Anti-allergen antibody and its use

Abstract

The present invention provides antibodies that bind to peanut allergens, particularly Ara h 2 and Ara h 3 or Ara h 6. The present invention further provides compositions and kits comprising separate antibodies that bind to separate, non-overlapping epitopes of Ara h 2, as well as multispecific antibodies that bind to separate, non-overlapping epitopes of Ara h 2. Furthermore, the present invention relates to the use of the above antibodies, compositions and kits, for example, for preventing or treating peanut allergy.

Description

Detailed Description of the Invention

[0001] The present invention relates to antibodies that bind to peanut allergens, particularly Ara h 2 and Ara h 3 or Ara h 6. The present invention further relates to compositions and kits comprising separate non-overlapping antibodies that bind to separate non-overlapping epitopes of Ara h 2, and to bispecific antibodies that bind to separate non-overlapping epitopes of Ara h 2. Furthermore, the present invention relates to the use of said antibodies, compositions and kits, for example, for preventing or treating peanut allergy.

[0002] Allergy is a disease caused by hypersensitivity of the immune system. When exposed to an allergen, allergen-binding immunoglobulin E (IgE) antibodies are produced, which are pre-bound to FcεRI receptors on mast cells and basophils, inducing the release of inflammatory compounds such as histamine, leukotrienes, and lipid mediators.

[0003] Peanut allergy is one of the most severe food allergies due to its prevalence, persistence, and potential severity of allergic reactions. Allergic reactions include clinical symptoms ranging from skin, respiratory, and gastrointestinal symptoms to severe and life-threatening reactions such as systemic anaphylaxis. Peanut allergy is the most common cause of food-induced anaphylaxis.

[0004] To date, at least 16 peanut proteins have been identified as allergens. Among these peanut allergens, Ara h 1, Ara h 2, Ara h 3, and Ara h 6 are considered major allergens, meaning they cause an immunological reaction in over 50% of the allergic population. In particular, Ara h 2 has been reported to be the dominant peanut allergen (Hemmings, Oliver et al. Ara h 2 is the dominant peanut allergen despite similarities with Ara h 6. The Journal of allergy and clinical immunology Vol. 146(3) (2020): 621-630.e5. doi:10.1016 / j.jaci.2020.03.026). Additionally, Ara h 6 has emerged as a common and potent peanut allergen (Blanc, F et al. (2009), Capacity of purified peanut allergens to induce degranulation in a functional in vitro assay: Ara h 2 and Ara h 6 are the most efficient elicitors. Clinical & Experimental Allergy, 39: 1277-1285.). Furthermore, Ara h 3, which accounts for 19% of the total proteins in peanut extracts, is classified as a major peanut allergen as it induces sensitization in peanut-allergic patients.

[0005] Despite the number of patients, to date, the only treatment for peanut allergy has been to strictly avoid peanuts and foods containing peanuts. However, complete avoidance can be complicated, especially when there is no declaration of raw materials. Allergen immunotherapy by repeated exposure to allergens, also known as desensitization, attempts to reduce allergy sensitivity but has recently been found to increase rather than decrease the risk of severe allergy (Chu DK, Wood RA, French S, et al. (April 2019). "Oral immunotherapy for peanut allergy (PACE): a systematic review and meta-analysis of efficacy and safety". The Lancet. 393 (10187): 2222-2232).

[0006] Recently, antibodies against peanut allergens have emerged as a promising option for treating peanut allergy. For example, WO 2018 / 234383 describes various human monoclonal antibodies against peanut allergens.

[0007] From the above, an object of the present invention is to provide an improved human-derived antibody against peanut allergens. Another object of the present invention is to provide a composition comprising at least three distinct potent antibodies that bind to distinct non-overlapping epitopes on the major peanut allergen Ara h 2. Furthermore, an object of the present invention is also to provide a potent multispecific antibody that binds to distinct non-overlapping epitopes on the major peanut allergen Ara h 2.

[0008] This object is achieved by the subject matter described below and in the appended claims.

[0009] The present invention will be described in detail below, but it should be understood that the present invention is not limited to the specific methodologies, protocols, and reagents described herein. It should also be understood that the terminology used herein is not intended to limit the scope of the present invention, which is limited only by the appended claims. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art.

[0010] The elements of the present invention will be described below. Although these elements are listed with specific embodiments, it should be understood that they can be combined in any manner and in any number to create additional embodiments. The various examples and embodiments described should not be construed as limiting the present invention to only the explicitly described embodiments. This specification should be understood to support and encompass both the explicitly described embodiments and embodiments that combine any number of the disclosed elements. Furthermore, any permutation and combination of all the described elements in this application should be considered to be disclosed by the description of this application, unless the context indicates otherwise.

[0011] Throughout this specification and the claims that follow, unless the context requires otherwise, the term "comprise", and variations such as "comprises" and "comprising", are to be construed as including the stated member, integer or step but not excluding other members, integers or steps not so stated. The term "consist of" is a particular embodiment of the term "comprise", and other members, integers or steps not so stated are excluded. In the context of the present invention, the term "comprise" encompasses the term "consist of". Thus, the term "comprising" encompasses "including" as well as "consisting", for example, a composition that "comprises" X may consist only of X or may include something additional such as, for example, X+Y.

[0012] The terms "a", "an", "the" and similar references used in the context of describing the present invention (particularly in the context of the claims) are to be construed as covering both the singular and the plural unless specifically indicated otherwise herein or the context clearly dictates otherwise. The recitation of a range of values herein is merely intended to serve as a shorthand way of referring individually to each separate value falling within the range. Unless otherwise indicated herein, each separate value is incorporated herein as if it were individually recited herein. No language in this specification should be construed as indicating any non-claimed element as essential to the practice of the present invention.

[0013] The term "substantially" does not exclude "completely". For example, a composition that is "substantially free of" Y may be completely free of Y. If so desired, the term "substantially" may be excluded from the definition of the present invention.

[0014] The term "about" with respect to a numerical value x means x ± 10%, for example x ± 5%, or x ± 7%, or x ± 10%, or x ± 12%, or x ± 15%, or x ± 20%.

[0015] As used herein, the term "disease" is generally synonymous with and intended to be used interchangeably with the terms "disorder" and "condition" (in a medical context) in that all reflect an abnormal condition of the body or a part thereof of a human or animal that impairs normal function and typically manifests by characteristic signs and symptoms and that reduces the length or quality of life of the human or animal.

[0016] References herein to "treatment" of a subject or patient are intended to include prevention, prophylaxis, attenuation, amelioration and therapy. As used herein, the terms "subject" or "patient" are used interchangeably to mean all mammals including humans. Examples of subjects include humans, cows, dogs, cats, horses, goats, sheep, pigs, and rabbits. In some embodiments, the subject or patient is a human.

[0017] Dosages are often expressed in relation to body weight. Thus, a dosage expressed as [g, mg, or other unit] / kg (or g, mg, etc.) usually means [g, mg, or other unit] "per body weight kg (or g, mg, etc.)" even if the term "body weight" is not explicitly stated.

[0018] The term "binding" and similar references typically mean "specifically binds" and do not include non-specific binding. In particular, specific binding of an antibody means that the antibody recognizes its target antigen and binds to that target with a higher affinity (or lower antibody concentration, e.g., EC50) than to antigens having structurally different antigens and / or antigens having modified or mutated sequences. Thus, "higher" affinity means at least 2-fold, 3-fold, 4-fold, 5-fold, 10-fold, 15-fold, 20-fold, 25-fold, 50-fold, 75-fold, 100-fold, 150-fold, 200-fold, 500-fold, 750-fold, 1,000-fold, 1,500-fold, 2,000-fold, 5,000-fold, 7,500-fold, 10,000-fold, or more affinity compared to binding to a control antigen. In some cases, antibody binding to a control antigen may not be detected (below the detection threshold), while antibody binding to a specific antigen may be adequately detected / determined.

[0019] As used herein, the term "antibody" includes, but is not limited to, intact antibodies, antibody fragments (such as antigen-binding fragments), humanized antibodies, chimeric antibodies, humanized antibodies, recombinant antibodies, and genetically modified antibodies (e.g., variant or mutant antibodies), etc., as long as the characteristic properties according to the present invention are retained, and encompasses various forms of antibodies. In some embodiments, the antibody is a human antibody. In some embodiments, the antibody is a monoclonal antibody. For example, the antibody may be a human monoclonal antibody.

[0020] As described above, the term "antibody" generally includes antibody fragments. Antibody fragments can retain the antigen-binding activity of the antibody. Such fragments are called "antigen-binding fragments". Antigen-binding fragments include, but are not limited to, single-chain antibodies, Fab, Fab’, F(ab’)2, Fv or scFv. Antibody fragments can be obtained from antibodies by methods including digestion with enzymes such as pepsin or papain, and / or cleavage of disulfide bonds by chemical reduction. Alternatively, antibody fragments can be obtained by recombinant means, such as cloning and expressing a portion (fragment) of the heavy and / or light chain sequences. The present invention also encompasses single-chain Fv fragments (scFv) derived from the heavy and light chains of the antibodies of the present invention. For example, the present invention includes scFv containing CDRs derived from the antibodies of the present invention. Also included are monomers and dimers of heavy or light chains, single-domain heavy-chain antibodies, single-domain light-chain antibodies, and single-chain antibodies, such as single-chain Fv in which the heavy and light chain variable domains are linked by a peptide linker. The antibody fragments of the present invention can be included in various structures known to those skilled in the art. Furthermore, the sequences of the present invention may be components of multispecific molecules in which the sequences of the present invention target the epitopes of the present invention and other regions of the molecule bind to other targets. In this specification, including the claims, there are explicit references to antigen-binding fragments, antibody fragments, variants and / or derivatives of antibodies, but the term "antibody" is understood to include all categories of antibodies, namely antigen-binding fragments, antibody fragments, variants and derivatives of antibodies.

[0021] Human antibodies are well known in the state-of-the-art technology (van Dijk, M. A., and van de Winkel, J. G., Curr. Opin. Chem. Biol. 5 (2001) 368-374). Human antibodies can also be produced in transgenic animals (e.g., mice and chickens) that can produce the entire repertoire or a selected repertoire of human antibodies by immunization in the absence of endogenous immunoglobulin production. Introduction of a human germline immunoglobulin gene array into such germline mutant mice results in the production of human antibodies upon antigen challenge (see, for example, Jakobovits, A., et al., Proc. Natl. Acad. Sci. USA 90 (1993) 2551-2555; Jakobovits, A., et al., Nature 362 (1993) 255-258; Bruggemann, M., et al., Year Immunol. 7 (1993) 3340). Human antibodies can also be generated in phage display libraries (Hoogenboom, H. R., and Winter, G., J. Mol. Biol. 227 (1992) 381-388; Marks, J. D., et al., J. Mol. Biol. 222 (1991) 581-597). The techniques of Cole et al. and Boerner et al. are also available for the preparation of human monoclonal antibodies (Cole et al., Monoclonal Antibodies and Cancer Therapy, Alan R. Liss, p. 77 (1985); and Boerner, P., et al., J. Immunol. 147 (1991) 86-95). As used herein, the expression "human antibody" typically includes non-naturally occurring sequence variants of human antibodies obtained by introducing one or more mutations into (naturally occurring) human antibodies. Such mutations include one or more mutations in the CDR or framework regions, as well as Fc modifications (e.g., those known in the art with respect to specific functionality).

[0022] As used herein, the term "variable region" (the variable region of the light chain (V L ), the variable region of the heavy chain (V H )) refers to each of the pair of light and heavy chains that are directly involved in the binding of an antibody to an antigen.

[0023] The antibodies of the present invention can be of any isotype (e.g., IgA, IgG, IgM, i.e., α, γ or μ heavy chains). Preferably, the antibody is of the IgG or IgA type. Among the IgG isotypes, the antibody may be of the IgG1, IgG2, IgG3 or IgG4 subclass, preferably IgG1 or IgG4. The antibodies of the present invention may have a κ or λ light chain.

[0024] The antibodies according to the present invention can be provided in a purified form. Typically, the antibody will be present in a composition that is substantially free of other polypeptides, e.g., less than 90% (by weight), usually less than 60%, more usually less than 50% of the composition is composed of other polypeptides.

[0025] The antibodies according to the present invention may be immunogenic in human and / or non-human (or heterologous) hosts, such as mice. For example, the antibody may have an idiotype that is immunogenic in a non-human host but not in a human host. The antibodies of the present invention for use in humans include those that cannot be easily isolated from hosts such as mice, goats, rabbits, rats, non-primate mammals, etc., and generally cannot be obtained from humanized or xenomice.

[0026] As used herein, the term "antigen" refers to any structural substance that functions as a target for receptors of the adaptive immune response, particularly as a target for antibodies, T cell receptors, and / or B cell receptors. An "epitope," also known as an "antigenic determinant," is a part (or fragment) of an antigen that is recognized by the immune system, particularly by antibodies, T cell receptors, and / or B cell receptors. Thus, one antigen has at least one epitope, i.e., one antigen has one or more epitopes. An antigen may be (i) a peptide, polypeptide, or protein, (ii) a polysaccharide, (iii) a lipid, (iv) a lipoprotein or lipopeptide, (v) a glycolipid, (vi) a nucleic acid, or (vii) a small molecule drug or toxin. Thus, an antigen may be a peptide, protein, polysaccharide, lipid, combinations thereof including lipoproteins and glycolipids, nucleic acids (e.g., DNA, siRNA, shRNA, antisense oligonucleotides, decoy DNA, plasmid), or small molecule drugs (e.g., cyclosporin A, paclitaxel, doxorubicin, methotrexate, 5-aminolevulinic acid), or any combination thereof. Preferably, the antigen is selected from (i) a peptide, polypeptide, or protein, (ii) a polysaccharide, (iii) a lipid, (iv) a lipoprotein or lipopeptide, and (v) a glycolipid, and more preferably, the antigen is a peptide, polypeptide, or protein.

[0027] As used herein, the term "mutation" relates to a change in a nucleic acid sequence and / or an amino acid sequence when compared to a reference sequence, e.g., a corresponding genomic sequence. For example, a mutation compared to a genomic sequence can be, e.g., a (naturally occurring) somatic mutation, a spontaneous mutation, an induced mutation induced by, e.g., an enzyme, a chemical or radiation, or a mutation obtained by site-directed mutagenesis (a molecular biology method for causing specific and intentional changes in a nucleic acid sequence and / or an amino acid sequence). Thus, the term "mutation" or "mutating" is understood to include, for example, physically mutating a nucleic acid sequence or an amino acid sequence. Mutations include substitutions, deletions, insertions of one or more nucleotides or amino acids, and inversions of a plurality of consecutive nucleotides or amino acids. To achieve a mutation in an amino acid sequence, a mutation can be introduced into the nucleotide sequence encoding said amino acid sequence in order to express a (recombinant) mutant polypeptide. Mutations can be achieved, for example, by site-directed mutagenesis, by modifying the codon of a nucleic acid molecule encoding an amino acid to a codon encoding a different amino acid, or, for example, by knowing the nucleotide sequence of a nucleic acid molecule encoding a polypeptide and designing the synthesis of a nucleic acid molecule comprising a nucleotide sequence encoding a variant of the polypeptide without the need to mutate one or more nucleotides of the nucleic acid molecule, thereby synthesizing a sequence variant.

[0028] As used herein (i.e., throughout this specification), the term "array variant" refers to any change compared to a reference array. The term "array variant" includes nucleotide sequence variants and amino acid sequence variants. Preferably, the reference array is an array listed in the "Table of Sequences and Sequence Numbers" (sequence listing), i.e., any of SEQ ID NO: 1 to SEQ ID NO: 99. In particular, the array variant shares at least 70% or at least 75%, preferably at least 80% or at least 85%, more preferably at least 90% or at least 93%, even more preferably at least 95% or at least 96%, still more preferably at least 97% or at least 98%, particularly preferably at least 99% sequence identity with its reference array. In some embodiments, the array variant shares at least 70%, at least 71%, at least 72%, at least 73%, at least 74%, at least 75%, at least 76%, at least 77%, at least 78%, at least 79%, at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% sequence identity. Thus, the higher the percentage of identity of the array variant, the more preferred. For example, an array variant having at least 84% sequence identity with a reference array is more preferred than an array variant having at least 75% but less than 84% sequence identity with the reference array. In some embodiments, the array variant maintains the (biological) function of the reference array. For example, an array variant related to an antibody of the present invention preferably maintains specific binding to a peanut allergen, particularly Ara h 2 (and optionally, further Ara h 3 or Ara h 6).

[0029] Sequence identity can be calculated as described below. Usually, an array variant can retain a specific function of the reference array. In some embodiments, an amino acid sequence variant has one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more) amino acids in the reference sequence deleted or substituted, or one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more) amino acids inserted or added to the sequence of the reference amino acid sequence, and has a modified sequence. As a result of the modification, the amino acid sequence variant has an amino acid sequence that is at least 70% or at least 75%, preferably at least 80% or at least 85%, more preferably at least 90% or at least 93%, even more preferably at least 95% or at least 96%, still more preferably at least 97% or at least 98%, particularly preferably at least 99% identical to the reference sequence. For example, a variant sequence that is at least 90% identical does not have more than 10 modifications per 100 amino acids of the reference sequence, i.e., any combination of deletions, insertions or substitutions. Of course, the same applies to nucleic acid sequences as well.

[0030] The "percent identity" of an array variant is usually determined relative to a reference array. It is usually calculated with respect to the full length of the reference array (i.e., the array described in this application). The percent identity as referred to herein can be determined by methods known in the art, such as BLAST using the default parameters specified by, for example, NCBI (National Center for Biotechnology Information; http: / / www.ncbi.nlm.nih.gov / ). [Blosum 62 matrix; gap open penalty = 11 and gap extension penalty = 1].

[0031] In general, non-conservative amino acid substitutions are also possible, but the substitutions are preferably conservative amino acid substitutions, and the substituted amino acids have structural or chemical properties similar to the corresponding amino acids in the reference sequence. As an example, conservative amino acid substitutions include substituting an aliphatic or hydrophobic amino acid such as alanine, valine, leucine, and isoleucine with another; substituting a hydroxyl-containing amino acid such as serine and threonine with another; substituting an acidic residue such as glutamic acid or aspartic acid with another; substituting one amide-containing residue such as asparagine and glutamine with another; substituting one aromatic residue such as phenylalanine and tyrosine with another; substituting one basic residue such as lysine, arginine, and histidine with another; substituting one small amino acid such as alanine, serine, threonine, cysteine, and glycine with another.

[0032] Throughout the text of this specification, several documents are cited. Each document cited herein (including all patents, patent applications, scientific publications, manufacturer's specifications, instructions, etc.) is hereby incorporated by reference in its entirety, regardless of whether it is mentioned above or below. Nothing in this specification shall be construed as an admission that the present invention has no right to antedate such disclosure by virtue of prior invention or the like.

[0033] It should be understood that the present invention is not limited to the specific methodologies, protocols, and reagents described herein as these may vary. It should also be understood that the terms used herein are for the purpose of describing particular embodiments only and are not intended to limit the scope of the present invention, which is limited only by the appended claims. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art.

[0034] [Antibodies and Their Antigen-Binding Fragments] In a first aspect, the present invention provides an (isolated) antibody or an antigen-binding fragment thereof that binds (specifically) to a peanut allergen, particularly Ara h 2 (Arachis hypogaea allergen 2). Ara h 2 is a major peanut allergen recognized by serum IgE in more than 90% of peanut allergy patients. Ara h 2 is a 2S albumin storage protein of approximately 17.5 kDa. Two Ara h 2 isoforms, namely Ara h 2.0101 (SEQ ID NO: 55) and Ara h 2.0201 (SEQ ID NO: 56) have been described, and Ara h 2.0201 contains an additional 12 amino acids (Hales, Belinda et al. (2004). Isoforms of the Major Peanut Allergen Ara h 2: IgE Binding in Children with Peanut Allergy. International archives of allergy and immunology. 135. 101-7. 10.1159 / 000080652). Accordingly, the antibody or antigen-binding fragment thereof of the present invention binds particularly to a polypeptide or protein having an amino acid sequence according to SEQ ID NO: 55 and / or 56.

[0035] Preferably, the (isolated) antibody or antigen-binding fragment thereof that (specifically) binds to Ara h 2 further (specifically) binds to Ara h 3 (Arachis hypogaea allergen 3; also referred to as "Ara h 3.0101", SEQ ID NO: 57), or Ara h 6 (Arachis hypogaea allergen 6; also referred to as "Ara h 6.0101", SEQ ID NO: 58). Ara h 3 and Ara h 6 are further major peanut allergens. Thus, the antibody or antigen-binding fragment thereof of the present invention preferably binds to a polypeptide or protein having an amino acid sequence according to SEQ ID NO: 57 or 58. Preferably, the antibody or antigen-binding fragment thereof of the present invention (specifically) binds to (i) Ara h 2 and Ara h 3; or (ii) Ara h 2 and Ara h 6.

[0036] Peanut allergens, particularly Ara h 2, Ara h 3 and / or Ara h 6, can be peanut-derived, recombinantly expressed or synthetic peanut peptides.

[0037] Standard methods for evaluating the binding of the antibody or antigen-binding fragment thereof according to the present invention are known to those skilled in the art and include, for example, ELISA (enzyme-linked immunosorbent assay). Thereby, the relative affinity of antibody binding can be determined by measuring the antibody concentration (EC 50 ) required to achieve 50% of the maximum binding in the saturation state. Specific examples of ELISA that can be used to evaluate the binding of the antibody are described in the Examples section of this specification.

[0038] Generally, an antibody or an antigen-binding fragment thereof according to the present invention may comprise (at least) three complementarity-determining regions (CDRs) on the heavy chain and (at least) three CDRs on the light chain. Generally, the complementarity-determining regions (CDRs) are hypervariable domains present in the heavy chain variable domain and the light chain variable domain. Typically, the CDRs of the heavy chain and the associated light chain of an antibody together form an antigen receptor. Usually, the three CDRs (CDR1, CDR2, CDR3) are arranged discontinuously within the variable domain. Since an antigen receptor typically consists of two variable domains (on two different polypeptide chains, i.e., the heavy chain and the light chain: the heavy chain variable region (VH) and the light chain variable region (VL)), each antigen receptor typically has six CDRs (heavy chain: CDRH1, CDRH2, and CDRH3; light chain: CDRL1, CDRL2, and CDRL3). For example, a classical IgG antibody molecule usually has two antigen receptors and thus contains 12 CDRs. The CDRs on the heavy chain and / or the light chain may be separated by framework regions, which are regions in the variable domain that are less "variable" than the CDRs. For example, a variable region (or each variable region) is composed of four framework regions separated by three CDRs.

