, wherein VH and VL comprise a set of amino acid sequences of SEQ ID NO. 3 and SEQ ID NO. 14 or 106; and (b) The S2-C binding site is composed of VH and VL, wherein VH and VL comprise a set of amino acid sequences of SEQ ID NO. 9 and SEQ ID NO. 20 or 112.

66. The bispecific antibody or antibody fragment thereof according to claim 62, wherein: The two different antigen binding sites are (a) an S1-A binding site, which is composed of VH and VL, wherein VH and VL comprise a set of amino acid sequences of SEQ ID NO. 6 and SEQ ID NO. 17 or 109; and (b) The S2-D binding site is composed of VH and VL, wherein VH and VL comprise a set of amino acid sequences of SEQ ID NO.10 and SEQ ID NO.21 or 113.

67. The bispecific antibody or antibody fragment thereof according to claim 62, wherein: The two different antigen binding sites are the S1-A binding site and the S2-D binding site. The S1-A binding site is composed of VH and VL, and the VH and VL contain any one of the amino acid sequences selected from the following sequence groups: (a) SEQ ID NO. 3 and SEQ ID NO. 14 or 106; (b) SEQ ID NO. 4 and SEQ ID NO. 15 or 107; and (c) SEQ ID NOs. 5 and 16, The S2-D binding site is composed of VH and VL, and the VH and VL contain the following set of amino acid sequences: (d) SEQ ID NO. 10 and SEQ ID NO. 21 or 113; or (e) SEQ ID NOs. 11 and 22.

68. The bispecific antibody or antibody fragment thereof according to any one of claims 63 to 67, wherein (a)(i) When the S1-A binding site constitutes an scFv, the VL constituting the scFv comprises an amino acid sequence selected from SEQ ID NOs. 12 to 17, (ii) in the case where the S1-A binding site constitutes part of a heavy chain / light chain complex, the VL constituting the light chain comprises an amino acid sequence selected from the group consisting of SEQ ID NOs. 106, 107 and 109, (b)(i) When the S2-C binding site constitutes an scFv, the VL constituting the scFv comprises the amino acid sequence of SEQ ID NO. 20, (ii) when the S2-C binding site constitutes part of the heavy chain / light chain complex, the VL constituting the light chain comprises the amino acid sequence of SEQ ID NO. 112, (c)(i) When the S2-D binding site constitutes an scFv, the VL constituting the scFv comprises the amino acid sequence of SEQ ID NO. 21 or 22, (ii) When the S2-D binding site constitutes a part of the heavy chain / light chain complex, the VL constituting the light chain comprises the amino acid sequence of SEQ ID NO.

113.

69. The bispecific antibody or antibody fragment thereof according to claim 62, wherein: The two different antigen binding sites are (a) an S1-A binding site, which is composed of VH and VL, wherein VH and VL comprise a set of amino acid sequences of SEQ ID NOs. 3 and 14; and (b) The S2-C binding site is composed of VH and VL, wherein VH and VL comprise a set of amino acid sequences of SEQ ID NOs. 9 and 112.

70. The bispecific antibody or antibody fragment thereof according to claim 62, wherein: The two different antigen binding sites are (a) an S1-A binding site, which is composed of VH and VL, wherein VH and VL comprise a set of amino acid sequences of SEQ ID NOs. 3 and 106; and (b) The S2-C binding site is composed of VH and VL, wherein VH and VL comprise a set of amino acid sequences of SEQ ID NOs. 9 and 20.

71. The bispecific antibody or antibody fragment thereof according to claim 62, wherein: The two different antigen binding sites are (a) an S1-A binding site, which is composed of VH and VL, wherein VH and VL comprise a set of amino acid sequences of SEQ ID NOs. 6 and 17; and (b) The S2-D binding site is composed of VH and VL, wherein VH and VL comprise a set of amino acid sequences of SEQ ID NOs. 10 and 113.

72. The bispecific antibody or antibody fragment thereof according to claim 62, wherein: The two different antigen binding sites are (a) an S1-A binding site, which is composed of VH and VL, wherein VH and VL comprise a set of amino acid sequences of SEQ ID NOs. 6 and 109; and (b) The S2-D binding site is composed of VH and VL, wherein VH and VL comprise a set of amino acid sequences of SEQ ID NOs. 10 and 21.