[0039] The sequences of the heavy and light chains of exemplary antibodies of the present invention, which contain three different CDRs on the heavy chain and three different CDRs on the light chain, were determined. The CDR amino acid sequences of CDR1 (CDRH1), CDR2 (CDRH2), CDR3 (CDRH3) of the heavy chain, CDR1 (CDRL1), CDR2 (CDRL2), and CDR3 (CDRL3) of the light chain of exemplary antibodies 17H9, 15E3, 2F8, and 7G6, and their exemplary variants are shown in Table 1 below.

[0040] The CDRs identified according to the present invention, particularly the three different CDRs on the heavy chain (CDR1, CDR2 and CDR3), and the three different CDRs on the light chain (CDR1, CDR2 and CDR3), can be grafted into any variable framework region, particularly any variable human framework region, without impairing their specificity.

[0041] The human variable framework regions of the heavy chain (VH) can be retrieved from the website: "https: / / www.imgt.org / genedb / resultPage.action;jsessionid=49EB34C22C79EAC51862C76108963216?gene.id.species=Homo+sapiens&molComponent=IG&geneTypeLike=variable&allele.fcode=functional&cloneName=&locusLike=IGH&mainLocusLike=IGH+locus&cosLocusLike=any&groupLike=any&subgroup=-1&geneLike=&selection=any", the content of which is incorporated herein by reference. Accordingly, the VH chain can be selected from the group consisting of the amino acid sequences encoded by the genes IGHV1-18, IGHV1-2, IGHV1-24, IGHV1-3, IGHV1-45, IGHV1-46, IGHV1-58, IGHV1-69, IGHV1-69-2, IGHV1-69D, IGHV1-8, IGHV2-26, IGHV2-5, IGHV2-70, IGHV2-70D, IGHV3-11, IGHV3-13, IGHV3-15, IGHV3-20, IGHV3-21, IGHV3-23, IGHV3-23D, IGHV3-30, IGHV3-30-3, IGHV3-30-5, IGHV3-33, IGHV3-35IGHV3-43, IGHV3-43D, IGHV3-48, IGHV3-49, IGHV3-53, IGHV3-62, IGHV3-64, IGHV3-64D, IGHV3-66, IGHV3-7, IGHV3-72, IGHV3-73, IGHV3-74, IGHV3-9, IGHV3-NL1, IGHV4-28, IGHV4-30-1, IGHV4-30-2, IGHV4-30-4, IGHV4-31, IGHV4-34, and IGHV4-38-2.

[0042] The human variable framework regions (VK, kappa) of the light and heavy chains can be retrieved from the website: 「https: / / www.imgt.org / genedb / resultPage.action;jsessionid=49EB34C22C79EAC51862C76108963216?gene.id.species=Homo+sapiens&molComponent=IG&geneTypeLike=variable&allele.fcode=functional&cloneName=&locusLike=IGK&mainLocusLike=IGK+locus&cosLocusLike=any&groupLike=any&subgroup=-1&geneLike=&selection=any」, the content of which is incorporated herein by reference. Accordingly, the VK (kappa) chain can be selected from the group consisting of the amino acid sequences encoded by the genes IGKV1-12, IGKV1-13, IGKV1-16, IGKV1-17, IGKV1-27, IGKV1-33, IGKV1-39, IGKV1-5, IGKV1-6, IGKV1-8, IGKV1-9, IGKV1-NL1, IGKV1D-12, IGKV1D-13, IGKV1D-16, IGKV1D-17, IGKV1D-33, IGKV1D-39, IGKV1D-43, IGKV1D-8, IGKV2-24, IGKV2-28, IGKV2-29, IGKV2-30, IGKV2-40, IGKV2D-26, IGKV2D-28, IGKV2D-29, IGKV2D-30, IGKV2D-40, IGKV3-11, IGKV3-15, IGKV3-20, IGKV3D-11, IGKV3D-15, IGKV3D-20, IGKV3D-7, IGKV4-1, IGKV5-2, IGKV6-21, and IGKV6D-21.

[0043] The human variable framework regions of the light and heavy chains (VL, lambda) can be searched from the website: 「https: / / www.imgt.org / genedb / resultPage.action;jsessionid=49EB34C22C79EAC51862C76108963216?gene.id.species=Homo+sapiens&molComponent=IG&geneTypeLike=variable&allele.fcode=functional&cloneName=&locusLike=IGL&mainLocusLike=IGL+locus&cosLocusLike=any&groupLike=any&subgroup=-1&geneLike=&selection=any」, the content of which is incorporated herein by reference. Accordingly, the VL (lambda) chain can be selected from the group consisting of amino acid sequences encoded by the genes IGLV1-36, IGLV1-40, IGLV1-44, IGLV1-47, IGLV1-51, IGLV10-54, IGLV2-11, IGLV2-14, IGLV2-18, IGLV2-23, IGLV2-8, IGLV3-1, IGLV3-10, IGLV3-12, IGLV3-16, IGLV3-19, IGLV3-21, IGLV3-22, IGLV3-25, IGLV3-27, IGLV3-9, IGLV4-3, IGLV4-60, IGLV4-69, IGLV5-37, IGLV5-39, IGLV5-45, IGLV5-52, IGLV6-57, IGLV7-43, IGLV7-46, IGLV8-61, and IGLV9-49.

[0044] The human variable framework regions of the heavy and light chains can also include the respective human HJ (heavy chain), and light chain KJ (kappa) or LJ (lambda) sequences.

[0045] The sequence of HJ can be retrieved from the website: 「https: / / www.imgt.org / genedb / resultPage.action?gene.id.species=Homo+sapiens&molComponent=IG&geneTypeLike=any&allele.fcode=functional&cloneName=&locusLike=IGH&mainLocusLike=IGH+locus&cosLocusLike=any&groupLike=IGHJ&subgroup=-1&geneLike=&selection=any」, the content of which is incorporated herein by reference. In particular, the HJ sequence can be selected from the amino acid sequences encoded by the genes consisting of the groups: IGHJ1, IGHJ2, IGHJ3, IGHJ4, IGHJ5, and IGHJ6.

[0046] The sequence of KJ can be retrieved from the website: 「https: / / www.imgt.org / genedb / resultPage.action?gene.id.species=Homo+sapiens&molComponent=IG&geneTypeLike=any&allele.fcode=functional&cloneName=&locusLike=IGK&mainLocusLike=IGK+locus&cosLocusLike=any&groupLike=IGKJ&subgroup=-1&geneLike=&selection=any」, the content of which is incorporated herein by reference. In particular, the KJ sequence can be selected from the amino acid sequences encoded by the genes consisting of the groups IGKJ1, IGKJ2, IGKJ3, IGKJ4, and IGKJ5.

[0047] The sequence of LJ can be retrieved from the website: 「https: / / www.imgt.org / genedb / resultPage.action?gene.id.species=Homo+sapiens&molComponent=IG&geneTypeLike=any&allele.fcode=functional&cloneName=&locusLike=IGL&mainLocusLike=IGL+locus&cosLocusLike=any&groupLike=IGLJ&subgroup=-1&geneLike=&selection=any」, the content of which is incorporated herein by reference. In particular, the LJ sequence can be selected from the amino acid sequences encoded by genes consisting of the groups: IGLJ1, IGLJ2, IGLJ3, IGLJ6, and IGLJ7.

[0048] The heavy chain CDR sequences (CDRH1, CDRH2, and CDRH3) of the present invention can be composed of a combination of a human heavy chain variable framework sequence defined by the human VH sequences described herein and a human HJ sequence described herein. Similarly, the light chain CDR sequences (CDRL1, CDRL2, and CDRL3) of the present invention can be composed of a combination of a human light chain variable framework sequence defined by the human VL or VK sequences described herein and a described human LJ or KJ sequence.

[0049] (i) A combination of a human VH sequence (each containing the CDRH1, CDRH2, and CDRH3 sequences described in the present invention) and a human VL sequence (each containing the CDRL1, CDRL2, and CDRL3 sequences of the present invention), or (ii) a combination of a human VH sequence (each containing the CDRH1, CDRH2, and CDRH3 sequences of the present invention) and a human VK sequence (each containing the CDRL1, CDRL2, and CDRL3 sequences of the present invention) can thus characterize the variable framework region and its binding region of the antibody according to the present invention. Further, the variable framework region can be characterized by (i) a combination of a human VH sequence and a human HJ sequence, and a human VL sequence and a human LJ sequence, or (ii) a combination of a human VH sequence and a human HJ sequence, and a human VK sequence and a human KJ sequence, thereby forming the variable framework region and its binding region of the antibody according to the present invention.

[0050] The CDR sequences of the present invention are inserted into the sites of the variable framework sequences presenting the CDR sequences, as shown, for example, by the gray boxes in FIGS. 18B, 19D, 20C, and 21B.

[0051] The numbering of the residues in the variable region was carried out according to the IMGT numbering system (IMGT: http: / / www.imgt.org / ; cf. Lefranc, M.-P. et al. (2009) Nucleic Acids Res. 37, D1006-D1012). To define the CDR regions, the Kabat CDR definition was applied (Tai Te Wu, Elvin A. Kabat; An analysis of the sequences of the variable regions of Bence Jones proteins and myeloma light chains and their implications for antibody complementarity. J Exp Med 1 August 1970; 132 (2): 211-250; George Johnson, Tai Te Wu, Kabat Database and its applications: 30 years after the first variability plot, Nucleic Acids Research, Volume 28, Issue 1, 1 January 2000, Pages 214-218).

[0052] [Table 1]

[0053] Furthermore, the amino acid sequences of the variable regions of the heavy chains (VH) and light chains (VL) of exemplary antibodies 17H9, 15E3, 2F8 and 7G6, and their exemplary variants, are shown in Table 2 below.

[0054] [Table 2]

[0055] Preferably, the antibody or antigen-binding fragment thereof of the present invention comprises a combination of the six CDR sequences of the exemplary antibodies shown in Table 1 (optionally, the VH and VL sequences of the exemplary antibodies shown in Table 2), or sequence variants thereof, as defined herein.

[0056] In some embodiments, the antibody, or antigen-binding fragment thereof, comprises CDRH1 having at least 70% identity to SEQ ID NO: 1, CDRH2 having at least 70% identity to SEQ ID NO: 2, CDRH3 having at least 70% identity to SEQ ID NO: 3, CDRL1 having at least 70% identity to SEQ ID NO: 4, CDRL2 having at least 70% identity to SEQ ID NO: 5, and CDRL3 having at least 70% identity to SEQ ID NO: 6: The heavy chain CDR1 sequence set forth in SEQ ID NO: 1; The heavy chain CDR2 sequence set forth in SEQ ID NO: 2; The heavy chain CDR3 sequence set forth in SEQ ID NO: 3; The light chain CDR1 sequence set forth in SEQ ID NO: 4; The light chain CDR2 sequence set forth in SEQ ID NO: 5; and The light chain CDR3 sequence set forth in SEQ ID NO: 6.

[0057] As shown in the attached examples, such antibodies (e.g., 17H9) specifically bind to Ara h 2 and Ara h 3.

[0058] In some embodiments, such an antibody of the invention, or an antigen-binding fragment thereof, comprises (i) a heavy chain variable region (VH) comprising an amino acid sequence having at least 70% (e.g., at least 70%, at least 71%, at least 72%, at least 73%, at least 74%, at least 75%, at least 76%, at least 77%, at least 78%, at least 79%, at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99%) identity to SEQ ID NO: 7, and a light chain variable region (VL) comprising an amino acid sequence having at least 70% (e.g., at least 70%, at least 71%, at least 72%, at least 73%, at least 74%, at least 75%, at least 76%, at least 77%, at least 78%, at least 79%, at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99%) identity to SEQ ID NO: 8. Thereby, the CDR sequences defined above (the heavy chain CDR1 sequence, CDR2 sequence, and CDR3 sequence set forth in SEQ ID NO: 1, SEQ ID NO: 2, and SEQ ID NO: 3, respectively; and the light chain CDR1 sequence, CDR2 sequence, and CDR3 sequence set forth in SEQ ID NO: 4, SEQ ID NO: 5, and SEQ ID NO: 6, respectively) are preferably maintained.

[0059] In some embodiments, such an antibody of the invention, or an antigen-binding fragment thereof, comprises a heavy chain variable region (VH) comprising an amino acid sequence having at least 70% (e.g., at least 70%, at least 71%, at least 72%, at least 73%, at least 74%, at least 75%, at least 76%, at least 77%, at least 78%, at least 79%, at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99%) identity to SEQ ID NO: 7, and a light chain variable region (VL) comprising an amino acid sequence having at least 70% (e.g., at least 70%, at least 71%, at least 72%, at least 73%, at least 74%, at least 75%, at least 76%, at least 77%, at least 78%, at least 79%, at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99%) identity to SEQ ID NO: 46. Thereby, the CDR sequences defined above (the heavy chain CDR1, CDR2, and CDR3 sequences set forth in SEQ ID NO: 1, SEQ ID NO: 2, and SEQ ID NO: 3, respectively; and the light chain CDR1, CDR2, and CDR3 sequences set forth in SEQ ID NO: 4, SEQ ID NO: 5, and SEQ ID NO: 6, respectively) are preferably maintained.

[0060] In some embodiments, such an antibody of the invention, or an antigen-binding fragment thereof, comprises a heavy chain variable region (VH) comprising an amino acid sequence having at least 70% (e.g., at least 70%, at least 71%, at least 72%, at least 73%, at least 74%, at least 75%, at least 76%, at least 77%, at least 78%, at least 79%, at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99%) identity to SEQ ID NO: 7, and a light chain variable region (VL) comprising an amino acid sequence having at least 70% (at least 70%, at least 71%, at least 72%, at least 73%, at least 74%, at least 75%, at least 76%, at least 77%, at least 78%, at least 79%, at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99%) identity to SEQ ID NO: 47. Thereby, the CDR sequences defined above (the heavy chain CDR1, CDR2, and CDR3 sequences set forth in SEQ ID NOs: 1, 2, and 3, respectively; and the light chain CDR1, CDR2, and CDR3 sequences set forth in SEQ ID NOs: 4, 5, and 6, respectively) are preferably maintained.

[0061] In some embodiments, such an antibody of the invention, or antigen-binding fragment thereof, comprises a heavy chain variable region (VH) comprising an amino acid sequence having at least 70% (e.g., at least 70%, at least 71%, at least 72%, at least 73%, at least 74%, at least 75%, at least 76%, at least 77%, at least 78%, at least 79%, at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99%) identity to SEQ ID NO: 7, and a light chain variable region (VL) comprising an amino acid sequence having at least 70% (e.g., at least 70%, at least 71%, at least 72%, at least 73%, at least 74%, at least 75%, at least 76%, at least 77%, at least 78%, at least 79%, at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99%) identity to SEQ ID NO: 48. Thereby, the CDR sequences defined above (the heavy chain CDR1 sequence, CDR2 sequence, and CDR3 sequence set forth in SEQ ID NO: 1, SEQ ID NO: 2, and SEQ ID NO: 3, respectively; and the light chain CDR1 sequence, CDR2 sequence, and CDR3 sequence set forth in SEQ ID NO: 4, SEQ ID NO: 5, and SEQ ID NO: 6, respectively) are preferably maintained.

[0062] In some embodiments, such an antibody of the invention, or an antigen-binding fragment thereof, comprises a heavy chain variable region (VH) comprising an amino acid sequence having at least 70% (e.g., at least 70%, at least 71%, at least 72%, at least 73%, at least 74%, at least 75%, at least 76%, at least 77%, at least 78%, at least 79%, at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99%) identity to SEQ ID NO: 7, and a light chain variable region (VL) comprising an amino acid sequence having at least 70% (e.g., at least 70%, at least 71%, at least 72%, at least 73%, at least 74%, at least 75%, at least 76%, at least 77%, at least 78%, at least 79%, at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99%) identity to SEQ ID NO: 49. Thereby, the CDR sequences defined above (the heavy chain CDR1 sequence, CDR2 sequence, and CDR3 sequence set forth in SEQ ID NO: 1, SEQ ID NO: 2, and SEQ ID NO: 3, respectively; and the light chain CDR1 sequence, CDR2 sequence, and CDR3 sequence set forth in SEQ ID NO: 4, SEQ ID NO: 5, and SEQ ID NO: 6, respectively) are preferably maintained.

[0063] In some embodiments, such an antibody of the invention, or an antigen-binding fragment thereof, comprises a heavy chain variable region (VH) comprising an amino acid sequence having at least 70% (e.g., at least 70%, at least 71%, at least 72%, at least 73%, at least 74%, at least 75%, at least 76%, at least 77%, at least 78%, at least 79%, at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99%) identity to SEQ ID NO: 44, and a light chain variable region (VL) comprising an amino acid sequence having at least 70% (e.g., at least 70%, at least 71%, at least 72%, at least 73%, at least 74%, at least 75%, at least 76%, at least 77%, at least 78%, at least 79%, at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99%) identity to SEQ ID NO: 8. Thereby, the CDR sequences defined above (the heavy chain CDR1 sequence, CDR2 sequence, and CDR3 sequence set forth in SEQ ID NOs: 1, 2, and 3, respectively; and the light chain CDR1 sequence, CDR2 sequence, and CDR3 sequence set forth in SEQ ID NOs: 4, 5, and 6, respectively) are preferably maintained.

[0064] In some embodiments, such an antibody of the invention, or an antigen-binding fragment thereof, comprises a heavy chain variable region (VH) comprising an amino acid sequence having at least 70% (e.g., at least 70%, at least 71%, at least 72%, at least 73%, at least 74%, at least 75%, at least 76%, at least 77%, at least 78%, at least 79%, at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99%) identity to SEQ ID NO: 44, and a light chain variable region (VL) comprising an amino acid sequence having at least 70% (e.g., at least 70%, at least 71%, at least 72%, at least 73%, at least 74%, at least 75%, at least 76%, at least 77%, at least 78%, at least 79%, at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99%) identity to SEQ ID NO: 46. Thereby, the CDR sequences defined above (the heavy chain CDR1, CDR2, and CDR3 sequences set forth in SEQ ID NO: 1, SEQ ID NO: 2, and SEQ ID NO: 3, respectively; and the light chain CDR1, CDR2, and CDR3 sequences set forth in SEQ ID NO: 4, SEQ ID NO: 5, and SEQ ID NO: 6, respectively) are preferably maintained.

[0065] In some embodiments, such an antibody of the invention, or antigen-binding fragment thereof, comprises a heavy chain variable region (VH) comprising an amino acid sequence having at least 70% (e.g., at least 70%, at least 71%, at least 72%, at least 73%, at least 74%, at least 75%, at least 76%, at least 77%, at least 78%, at least 79%, at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99%) identity to SEQ ID NO: 44, and a light chain variable region (VL) comprising an amino acid sequence having at least 70% (e.g., at least 70%, at least 71%, at least 72%, at least 73%, at least 74%, at least 75%, at least 76%, at least 77%, at least 78%, at least 79%, at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99%) identity to SEQ ID NO: 47. Thereby, the CDR sequences defined above (the heavy chain CDR1, CDR2, and CDR3 sequences set forth in SEQ ID NO: 1, SEQ ID NO: 2, and SEQ ID NO: 3, respectively; and the light chain CDR1, CDR2, and CDR3 sequences set forth in SEQ ID NO: 4, SEQ ID NO: 5, and SEQ ID NO: 6, respectively) are preferably maintained.

[0066] In some embodiments, such an antibody of the invention, or an antigen-binding fragment thereof, comprises (i) a heavy chain variable region (VH) comprising an amino acid sequence having at least 70% (e.g., at least 70%, at least 71%, at least 72%, at least 73%, at least 74%, at least 75%, at least 76%, at least 77%, at least 78%, at least 79%, at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99%) identity to SEQ ID NO: 44, and a light chain variable region (VL) comprising an amino acid sequence having at least 70% (e.g., at least 70%, at least 71%, at least 72%, at least 73%, at least 74%, at least 75%, at least 76%, at least 77%, at least 78%, at least 79%, at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99%) identity to SEQ ID NO: 48. Thereby, the CDR sequences defined above (the heavy chain CDR1, CDR2, and CDR3 sequences set forth in SEQ ID NO: 1, SEQ ID NO: 2, and SEQ ID NO: 3, respectively; and the light chain CDR1, CDR2, and CDR3 sequences set forth in SEQ ID NO: 4, SEQ ID NO: 5, and SEQ ID NO: 6, respectively) are preferably maintained.

[0067] In some embodiments, such an antibody of the invention, or an antigen-binding fragment thereof, comprises a heavy chain variable region (VH) comprising an amino acid sequence having at least 70% (e.g., at least 70%, at least 71%, at least 72%, at least 73%, at least 74%, at least 75%, at least 76%, at least 77%, at least 78%, at least 79%, at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99%) identity to SEQ ID NO: 44, and a light chain variable region (VL) comprising an amino acid sequence having at least 70% (e.g., at least 70%, at least 71%, at least 72%, at least 73%, at least 74%, at least 75%, at least 76%, at least 77%, at least 78%, at least 79%, at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99%) identity to SEQ ID NO: 49. Thereby, the CDR sequences defined above (the heavy chain CDR1 sequence, CDR2 sequence, and CDR3 sequence set forth in SEQ ID NOs: 1, 2, and 3, respectively; and the light chain CDR1 sequence, CDR2 sequence, and CDR3 sequence set forth in SEQ ID NOs: 4, 5, and 6, respectively) are preferably maintained.