73. The bispecific antibody or antibody fragment thereof according to claim 62, wherein: The two different antigen binding sites are (a) an S1-A binding site, which is composed of VH and VL, wherein VH and VL comprise a set of amino acid sequences of SEQ ID NOs. 3 and 14; and (b) The S2-D binding site is composed of VH and VL, wherein VH and VL comprise a set of amino acid sequences of SEQ ID NOs. 10 and 113.

74. The bispecific antibody or antibody fragment thereof according to claim 62, wherein: The two different antigen binding sites are (a) an S1-A binding site, which is composed of VH and VL, wherein VH and VL comprise a set of amino acid sequences of SEQ ID NOs. 4 and 15; and (b) The S2-D binding site is composed of VH and VL, wherein VH and VL comprise a set of amino acid sequences of SEQ ID NOs. 10 and 113.

75. The bispecific antibody or antibody fragment thereof according to claim 62, wherein: The two different antigen binding sites are (a) an S1-A binding site, which is composed of VH and VL, wherein VH and VL comprise a set of amino acid sequences of SEQ ID NOs. 5 and 16; and (b) The S2-D binding site is composed of VH and VL, wherein VH and VL comprise a set of amino acid sequences of SEQ ID NOs. 10 and 113.

76. The bispecific antibody or antibody fragment thereof according to claim 62, wherein: The two different antigen binding sites are (a) an S1-A binding site, which is composed of VH and VL, wherein VH and VL comprise a set of amino acid sequences of SEQ ID NOs. 3 and 106; and (b) The S2-D binding site is composed of VH and VL, wherein VH and VL comprise a set of amino acid sequences of SEQ ID NOs. 10 and 21.

77. The bispecific antibody or antibody fragment thereof according to claim 62, wherein: The two different antigen binding sites are (a) an S1-A binding site, which is composed of VH and VL, wherein VH and VL comprise a set of amino acid sequences of SEQ ID NOs. 4 and 107; and (b) The S2-D binding site is composed of VH and VL, wherein VH and VL comprise a set of amino acid sequences of SEQ ID NOs. 11 and 22.

78. The bispecific antibody or antibody fragment thereof according to any one of claims 62 to 77, wherein VH and VL constituting the scFv are linked to each other via a peptide linker comprising SEQ ID NO. 74 in the order of VL and VH from the N-terminal side thereof.

79. The bispecific antibody or antibody fragment thereof according to any one of claims 62 to 78, wherein The scFv is linked to the C-terminus of the heavy chain via a peptide linker comprising SEQ ID NO.

73.

80. The bispecific antibody or antibody fragment thereof according to any one of claims 1 to 79, wherein The epitope specifically bound by the S1-A binding site is composed of at least one or more of or all of phenylalanine at position 70, arginine at position 71, arginine at position 72, lysine at position 73, histidine at position 75, leucine at position 76, histidine at position 96, glutamic acid at position 97, lysine at position 102, lysine at position 104, and tyrosine at position 113 of allergen-1 comprising the amino acid sequence represented by SEQ ID NO. 115, The epitope to which the S2-D binding site specifically binds is composed of at least one or more of the isoleucine at position 132, the methionine at position 133, the valine at position 134, the isoleucine at position 135, the glutamine at position 136, the threonine at position 137, the glutamic acid at position 138, the histidine at position 146, and the proline at position 215 of the allergen-1, The epitope specifically bound by the S1-B binding site is different from the epitope specifically bound by the S1-A binding site, which is represented by at least the amino acids described above. The epitope specifically bound by the S2-C binding site is different from the epitope specifically bound by the S2-D binding site, which is represented by at least the amino acids described above.