[0068] In some embodiments, such an antibody of the invention, or an antigen-binding fragment thereof, comprises (i) a heavy chain variable region (VH) comprising an amino acid sequence having at least 70% (e.g., at least 70%, at least 71%, at least 72%, at least 73%, at least 74%, at least 75%, at least 76%, at least 77%, at least 78%, at least 79%, at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99%) identity to SEQ ID NO: 45, and a light chain variable region (VL) comprising an amino acid sequence having at least 70% (e.g., at least 70%, at least 71%, at least 72%, at least 73%, at least 74%, at least 75%, at least 76%, at least 77%, at least 78%, at least 79%, at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99%) identity to SEQ ID NO: 8. Thereby, the CDR sequences defined above (the heavy chain CDR1 sequence, CDR2 sequence, and CDR3 sequence set forth in SEQ ID NO: 1, SEQ ID NO: 2, and SEQ ID NO: 3, respectively; and the light chain CDR1 sequence, CDR2 sequence, and CDR3 sequence set forth in SEQ ID NO: 4, SEQ ID NO: 5, and SEQ ID NO: 6, respectively) are preferably maintained.

[0069] In some embodiments, such an antibody of the invention, or antigen-binding fragment thereof, comprises (i) a heavy chain variable region (VH) comprising an amino acid sequence having at least 70% (e.g., at least 70%, at least 71%, at least 72%, at least 73%, at least 74%, at least 75%, at least 76%, at least 77%, at least 78%, at least 79%, at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99%) identity to SEQ ID NO: 45, and a light chain variable region (VL) comprising an amino acid sequence having at least 70% (e.g., at least 70%, at least 71%, at least 72%, at least 73%, at least 74%, at least 75%, at least 76%, at least 77%, at least 78%, at least 79%, at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99%) identity to SEQ ID NO: 46. Thereby, the CDR sequences defined above (the heavy chain CDR1 sequence, CDR2 sequence, and CDR3 sequence set forth in SEQ ID NO: 1, SEQ ID NO: 2, and SEQ ID NO: 3, respectively; and the light chain CDR1 sequence, CDR2 sequence, and CDR3 sequence set forth in SEQ ID NO: 4, SEQ ID NO: 5, and SEQ ID NO: 6, respectively) are preferably maintained.

[0070] In some embodiments, such an antibody of the invention, or an antigen-binding fragment thereof, comprises a heavy chain variable region (VH) comprising an amino acid sequence having at least 70% (e.g., at least 70%, at least 71%, at least 72%, at least 73%, at least 74%, at least 75%, at least 76%, at least 77%, at least 78%, at least 79%, at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99%) identity to SEQ ID NO: 45, and a light chain variable region (VL) comprising an amino acid sequence having at least 70% (e.g., at least 70%, at least 71%, at least 72%, at least 73%, at least 74%, at least 75%, at least 76%, at least 77%, at least 78%, at least 79%, at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99%) identity to SEQ ID NO: 47. Thereby, the CDR sequences defined above (the heavy chain CDR1, CDR2, and CDR3 sequences set forth in SEQ ID NO: 1, SEQ ID NO: 2, and SEQ ID NO: 3, respectively; and the light chain CDR1, CDR2, and CDR3 sequences set forth in SEQ ID NO: 4, SEQ ID NO: 5, and SEQ ID NO: 6, respectively) are preferably maintained.

[0071] In some embodiments, such an antibody of the invention, or an antigen-binding fragment thereof, comprises (i) a heavy chain variable region (VH) comprising an amino acid sequence having at least 70% (e.g., at least 70%, at least 71%, at least 72%, at least 73%, at least 74%, at least 75%, at least 76%, at least 77%, at least 78%, at least 79%, at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99%) identity to SEQ ID NO: 45, and a light chain variable region (VL) comprising an amino acid sequence having at least 70% (e.g., at least 70%, at least 71%, at least 72%, at least 73%, at least 74%, at least 75%, at least 76%, at least 77%, at least 78%, at least 79%, at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99%) identity to SEQ ID NO: 48. Thereby, the CDR sequences defined above (the heavy chain CDR1 sequence, CDR2 sequence, and CDR3 sequence described in SEQ ID NO: 1, SEQ ID NO: 2, and SEQ ID NO: 3, respectively; and the light chain CDR1 sequence, CDR2 sequence, and CDR3 sequence described in SEQ ID NO: 4, SEQ ID NO: 5, and SEQ ID NO: 6, respectively) are preferably maintained.

[0072] Preferably, such an antibody of the present invention, or an antigen-binding fragment thereof, comprises (i) a heavy chain variable region (VH) comprising an amino acid sequence having at least 70% (e.g., at least 70%, at least 71%, at least 72%, at least 73%, at least 74%, at least 75%, at least 76%, at least 77%, at least 78%, at least 79%, at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99%) identity to SEQ ID NO: 45, and a light chain variable region (VL) comprising an amino acid sequence having at least 70% (e.g., at least 70%, at least 71%, at least 72%, at least 73%, at least 74%, at least 75%, at least 76%, at least 77%, at least 78%, at least 79%, at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99%) identity to SEQ ID NO: 49. Thereby, the CDR sequences defined above (the heavy chain CDR1 sequence, CDR2 sequence, and CDR3 sequence described in SEQ ID NO: 1, SEQ ID NO: 2, and SEQ ID NO: 3, respectively; and the light chain CDR1 sequence, CDR2 sequence, and CDR3 sequence described in SEQ ID NO: 4, SEQ ID NO: 5, and SEQ ID NO: 6, respectively) are preferably maintained.

[0073] In some embodiments, the antibody, or an antigen-binding fragment thereof, comprises a heavy chain variable region comprising, or consisting of, the amino acid sequence set forth in SEQ ID NO: 7, and a light chain variable region comprising, or consisting of, the amino acid sequence set forth in SEQ ID NO: 8.

[0074] In some embodiments, the antibody, or an antigen-binding fragment thereof, comprises a heavy chain variable region comprising or consisting of the amino acid sequence set forth in SEQ ID NO: 7, and a light chain variable region comprising or consisting of the amino acid sequence set forth in SEQ ID NO: 46.

[0075] In some embodiments, the antibody, or an antigen-binding fragment thereof, comprises a heavy chain variable region comprising or consisting of the amino acid sequence set forth in SEQ ID NO: 7, and a light chain variable region comprising or consisting of the amino acid sequence set forth in SEQ ID NO: 47.

[0076] In some embodiments, the antibody, or an antigen-binding fragment thereof, comprises a heavy chain variable region comprising or consisting of the amino acid sequence set forth in SEQ ID NO: 7, and a light chain variable region comprising or consisting of the amino acid sequence set forth in SEQ ID NO: 48.

[0077] In some embodiments, the antibody, or an antigen-binding fragment thereof, comprises a heavy chain variable region comprising or consisting of the amino acid sequence set forth in SEQ ID NO: 7, and a light chain variable region comprising or consisting of the amino acid sequence set forth in SEQ ID NO: 49.

[0078] In some embodiments, the antibody, or an antigen-binding fragment thereof, comprises a heavy chain variable region comprising or consisting of the amino acid sequence set forth in SEQ ID NO: 44, and a light chain variable region comprising or consisting of the amino acid sequence set forth in SEQ ID NO: 8.

[0079] In some embodiments, the antibody, or an antigen-binding fragment thereof, comprises a heavy chain variable region comprising or consisting of the amino acid sequence set forth in SEQ ID NO: 44, and a light chain variable region comprising or consisting of the amino acid sequence set forth in SEQ ID NO: 46.

[0080] In some embodiments, the antibody, or antigen-binding fragment thereof, comprises a heavy chain variable region comprising or consisting of the amino acid sequence set forth in SEQ ID NO: 44, and a light chain variable region comprising or consisting of the amino acid sequence set forth in SEQ ID NO: 47.

[0081] In some embodiments, the antibody, or antigen-binding fragment thereof, comprises a heavy chain variable region comprising or consisting of the amino acid sequence set forth in SEQ ID NO: 44, and a light chain variable region comprising or consisting of the amino acid sequence set forth in SEQ ID NO: 48.

[0082] In some embodiments, the antibody, or antigen-binding fragment thereof, comprises a heavy chain variable region comprising or consisting of the amino acid sequence set forth in SEQ ID NO: 44, and a light chain variable region comprising or consisting of the amino acid sequence set forth in SEQ ID NO: 49.

[0083] In some embodiments, the antibody, or antigen-binding fragment thereof, comprises a heavy chain variable region comprising or consisting of the amino acid sequence set forth in SEQ ID NO: 45, and a light chain variable region comprising or consisting of the amino acid sequence set forth in SEQ ID NO: 8.

[0084] In some embodiments, the antibody, or antigen-binding fragment thereof, comprises a heavy chain variable region comprising or consisting of the amino acid sequence set forth in SEQ ID NO: 45, and a light chain variable region comprising or consisting of the amino acid sequence set forth in SEQ ID NO: 46.

[0085] In some embodiments, the antibody, or antigen-binding fragment thereof, comprises a heavy chain variable region comprising or consisting of the amino acid sequence set forth in SEQ ID NO: 45, and a light chain variable region comprising or consisting of the amino acid sequence set forth in SEQ ID NO: 47.

[0086] In some embodiments, the antibody, or antigen-binding fragment thereof, comprises a heavy chain variable region comprising or consisting of the amino acid sequence set forth in SEQ ID NO: 45, and a light chain variable region comprising or consisting of the amino acid sequence set forth in SEQ ID NO: 48.

[0087] Preferably, the antibody, or antigen-binding fragment thereof, comprises a heavy chain variable region comprising or consisting of the amino acid sequence set forth in SEQ ID NO: 45, and a light chain variable region comprising or consisting of the amino acid sequence set forth in SEQ ID NO: 49.

[0088] In some embodiments, the antibody or antigen-binding fragment thereof comprises CDRH1 having at least 70% identity with SEQ ID NO: 9, CDRH2 having at least 70% identity with SEQ ID NO: 10, CDRH3 having at least 70% identity with SEQ ID NO: 11, CDRL1 having at least 70% identity with SEQ ID NO: 12, CDRL2 having at least 70% identity with SEQ ID NO: 13, and CDRL3 having at least 70% identity with SEQ ID NO: 14. Preferably, the antibody or antigen-binding fragment thereof comprises: The heavy chain CDR1 sequence set forth in SEQ ID NO: 9; The heavy chain CDR2 sequence set forth in SEQ ID NO: 10; The heavy chain CDR3 sequence set forth in SEQ ID NO: 11; The light chain CDR1 sequence set forth in SEQ ID NO: 12; The light chain CDR2 sequence set forth in SEQ ID NO: 13; and The light chain CDR3 sequence set forth in SEQ ID NO: 14.

[0089] As shown in the accompanying examples, such antibodies (e.g., 15E3) specifically bind to Ara h 2 and Ara h 6.

[0090] In some embodiments, such an antibody of the invention, or an antigen-binding fragment thereof, comprises (i) a heavy chain variable region (VH) comprising an amino acid sequence having at least 70% (e.g., at least 70%, at least 71%, at least 72%, at least 73%, at least 74%, at least 75%, at least 76%, at least 77%, at least 78%, at least 79%, at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99%) identity to SEQ ID NO: 15, and a light chain variable region (VL) comprising an amino acid sequence having at least 70% (e.g., at least 70%, at least 71%, at least 72%, at least 73%, at least 74%, at least 75%, at least 76%, at least 77%, at least 78%, at least 79%, at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99%) identity to SEQ ID NO: 16. Thereby, the CDR sequences defined above (the heavy chain CDR1 sequence, CDR2 sequence, and CDR3 sequence described in SEQ ID NO: 9, SEQ ID NO: 10, and SEQ ID NO: 11, respectively; and the light chain CDR1 sequence, CDR2 sequence, and CDR3 sequence described in SEQ ID NO: 12, SEQ ID NO: 13, and SEQ ID NO: 14, respectively) are preferably maintained.

[0091] In some embodiments, such an antibody of the invention, or an antigen-binding fragment thereof, comprises (i) a heavy chain variable region (VH) comprising an amino acid sequence having at least 70% (e.g., at least 70%, at least 71%, at least 72%, at least 73%, at least 74%, at least 75%, at least 76%, at least 77%, at least 78%, at least 79%, at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99%) identity to SEQ ID NO: 15, and a light chain variable region (VL) comprising an amino acid sequence having at least 70% (e.g., at least 70%, at least 71%, at least 72%, at least 73%, at least 74%, at least 75%, at least 76%, at least 77%, at least 78%, at least 79%, at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99%) identity to SEQ ID NO: 39. Thereby, the CDR sequences defined above (the heavy chain CDR1 sequence, CDR2 sequence, and CDR3 sequence described in SEQ ID NO: 9, SEQ ID NO: 10, and SEQ ID NO: 11, respectively; and the light chain CDR1 sequence, CDR2 sequence, and CDR3 sequence described in SEQ ID NO: 12, SEQ ID NO: 13, and SEQ ID NO: 14, respectively) are preferably maintained.

[0092] In some embodiments, such an antibody of the invention, or an antigen-binding fragment thereof, comprises (i) a heavy chain variable region (VH) comprising an amino acid sequence having at least 70% (e.g., at least 70%, at least 71%, at least 72%, at least 73%, at least 74%, at least 75%, at least 76%, at least 77%, at least 78%, at least 79%, at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99%) identity to SEQ ID NO: 15, and a light chain variable region (VL) comprising an amino acid sequence having at least 70% (e.g., at least 70%, at least 71%, at least 72%, at least 73%, at least 74%, at least 75%, at least 76%, at least 77%, at least 78%, at least 79%, at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99%) identity to SEQ ID NO: 40. Thereby, the CDR sequences defined above (the heavy chain CDR1, CDR2, and CDR3 sequences set forth in SEQ ID NOs: 9, 10, and 11, respectively; and the light chain CDR1, CDR2, and CDR3 sequences set forth in SEQ ID NOs: 12, 13, and 14, respectively) are preferably maintained.

[0093] In some embodiments, such an antibody of the invention, or an antigen-binding fragment thereof, comprises a heavy chain variable region (VH) comprising an amino acid sequence having at least 70% (e.g., at least 70%, at least 71%, at least 72%, at least 73%, at least 74%, at least 75%, at least 76%, at least 77%, at least 78%, at least 79%, at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99%) identity to SEQ ID NO: 37, and a light chain variable region (VL) comprising an amino acid sequence having at least 70% (e.g., at least 70%, at least 71%, at least 72%, at least 73%, at least 74%, at least 75%, at least 76%, at least 77%, at least 78%, at least 79%, at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99%) identity to SEQ ID NO: 16. Thereby, the CDR sequences defined above (the heavy chain CDR1 sequence, CDR2 sequence, and CDR3 sequence set forth in SEQ ID NOs: 9, 10, and 11, respectively; and the light chain CDR1 sequence, CDR2 sequence, and CDR3 sequence set forth in SEQ ID NOs: 12, 13, and 14, respectively) are preferably maintained.

[0094] In some embodiments, such an antibody of the invention, or antigen-binding fragment thereof, comprises a heavy chain variable region (VH) comprising an amino acid sequence having at least 70% (e.g., at least 70%, at least 71%, at least 72%, at least 73%, at least 74%, at least 75%, at least 76%, at least 77%, at least 78%, at least 79%, at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99%) identity to SEQ ID NO: 37, and a light chain variable region (VL) comprising an amino acid sequence having at least 70% (e.g., at least 70%, at least 71%, at least 72%, at least 73%, at least 74%, at least 75%, at least 76%, at least 77%, at least 78%, at least 79%, at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99%) identity to SEQ ID NO: 39. Thereby, the CDR sequences defined above (the heavy chain CDR1 sequence, CDR2 sequence, and CDR3 sequence set forth in SEQ ID NOs: 9, 10, and 11, respectively; and the light chain CDR1 sequence, CDR2 sequence, and CDR3 sequence set forth in SEQ ID NOs: 12, 13, and 14, respectively) are preferably maintained.

[0095] In some embodiments, such an antibody of the invention, or an antigen-binding fragment thereof, comprises a heavy chain variable region (VH) comprising an amino acid sequence having at least 70% (e.g., at least 70%, at least 71%, at least 72%, at least 73%, at least 74%, at least 75%, at least 76%, at least 77%, at least 78%, at least 79%, at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99%) identity to SEQ ID NO: 37, and a light chain variable region (VL) comprising an amino acid sequence having at least 70% (e.g., at least 70%, at least 71%, at least 72%, at least 73%, at least 74%, at least 75%, at least 76%, at least 77%, at least 78%, at least 79%, at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99%) identity to SEQ ID NO: 40. Thereby, the CDR sequences defined above (the heavy chain CDR1 sequence, CDR2 sequence, and CDR3 sequence set forth in SEQ ID NO: 9, SEQ ID NO: 10, and SEQ ID NO: 11, respectively; and the light chain CDR1 sequence, CDR2 sequence, and CDR3 sequence set forth in SEQ ID NO: 12, SEQ ID NO: 13, and SEQ ID NO: 14, respectively) are preferably maintained.

[0096] In some embodiments, such an antibody of the invention, or an antigen-binding fragment thereof, comprises a heavy chain variable region (VH) comprising an amino acid sequence having at least 70% (e.g., at least 70%, at least 71%, at least 72%, at least 73%, at least 74%, at least 75%, at least 76%, at least 77%, at least 78%, at least 79%, at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99%) identity to SEQ ID NO: 38, and a light chain variable region (VL) comprising an amino acid sequence having at least 70% (e.g., at least 70%, at least 71%, at least 72%, at least 73%, at least 74%, at least 75%, at least 76%, at least 77%, at least 78%, at least 79%, at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99%) identity to SEQ ID NO: 16. Thereby, the CDR sequences defined above (the heavy chain CDR1 sequence, CDR2 sequence, and CDR3 sequence set forth in SEQ ID NOs: 9, 10, and 11, respectively; and the light chain CDR1 sequence, CDR2 sequence, and CDR3 sequence set forth in SEQ ID NOs: 12, 13, and 14, respectively) are preferably maintained.

[0097] In some embodiments, such an antibody of the invention, or an antigen-binding fragment thereof, comprises (i) a heavy chain variable region (VH) comprising an amino acid sequence having at least 70% (e.g., at least 70%, at least 71%, at least 72%, at least 73%, at least 74%, at least 75%, at least 76%, at least 77%, at least 78%, at least 79%, at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99%) identity to SEQ ID NO: 38, and a light chain variable region (VL) comprising an amino acid sequence having at least 70% (e.g., at least 70%, at least 71%, at least 72%, at least 73%, at least 74%, at least 75%, at least 76%, at least 77%, at least 78%, at least 79%, at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99%) identity to SEQ ID NO: 40. Thereby, the CDR sequences defined above (the heavy chain CDR1 sequence, CDR2 sequence, and CDR3 sequence set forth in SEQ ID NOs: 9, 10, and 11, respectively; and the light chain CDR1 sequence, CDR2 sequence, and CDR3 sequence set forth in SEQ ID NOs: 12, 13, and 14, respectively) are preferably maintained.

[0098] Preferably, such an antibody of the present invention, or an antigen-binding fragment thereof, comprises a heavy-chain variable region (VH) comprising an amino acid sequence having at least 70% (e.g., at least 70%, at least 71%, at least 72%, at least 73%, at least 74%, at least 75%, at least 76%, at least 77%, at least 78%, at least 79%, at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99%) identity to SEQ ID NO: 38, and a light-chain variable region (VL) comprising an amino acid sequence having at least 70% (e.g., at least 70%, at least 71%, at least 72%, at least 73%, at least 74%, at least 75%, at least 76%, at least 77%, at least 78%, at least 79%, at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99%) identity to SEQ ID NO: 39. Thereby, the CDR sequences defined above (the heavy-chain CDR1 sequence, CDR2 sequence, and CDR3 sequence described in SEQ ID NOs: 9, 10, and 11, respectively; and the light-chain CDR1 sequence, CDR2 sequence, and CDR3 sequence described in SEQ ID NOs: 12, 13, and 14, respectively) are preferably maintained.

[0099] In some embodiments, the antibody, or an antigen-binding fragment thereof, comprises a heavy-chain variable region comprising, or consisting of, the amino acid sequence set forth in SEQ ID NO: 15, and a light-chain variable region comprising, or consisting of, the amino acid sequence set forth in SEQ ID NO: 16.

[0100] In some embodiments, the antibody, or an antigen-binding fragment thereof, comprises a heavy chain variable region comprising or consisting of the amino acid sequence set forth in SEQ ID NO: 15, and a light chain variable region comprising or consisting of the amino acid sequence set forth in SEQ ID NO: 39.

[0101] In some embodiments, the antibody, or an antigen-binding fragment thereof, comprises a heavy chain variable region comprising or consisting of the amino acid sequence set forth in SEQ ID NO: 15, and a light chain variable region comprising or consisting of the amino acid sequence set forth in SEQ ID NO: 40.

[0102] In some embodiments, the antibody, or an antigen-binding fragment thereof, comprises a heavy chain variable region comprising or consisting of the amino acid sequence set forth in SEQ ID NO: 37, and a light chain variable region comprising or consisting of the amino acid sequence set forth in SEQ ID NO: 16.

[0103] In some embodiments, the antibody, or an antigen-binding fragment thereof, comprises a heavy chain variable region comprising or consisting of the amino acid sequence set forth in SEQ ID NO: 37, and a light chain variable region comprising or consisting of the amino acid sequence set forth in SEQ ID NO: 39.

[0104] In some embodiments, the antibody, or an antigen-binding fragment thereof, comprises a heavy chain variable region comprising or consisting of the amino acid sequence set forth in SEQ ID NO: 37, and a light chain variable region comprising or consisting of the amino acid sequence set forth in SEQ ID NO: 40.

[0105] In some embodiments, the antibody, or an antigen-binding fragment thereof, comprises a heavy chain variable region comprising or consisting of the amino acid sequence set forth in SEQ ID NO: 38, and a light chain variable region comprising or consisting of the amino acid sequence set forth in SEQ ID NO: 16.

[0106] In some embodiments, the antibody, or antigen-binding fragment thereof, comprises a heavy chain variable region comprising or consisting of the amino acid sequence set forth in SEQ ID NO: 38, and a light chain variable region comprising or consisting of the amino acid sequence set forth in SEQ ID NO: 40.

[0107] Preferably, the antibody, or antigen-binding fragment thereof, comprises a heavy chain variable region comprising or consisting of the amino acid sequence set forth in SEQ ID NO: 38, and a light chain variable region comprising or consisting of the amino acid sequence set forth in SEQ ID NO: 39.

[0108] In some embodiments, the antibody, or antigen-binding fragment thereof, comprises a CDRH1 having at least 70% identity with SEQ ID NO: 17, a CDRH2 having at least 70% identity with SEQ ID NO: 18, a CDRH3 having at least 70% identity with SEQ ID NO: 51, a CDRL1 having at least 70% identity with SEQ ID NO: 20, a CDRL2 having at least 70% identity with SEQ ID NO: 21, and a CDRL3 having at least 70% identity with SEQ ID NO: 22. Preferably, the antibody or antigen-binding fragment thereof comprises: The heavy chain CDR1 sequence set forth in SEQ ID NO: 17; The heavy chain CDR2 sequence set forth in SEQ ID NO: 18; The heavy chain CDR3 sequence set forth in SEQ ID NO: 51; The light chain CDR1 sequence set forth in SEQ ID NO: 20; The light chain CDR2 sequence set forth in SEQ ID NO: 21; and The light chain CDR3 sequence set forth in SEQ ID NO: 22.

[0109] As shown in the attached examples, such antibodies (e.g., 2F8 CDRH3 variants) specifically bind to Ara h 2 and Ara h 6. Furthermore, compared to wild-type 2F8, variant 2F8 containing the modified CDRH3 results in a more homogeneous product, thereby increasing the productivity of the antibody, as shown in the attached examples.

[0110] In some embodiments, such an antibody of the invention, or an antigen-binding fragment thereof, comprises (i) a heavy chain variable region (VH) comprising an amino acid sequence having at least 70% (e.g., at least 70%, at least 71%, at least 72%, at least 73%, at least 74%, at least 75%, at least 76%, at least 77%, at least 78%, at least 79%, at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99%) identity to SEQ ID NO: 53, and a light chain variable region (VL) comprising an amino acid sequence having at least 70% (e.g., at least 70%, at least 71%, at least 72%, at least 73%, at least 74%, at least 75%, at least 76%, at least 77%, at least 78%, at least 79%, at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99%) identity to SEQ ID NO: 24. Thereby, the CDR sequences defined above (the heavy chain CDR1 sequence, CDR2 sequence, and CDR3 sequence set forth in SEQ ID NOs: 17, 18, and 51, respectively; and the light chain CDR1 sequence, CDR2 sequence, and CDR3 sequence set forth in SEQ ID NOs: 20, 21, and 22, respectively) are preferably maintained.

[0111] In some embodiments, such an antibody of the invention, or antigen-binding fragment thereof, comprises a heavy chain variable region (VH) comprising an amino acid sequence having at least 70% (e.g., at least 70%, at least 71%, at least 72%, at least 73%, at least 74%, at least 75%, at least 76%, at least 77%, at least 78%, at least 79%, at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99%) identity to SEQ ID NO: 53, and a light chain variable region (VL) comprising an amino acid sequence having at least 70% (e.g., at least 70%, at least 71%, at least 72%, at least 73%, at least 74%, at least 75%, at least 76%, at least 77%, at least 78%, at least 79%, at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99%) identity to SEQ ID NO: 42. Thereby, the CDR sequences defined above (the heavy chain CDR1, CDR2, and CDR3 sequences set forth in SEQ ID NOs: 17, 18, and 51, respectively; and the light chain CDR1, CDR2, and CDR3 sequences set forth in SEQ ID NOs: 20, 21, and 22, respectively) are preferably maintained.

[0112] Preferably, such an antibody of the present invention, or an antigen-binding fragment thereof, comprises a heavy-chain variable region (VH) comprising an amino acid sequence having at least 70% (e.g., at least 70%, at least 71%, at least 72%, at least 73%, at least 74%, at least 75%, at least 76%, at least 77%, at least 78%, at least 79%, at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99%) identity to SEQ ID NO: 53, and a light-chain variable region (VL) comprising an amino acid sequence having at least 70% (e.g., at least 70%, at least 71%, at least 72%, at least 73%, at least 74%, at least 75%, at least 76%, at least 77%, at least 78%, at least 79%, at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99%) identity to SEQ ID NO: 43. Thereby, the CDR sequences defined above (the heavy-chain CDR1 sequence, CDR2 sequence, and CDR3 sequence described in SEQ ID NOs: 17, 18, and 51, respectively; and the light-chain CDR1 sequence, CDR2 sequence, and CDR3 sequence described in SEQ ID NOs: 20, 21, and 22, respectively) are preferably maintained.

[0113] In some embodiments, the antibody, or an antigen-binding fragment thereof, comprises a heavy-chain variable region comprising or consisting of the amino acid sequence set forth in SEQ ID NO: 53, and a light-chain variable region comprising or consisting of the amino acid sequence set forth in SEQ ID NO: 24.

[0114] In some embodiments, the antibody, or antigen-binding fragment thereof, comprises a heavy chain variable region comprising or consisting of the amino acid sequence set forth in SEQ ID NO: 53, and a light chain variable region comprising or consisting of the amino acid sequence set forth in SEQ ID NO: 42.

[0115] Preferably, the antibody, or antigen-binding fragment thereof, comprises a heavy chain variable region comprising or consisting of the amino acid sequence set forth in SEQ ID NO: 53, and a light chain variable region comprising or consisting of the amino acid sequence set forth in SEQ ID NO: 43.

[0116] The present invention also provides an antibody, or antigen-binding fragment thereof, that specifically binds to Ara h 2 and / or Ara h 6, wherein the antibody, or antigen-binding fragment thereof, comprises a VH having at least 70% identity with SEQ ID NO: 23; and a VL having at least 70% identity with SEQ ID NO: 42 or 43. Thereby, the heavy chain CDR1 sequence, CDR2 sequence, and CDR3 sequence set forth in SEQ ID NO: 17, SEQ ID NO: 18, and SEQ ID NO: 19, respectively; and the light chain CDR1 sequence, CDR2 sequence, and CDR3 sequence set forth in SEQ ID NO: 20, SEQ ID NO: 21, and SEQ ID NO: 22, respectively, are preferably maintained. In some embodiments, such an antibody, or antigen-binding fragment thereof, comprises a VH set forth in SEQ ID NO: 23; and a VL set forth in SEQ ID NO: 42 or 43.

[0117] The present invention also provides an antibody, or an antigen-binding fragment thereof, that specifically binds to Ara h 2 and / or Ara h 6, wherein the antibody, or the antigen-binding fragment thereof, comprises a VH having at least 70% identity with SEQ ID NO: 41 or 50; and a VL having at least 70% identity with SEQ ID NO: 24. Thereby, the heavy-chain CDR1 sequence, CDR2 sequence, and CDR3 sequence described in SEQ ID NO: 17, SEQ ID NO: 18, and SEQ ID NO: 19, respectively; and the light-chain CDR1 sequence, CDR2 sequence, and CDR3 sequence described in SEQ ID NO: 20, SEQ ID NO: 21, and SEQ ID NO: 22, respectively, are preferably maintained. In some embodiments, such an antibody, or an antigen-binding fragment thereof, comprises a VH described in SEQ ID NO: 41 or 50; and a VL described in SEQ ID NO: 24.

[0118] The present invention also provides an antibody, or an antigen-binding fragment thereof, that specifically binds to Ara h 2 and / or Ara h 6, wherein the antibody, or the antigen-binding fragment thereof, comprises a VH having at least 70% identity with SEQ ID NO: 41 or 50; and a VL having at least 70% identity with SEQ ID NO: 42 or 43. Thereby, the heavy-chain CDR1 sequence, CDR2 sequence, and CDR3 sequence described in SEQ ID NO: 17, SEQ ID NO: 18, and SEQ ID NO: 19, respectively; and the light-chain CDR1 sequence, CDR2 sequence, and CDR3 sequence described in SEQ ID NO: 20, SEQ ID NO: 21, and SEQ ID NO: 22, respectively, are preferably maintained.

[0119] In some embodiments, such an antibody of the invention, or an antigen-binding fragment thereof, comprises (i) a heavy chain variable region (VH) comprising an amino acid sequence having at least 70% (e.g., at least 70%, at least 71%, at least 72%, at least 73%, at least 74%, at least 75%, at least 76%, at least 77%, at least 78%, at least 79%, at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99%) identity to SEQ ID NO: 41, and a light chain variable region (VL) comprising an amino acid sequence having at least 70% (e.g., at least 70%, at least 71%, at least 72%, at least 73%, at least 74%, at least 75%, at least 76%, at least 77%, at least 78%, at least 79%, at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99%) identity to SEQ ID NO: 42. Thereby, the CDR sequences defined above (the heavy chain CDR1, CDR2, and CDR3 sequences set forth in SEQ ID NOs: 17, 18, and 19, respectively; and the light chain CDR1, CDR2, and CDR3 sequences set forth in SEQ ID NOs: 20, 21, and 22, respectively) are preferably maintained.

[0120] In some embodiments, such an antibody of the invention, or an antigen-binding fragment thereof, comprises a heavy chain variable region (VH) comprising an amino acid sequence having at least 70% (e.g., at least 70%, at least 71%, at least 72%, at least 73%, at least 74%, at least 75%, at least 76%, at least 77%, at least 78%, at least 79%, at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99%) identity to SEQ ID NO: 41, and a light chain variable region (VL) comprising an amino acid sequence having at least 70% (e.g., at least 70%, at least 71%, at least 72%, at least 73%, at least 74%, at least 75%, at least 76%, at least 77%, at least 78%, at least 79%, at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99%) identity to SEQ ID NO: 43. Thereby, the CDR sequences defined above (the heavy chain CDR1 sequence, CDR2 sequence, and CDR3 sequence set forth in SEQ ID NO: 17, SEQ ID NO: 18, and SEQ ID NO: 19, respectively; and the light chain CDR1 sequence, CDR2 sequence, and CDR3 sequence set forth in SEQ ID NO: 20, SEQ ID NO: 21, and SEQ ID NO: 22, respectively) are preferably maintained.

[0121] In some embodiments, such an antibody of the invention, or an antigen-binding fragment thereof, comprises a heavy chain variable region (VH) comprising an amino acid sequence having at least 70% (e.g., at least 70%, at least 71%, at least 72%, at least 73%, at least 74%, at least 75%, at least 76%, at least 77%, at least 78%, at least 79%, at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99%) identity to SEQ ID NO: 50, and a light chain variable region (VL) comprising an amino acid sequence having at least 70% (e.g., at least 70%, at least 71%, at least 72%, at least 73%, at least 74%, at least 75%, at least 76%, at least 77%, at least 78%, at least 79%, at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99%) identity to SEQ ID NO: 42. Thereby, the CDR sequences defined above (the heavy chain CDR1, CDR2, and CDR3 sequences set forth in SEQ ID NOs: 17, 18, and 19, respectively; and the light chain CDR1, CDR2, and CDR3 sequences set forth in SEQ ID NOs: 20, 21, and 22, respectively) are preferably maintained.

[0122] In some embodiments, such an antibody of the invention, or an antigen-binding fragment thereof, comprises a heavy chain variable region (VH) comprising an amino acid sequence having at least 70% (e.g., at least 70%, at least 71%, at least 72%, at least 73%, at least 74%, at least 75%, at least 76%, at least 77%, at least 78%, at least 79%, at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99%) identity to SEQ ID NO: 50, and a light chain variable region (VL) comprising an amino acid sequence having at least 70% (e.g., at least 70%, at least 71%, at least 72%, at least 73%, at least 74%, at least 75%, at least 76%, at least 77%, at least 78%, at least 79%, at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99%) identity to SEQ ID NO: 43. Thereby, the CDR sequences defined above (the heavy chain CDR1 sequence, CDR2 sequence, and CDR3 sequence set forth in SEQ ID NOs: 17, 18, and 19, respectively; and the light chain CDR1 sequence, CDR2 sequence, and CDR3 sequence set forth in SEQ ID NOs: 20, 21, and 22, respectively) are preferably maintained.

[0123] In some embodiments, the antibody, or antigen-binding fragment thereof, comprises a heavy chain variable region comprising or consisting of the amino acid sequence set forth in SEQ ID NO: 41, and a light chain variable region comprising or consisting of the amino acid sequence set forth in SEQ ID NO: 42.

[0124] In some embodiments, the antibody, or antigen-binding fragment thereof, comprises a heavy chain variable region comprising or consisting of the amino acid sequence set forth in SEQ ID NO: 41, and a light chain variable region comprising or consisting of the amino acid sequence set forth in SEQ ID NO: 43.

[0125] In some embodiments, the antibody, or antigen-binding fragment thereof, comprises a heavy chain variable region comprising or consisting of the amino acid sequence set forth in SEQ ID NO: 50, and a light chain variable region comprising or consisting of the amino acid sequence set forth in SEQ ID NO: 42.

[0126] In some embodiments, the antibody, or antigen-binding fragment thereof, comprises a heavy chain variable region comprising or consisting of the amino acid sequence set forth in SEQ ID NO: 50, and a light chain variable region comprising or consisting of the amino acid sequence set forth in SEQ ID NO: 43.

[0127] In some embodiments, the antibody, or antigen-binding fragment thereof, comprises CDRH1 having at least 70% identity with SEQ ID NO: 25, CDRH2 having at least 70% identity with SEQ ID NO: 26, CDRH3 having at least 70% identity with SEQ ID NO: 27, CDRL1 having at least 70% identity with SEQ ID NO: 28, CDRL2 having at least 70% identity with SEQ ID NO: 52, and CDRL3 having at least 70% identity with SEQ ID NO: 30. Preferably, the antibody or antigen-binding fragment thereof comprises: The heavy chain CDR1 sequence set forth in SEQ ID NO: 25; The heavy chain CDR2 sequence set forth in SEQ ID NO: 26; The heavy chain CDR3 sequence set forth in SEQ ID NO: 27; The light chain CDR1 sequence set forth in SEQ ID NO: 28; The light chain CDR2 sequence set forth in SEQ ID NO: 52; and The light chain CDR3 sequence set forth in SEQ ID NO: 30.

[0128] As shown in the attached examples, such antibodies (e.g., 7G6 CDRL2 variant) specifically bind to Ara h 2 and Ara h 6. Further, compared to wild-type 7G6, the variant 7G6 containing the modified CDRL2 shows less non-specific binding as shown in the attached examples, thereby increasing the productivity of the antibody.

[0129] In some embodiments, such an antibody of the invention, or an antigen-binding fragment thereof, comprises a heavy chain variable region (VH) comprising an amino acid sequence having at least 70% (e.g., at least 70%, at least 71%, at least 72%, at least 73%, at least 74%, at least 75%, at least 76%, at least 77%, at least 78%, at least 79%, at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99%) identity to SEQ ID NO: 31, and a light chain variable region (VL) comprising an amino acid sequence having at least 70% (e.g., at least 70%, at least 71%, at least 72%, at least 73%, at least 74%, at least 75%, at least 76%, at least 77%, at least 78%, at least 79%, at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99%) identity to SEQ ID NO: 54. Thereby, the CDR sequences defined above (the heavy chain CDR1, CDR2, and CDR3 sequences set forth in SEQ ID NO: 25, SEQ ID NO: 26, and SEQ ID NO: 27, respectively; and the light chain CDR1, CDR2, and CDR3 sequences set forth in SEQ ID NO: 28, SEQ ID NO: 29, and SEQ ID NO: 30, respectively) are preferably maintained.

[0130] In some embodiments, such an antibody of the invention, or antigen-binding fragment thereof, comprises a heavy chain variable region (VH) comprising an amino acid sequence having at least 70% (e.g., at least 70%, at least 71%, at least 72%, at least 73%, at least 74%, at least 75%, at least 76%, at least 77%, at least 78%, at least 79%, at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99%) identity to SEQ ID NO: 33, and a light chain variable region (VL) comprising an amino acid sequence having at least 70% (e.g., at least 70%, at least 71%, at least 72%, at least 73%, at least 74%, at least 75%, at least 76%, at least 77%, at least 78%, at least 79%, at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99%) identity to SEQ ID NO: 54. Thereby, the CDR sequences defined above (the heavy chain CDR1 sequence, CDR2 sequence, and CDR3 sequence set forth in SEQ ID NO: 25, SEQ ID NO: 26, and SEQ ID NO: 27, respectively; and the light chain CDR1 sequence, CDR2 sequence, and CDR3 sequence set forth in SEQ ID NO: 28, SEQ ID NO: 29, and SEQ ID NO: 30, respectively) are preferably maintained.

[0131] Preferably, such an antibody of the present invention, or an antigen-binding fragment thereof, comprises (i) a heavy chain variable region (VH) comprising an amino acid sequence having at least 70% (e.g., at least 70%, at least 71%, at least 72%, at least 73%, at least 74%, at least 75%, at least 76%, at least 77%, at least 78%, at least 79%, at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99%) identity to SEQ ID NO: 34, and a light chain variable region (VL) comprising an amino acid sequence having at least 70% (e.g., at least 70%, at least 71%, at least 72%, at least 73%, at least 74%, at least 75%, at least 76%, at least 77%, at least 78%, at least 79%, at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99%) identity to SEQ ID NO: 54. Thereby, the CDR sequences defined above (the heavy chain CDR1 sequence, CDR2 sequence, and CDR3 sequence described in SEQ ID NO: 25, SEQ ID NO: 26, and SEQ ID NO: 27, respectively; and the light chain CDR1 sequence, CDR2 sequence, and CDR3 sequence described in SEQ ID NO: 28, SEQ ID NO: 29, and SEQ ID NO: 30, respectively) are preferably maintained.

[0132] In some embodiments, the antibody, or an antigen-binding fragment thereof, comprises a heavy chain variable region comprising or consisting of the amino acid sequence set forth in SEQ ID NO: 31, and a light chain variable region comprising or consisting of the amino acid sequence set forth in SEQ ID NO: 54.

[0133] In some embodiments, the antibody, or antigen-binding fragment thereof, comprises a heavy chain variable region comprising or consisting of the amino acid sequence set forth in SEQ ID NO: 33, and a light chain variable region comprising or consisting of the amino acid sequence set forth in SEQ ID NO: 54.

[0134] Preferably, the antibody, or antigen-binding fragment thereof, comprises a heavy chain variable region comprising or consisting of the amino acid sequence set forth in SEQ ID NO: 34, and a light chain variable region comprising or consisting of the amino acid sequence set forth in SEQ ID NO: 54.

[0135] The present invention also provides an antibody, or antigen-binding fragment thereof, that specifically binds to Ara h 2 and / or Ara h 6, the antibody, or antigen-binding fragment thereof, comprising a VH having at least 70% identity with SEQ ID NO: 31; and a VL having at least 70% identity with SEQ ID NO: 35 or 36. Thereby, the heavy chain CDR1 sequence, CDR2 sequence, and CDR3 sequence set forth in SEQ ID NO: 25, SEQ ID NO: 26, and SEQ ID NO: 27, respectively; and the light chain CDR1 sequence, CDR2 sequence, and CDR3 sequence set forth in SEQ ID NO: 28, SEQ ID NO: 29, and SEQ ID NO: 30, respectively, are preferably maintained. In some embodiments, such an antibody, or antigen-binding fragment thereof, comprises a VH set forth in SEQ ID NO: 31; and a VL set forth in SEQ ID NO: 35 or 36.

[0136] The present invention also provides an antibody that specifically binds to Ara h 2 and / or Ara h 6, or an antigen-binding fragment thereof, wherein the antibody, or the antigen-binding fragment thereof, comprises a VH having at least 70% identity with SEQ ID NO: 33 or 34; and a VL having at least 70% identity with SEQ ID NO: 32. Thereby, the heavy-chain CDR1 sequence, CDR2 sequence, and CDR3 sequence described in SEQ ID NO: 25, SEQ ID NO: 26, and SEQ ID NO: 27, respectively; and the light-chain CDR1 sequence, CDR2 sequence, and CDR3 sequence described in SEQ ID NO: 28, SEQ ID NO: 29, and SEQ ID NO: 30, respectively, are preferably maintained. In some embodiments, such an antibody, or an antigen-binding fragment thereof, comprises a VH described in SEQ ID NO: 33 or 34; and a VL described in SEQ ID NO: 32.

[0137] The present invention also provides an antibody that specifically binds to Ara h 2 and / or Ara h 6, or an antigen-binding fragment thereof, wherein the antibody, or the antigen-binding fragment thereof, comprises a VH having at least 70% identity with SEQ ID NO: 33 or 34; and a VL having at least 70% identity with SEQ ID NO: 35 or 36. Thereby, the heavy-chain CDR1 sequence, CDR2 sequence, and CDR3 sequence described in SEQ ID NO: 25, SEQ ID NO: 26, and SEQ ID NO: 27, respectively; and the light-chain CDR1 sequence, CDR2 sequence, and CDR3 sequence described in SEQ ID NO: 28, SEQ ID NO: 29, and SEQ ID NO: 30, respectively, are preferably maintained.

[0138] In some embodiments, such an antibody of the invention, or an antigen-binding fragment thereof, comprises a heavy-chain variable region (VH) comprising an amino acid sequence having at least 70% (e.g., at least 70%, at least 71%, at least 72%, at least 73%, at least 74%, at least 75%, at least 76%, at least 77%, at least 78%, at least 79%, at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99%) identity to SEQ ID NO: 33, and a light-chain variable region (VL) comprising an amino acid sequence having at least 70% (e.g., at least 70%, at least 71%, at least 72%, at least 73%, at least 74%, at least 75%, at least 76%, at least 77%, at least 78%, at least 79%, at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99%) identity to SEQ ID NO: 35. Thereby, the CDR sequences defined above (the heavy-chain CDR1, CDR2, and CDR3 sequences set forth in SEQ ID NO: 25, SEQ ID NO: 26, and SEQ ID NO: 27, respectively; and the light-chain CDR1, CDR2, and CDR3 sequences set forth in SEQ ID NO: 28, SEQ ID NO: 29, and SEQ ID NO: 30, respectively) are preferably maintained.