81. A bispecific antibody or antibody fragment thereof against Allergen-1, comprising two different antigen binding sites selected from the group consisting of S1-A binding site, S1-B binding site, S2-C binding site and S2-D binding site, wherein: (a) the epitope to which the S1-A binding site specifically binds, i.e., the S1-A epitope, is composed of at least one or more of or all of phenylalanine at position 70, arginine at position 71, arginine at position 72, lysine at position 73, histidine at position 75, leucine at position 76, histidine at position 96, glutamic acid at position 97, lysine at position 102, lysine at position 104, and tyrosine at position 113 of allergen-1 comprising the amino acid sequence represented by SEQ ID NO. 115, (b) the epitope to which the S2-D binding site specifically binds, i.e., the S2-D epitope, is composed of at least one or more of the isoleucine at position 132, the methionine at position 133, the valine at position 134, the isoleucine at position 135, the glutamine at position 136, the threonine at position 137, the glutamic acid at position 138, the histidine at position 146, and the proline at position 215 of the allergen-1, (c) the epitope to which the S1-B binding site specifically binds is at least different from the S1-A epitope represented by said amino acids, (d) The epitope specifically bound by the S2-C binding site is at least different from the S2-D epitope represented by the amino acids.

82. The bispecific antibody or antibody fragment thereof according to any one of claims 42 to 81, wherein The heavy chain and light chain are both derived from IgG antibodies.

83. The bispecific antibody or antibody fragment thereof according to claim 82, wherein: The IgG antibody is an IgG1 antibody.

84. The bispecific antibody or antibody fragment thereof according to claim 83, wherein: Lysine at position 447 based on the EU numbering system in both heavy chain constant regions of the IgG1 antibody is each deleted.

85. The bispecific antibody or antibody fragment thereof according to any one of claims 42 to 84, wherein The heavy chain constant region of the heavy chain comprises the amino acid sequence of SEQ ID NO. 23 or 99.

86. The bispecific antibody or antibody fragment thereof according to any one of claims 42 to 85, wherein The light chain constant region of the light chain comprises the amino acid sequence of SEQ ID NO.

24.

87. The bispecific antibody or antibody fragment thereof according to any one of claims 42 to 83, wherein The heavy chain constant region of the heavy chain and the light chain constant region of the light chain each comprise the amino acid sequence of SEQ ID NO. 23 or 99 and SEQ ID NO.

24.

88. A bispecific antibody against Allergen-1, which satisfies (i) or (ii), (i) having a heavy chain and a light chain comprising an amino acid sequence selected from any one of the following sequence groups: (a) SEQ ID NOs. 75 and 76; (b) SEQ ID NOs. 77 and 78; (c) SEQ ID NOs. 79 and 78; (d) SEQ ID NOs. 80 and 78; (e) SEQ ID NOs. 81 and 82; (f) SEQ ID NOs. 83 and 82; (g) SEQ ID NOs. 84 and 85; (h) SEQ ID NOs. 86 and 87; (i) SEQ ID NOs. 88 and 89; (j) SEQ ID NOs. 90 and 91; (k) SEQ ID NOs. 90 and 92; (l) SEQ ID NOs. 93 and 94; (m) SEQ ID NOs. 93 and 95; (n) SEQ ID NOs. 96 and 97; (o) SEQ ID NOs. 98 and 78; (p) SEQ ID NOs. 100 and 78; (q) SEQ ID NOs. 101 and 78; (r) SEQ ID NOs. 102 and 78; and (s) SEQ ID NO. 103 and 85, (ii) comprising two identical heavy chain / light chain complexes consisting of the heavy chain and light chain described in item (i).

89. A bispecific antibody against Allergen-1, which satisfies (i) or (ii), (i) having a heavy chain and a light chain comprising an amino acid sequence selected from any one of the following sequence groups: (a) SEQ ID NOs. 77 and 78; (b) SEQ ID NOs. 79 and 78; (c) SEQ ID NOs. 83 and 82; (d) SEQ ID NOs. 84 and 85; (e) SEQ ID NOs. 98 and 78; (f) SEQ ID NOs. 100 and 78; (g) SEQ ID NOs. 101 and 78; (h) SEQ ID NOs. 102 and 78; and (j) SEQ ID NOs. 103 and 85, (ii) comprising two identical heavy chain / light chain complexes consisting of the heavy chain and light chain described in item (i).