[0139] In some embodiments, such an antibody of the invention, or an antigen-binding fragment thereof, comprises a heavy chain variable region (VH) comprising an amino acid sequence having 70% or more (e.g., at least 70%, at least 71%, at least 72%, at least 73%, at least 74%, at least 75%, at least 76%, at least 77%, at least 78%, at least 79%, at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99%) identity to SEQ ID NO: 33, and a light chain variable region (VL) comprising an amino acid sequence having 70% or more (e.g., at least 70%, at least 71%, at least 72%, at least 73%, at least 74%, at least 75%, at least 76%, at least 77%, at least 78%, at least 79%, at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99%) identity to SEQ ID NO: 36. Thereby, the CDR sequences defined above (the heavy chain CDR1 sequence, CDR2 sequence, and CDR3 sequence set forth in SEQ ID NO: 25, SEQ ID NO: 26, and SEQ ID NO: 27, respectively; and the light chain CDR1 sequence, CDR2 sequence, and CDR3 sequence set forth in SEQ ID NO: 28, SEQ ID NO: 29, and SEQ ID NO: 30, respectively) are preferably maintained.

[0140] In some embodiments, such an antibody of the invention, or an antigen-binding fragment thereof, comprises (i) a heavy chain variable region (VH) comprising an amino acid sequence having at least 70% (e.g., at least 70%, at least 71%, at least 72%, at least 73%, at least 74%, at least 75%, at least 76%, at least 77%, at least 78%, at least 79%, at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99%) identity to SEQ ID NO: 34, and a light chain variable region (VL) comprising an amino acid sequence having at least 70% (e.g., at least 70%, at least 71%, at least 72%, at least 73%, at least 74%, at least 75%, at least 76%, at least 77%, at least 78%, at least 79%, at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99%) identity to SEQ ID NO: 36. Thereby, the CDR sequences defined above (the heavy chain CDR1, CDR2, and CDR3 sequences set forth in SEQ ID NO: 25, SEQ ID NO: 26, and SEQ ID NO: 27, respectively; and the light chain CDR1, CDR2, and CDR3 sequences set forth in SEQ ID NO: 28, SEQ ID NO: 29, and SEQ ID NO: 30, respectively) are preferably maintained.

[0141] Preferably, such an antibody of the present invention, or an antigen-binding fragment thereof, comprises (i) a heavy chain variable region (VH) comprising an amino acid sequence having 70% or more (e.g., at least 70%, at least 71%, at least 72%, at least 73%, at least 74%, at least 75%, at least 76%, at least 77%, at least 78%, at least 79%, at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99%) identity to SEQ ID NO: 34, and a light chain variable region (VL) comprising an amino acid sequence having 70% or more (e.g., at least 70%, at least 71%, at least 72%, at least 73%, at least 74%, at least 75%, at least 76%, at least 77%, at least 78%, at least 79%, at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99%) identity to SEQ ID NO: 35. Thereby, the CDR sequences defined above (the heavy chain CDR1 sequence, CDR2 sequence, and CDR3 sequence described in SEQ ID NO: 25, SEQ ID NO: 26, and SEQ ID NO: 27, respectively; and the light chain CDR1 sequence, CDR2 sequence, and CDR3 sequence described in SEQ ID NO: 28, SEQ ID NO: 29, and SEQ ID NO: 30, respectively) are preferably maintained.

[0142] In some embodiments, the antibody, or an antigen-binding fragment thereof, comprises a heavy chain variable region comprising or consisting of the amino acid sequence set forth in SEQ ID NO: 33, and a light chain variable region comprising or consisting of the amino acid sequence set forth in SEQ ID NO: 35.

[0143] In some embodiments, the antibody, or antigen-binding fragment thereof, comprises a heavy chain variable region comprising or consisting of the amino acid sequence set forth in SEQ ID NO: 33, and a light chain variable region comprising or consisting of the amino acid sequence set forth in SEQ ID NO: 36.

[0144] In some embodiments, the antibody, or antigen-binding fragment thereof, comprises a heavy chain variable region comprising or consisting of the amino acid sequence set forth in SEQ ID NO: 34, and a light chain variable region comprising or consisting of the amino acid sequence set forth in SEQ ID NO: 36.

[0145] Preferably, the antibody, or antigen-binding fragment thereof, comprises a heavy chain variable region comprising or consisting of the amino acid sequence set forth in SEQ ID NO: 34, and a light chain variable region comprising or consisting of the amino acid sequence set forth in SEQ ID NO: 35.

[0146] Generally, the antibodies or antigen-binding fragments of the present invention can reduce, inhibit or neutralize the biological activity mediated by allergens. In particular, the antibodies can reduce or inhibit the binding of IgE antibodies to peanut allergens, particularly Ara h 2, Ara h 3 and / or Ara h 6 as described herein. Thus, the antibodies or binding fragments thereof according to the present invention can reduce or inhibit the activation of mast cells or basophils and, therefore, can reduce or prevent the release of mediators (e.g., histamine, lipid mediators, leukotrienes). Thereby, the antibodies described herein can inhibit allergic symptoms that would normally occur in a patient after contact with an allergen (e.g., contact with the eyes, nose or mouth, or food ingestion). Thus, the antibodies described herein can reduce, inhibit or neutralize the biological activity mediated by allergens. In particular, the antibodies can reduce or inhibit the binding of IgE antibodies to peanut allergens, particularly Ara h 2, Ara h 3 and / or Ara h 6.

[0147] In some embodiments, the CDRs, or variable regions, of the antibody or antigen-binding fragment thereof are human CDR or variable region sequences or are derived from human CDR or variable region sequences. Exemplary antibodies 2F8, 7G6, 17H9, and 15E3 (wild-type) are human antibodies isolated from human patients. "Human-derived" CDR or VH / VL sequences include modified human antibody sequences in which mutations have been introduced into the original human CDR or VH / VL sequences. For example, a human-derived CDR can differ from a fully human (wild-type) CDR sequence in that it contains up to 5, i.e., 1, 2, 3, 4, or 5 mutations, preferably up to 4 mutations, more preferably up to 3 mutations. For example, a human-derived VH or VL sequence can differ from a fully human (wild-type) VH or VL sequence in that it contains up to 10, i.e., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 mutations, preferably up to 7 mutations, more preferably up to 5 mutations (e.g., in the framework region).

[0148] In some embodiments, the antibody, or antigen-binding fragment thereof, is a human antibody. In some embodiments, the antibody, or antigen-binding fragment thereof, is a monoclonal antibody. For example, the antibody, or antigen-binding fragment thereof, can be a human monoclonal antibody.

[0149] Human antibodies are advantageous compared to non-human-derived antibodies. This is because non-human antibodies, including chimeric and humanized antibodies, can cause adverse immune reactions and may cause symptoms such as nausea, diarrhea, and influenza. In more severe cases, these side effects can even be fatal. Non-human antibody segments often induce a human immune response (anti-drug antibody (ADA)), causing not only undesirable side effects but also reducing the effectiveness of non-human antibodies in humans. In contrast, antibodies obtained from humans have been shown to have a higher safety profile due to their tolerance in the human body combined with the typical excellent affinity maturation of the human immune system. As used herein, the term "human antibody" includes not only antibodies that originally exist in humans but also sequence variants in which specific amino acid residues (not the entire antibody segment) have been mutated. Usually, in contrast to non-human antibodies and humanized antibodies, which include the entire non-human-derived antibody segment (such as the entire set of CDR sequences), sequence variants of human antibodies usually contain only selective / specific mutations within the selected antibody segment (e.g., within the CDR or framework region and / or within the constant region; e.g., to modify the affinity, functionality, half-life, etc. of the antibody).

[0150] For example, human antibodies according to the present invention may contain only a limited number of mutations per CDR (e.g., 6 or fewer, preferably 5 or fewer, more preferably 4 or fewer, even more preferably 3 or fewer, still more preferably 2 or fewer, particularly preferably only a single mutation) compared to the sequences shown in Table 1. If there are more than two mutations, they cannot occur consecutively (so as not to create a non-human sequence segment). The same applies to the framework region (or the entire VH / VL sequence) and the constant region. The latter can carry specific modifications known in the art, as described later herein, for example, to modify the functionality (related to Fc) of the antibody.

[0151] Preferably, the antibody is an IgG or IgA antibody. IgG and IgA usually compete with IgE at the binding site of the allergen and prevent the recognition of the allergen by IgE bound to the Fcε receptors on the surface of mast cells and basophils. This can include direct competition by binding to the same epitope or competition by steric hindrance. Furthermore, IgG antibodies bound to the allergen cause cross-linking of Fcγ and inhibitory FcγRIIB receptors, resulting in a decrease in the activity of effector cells. Thus, the IgG and IgA antibodies or binding fragments thereof according to the present invention can be used for effective prevention or treatment of allergies. In some embodiments, the variable region or CDR of the antibody as defined herein is derived from a (human) IgE antibody and grafted onto the scaffold of an IgG or IgA antibody. Preferably, the scaffold is human IgG or IgA. Thus, the variable region, a part thereof, or the CDR may be human and may be grafted into the antibody framework, preferably of human origin, but a distinct antibody type such as IgG or IgA instead of IgE. Typically, the human-derived part of the variable region grafted into the antibody framework includes the CDR. Among IgG, IgG1 and IgG4 are preferred.

[0152] Thus, the antibody or antigen-binding fragment thereof according to the present invention may contain an Fc substructure. The Fc substructure may be of human origin, for example, human IgA or IgG, such as IgG1, IgG2, IgG3, and / or IgG4, such as human IgG1.

[0153] As used herein, the term "Fc sub-structure" refers to a sequence derived from a portion of an immunoglobulin heavy chain that begins at the hinge region (e.g., 216 residues in native IgG, with the first residue of the heavy chain constant region being 114) immediately upstream of the papain cleavage site and ends at the C-terminus of the immunoglobulin heavy chain. Thus, the Fc sub-structure may be a complete Fc sub-structure or a part (e.g., a domain) thereof. A complete Fc sub-structure includes at least the hinge domain, CH2 domain, and CH3 domain (e.g., EU amino acid positions 216-446). Additional lysine residues (K) may be present at the extreme C-terminus of the Fc sub-structure, but are often cleaved from the mature antibody.

[0154] In some embodiments, in the context of the present invention, the Fc sub-structure includes at least one of the hinge (e.g., upper, middle, and / or lower hinge region) domain, CH2 domain, CH3 domain, or variants, parts, or fragments thereof. The Fc sub-structure may include at least the hinge domain, CH2 domain, or CH3 domain. The Fc sub-structure may be a complete Fc sub-structure. The Fc sub-structure may also include one or more amino acid insertions, deletions, or substitutions relative to the naturally occurring Fc sub-structure. For example, at least one of the hinge domain, CH2 domain, or CH3 domain (or a part thereof) may be deleted.

[0155] One of ordinary skill in the art will understand that the Fc sub-structure can be modified to have an amino acid sequence different from that of the complete Fc sub-structure of a naturally occurring immunoglobulin molecule, but retain at least one desirable function conferred by the naturally occurring Fc sub-structure. Such functions include Fc receptor (FcR) binding, antibody half-life modulation, ADCC function, protein A binding, protein G binding, and complement binding. Among the naturally occurring Fc sub-structures, the parts and / or essential parts responsible for such functions are well known to those of ordinary skill in the art. In some embodiments, the antibodies according to the present invention include a (complete) Fc sub-structure / Fc region such that the interaction / binding with the Fc receptor is not impaired.

[0156] Generally, the binding of an antibody to an Fc receptor can be determined by various methods known to those skilled in the art, such as ELISA (Hessell AJ, Hangartner L, Hunter M, Havenith CEG, Beurskens FJ, Bakker JM, Lanigan CMS, Landucci G, Forthal DN, Parren PWHI, et al.: Fc receptor but not complement binding is important in antibody protection against HIV. Nature 2007, 449:101-104; Grevys A, Bern M, Foss S, Bratlie DB, Moen A, Gunnarsen KS, Aase A, Michaelsen TE, Sandlie I, Andersen JT: Fc Engineering of Human IgG1 for Altered Binding to the Neonatal Fc Receptor Affects Fc Effector Functions. 2015, 194:5497-5508), or flow cytometry (Perez LG, Costa MR, Todd CA, Haynes BF, Montefiori DC: Utilization of immunoglobulin G Fc receptors by human immunodeficiency virus type 1: a specific role for antibodies against the membrane-proximal external region of gp41. J Virol 2009, 83:7397-7410; Piccoli L, Campo I, Fregni CS, Rodriguez BMF, Minola A, Sallusto F, Luisetti M, Corti D, Lanzavecchia A: Neutralization and clearance of GM-CSF by autoantibodies in pulmonary alveolar proteinosis.It can be evaluated by, for example, Nat Commun 2015, 6:1-9).

[0157] In some embodiments, the antibody or antigen-binding fragment thereof according to the present invention comprises an Fc region. As used herein, the term "Fc region" refers to the portion of an immunoglobulin formed by two or more Fc substructures of an antibody heavy chain. For example, the Fc region can be a monomeric or "single-chain" Fc region (i.e., scFc region). A single-chain Fc region is composed of Fc substructures linked within a single polypeptide chain (e.g., encoded by a single continuous nucleic acid sequence). An exemplary scFc region is disclosed in WO 2008 / 143954 A2. The Fc region may be a dimer. "Dimeric Fc region" or "dcFc" refers to a dimer formed by the Fc substructures of two separate immunoglobulin heavy chains. The dimeric Fc region may be a homodimer of two identical Fc substructures (e.g., the Fc region of a naturally occurring immunoglobulin) or a heterodimer of two non-identical Fc substructures.

[0158] In some embodiments, the Fc substructure or Fc region comprises, or consists of, an amino acid sequence derived from a human immunoglobulin sequence (e.g., an Fc region or Fc substructure derived from a human IgG molecule). However, the Fc substructure or Fc region may contain one or more amino acids from other mammalian species. For example, a primate Fc substructure or primate binding site may be included in the antibody or antigen-binding fragment. Alternatively, one or more mouse amino acids may be present in the Fc substructure or Fc region.

[0159] The Fc substructures of the Fc region may be of the same or different classes and / or subclasses. For example, the Fc substructure may be derived from an immunoglobulin of the IgG1, IgG2, IgG3 or IgG4 subclass (e.g., a human immunoglobulin).

[0160] Accordingly, the antibodies of the present invention can be of any isotype (e.g., IgA, IgG, IgM, i.e., α, γ, or μ heavy chains). Preferably, the antibodies can be of the IgA or IgG type. Among the IgG isotypes, the antibodies can be of the IgG1, IgG2, IgG3, or IgG4 subclass, preferably IgG1 or IgG4. Exemplary sequences of the IgG1 and IgG4 constant regions useful in the antibodies described herein are provided in SEQ ID NO: 59 (IgG1) and SEQ ID NO: 60 (IgG4). Accordingly, the antibodies of the present invention can include the amino acid sequences set forth in SEQ ID NO: 59 or 60, or sequence variants thereof described herein. The human IgG4 constant region sequence of SEQ ID NO: 60 contains the stabilizing hinge mutation S228P (S. Angal, D.J. King, M.W. Bodmer, A. Turner, A.D.G. Lawson, G. Roberts, B. Pedley, J.R. Adair, A single amino acid substitution abolishes the heterogeneity of chimeric mouse / human (IgG4) antibody, Molecular Immunology, Volume 30, Issue 1, 1993, Pages 105-108, ISSN 0161-5890, https: / / doi.org / 10.1016 / 0161-5890(93)90432-B). The antibodies of the present invention may have a κ or λ light chain. Exemplary sequences of the κ and λ light chain constant regions useful in the antibodies described herein are provided in SEQ ID NO: 61 (kappa) and SEQ ID NO: 62 (lambda). Accordingly, the antibodies of the present invention can include the amino acid sequences according to SEQ ID NO: 61 or 62, or sequence variants thereof described herein.

[0161] As described above, the present invention encompasses antigen-binding fragments. The antigen-binding fragments may or may not contain an Fc substructure, particularly a part of the complete Fc region. In some embodiments, the antibody or its antigen-binding fragment is selected from Fab, Fab’, F(ab’)2, Fv or scFv. For example, F(ab’)2 (which can be obtained by pepsin cleavage or recombinant expression) as well as Fab’ (which can be obtained from F(ab’)2 or by recombinant expression) usually contain a hinge region. For example, an exemplary CH1 sequence that can be used as the constant region of Fab is provided in SEQ ID NO: 63. Accordingly, the antibody or its antigen-binding fragment of the present invention may contain the amino acid sequence according to SEQ ID NO: 63, or sequence variants thereof described herein.

[0162] In some embodiments, the antibody, or antigen-binding fragment, can be a single-chain antibody (or fragment). The single-chain antibody (or fragment) may encode a complete set of six CDRs, i.e., may contain three heavy-chain CDRs and three light-chain CDRs. More specifically, a single-chain antibody (or fragment) can contain a heavy-chain variable region (VH) and a light-chain variable region (VL), and can contain, for example, the VH and VL sequences described above.

[0163] Variant antibodies are also included within the scope of the present invention. Accordingly, variants of the sequences described herein in the present application are also included within the scope of the present invention. Such variants include natural variants that arise by somatic mutations in vivo during an immune response or in vitro during culturing of immortalized B cell clones. Alternatively, variants can arise due to degeneracy of the genetic code or by errors in transcription or translation.

[0164] The antibody of the present invention, or an antigen-binding fragment thereof, can be provided in a purified form. Typically, the antibody, or antigen-binding fragment, will be present in a composition that is substantially free of other polypeptides, e.g., a composition in which less than 90% (by weight), usually less than 60%, more usually less than 50% of the composition is composed of other polypeptides.

[0165] The antibody of the present invention may be immunogenic in a non-human (or heterologous) host, such as a mouse. In particular, the antibody may have idiotopes that are immunogenic in a non-human host but not in a human host. In particular, the antibodies of the present invention for use in humans include those that cannot be easily isolated from hosts such as mice, goats, rabbits, rats, non-primate mammals, etc., and generally cannot be obtained from humanized or xenomice.

[0166] The antibodies of the present invention also include hybrid antibody molecules comprising six CDRs derived from the antibodies of the present invention as defined above and one or more CDRs derived from another antibody against the antigen. For example, the antibody may be multispecific. In other embodiments, the antibody, or an antigen-binding fragment thereof, may be monospecific.

[0167] [Multispecific antibody or antigen-binding fragment] Accordingly, the antibodies, or antigen-binding fragments thereof, described herein can be multispecific antibodies or multispecific antigen-binding fragments.

[0168] As used herein, the term "multispecific" refers to the ability to bind to at least two different epitopes, for example, on different antigens or on the same antigen. Conventional monospecific IgG antibodies typically have two identical epitope-binding sites (paratopes) and can therefore bind only to the same epitope (and not to different epitopes). In contrast, a multispecific antibody has at least two different types of paratopes (antigen-binding sites) and can therefore bind to at least two different epitopes. As used herein, "paratope" refers to the antigen-binding site (or epitope-binding site) of an antibody. Further, a single "specificity" can refer to one, two, three, or more identical paratopes in a single antibody (the actual number of paratopes in a single antibody molecule is referred to as the "valence"). For example, a single native IgG antibody has two identical paratopes and is thus monospecific and bivalent. Thus, a multispecific antibody contains at least two (different) paratopes. Therefore, the term "multispecific antibody" refers to an antibody that has more than one paratope and the ability to bind to two or more different epitopes. The term "multispecific antibody" includes, in particular, bispecific antibodies, but typically also includes proteins that bind to at least three different epitopes, such as antibody scaffolds, i.e., antibodies that have three or more different paratopes.

[0169] In particular, the multispecific antibody or multispecific antigen-binding fragment of the present invention may comprise two or more paratopes, where one or more of the paratopes may be identical, such that all of the paratopes of the antibody belong to at least two different types of paratopes, and thus the antibody has at least two specificities. For example, the multispecific antibody or antigen-binding fragment thereof according to the present invention may comprise four paratopes, in which case each two paratopes are identical (i.e., have the same specificity), and thus the antibody or its fragment is bispecific and tetravalent (two identical paratopes for each of the two specificities). Thus, "one specificity" refers in particular to one or more paratopes that exhibit the same specificity (which typically means that such one or more paratopes are identical), and thus "two specificities" can be achieved by two, three, four, five, six or more paratopes, as long as only two specificities are referred to. In some embodiments, the multispecific antibody comprises one single paratope for each (at least two) specificities, i.e., the multispecific antibody comprises in total at least two paratopes. For example, a bispecific antibody may comprise one single paratope for each of the two specificities, i.e., the antibody may comprise in total two paratopes. In other embodiments, the antibody comprises two (identical) paratopes for one or more specificities.

[0170] Preferably, the multispecific antibody or multispecific antigen-binding fragment is bispecific, trispecific or tetravalent. As used herein, terms such as "bispecific", "trispecific", "tetravalent" refer to the number of different epitopes to which an antibody can bind. For example, a "bispecific" antibody has exactly two different specificities (two different antigen-binding sites, where each of the two different antigen-binding sites may occur independently one or more times, e.g., twice). For example, a "trispecific" antibody has exactly three different specificities (three different antigen-binding sites, where each of the three different antigen-binding sites may occur independently one or more times, e.g., twice). For example, a "tetravalent" antibody has exactly four different specificities (four different antigen-binding sites, where each of the four different antigen-binding sites may occur independently one or more times, e.g., twice).

[0171] Such various multispecific antibody formats and methods for obtaining multispecific antibodies are known in the art. For example, building blocks for bispecific and trispecific antibodies are described in Xiufeng Wu, Stephen J. Demarest, Building blocks for bispecific and trispecific antibodies, Methods, Volume 154, 2019, Pages 3-9, ISSN 1046-2023, https: / / doi.org / 10.1016 / j.ymeth.2018.08.010 (incorporated herein by reference). Methods for obtaining multispecific antibodies and additional multispecific antibody formats are described in Amaral M, Holper S, Lange C, Jung J, Sjuts H, Weil S, Fischer M, Radoevic K, Rao E. Engineered Technologies and Bioanalysis of multispecific antibody formats. J Appl Bioanal 6(1), 26-51 (2020) (incorporated herein by reference).

[0172] In some embodiments, the multispecific antibody or multispecific antigen-binding fragment of the invention is a bispecific antibody or bispecific antigen-binding fragment. A bispecific antibody contains (exactly) two specificities. In the context of the present invention, a bispecific antibody can be in any format of bispecific antibody known in the art, as described, for example, in Spiess C., Zhai Q. and Carter P.J. (2015) Molecular Immunology 67: 95-106. For example, a bispecific antibody can be a whole antibody such as a whole IgG-like molecule, or a fragment thereof that is not a whole antibody but retains antibody properties. These can be in small recombinant formats, such as tandem single-chain variable fragment molecules (taFvs), diabodies (Dbs), single-chain diabodies (scDbs), and various other derivatives thereof (for example, as described in Byrne H. et al. (2013) Trends Biotech, 31 (11): 621-632. Figure 2 of the same reference shows various bispecific antibody formats). In some embodiments, the bispecific antibody can be an IgG(H)-scFv fusion as described in Coloma, M., Morrison, S. Design and production of novel tetravalent bispecific antibodies. Nat Biotechnol 15, 159-163 (1997). https: / / doi.org / 10.1038 / nbt0297-159. Preferred bispecific antibody formats are those as described in Example 6.

[0173] In some embodiments, the multispecific antibody, or multispecific antigen-binding fragment, according to the invention is a trispecific antibody or trispecific antigen-binding fragment. A trispecific antibody comprises (exactly) three specificities. A trispecific antibody in the context of the present invention can be any trispecific antibody format known in the art. In some embodiments, the trispecific antibody can be a heterodimer of IgG(H)-scFv having the same Fab domains, using "knob-into-hole" CH3 as described in Ridgway JB, Presta LG, Carter P. 'Knobs-into-holes' engineering of antibody CH3 domains for heavy chain heterodimerization. Protein Eng. 1996 Jul;9(7):617-21. doi: 10.1093 / protein / 9.7.617. A preferred trispecific antibody format is the trispecific format as described in Example 6.

[0174] In some embodiments, the multispecific antibody, or multispecific antigen-binding fragment, according to the invention is a tetravalent antibody or tetravalent antigen-binding fragment. A tetravalent antibody comprises (exactly) four specificities. A tetravalent antibody in the context of the present invention may be in any tetravalent antibody format known in the art. In some embodiments, the tetravalent antibody is an IgG(H)-scFv and scFv-Fc-scFv heterodimer using the "knob-into-hole" CH3 as described for tetravalent antibodies in Ridgway JB, Presta LG, Carter P. 'Knobs-into-holes' engineering of antibody CH3 domains for heavy chain heterodimerization. Protein Eng. 1996 Jul;9(7):617-21. doi: 10.1093 / protein / 9.7.617 In other embodiments, the tetravalent antibody may be an IgG4 heavy chain heterodimer. A preferred format for the tetravalent antibody is as described in Example 6.

[0175] Typically, a multispecific antibody or multispecific antigen-binding fragment is at least bivalent. That is, it has at least two paratopes. Preferably, the multispecific antibody or multispecific antigen-binding fragment is bivalent, trivalent, tetravalent or hexavalent. More preferably, the multispecific antibody or multispecific antigen-binding fragment is tetravalent. Even more preferably, the multispecific antibody or multispecific antigen-binding fragment is tetravalent and bispecific, trispecific or tetravalent.

[0176] Preferably, the multispecific antibody or multispecific antigen-binding fragment binds (specifically) to distinct, non-overlapping epitopes of Ara h 2. Thus, the antigen-binding sites (paratopes) of the multispecific antibody, or multispecific antigen-binding fragment, preferably target the same antigen, i.e., different, non-overlapping epitopes on Ara h 2. For this purpose, the antigen-binding sites (paratopes) of the multispecific antibody, or multispecific antigen-binding fragment, can be selected from the four different antibodies 17H9, 15E3, 2F8, and 7G6, or variants thereof, described above. As shown in the appended examples, 17H9, 15E3, 2F8, and 7G6 bind to distinct, non-overlapping epitopes of Ara h 2. Methods for obtaining multispecific antibodies using, for example, the binding sites of the above-described monospecific antibodies are known to those skilled in the art.

[0177] Thus, the multispecific antibody or multispecific antigen-binding fragment can comprise at least two of the following: (i) an antigen-binding site comprising (a) the CDRH1, CDRH2, CDRH3, CDRL1, CDRL2, and CDRL3 sequences and / or (b) the VH and VL sequences of 17H9, or sequence variants thereof as described above; (ii) an antigen-binding site comprising (a) the CDRH1, CDRH2, CDRH3, CDRL1, CDRL2, and CDRL3 sequences and / or (b) the VH and VL sequences of 15E3, or sequence variants thereof as described above; (iii) an antigen-binding site comprising (a) the CDRH1, CDRH2, CDRH3, CDRL1, CDRL2, and CDRL3 sequences and / or (b) the VH and VL sequences of 2F8, and / or, (iv) an antigen-binding site comprising (a) the CDRH1, CDRH2, CDRH3, CDRL1, CDRL2, and CDRL3 sequences and / or (b) the VH and VL sequences of 7G6, or sequence variants thereof as described above.

[0178] In some embodiments, the multispecific antibody, or multispecific antigen-binding fragment, may comprise: (i) an antigen-binding site comprising the (a) CDRH1, CDRH2, CDRH3, CDRL1, CDRL2, and CDRL3 sequences and / or (b) VH and VL sequences of 17H9, or sequence variants thereof as described above; and (ii) an antigen-binding site comprising the (a) CDRH1, CDRH2, CDRH3, CDRL1, CDRL2, and CDRL3 sequences and / or (b) VH and VL sequences of (wild-type) 2F8, or sequence variants thereof as described, for example, in Tables 1 and 2 herein. Optionally, such an antibody may further comprise an antigen-binding site comprising the CDR and / or VH / VL sequences of 15E3 (or a sequence variant thereof), and / or an antigen-binding site comprising the CDR and / or VH / VL sequences of 7G6 (or a sequence variant thereof).

[0179] In some embodiments, the multispecific antibody, or multispecific antigen-binding fragment, may comprise: (i) an antigen-binding site comprising the (a) CDRH1, CDRH2, CDRH3, CDRL1, CDRL2, and CDRL3 sequences and / or (b) VH and VL sequences of 15E3, or sequence variants thereof as described above; and (ii) an antigen-binding site comprising the (a) CDRH1, CDRH2, CDRH3, CDRL1, CDRL2, and CDRL3 sequences and / or (b) VH and VL sequences of (wild-type) 7G6, or sequence variants thereof as described, for example, in Tables 1 and 2 herein. Optionally, such an antibody may further comprise an antigen-binding site comprising the CDR and / or VH / VL sequences of 17H9 (or a sequence variant thereof), and / or an antigen-binding site comprising the CDR and / or VH / VL sequences of 2F8 (or a sequence variant thereof).

[0180] In some embodiments, the multispecific antibody, or multispecific antigen-binding fragment, may comprise (i) an antigen-binding site comprising (a) the CDRH1, CDRH2, CDRH3, CDRL1, CDRL2, and CDRL3 sequences and / or (b) the VH and VL sequences of 17H9, or sequence variants thereof as described above; and (ii) an antigen-binding site comprising (a) the CDRH1, CDRH2, CDRH3, CDRL1, CDRL2, and CDRL3 sequences and / or (b) the VH and VL sequences of 15E3, or sequence variants thereof as described, for example, in Tables 1 and 2 herein. Optionally, such an antibody may further comprise an antigen-binding site comprising the CDRs and / or VH / VL sequences (or sequence variants thereof) of 2F8, and / or an antigen-binding site comprising the CDRs and / or VH / VL sequences (or sequence variants thereof) of 7G6.

[0181] Preferably, the multispecific antibody, or multispecific antigen-binding fragment, may comprise (i) an antigen-binding site comprising (a) the CDRH1, CDRH2, CDRH3, CDRL1, CDRL2, and CDRL3 sequences and / or (b) the VH and VL sequences of 15E3, or sequence variants thereof as described above; and (ii) an antigen-binding site comprising (a) the CDRH1, CDRH2, CDRH3, CDRL1, CDRL2, and CDRL3 sequences and / or (b) the VH and VL sequences of (wild-type) 2F8, or sequence variants thereof as described, for example, in Tables 1 and 2 herein. Optionally, such an antibody may further comprise an antigen-binding site comprising the CDRs and / or VH / VL sequences (or sequence variants thereof) of 17H9, and / or an antigen-binding site comprising the CDRs and / or VH / VL sequences (or sequence variants thereof) of 7G6.

[0182] More preferably, the multispecific antibody or multispecific antigen-binding fragment comprises: (i) an antigen-binding site comprising the (a) CDRH1, CDRH2, CDRH3, CDRL1, CDRL2, and CDRL3 sequences and / or (b) VH and VL sequences of 17H9, or sequence variants thereof as described above; and (ii) an antigen-binding site comprising the (a) CDRH1, CDRH2, CDRH3, CDRL1, CDRL2, and CDRL3 sequences and / or (b) VH and VL sequences of (wild-type) 7G6, or sequence variants thereof described, for example, in Tables 1 and 2 herein. Optionally, such an antibody may further comprise an antigen-binding site comprising the CDRs and / or VH / VL sequences of 15E3 (or a sequence variant thereof), and / or an antigen-binding site comprising the CDRs and / or VH / VL sequences of 2F8 (or a sequence variant thereof).

[0183] In some embodiments, the multispecific antibody or multispecific antigen-binding fragment may be a bispecific antibody or bispecific antigen-binding fragment comprising: (i) an antigen-binding site comprising the (a) CDRH1, CDRH2, CDRH3, CDRL1, CDRL2, and CDRL3 sequences and / or (b) VH and VL sequences of 17H9, or sequence variants thereof as described above; and (ii) an antigen-binding site comprising the (a) CDRH1, CDRH2, CDRH3, CDRL1, CDRL2, and CDRL3 sequences and / or (b) VH and VL sequences of 15E3, or sequence variants thereof as described above.

[0184] In some embodiments, the multispecific antibody or multispecific antigen-binding fragment may be a bispecific antibody or bispecific antigen-binding fragment comprising: (i) an antigen-binding site comprising the (a) CDRH1, CDRH2, CDRH3, CDRL1, CDRL2, and CDRL3 sequences and / or (b) VH and VL sequences of 17H9, or sequence variants thereof as described above; and (iii) an antigen-binding site of 2F8 comprising (a) CDRH1, CDRH2, CDRH3, CDRL1, CDRL2 and CDRL3 sequences and / or (b) VH and VL sequences, or sequence variants thereof as described above.

[0185] In some embodiments, the multispecific antibody or multispecific antigen-binding fragment may be a bispecific antibody or bispecific antigen-binding fragment comprising: (ii) an antigen-binding site of 15E3 comprising (a) CDRH1, CDRH2, CDRH3, CDRL1, CDRL2 and CDRL3 sequences and / or (b) VH and VL sequences, or sequence variants thereof as described above; and, (iv) an antigen-binding site of 7G6 comprising (a) CDRH1, CDRH2, CDRH3, CDRL1, CDRL2 and CDRL3 sequences and / or (b) VH and VL sequences, or sequence variants thereof as described above.

[0186] In some embodiments, the multispecific antibody or multispecific antigen-binding fragment may be a bispecific antibody or bispecific antigen-binding fragment comprising: (iii) an antigen-binding site of 2F8 comprising (a) CDRH1, CDRH2, CDRH3, CDRL1, CDRL2 and CDRL3 sequences and / or (b) VH and VL sequences, or sequence variants thereof as described above; and, (iv) an antigen-binding site of 7G6 comprising (a) CDRH1, CDRH2, CDRH3, CDRL1, CDRL2 and CDRL3 sequences and / or (b) VH and VL sequences, or sequence variants thereof as described above.

[0187] Preferably, the multispecific antibody or multispecific antigen-binding fragment may be a bispecific antibody or bispecific antigen-binding fragment comprising: (ii) an antigen-binding site comprising (a) the CDRH1, CDRH2, CDRH3, CDRL1, CDRL2, and CDRL3 sequences and / or (b) the VH and VL sequences of 15E3, or sequence variants thereof as described above; and, (iii) an antigen-binding site comprising (a) the CDRH1, CDRH2, CDRH3, CDRL1, CDRL2, and CDRL3 sequences and / or (b) the VH and VL sequences of 2F8, or sequence variants thereof as described above.

[0188] More preferably, the multispecific antibody or multispecific antigen-binding fragment may be a bispecific antibody or bispecific antigen-binding fragment comprising: (i) an antigen-binding site comprising (a) the CDRH1, CDRH2, CDRH3, CDRL1, CDRL2, and CDRL3 sequences and / or (b) the VH and VL sequences of 17H9, or sequence variants thereof as described above; and, (iv) an antigen-binding site comprising (a) the CDRH1, CDRH2, CDRH3, CDRL1, CDRL2, and CDRL3 sequences and / or (b) the VH and VL sequences of 7G6, or sequence variants thereof as described above.

[0189] In some embodiments, the multispecific antibody or multispecific antigen-binding fragment may be a trispecific antibody or trispecific antigen-binding fragment comprising: (i) an antigen-binding site comprising (a) the CDRH1, CDRH2, CDRH3, CDRL1, CDRL2, and CDRL3 sequences and / or (b) the VH and VL sequences of 17H9, or sequence variants thereof as described above; (ii) an antigen-binding site comprising (a) the CDRH1, CDRH2, CDRH3, CDRL1, CDRL2, and CDRL3 sequences and / or (b) the VH and VL sequences of 15E3, or sequence variants thereof as described above; and, (iii) The antigen-binding site of 2F8 comprising (a) the CDRH1, CDRH2, CDRH3, CDRL1, CDRL2 and CDRL3 sequences and / or (b) the VH and VL sequences, or sequence variants thereof as described above.

[0190] In some embodiments, the multispecific antibody or multispecific antigen-binding fragment may be a trispecific antibody or trispecific antigen-binding fragment comprising: (ii) The antigen-binding site of 15E3 comprising (a) the CDRH1, CDRH2, CDRH3, CDRL1, CDRL2 and CDRL3 sequences and / or (b) the VH and VL sequences, or sequence variants thereof as described above; (iii) The antigen-binding site of 2F8 comprising (a) the CDRH1, CDRH2, CDRH3, CDRL1, CDRL2 and CDRL3 sequences and / or (b) the VH and VL sequences, or sequence variants thereof as described above; and (iv) The antigen-binding site of 7G6 comprising (a) the CDRH1, CDRH2, CDRH3, CDRL1, CDRL2 and CDRL3 sequences and / or (b) the VH and VL sequences, or sequence variants thereof as described above.

[0191] In some embodiments, the multispecific antibody or multispecific antigen-binding fragment may be a trispecific antibody or trispecific antigen-binding fragment comprising: (i) The antigen-binding site of 17H9 comprising (a) the CDRH1, CDRH2, CDRH3, CDRL1, CDRL2 and CDRL3 sequences and / or (b) the VH and VL sequences, or sequence variants thereof as described above; (ii) The antigen-binding site of 2F8 comprising (a) the CDRH1, CDRH2, CDRH3, CDRL1, CDRL2 and CDRL3 sequences and / or (b) the VH and VL sequences, or sequence variants thereof as described above; and (iv) An antigen-binding site comprising (a) the CDRH1, CDRH2, CDRH3, CDRL1, CDRL2, and CDRL3 sequences and / or (b) the VH and VL sequences of 7G6, or sequence variants thereof as described above.

[0192] Preferably, the multispecific antibody or multispecific antigen-binding fragment may be a trispecific antibody or trispecific antigen-binding fragment comprising: (i) An antigen-binding site comprising (a) the CDRH1, CDRH2, CDRH3, CDRL1, CDRL2, and CDRL3 sequences and / or (b) the VH and VL sequences of 17H9, or sequence variants thereof as described above; (ii) An antigen-binding site comprising (a) the CDRH1, CDRH2, CDRH3, CDRL1, CDRL2, and CDRL3 sequences and / or (b) the VH and VL sequences of 15E3, or sequence variants thereof as described above; and (iv) An antigen-binding site comprising (a) the CDRH1, CDRH2, CDRH3, CDRL1, CDRL2, and CDRL3 sequences and / or (b) the VH and VL sequences of 7G6, or sequence variants thereof as described above.

[0193] The multispecific antibody or multispecific antigen-binding fragment is preferably a quadrispecific antibody or quadrispecific antigen-binding fragment comprising: (i) An antigen-binding site comprising (a) the CDRH1, CDRH2, CDRH3, CDRL1, CDRL2, and CDRL3 sequences and / or (b) the VH and VL sequences of 17H9, or sequence variants thereof as described above; (ii) An antigen-binding site comprising (a) the CDRH1, CDRH2, CDRH3, CDRL1, CDRL2, and CDRL3 sequences and / or (b) the VH and VL sequences of 15E3, or sequence variants thereof as described above; (iii) An antigen-binding site comprising (a) the CDRH1, CDRH2, CDRH3, CDRL1, CDRL2, and CDRL3 sequences and / or (b) the VH and VL sequences of 2F8, or sequence variants thereof as described above; and, (iv) An antigen-binding site comprising (a) the CDRH1, CDRH2, CDRH3, CDRL1, CDRL2, and CDRL3 sequences and / or (b) the VH and VL sequences of 7G6, or sequence variants thereof as described above.

[0194] The present invention also provides a multispecific antibody, or a multispecific antigen-binding fragment, that binds to distinct non-overlapping epitopes of Ara h 2. Here, the antibody, or the antigen-binding fragment, comprises at least two of the following: (i) An antigen-binding site comprising a CDRH1 having at least 70% identity with SEQ ID NO: 1, a CDRH2 having at least 70% identity with SEQ ID NO: 2, a CDRH3 having at least 70% identity with SEQ ID NO: 3, a CDRL1 having at least 70% identity with SEQ ID NO: 4, a CDRL2 having at least 70% identity with SEQ ID NO: 5, and a CDRL3 having at least 70% identity with SEQ ID NO: 6; (ii) An antigen-binding site comprising a CDRH1 having at least 70% identity with SEQ ID NO: 9, a CDRH2 having at least 70% identity with SEQ ID NO: 10, a CDRH3 having at least 70% identity with SEQ ID NO: 11, a CDRL1 having at least 70% identity with SEQ ID NO: 12, a CDRL2 having at least 70% identity with SEQ ID NO: 13, and a CDRL3 having at least 70% identity with SEQ ID NO: 14; (iii) An antigen-binding site comprising a CDRH1 having at least 70% identity with SEQ ID NO: 17, a CDRH2 having at least 70% identity with SEQ ID NO: 18, a CDRH3 having at least 70% identity with SEQ ID NO: 19 or 51, a CDRL1 having at least 70% identity with SEQ ID NO: 20, a CDRL2 having at least 70% identity with SEQ ID NO: 21, and a CDRL3 having at least 70% identity with SEQ ID NO: 22; and / or, (iv) An antigen-binding site comprising CDRH1 having at least 70% identity with SEQ ID NO: 25, CDRH2 having at least 70% identity with SEQ ID NO: 26, CDRH3 having at least 70% identity with SEQ ID NO: 27, CDRL1 having at least 70% identity with SEQ ID NO: 28, CDRL2 having at least 70% identity with SEQ ID NO: 29 or 52, and CDRL3 having at least 70% identity with SEQ ID NO: 30.

[0195] Preferably, the multispecific antibody or multispecific antigen-binding fragment comprises at least two of the following: (i) An antigen-binding site comprising CDRH1 set forth in SEQ ID NO: 1, CDRH2 set forth in SEQ ID NO: 2, CDRH3 set forth in SEQ ID NO: 3, CDRL1 set forth in SEQ ID NO: 4, CDRL2 set forth in SEQ ID NO: 5, and CDRL3 set forth in SEQ ID NO: 6; (ii) An antigen-binding site comprising CDRH1 set forth in SEQ ID NO: 9, CDRH2 set forth in SEQ ID NO: 10, CDRH3 set forth in SEQ ID NO: 11, CDRL1 set forth in SEQ ID NO: 12, CDRL2 set forth in SEQ ID NO: 13, and CDRL3 set forth in SEQ ID NO: 14; (iii) An antigen-binding site comprising CDRH1 set forth in SEQ ID NO: 17, CDRH2 set forth in SEQ ID NO: 18, CDRH3 set forth in SEQ ID NO: 19 or 51, CDRL1 set forth in SEQ ID NO: 20, CDRL2 set forth in SEQ ID NO: 21, and CDRL3 set forth in SEQ ID NO: 22; and / or, (iv) An antigen-binding site comprising CDRH1 set forth in SEQ ID NO: 25, CDRH2 set forth in SEQ ID NO: 26, CDRH3 of SEQ ID NO: 27, CDRL1 set forth in SEQ ID NO: 28, CDRL2 set forth in SEQ ID NO: 29 or 52, and CDRL3 of SEQ ID NO: 30.

[0196] More preferably, the multispecific antibody or multispecific antigen-binding fragment comprises at least two of the following: (i) An antibody binding site comprising a VH having at least 70% identity to any one of SEQ ID NOs: 7, 44, and 45, and a VL having at least 70% identity to any one of SEQ ID NOs: 8, 46, 47, 48, and 49; wherein the CDRH1 set forth in SEQ ID NO: 1, the CDRH2 set forth in SEQ ID NO: 2, the CDRH3 set forth in SEQ ID NO: 3, the CDRL1 set forth in SEQ ID NO: 4, the CDRL2 set forth in SEQ ID NO: 5, and the CDRL3 set forth in SEQ ID NO: 6 are preferably maintained; (ii) An antibody binding site comprising a VH having at least 70% identity to any one of SEQ ID NOs: 15, 37, and 38; and a VL having at least 70% identity to any one of SEQ ID NOs: 16, 39, and 40; wherein the CDRH1 set forth in SEQ ID NO: 9, the CDRH2 set forth in SEQ ID NO: 10, the CDRH3 set forth in SEQ ID NO: 11, the CDRL1 set forth in SEQ ID NO: 12, the CDRL2 set forth in SEQ ID NO: 13, and the CDRL3 set forth in SEQ ID NO: 14 are preferably maintained; (iii) An antigen-binding site comprising a VH having at least 70% identity to any one of SEQ ID NOs: 23, 41, 50, and 53; and a VL having at least 70% identity to any one of SEQ ID NOs: 24, 42, and 43; wherein the CDRH1 set forth in SEQ ID NO: 17, the CDRH2 set forth in SEQ ID NO: 18, the CDRH3 set forth in SEQ ID NO: 19 or 51, the CDRL1 set forth in SEQ ID NO: 20, the CDRL2 set forth in SEQ ID NO: 21, and the CDRL3 set forth in SEQ ID NO: 22 are preferably maintained; and / or, (iv) An antigen-binding site comprising a VH having at least 70% identity to any one of SEQ ID NOs: 31, 33, and 34; and a VL having at least 70% identity to any one of SEQ ID NOs: 32, 35, 36, and 54; wherein the CDRH1 set forth in SEQ ID NO: 25, the CDRH2 set forth in SEQ ID NO: 26, the CDRH3 set forth in SEQ ID NO: 27, the CDRL1 set forth in SEQ ID NO: 28, the CDRL2 set forth in SEQ ID NO: 29 or 52, and the CDRL3 set forth in SEQ ID NO: 30 are preferably maintained.