90. The bispecific antibody against Allergen-1 according to claim 88 or 89, wherein: Alanine at position 299 in SEQ ID NOs. 75, 81, 83, 86, 88, 93 and 96 and at position 301 in SEQ ID NOs. 80 and 90, corresponding to position 297 based on the EU numbering system in the constant region of the heavy chain, are each independently substituted with asparagine.

91. The bispecific antibody or antibody fragment thereof according to any one of claims 1 to 90, which substantially reduces cytokine production during administration or within 24 hours of administration.

92. The bispecific antibody or antibody fragment thereof according to claim 91, wherein: The cytokine includes at least one selected from the group consisting of IL-2, IL-4, IL-6, IL-10, IFN-γ and TNF-α.

93. The bispecific antibody or antibody fragment thereof according to any one of claims 1 to 92, wherein: Allergen-1 is human allergen-1.

94. The bispecific antibody or antibody fragment thereof according to claim 93, wherein: The human allergen-1 is any one or more human allergen-1 selected from the group consisting of human allergen-1L, human allergen-1S1 and human allergen-1S2.

95. A pharmaceutical composition comprising the anti-allergen-1 bispecific antibody or the antibody fragment thereof according to any one of claims 1 to 94 as an active ingredient.

96. The pharmaceutical composition of claim 95, further comprising at least one pharmaceutically acceptable carrier.

97. An agent for inhibiting symptom progression, inhibiting recurrence and / or treating cancer, comprising as an active ingredient an anti-allergen-1 bispecific antibody or an antibody fragment thereof selected from any one of claims 1 to 94.

98. The agent according to claim 97, wherein The cancer is a solid cancer or a blood cancer.

99. The agent according to claim 98, wherein The cancer is a solid cancer, and the solid cancer is one or more cancers selected from the following cancers: malignant melanoma, non-small cell lung cancer, small cell lung cancer, head and neck cancer, renal cell carcinoma, breast cancer, ovarian cancer, anal cancer, colorectal cancer, rectal cancer, colon cancer, hepatocellular carcinoma, esophageal cancer, gastric cancer, esophagogastric junction cancer, pancreatic cancer, urothelial carcinoma, prostate cancer, fallopian tube cancer, primary peritoneal cancer, malignant pleural mesothelioma, gallbladder cancer, bile duct cancer, biliary tract cancer, skin cancer, testicular cancer, vaginal cancer, vulvar cancer, penile cancer, small intestine cancer, endocrine carcinoid, thyroid cancer, parathyroid cancer, adrenal cancer, spinal tumors, neuroblastoma, medulloblastoma, retinoblastoma, neuroendocrine tumors, brain tumors and squamous cell carcinoma.

100. The agent according to any one of claims 97 to 99, which is further used in combination with other anti-tumor agents.

101. The agent according to claim 100, wherein The other anti-tumor agent is a tumor immunotherapy drug, and the tumor immunotherapy drug is an anti-PD-1 antibody, an anti-PD-L1 antibody or an anti-CTLA-4 antibody.

102. The agent according to claim 101, wherein The anti-PD-1 antibody is an antibody selected from the following: nivolumab, cemiprilimab-rwlc, pembrolizumab, spartalizumab, tislelizumab, dotalimumab, toripalimab, carrelizumab, genomumab, sintilimab, lodalimab, rivalimab, batilizumab, srulimab, bruglimab, palollimab, saxanalizumab, silimumab, sepalizumab, gelolimab, AMP-514, STI-A1110, ENUM 388D4, ENUM 244C8, sepalizumab, CS1003, BAT-1306, penicillin, AK103, ebenalizumab, LZM009, CMAB819, Sym021, SSI-361, JY034, putalimab, ISU106, and CX-188.

103. The agent according to claim 101, wherein The anti-PD-L1 antibody is an antibody selected from the following: atezolizumab, avelumab, durvalumab, manelizumab, pacmilimab, envolimab, coxilimab, sugemalimab, BMS-936559, STI-1014, HLX20, adebelimumab, MSB2311, BGB-A333, KL-A167, AK106, socazolimab, FAZ053, CBT-502 and JS003.

104. The agent according to claim 101, wherein The anti-CTLA-4 antibody is an antibody selected from the group consisting of ipilimumab, zeflalimab, norelizumab and tremelimumab.

Images