[0197] More preferably, the multispecific antibody or multispecific antigen-binding fragment comprises at least two of the following: (i) an antigen-binding site comprising a VH as set forth in any one of SEQ ID NOs: 7, 44 and 45; and a VL as set forth in any one of SEQ ID NOs: 8, 46, 47, 48 and 49; (ii) an antigen-binding site comprising a VH as set forth in any one of SEQ ID NOs: 15, 37 and 38; and a VL as set forth in any one of SEQ ID NOs: 16, 39 and 40; (iii) an antigen-binding site comprising a VH as set forth in any one of SEQ ID NOs: 23, 41, 50 and 53; and a VL as set forth in any one of SEQ ID NOs: 24, 42 and 43; and / or, (iv) an antigen-binding site comprising a VH as set forth in any one of SEQ ID NOs: 31, 33 and 34; and a VL as set forth in any one of SEQ ID NOs: 32, 35, 36 and 54.

[0198] In some embodiments, the multispecific antibody or multispecific antigen-binding fragment may be a bispecific antibody or bispecific antigen-binding fragment comprising: (i) an antigen-binding site comprising: an antigen-binding site comprising CDRH1 having at least 70% identity with SEQ ID NO: 1, CDRH2 having at least 70% identity with SEQ ID NO: 2, CDRH3 having at least 70% identity with SEQ ID NO: 3, CDRL1 having at least 70% identity with SEQ ID NO: 4, CDRL2 having at least 70% identity with SEQ ID NO: 5, and CDRL3 having at least 70% identity with SEQ ID NO: 6; In particular, CDRH1 as set forth in SEQ ID NO: 1, CDRH2 as set forth in SEQ ID NO: 2, CDRH3 as set forth in SEQ ID NO: 3, CDRL1 as set forth in SEQ ID NO: 4, CDRL2 as set forth in SEQ ID NO: 5, and CDRL3 as set forth in SEQ ID NO: 6; In some embodiments, a VH having at least 70% identity with any one of SEQ ID NO: 7, 44, and 45; and a VL having at least 70% identity with any one of SEQ ID NO: 8, 46, 47, 48, and 49; wherein the CDRH1 set forth in SEQ ID NO: 1, the CDRH2 set forth in SEQ ID NO: 2, the CDRH3 set forth in SEQ ID NO: 3, the CDRL1 set forth in SEQ ID NO: 4, the CDRL2 set forth in SEQ ID NO: 5, and the CDRL3 set forth in SEQ ID NO: 6 are preferably maintained; For example, a VH set forth in any one of SEQ ID NO: 7, 44, and 45; and a VL set forth in any one of SEQ ID NO: 8, 46, 47, 48, and 49; and, (ii) an antigen-binding site comprising the following A CDRH1 having at least 70% identity with SEQ ID NO: 9, a CDRH2 having at least 70% identity with SEQ ID NO: 10, a CDRH3 having at least 70% identity with SEQ ID NO: 11, a CDRL1 having at least 70% identity with SEQ ID NO: 12, a CDRL2 having at least 70% identity with SEQ ID NO: 13, and a CDRL3 having at least 70% identity with SEQ ID NO: 14; In particular, the CDRH1 set forth in SEQ ID NO: 9, the CDRH2 set forth in SEQ ID NO: 10, the CDRH3 set forth in SEQ ID NO: 11, the CDRL1 set forth in SEQ ID NO: 12, the CDRL2 set forth in SEQ ID NO: 13, and the CDRL3 set forth in SEQ ID NO: 14; In some embodiments, a VH having at least 70% identity with any one of SEQ ID NO: 15, 37, and 38; and a VL having at least 70% identity with any one of SEQ ID NO: 16, 39, and 40; wherein the CDRH1 according to SEQ ID NO: 9, CDRH2 according to SEQ ID NO: 9, 10, the CDRH3 set forth in SEQ ID NO: 11, the CDRL1 set forth in SEQ ID NO: 12, the CDRL2 set forth in SEQ ID NO: 13, and the CDRL3 set forth in SEQ ID NO: 14 are preferably maintained; For example, a VH set forth in any one of SEQ ID NO: 15, 37, and 38; and a VL set forth in any one of SEQ ID NO: 16, 39, and 40.

[0199] In some embodiments, the multispecific antibody or multispecific antigen-binding fragment may be a bispecific antibody or bispecific antigen-binding fragment comprising: (i) an antigen-binding site comprising: CDRH1 having at least 70% identity with SEQ ID NO: 1, CDRH2 having at least 70% identity with SEQ ID NO: 2, CDRH3 having at least 70% identity with SEQ ID NO: 3, CDRL1 having at least 70% identity with SEQ ID NO: 4, CDRL2 having at least 70% identity with SEQ ID NO: 5, and CDRL3 having at least 70% identity with SEQ ID NO: 6; In particular, CDRH1 as set forth in SEQ ID NO: 1, CDRH2 as set forth in SEQ ID NO: 2, CDRH3 as set forth in SEQ ID NO: 3, CDRL1 as set forth in SEQ ID NO: 4, CDRL2 as set forth in SEQ ID NO: 5, and CDRL3 as set forth in SEQ ID NO: 6; In some embodiments, VH having at least 70% identity with any one of SEQ ID NOs: 7, 44 and 45; and VL having at least 70% identity with any one of SEQ ID NOs: 8, 46, 47, 48 and 49; wherein CDRH1, CDRH2 as set forth in SEQ ID NO: 2, CDRH3 as set forth in SEQ ID NO: 3, CDRL1 as set forth in SEQ ID NO: 4, CDRL2 as set forth in SEQ ID NO: 5, and CDRL3 as set forth in SEQ ID NO: 6 are preferably maintained; VH as set forth in any one of SEQ ID NOs: 7, 44 and 45; and VL as set forth in any one of SEQ ID NOs: 8, 46, 47, 48 and 49; and, (iii) an antigen-binding site comprising: CDRH1 having at least 70% identity with SEQ ID NO: 17, CDRH2 having at least 70% identity with SEQ ID NO: 18, CDRH3 having at least 70% identity with SEQ ID NO: 19 or 51, CDRL1 having at least 70% identity with SEQ ID NO: 20, CDRL2 having at least 70% identity with SEQ ID NO: 21, and CDRL3 having at least 70% identity with SEQ ID NO: 22; Particularly, CDRH1 set forth in SEQ ID NO: 17, CDRH2 set forth in SEQ ID NO: 18, CDRH3 set forth in SEQ ID NO: 19 or 51, CDRL1 set forth in SEQ ID NO: 20, CDRL2 set forth in SEQ ID NO: 21, and CDRL3 set forth in SEQ ID NO: 22; In some embodiments, a VH having at least 70% identity to any one of SEQ ID NOs: 23, 41, 50, and 53; and a VL having at least 70% identity to any one of SEQ ID NOs: 24, 42, and 43; wherein CDRH1 set forth in SEQ ID NO: 17, CDRH2 set forth in SEQ ID NO: 18, CDRH3 set forth in SEQ ID NO: 19 or 51, CDRL1 set forth in SEQ ID NO: 20, CDRL2 set forth in SEQ ID NO: 21, and CDRL3 set forth in SEQ ID NO: 22 are preferably maintained; For example, a VH set forth in any one of SEQ ID NO. 23, 41, 50, and 53; and a VL set forth in any one of SEQ ID NOs: 24, 42, and 43.

[0200] In some embodiments, the multispecific antibody or multispecific antigen-binding fragment may be a bispecific antibody or bispecific antigen-binding fragment comprising: (ii) an antigen-binding site comprising: CDRH1 having at least 70% identity to SEQ ID NO: 9, CDRH2 having at least 70% identity to SEQ ID NO: 10, CDRH3 having at least 70% identity to SEQ ID NO: 11, CDRL1 having at least 70% identity to SEQ ID NO: 12, CDRL2 having at least 70% identity to SEQ ID NO: 13, and CDRL3 having at least 70% identity to SEQ ID NO: 14; Particularly, CDRH1 set forth in SEQ ID NO: 9, CDRH2 set forth in SEQ ID NO: 10, CDRH3 set forth in SEQ ID NO: 11, CDRL1 set forth in SEQ ID NO: 12, CDRL2 set forth in SEQ ID NO: 13, and CDRL3 set forth in SEQ ID NO: 14; In some embodiments, a VH having at least 70% identity to any one of SEQ ID NOs: 15, 37, and 38; and a VL having at least 70% identity to any one of SEQ ID NOs: 16, 39, and 40; wherein the CDRH1 set forth in SEQ ID NO: 9, the CDRH2 set forth in SEQ ID NOs: 9 and 10, the CDRH3 set forth in SEQ ID NO: 11, the CDRL1 set forth in SEQ ID NO: 12, the CDRL2 set forth in SEQ ID NO: 13, and the CDRL3 set forth in SEQ ID NO: 14 are preferably maintained; A VH as set forth in any one of SEQ ID NOs: 15, 37, and 38; and a VL as set forth in any one of SEQ ID NOs: 16, 39, and 40; and, (iv) an antigen-binding site comprising: A CDRH1 having at least 70% identity to SEQ ID NO: 25, a CDRH2 having at least 70% identity to SEQ ID NO: 26, a CDRH3 having at least 70% identity to SEQ ID NO: 27, a CDRL1 having at least 70% identity to SEQ ID NO: 28, a CDRL2 having at least 70% identity to SEQ ID NO: 29 or 52, and a CDRL3 having at least 70% identity to SEQ ID NO: 30; In particular, a CDRH1 as set forth in SEQ ID NO: 25, a CDRH2 as set forth in SEQ ID NO: 26, a CDRH3 as set forth in SEQ ID NO: 27, a CDRL1 as set forth in SEQ ID NO: 28, a CDRL2 as set forth in SEQ ID NO: 29 or 52, and a CDRL3 as set forth in SEQ ID NO: 30; In some embodiments, a VH having at least 70% identity to any one of SEQ ID NOs: 31, 33, and 34; and a VL having at least 70% identity to any one of SEQ ID NOs: 32, 35, 36, and 54; wherein the CDRH1 set forth in SEQ ID NO: 25, the CDRH2 set forth in SEQ ID NO: 26, the CDRH3 set forth in SEQ ID NO: 27, the CDRL1 set forth in SEQ ID NO: 28, the CDRL2 set forth in SEQ ID NO: 29 or 52, and the CDRL3 set forth in SEQ ID NO: 30 are preferably maintained; For example, a VH as set forth in any one of SEQ ID NOs: 31, 33, and 34; and a VL as set forth in any one of SEQ ID NOs: 32, 35, 36, and 54.

[0201] In some embodiments, the multispecific antibody or multispecific antigen-binding fragment may be a bispecific antibody or bispecific antigen-binding fragment comprising: (iii) an antigen-binding site comprising: CDRH1 having at least 70% identity with SEQ ID NO: 17, CDRH2 having at least 70% identity with SEQ ID NO: 18, CDRH3 having at least 70% identity with SEQ ID NO: 19 or 51, CDRL1 having at least 70% identity with SEQ ID NO: 20, CDRL2 having at least 70% identity with SEQ ID NO: 21, and CDRL3 having at least 70% identity with SEQ ID NO: 22; In particular, CDRH1 as set forth in SEQ ID NO: 17, CDRH2 as set forth in SEQ ID NO: 18, CDRH3 as set forth in SEQ ID NO: 19 or 51, CDRL1 as set forth in SEQ ID NO: 20, CDRL2 as set forth in SEQ ID NO: 21, and CDRL3 as set forth in SEQ ID NO: 22; In some embodiments, VH having at least 70% identity with any one of SEQ ID NOs: 23, 41, 50, and 53; and VL having at least 70% identity with any one of SEQ ID NOs: 24, 42, and 43; wherein CDRH1 as set forth in SEQ ID NO: 17, CDRH2 as set forth in SEQ ID NO: 18, CDRH3 as set forth in SEQ ID NO: 19 or 51, CDRL1 as set forth in SEQ ID NO: 20, CDRL2 as set forth in SEQ ID NO: 20, and CDRL3 as set forth in SEQ ID NO: 22 are preferably maintained; VH as set forth in any one of SEQ ID NOs: 23, 41, 50, and 53; and VL as set forth in any one of SEQ ID NOs: 24, 42, and 43; and, (iv) an antigen-binding site comprising: CDRH1 having at least 70% identity with SEQ ID NO: 25, CDRH2 having at least 70% identity with SEQ ID NO: 26, CDRH3 having at least 70% identity with SEQ ID NO: 27, CDRL1 having at least 70% identity with SEQ ID NO: 28, CDRL2 having at least 70% identity with SEQ ID NO: 29 or 52, and CDRL3 having at least 70% identity with SEQ ID NO: 30; In particular, CDRH1 set forth in SEQ ID NO: 25, CDRH2 set forth in SEQ ID NO: 26, CDRH3 set forth in SEQ ID NO: 27, CDRL1 set forth in SEQ ID NO: 28, CDRL2 set forth in SEQ ID NO: 29 or 52, and CDRL3 set forth in SEQ ID NO: 30; In some embodiments, a VH having at least 70% identity to any one of SEQ ID NOs: 31, 33, and 34; and a VL having at least 70% identity to any one of SEQ ID NOs: 32, 35, 36, and 54; wherein the CDRH1 set forth in SEQ ID NO: 25, the CDRH2 set forth in SEQ ID NO: 26, the CDRH3 set forth in SEQ ID NO: 27, the CDRL1 set forth in SEQ ID NO: 28, the CDRL2 set forth in SEQ ID NO: 29 or 52, and the CDRL3 set forth in SEQ ID NO: 30 are preferably maintained; For example, a VH set forth in any one of SEQ ID NOs: 31, 33, and 34; and a VL set forth in any one of SEQ ID NOs: 32, 35, 36, and 54.

[0202] Preferably, the multispecific antibody or multispecific antigen-binding fragment is a bispecific antibody or bispecific antigen-binding fragment comprising: (ii) an antigen-binding site comprising: a CDRH1 having at least 70% identity to SEQ ID NO: 9, a CDRH2 having at least 70% identity to SEQ ID NO: 10, a CDRH3 having at least 70% identity to SEQ ID NO: 11, a CDRL1 having at least 70% identity to SEQ ID NO: 12, a CDRL2 having at least 70% identity to SEQ ID NO: 13, and a CDRL3 having at least 70% identity to SEQ ID NO: 14; In particular, CDRH1 set forth in SEQ ID NO: 9, CDRH2 set forth in SEQ ID NO: 10, CDRH3 set forth in SEQ ID NO: 11, CDRL1 set forth in SEQ ID NO: 12, CDRL2 set forth in SEQ ID NO: 13, and CDRL3 set forth in SEQ ID NO: 14; In some embodiments, a VH having at least 70% identity with any one of SEQ ID NO: 15, 37, and 38; and a VL having at least 70% identity with any one of SEQ ID NO: 16, 39, and 40; wherein the CDRH1 set forth in SEQ ID NO: 9, the CDRH2 set forth in SEQ ID NO: 9 and SEQ ID NO: 10, the CDRH3 set forth in SEQ ID NO: 11, the CDRL1 set forth in SEQ ID NO: 12, the CDRL2 set forth in SEQ ID NO: 13, and the CDRL3 set forth in SEQ ID NO: 14 are preferably maintained; A VH set forth in any one of SEQ ID NO: 15, 37, and 38; and a VL set forth in any one of SEQ ID NO: 16, 39, and 40; and, (iii) an antigen-binding site comprising: A CDRH1 having at least 70% identity with SEQ ID NO: 17, a CDRH2 having at least 70% identity with SEQ ID NO: 18, a CDRH3 having at least 70% identity with SEQ ID NO: 19 or 51, a CDRL1 having at least 70% identity with SEQ ID NO: 20, a CDRL2 having at least 70% identity with SEQ ID NO: 21, and a CDRL3 having at least 70% identity with SEQ ID NO: 22; In particular, the CDRH1 set forth in SEQ ID NO: 17, the CDRH2 set forth in SEQ ID NO: 18, the CDRH3 set forth in SEQ ID NO: 19 or 51, the CDRL1 set forth in SEQ ID NO: 20, the CDRL2 set forth in SEQ ID NO: 21, and the CDRL3 set forth in SEQ ID NO: 22; In some embodiments, a VH having at least 70% identity with any one of SEQ ID NO: 23, 41, 50, and 53; and a VL having at least 70% identity with any one of SEQ ID NO: 24, 42, and 43; wherein the CDRH1 set forth in SEQ ID NO: 17, the CDRH2 set forth in SEQ ID NO: 18, the CDRH3 according to SEQ ID NO: 19 or 51, the CDRL1 set forth in SEQ ID NO: 20, the CDRL2 set forth in SEQ ID NO: 21, and the CDRL3 set forth in SEQ ID NO: 22 are preferably maintained; For example, a VH set forth in any one of SEQ ID NO: 23, 41, 50, and 53; and a VL set forth in any one of SEQ ID NO: 24, 42, and 43.

[0203] More preferably, the multispecific antibody or multispecific antigen-binding fragment may be a bispecific antibody or bispecific antigen-binding fragment comprising: (i) Antigen-binding site: CDRH1 having at least 70% identity with SEQ ID NO: 1, CDRH2 having at least 70% identity with SEQ ID NO: 2, CDRH3 having at least 70% identity with SEQ ID NO: 3, CDRL1 having at least 70% identity with SEQ ID NO: 4, CDRL2 having at least 70% identity with SEQ ID NO: 5, and CDRL3 having at least 70% identity with SEQ ID NO: 6; In particular, CDRH1 as set forth in SEQ ID NO: 1, CDRH2 as set forth in SEQ ID NO: 2, CDRH3 as set forth in SEQ ID NO: 3, CDRL1 as set forth in SEQ ID NO: 4, CDRL2 as set forth in SEQ ID NO: 5, and CDRL3 as set forth in SEQ ID NO: 6; In some embodiments, VH having at least 70% identity with any one of SEQ ID NOs: 7, 44 and 45; and VL having at least 70% identity with any one of SEQ ID NOs: 8, 46, 47, 48 and 49; wherein CDRH1 as set forth in SEQ ID NO: 1, CDRH2 as set forth in SEQ ID NO: 2, CDRH3 as set forth in SEQ ID NO: 3, CDRL1 as set forth in SEQ ID NO: 4, CDRL2 as set forth in SEQ ID NO: 5, and CDRL3 as set forth in SEQ ID NO: 6 are preferably maintained; VH as set forth in any one of SEQ ID NOs: 7, 44 and 45; and VL as set forth in any one of SEQ ID NOs: 8, 46, 47, 48 and 49; and, (iv) Antigen-binding site comprising: CDRH1 having at least 70% identity with SEQ ID NO: 25, CDRH2 having at least 70% identity with SEQ ID NO: 26, CDRH3 having at least 70% identity with SEQ ID NO: 27, CDRL1 having at least 70% identity with SEQ ID NO: 28, CDRL2 having at least 70% identity with SEQ ID NO: 29 or 52, and CDRL3 having at least 70% identity with SEQ ID NO: 30; Particularly, CDRH1 set forth in SEQ ID NO: 25, CDRH2 set forth in SEQ ID NO: 26, CDRH3 set forth in SEQ ID NO: 27, CDRL1 set forth in SEQ ID NO: 28, CDRL2 set forth in SEQ ID NO: 29 or 52, and CDRL3 set forth in SEQ ID NO: 30; In some embodiments, a VH having at least 70% identity with any one of SEQ ID NOs: 31, 33, and 34; and a VL having at least 70% identity with any one of SEQ ID NOs: 32, 35, 36, and 54; wherein the CDRH1 set forth in SEQ ID NO: 25, the CDRH2 set forth in SEQ ID NO: 26, the CDRH3 set forth in SEQ ID NO: 27, the CDRL1 set forth in SEQ ID NO: 28, the CDRL2 set forth in SEQ ID NO: 29 or 52, and the CDRL3 set forth in SEQ ID NO: 30 are preferably maintained; For example, a VH set forth in any one of SEQ ID NOs: 31, 33, and 34; and a VL set forth in any one of SEQ ID NOs: 32, 35, 36, and 54.

[0204] In some embodiments, the multispecific antibody or multispecific antigen-binding fragment may be a trispecific antibody or trispecific antigen-binding fragment comprising: (i) an antigen-binding site comprising: a CDRH1 having at least 70% identity with SEQ ID NO: 1, a CDRH2 having at least 70% identity with SEQ ID NO: 2, a CDRH3 having at least 70% identity with SEQ ID NO: 3, a CDRL1 having at least 70% identity with SEQ ID NO: 4, a CDRL2 having at least 70% identity with SEQ ID NO: 5, and a CDRL3 having at least 70% identity with SEQ ID NO: 6; Particularly, CDRH1 set forth in SEQ ID NO: 1, CDRH2 set forth in SEQ ID NO: 2, CDRH3 set forth in SEQ ID NO: 3, CDRL1 set forth in SEQ ID NO: 4, CDRL2 set forth in SEQ ID NO: 5, and CDRL3 set forth in SEQ ID NO: 6; In some embodiments, a VH having at least 70% identity with any one of SEQ ID NO: 7, 44, and 45; and a VL having at least 70% identity with any one of SEQ ID NO: 8, 46, 47, 48, and 49; wherein CDRH1 set forth in SEQ ID NO: 1, CDRH2 set forth in SEQ ID NO: 1 and SEQ ID NO: 2, CDRH3 set forth in SEQ ID NO: 3, CDRL1 set forth in SEQ ID NO: 4, CDRL2 set forth in SEQ ID NO: 5, and CDRL3 set forth in SEQ ID NO: 6 are preferably maintained; For example, a VH set forth in any one of SEQ ID NO: 7, 44, and 45; and a VL set forth in any one of SEQ ID NO: 8, 46, 47, 48, and 49; etc.; (ii) An antigen-binding site comprising: CDRH1 having at least 70% identity with SEQ ID NO: 9, CDRH2 having at least 70% identity with SEQ ID NO: 10, CDRH3 having at least 70% identity with SEQ ID NO: 11, CDRL1 having at least 70% identity with SEQ ID NO: 12, CDRL2 having at least 70% identity with SEQ ID NO: 13, and CDRL3 having at least 70% identity with SEQ ID NO: 14; In particular, CDRH1 set forth in SEQ ID NO: 9, CDRH2 set forth in SEQ ID NO: 10, CDRH3 set forth in SEQ ID NO: 11, CDRL1 set forth in SEQ ID NO: 12, CDRL2 set forth in SEQ ID NO: 13, and CDRL3 set forth in SEQ ID NO: 14; In some embodiments, a VH having at least 70% identity with any one of SEQ ID NO: 15, 37, and 38; and a VL having at least 70% identity with any one of SEQ ID NO: 16, 39, and 40; wherein CDRH1 set forth in SEQ ID NO: 9, CDRH2 set forth in SEQ ID NO: 10, CDRH3 set forth in SEQ ID NO: 11, CDRL1 set forth in SEQ ID NO: 12, CDRL2 set forth in SEQ ID NO: 13, and CDRL3 set forth in SEQ ID NO: 14 are preferably maintained; A VH set forth in any one of SEQ ID NO: 15, 37, and 38; and a VL set forth in any one of SEQ ID NO: 16, 39, and 40; and, (iii) An antigen-binding site comprising: CDRH1 having at least 70% identity with SEQ ID NO: 17, CDRH2 having at least 70% identity with SEQ ID NO: 18, CDRH3 having at least 70% identity with SEQ ID NO: 19 or 51, CDRL1 having at least 70% identity with SEQ ID NO: 20, CDRL2 having at least 70% identity with SEQ ID NO: 21, and CDRL3 having at least 70% identity with SEQ ID NO: 22; In particular, CDRH1 as described in SEQ ID NO: 17, CDRH2 as described in SEQ ID NO: 18, CDRH3 as described in SEQ ID NO: 19 or 51, CDRL1 as described in SEQ ID NO: 20, CDRL2 as described in SEQ ID NO: 21, and CDRL3 as described in SEQ ID NO: 22; In some embodiments, VH having at least 70% identity with any one of SEQ ID NOs: 23, 41, 50 and 53; and VL having at least 70% identity with any one of SEQ ID NOs: 24, 42 and 43; wherein CDRH1 as described in SEQ ID NO: 17, CDRH2 as described in SEQ ID NO: 18, CDRH3 as described in SEQ ID NO: 19 or 51, CDRL1 as described in SEQ ID NO: 20, CDRL2 as described in SEQ ID NO: 20, and CDRL3 as described in SEQ ID NO: 22 are preferably maintained; For example, VH as described in any one of SEQ ID NOs: 23, 41, 50 and 53; and VL as described in any one of SEQ ID NOs: 24, 42 and 43.

[0205] In some embodiments, the multispecific antibody or multispecific antigen-binding fragment may be a trispecific antibody or trispecific antigen-binding fragment comprising: (i) an antigen-binding site comprising: CDRH1 having at least 70% identity with SEQ ID NO: 1, CDRH2 having at least 70% identity with SEQ ID NO: 2, CDRH3 having at least 70% identity with SEQ ID NO: 3, CDRL1 having at least 70% identity with SEQ ID NO: 4, CDRL2 having at least 70% identity with SEQ ID NO: 5, and CDRL3 having at least 70% identity with SEQ ID NO: 6; In particular, CDRH1 set forth in SEQ ID NO: 1, CDRH2 set forth in SEQ ID NO: 2, CDRH3 set forth in SEQ ID NO: 3, CDRL1 set forth in SEQ ID NO: 4, CDRL2 set forth in SEQ ID NO: 5, and CDRL3 set forth in SEQ ID NO: 6; In some embodiments, a VH having at least 70% identity to any one of SEQ ID NOs: 7, 44, and 45; and a VL having at least 70% identity to any one of SEQ ID NOs: 8, 46, 47, 48, and 49; wherein the CDRH1 set forth in SEQ ID NO: 1, the CDRH2 set forth in SEQ ID NO: 2, the CDRH3 set forth in SEQ ID NO: 3, the CDRL1 set forth in SEQ ID NO: 4, the CDRL2 set forth in SEQ ID NO: 5, and the CDRL3 set forth in SEQ ID NO: 6 are preferably maintained; For example, a VH set forth in any one of SEQ ID NOs: 7, 44, and 45; and a VL by any one of SEQ ID NOs: 8, 46, 47, 48, and 49; and the like. (ii) An antigen-binding site comprising the following: A CDRH1 having at least 70% identity to SEQ ID NO: 17, a CDRH2 having at least 70% identity to SEQ ID NO: 18, a CDRH3 having at least 70% identity to SEQ ID NO: 19 or 51, a CDRL1 having at least 70% identity to SEQ ID NO: 20, a CDRL2 having at least 70% identity to SEQ ID NO: 21, and a CDRL3 having at least 70% identity to SEQ ID NO: 22; In particular, CDRH1 set forth in SEQ ID NO: 17, CDRH2 set forth in SEQ ID NO: 18, CDRH3 set forth in SEQ ID NO: 19 or 51, CDRL1 set forth in SEQ ID NO: 20, CDRL2 set forth in SEQ ID NO: 21, and CDRL3 set forth in SEQ ID NO: 22; In some embodiments, a VH having at least 70% identity to any one of SEQ ID NOs: 23, 41, 50, and 53; and a VL having at least 70% identity to any one of SEQ ID NOs: 24, 42, and 43; wherein the CDRH1 set forth in SEQ ID NO: 17, the CDRH2 set forth in SEQ ID NO: 18, the CDRH3 set forth in SEQ ID NO: 19 or 51, the CDRL1 set forth in SEQ ID NO: 20, the CDRL2 set forth in SEQ ID NO: 21, and the CDRL3 set forth in SEQ ID NO: 22 are preferably maintained; VH as described in any one of SEQ ID NOs: 23, 41, 50 and 53; and VL as described in any one of SEQ ID NOs: 24, 42 and 43; and, (iv) an antigen-binding site comprising: CDRH1 having at least 70% identity with SEQ ID NO: 25, CDRH2 having at least 70% identity with SEQ ID NO: 26, CDRH3 having at least 70% identity with SEQ ID NO: 27, CDRL1 having at least 70% identity with SEQ ID NO: 28, CDRL2 having at least 70% identity with SEQ ID NO: 29 or 52, and CDRL3 having at least 70% identity with SEQ ID NO: 30; In particular, CDRH1 as described in SEQ ID NO: 25, CDRH2 as described in SEQ ID NO: 26, CDRH3 as described in SEQ ID NO: 27, CDRL1 as described in SEQ ID NO: 28, CDRL2 as described in SEQ ID NO: 29 or 52, and CDRL3 as described in SEQ ID NO: 30; In some embodiments, a VH having at least 70% identity with any one of SEQ ID NOs: 31, 33 and 34; and a VL having at least 70% identity with any one of SEQ ID NOs: 32, 35, 36 and 54; wherein CDRH1 as described in SEQ ID NO: 25, CDRH2 as described in SEQ ID NO: 26, CDRH3 as described in SEQ ID NO: 27, CDRL1 as described in SEQ ID NO: 28, CDRL2 as described in SEQ ID NO: 29 or 52, and CDRL3 as described in SEQ ID NO: 30 are preferably maintained; For example, VH as described in any one of SEQ ID NOs: 31, 33 and 34; and VL as described in any one of SEQ ID NOs: 32, 35, 36 and 54.

[0206] In some embodiments, the multispecific antibody or multispecific antigen-binding fragment may comprise a trispecific antibody or trispecific antigen-binding fragment comprising: (ii) an antigen-binding site comprising: CDRH1 having at least 70% identity with SEQ ID NO: 9, CDRH2 having at least 70% identity with SEQ ID NO: 10, CDRH3 having at least 70% identity with SEQ ID NO: 11, CDRL1 having at least 70% identity with SEQ ID NO: 12, CDRL2 having at least 70% identity with SEQ ID NO: 13, and CDRL3 having at least 70% identity with SEQ ID NO: 14; In particular, CDRH1 as described in SEQ ID NO: 9, CDRH2 as described in SEQ ID NO: 10, CDRH3 as described in SEQ ID NO: 11, CDRL1 as described in SEQ ID NO: 12, CDRL2 as described in SEQ ID NO: 13, and CDRL3 as described in SEQ ID NO: 14; In some embodiments, VH having at least 70% identity with any one of SEQ ID NOs: 15, 37, and 38; and VL having at least 70% identity with any one of SEQ ID NOs: 16, 39, and 40; wherein CDRH1 as described in SEQ ID NO: 9, CDRH2 as described in SEQ ID NO: 10, CDRH3 as described in SEQ ID NO: 11, CDRL1 as described in SEQ ID NO: 12, CDRL2 as described in SEQ ID NO: 13, and CDRL3 as described in SEQ ID NO: 14 are preferably maintained; For example, VH as described in any one of SEQ ID NOs: 15, 37, and 38; and VL as described in any one of SEQ ID NOs: 16, 39, and 40; (iii) An antigen-binding site comprising the following: CDRH1 having at least 70% identity with SEQ ID NO: 17, CDRH2 having at least 70% identity with SEQ ID NO: 18, CDRH3 having at least 70% identity with SEQ ID NO: 19 or 51, CDRL1 having at least 70% identity with SEQ ID NO: 20, CDRL2 having at least 70% identity with SEQ ID NO: 21, and CDRL3 having at least 70% identity with SEQ ID NO: 22; In particular, CDRH1 as described in SEQ ID NO: 17, CDRH2 as described in SEQ ID NO: 18, CDRH3 as described in SEQ ID NO: 19 or 51, CDRL1 as described in SEQ ID NO: 20, CDRL2 as described in SEQ ID NO: 21, and CDRL3 as described in SEQ ID NO: 22; In some embodiments, a VH having at least 70% identity with any one of SEQ ID NO: 23, 41, 50, and 53; and a VL having at least 70% identity with any one of SEQ ID NO: 24, 42, and 43; wherein the CDRH1 set forth in SEQ ID NO: 17, the CDRH2 set forth in SEQ ID NO: 18, the CDRH3 set forth in SEQ ID NO: 19 or 51, the CDRL1 set forth in SEQ ID NO: 20, the CDRL2 set forth in SEQ ID NO: 21, and the CDRL3 set forth in SEQ ID NO: 22 are preferably maintained; A VH as set forth in any one of SEQ ID NO: 23, 41, 50, and 53; and a VL as set forth in any one of SEQ ID NO: 24, 42, and 43; and, (iv) an antigen-binding site comprising: A CDRH1 having at least 70% identity with SEQ ID NO: 25, a CDRH2 having at least 70% identity with SEQ ID NO: 26, a CDRH3 having at least 70% identity with SEQ ID NO: 27, a CDRL1 having at least 70% identity with SEQ ID NO: 28, a CDRL2 having at least 70% identity with SEQ ID NO: 29 or 52, and a CDRL3 having at least 70% identity with SEQ ID NO: 30; In particular, the CDRH1 set forth in SEQ ID NO: 25, the CDRH2 set forth in SEQ ID NO: 26, the CDRH3 set forth in SEQ ID NO: 27, the CDRL1 set forth in SEQ ID NO: 28, the CDRL2 set forth in SEQ ID NO: 29 or 52, and the CDRL3 set forth in SEQ ID NO: 30; In some embodiments, a VH having at least 70% identity with any one of SEQ ID NO: 31, 33, and 34; and a VL having at least 70% identity with any one of SEQ ID NO: 32, 35, 36, and 54; wherein the CDRH1 set forth in SEQ ID NO: 25, the CDRH2 set forth in SEQ ID NO: 26, the CDRH3 set forth in SEQ ID NO: 27, the CDRL1 set forth in SEQ ID NO: 28, the CDRL2 set forth in SEQ ID NO: 29 or 52, and the CDRL3 set forth in SEQ ID NO: 30 are preferably maintained; For example, a VH as set forth in any one of SEQ ID NO: 31, 33, and 34; and a VL as set forth in any one of SEQ ID NO: 32, 35, 36, and 54.

[0207] Preferably, the multispecific antibody or multispecific antigen-binding fragment may be a trispecific antibody or trispecific antigen-binding fragment comprising: (i) An antigen-binding site comprising: CDRH1 having at least 70% identity with SEQ ID NO: 1, CDRH2 having at least 70% identity with SEQ ID NO: 2, CDRH3 having at least 70% identity with SEQ ID NO: 3, CDRL1 having at least 70% identity with SEQ ID NO: 4, CDRL2 having at least 70% identity with SEQ ID NO: 5, and CDRL3 having at least 70% identity with SEQ ID NO: 6; In particular, CDRH1 set forth in SEQ ID NO: 1, CDRH2 set forth in SEQ ID NO: 2, CDRH3 set forth in SEQ ID NO: 3, CDRL1 set forth in SEQ ID NO: 4, CDRL2 set forth in SEQ ID NO: 5, and CDRL3 set forth in SEQ ID NO: 6; In some embodiments, VH having at least 70% identity with any one of SEQ ID NOs: 7, 44 and 45; and VL having at least 70% identity with any one of SEQ ID NOs: 8, 46, 47, 48 and 49; wherein CDRH1 set forth in SEQ ID NO: 1, CDRH2 set forth in SEQ ID NO: 2, CDRH3 set forth in SEQ ID NO: 3, CDRL1 set forth in SEQ ID NO: 4, CDRL2 set forth in SEQ ID NO: 5, and CDRL3 set forth in SEQ ID NO: 6 are preferably maintained; For example, VH set forth in any one of SEQ ID NOs: 7, 44 and 45; and VL set forth in any one of SEQ ID NOs: 8, 46, 47, 48 and 49; (ii) An antigen-binding site comprising: CDRH1 having at least 70% identity with SEQ ID NO: 9, CDRH2 having at least 70% identity with SEQ ID NO: 10, CDRH3 having at least 70% identity with SEQ ID NO: 11, CDRL1 having at least 70% identity with SEQ ID NO: 12, CDRL2 having at least 70% identity with SEQ ID NO: 13, and CDRL3 having at least 70% identity with SEQ ID NO: 14; In particular, CDRH1 set forth in SEQ ID NO: 9, CDRH2 set forth in SEQ ID NO: 10, CDRH3 set forth in SEQ ID NO: 11, CDRL1 set forth in SEQ ID NO: 12, CDRL2 set forth in SEQ ID NO: 13, and CDRL3 set forth in SEQ ID NO: 14; In some embodiments, a VH having at least 70% identity to any one of SEQ ID NOs: 15, 37, and 38; and a VL having at least 70% identity to any one of SEQ ID NOs: 16, 39, and 40; wherein the CDRH1 set forth in SEQ ID NO: 9, CDRH2 set forth in SEQ ID NO: 10, CDRH3 set forth in SEQ ID NO: 11, CDRL1 set forth in SEQ ID NO: 12, CDRL2 set forth in SEQ ID NO: 13, and CDRL3 set forth in SEQ ID NO: 14 are preferably maintained; VH set forth in any one of SEQ ID NOs: 15, 37, and 38; and VL set forth in any one of SEQ ID NOs: 16, 39, and 40; and, (iv) an antigen-binding site comprising: CDRH1 having at least 70% identity to SEQ ID NO: 25, CDRH2 having at least 70% identity to SEQ ID NO: 26, CDRH3 having at least 70% identity to SEQ ID NO: 27, CDRL1 having at least 70% identity to SEQ ID NO: 28, CDRL2 having at least 70% identity to SEQ ID NO: 29 or 52, and CDRL3 having at least 70% identity to SEQ ID NO: 30; In particular, CDRH1 set forth in SEQ ID NO: 25, CDRH2 set forth in SEQ ID NO: 26, CDRH3 set forth in SEQ ID NO: 27, CDRL1 set forth in SEQ ID NO: 28, CDRL2 set forth in SEQ ID NO: 29 or 52, and CDRL3 set forth in SEQ ID NO: 30; In some embodiments, a VH having at least 70% identity to any one of SEQ ID NOs: 31, 33, and 34; and a VL having at least 70% identity to any one of SEQ ID NOs: 32, 35, 36, and 54; wherein the CDRH1 set forth in SEQ ID NO: 25, CDRH2 set forth in SEQ ID NO: 26, CDRH3 set forth in SEQ ID NO: 27, CDRL1 set forth in SEQ ID NO: 28, CDRL2 set forth in SEQ ID NO: 29 or 52, and CDRL3 set forth in SEQ ID NO: 30 are preferably maintained; For example, a VH described in any one of SEQ ID NOs: 31, 33, and 34; and a VL described in any one of SEQ ID NOs: 32, 35, 36, and 54.

[0208] The multispecific antibody or multispecific antigen-binding fragment is preferably a tetravalent multispecific antibody or tetravalent multispecific antigen-binding fragment comprising: (i) An antigen-binding site comprising: CDRH1 having at least 70% identity with SEQ ID NO: 1, CDRH2 having at least 70% identity with SEQ ID NO: 2, CDRH3 having at least 70% identity with SEQ ID NO: 3, CDRL1 having at least 70% identity with SEQ ID NO: 4, CDRL2 having at least 70% identity with SEQ ID NO: 5, and CDRL3 having at least 70% identity with SEQ ID NO: 6; In particular, CDRH1 described in SEQ ID NO: 1, CDRH2 described in SEQ ID NO: 2, CDRH3 described in SEQ ID NO: 3, CDRL1 described in SEQ ID NO: 4, CDRL2 described in SEQ ID NO: 5, and CDRL3 described in SEQ ID NO: 6; In some embodiments, a VH having at least 70% identity with any one of SEQ ID NOs: 7, 44, and 45; and a VL having at least 70% identity with any one of SEQ ID NOs: 8, 46, 47, 48, and 49; wherein CDRH1 described in SEQ ID NO: 1, CDRH2 described in SEQ ID NO: 2, CDRH3 described in SEQ ID NO: 3, CDRL1 described in SEQ ID NO: 4, CDRL2 described in SEQ ID NO: 5, and CDRL3 described in SEQ ID NO: 6 are preferably maintained; For example, a VH described in any one of SEQ ID NOs: 7, 44, and 45; and a VL described in any one of SEQ ID NOs: 8, 46, 47, 48, and 49; and the like; (ii) An antigen-binding site comprising: CDRH1 having at least 70% identity with SEQ ID NO: 9, CDRH2 having at least 70% identity with SEQ ID NO: 10, CDRH3 having at least 70% identity with SEQ ID NO: 11, CDRL1 having at least 70% identity with SEQ ID NO: 12, CDRL2 having at least 70% identity with SEQ ID NO: 13, and CDRL3 having at least 70% identity with SEQ ID NO: 14; In particular, CDRH1 described in SEQ ID NO: 9, CDRH2 described in SEQ ID NO: 10, CDRH3 described in SEQ ID NO: 11, CDRL1 described in SEQ ID NO: 12, CDRL2 described in SEQ ID NO: 13, and CDRL3 described in SEQ ID NO: 14; In some embodiments, VH having at least 70% identity with any one of SEQ ID NOs: 15, 37, and 38; and VL having at least 70% identity with any one of SEQ ID NOs: 16, 39, and 40; wherein CDRH1 described in SEQ ID NO: 9, CDRH2 described in SEQ ID NO: 9, SEQ ID NO: 10, CDRH3 described in SEQ ID NO: 11, CDRL1 described in SEQ ID NO: 12, CDRL2 according to SEQ ID NO: 13, and CDRL3 according to SEQ ID NO: 14 are preferably maintained; For example, VH described in any one of SEQ ID NOs: 15, 37, and 38; and VL described in any one of SEQ ID NOs: 16, 39, and 40; (iii) An antigen-binding site comprising the following: CDRH1 having at least 70% identity with SEQ ID NO: 17, CDRH2 having at least 70% identity with SEQ ID NO: 18, CDRH3 having at least 70% identity with SEQ ID NO: 19 or 51, CDRL1 having at least 70% identity with SEQ ID NO: 20, CDRL2 having at least 70% identity with SEQ ID NO: 21, and CDRL3 having at least 70% identity with SEQ ID NO: 22; In particular, CDRH1 described in SEQ ID NO: 17, CDRH2 described in SEQ ID NO: 18, CDRH3 described in SEQ ID NO: 19 or 51, CDRL1 described in SEQ ID NO: 20, CDRL2 described in SEQ ID NO: 21, and CDRL3 described in SEQ ID NO: 22; In some embodiments, a VH having at least 70% identity with any one of SEQ ID NO: 23, 41, 50, and 53; and a VL having at least 70% identity with any one of SEQ ID NO: 24, 42, and 43; wherein the CDRH1 set forth in SEQ ID NO: 17, the CDRH2 set forth in SEQ ID NO: 18, the CDRH3 set forth in SEQ ID NO: 19 or 51, the CDRL1 set forth in SEQ ID NO: 20, the CDRL2 set forth in SEQ ID NO: 20, and the CDRL3 set forth in SEQ ID NO: 22 are preferably maintained; A VH as set forth in any one of SEQ ID NO: 23, 41, 50, and 53; and a VL as set forth in any one of SEQ ID NO: 24, 42, and 43; and, (iv) an antigen-binding site comprising: A CDRH1 having at least 70% identity with SEQ ID NO: 25, a CDRH2 having at least 70% identity with SEQ ID NO: 26, a CDRH3 having at least 70% identity with SEQ ID NO: 27, a CDRL1 having at least 70% identity with SEQ ID NO: 28, a CDRL2 having at least 70% identity with SEQ ID NO: 29 or 52, and a CDRL3 having at least 70% identity with SEQ ID NO: 30; In particular, the CDRH1 set forth in SEQ ID NO: 25, the CDRH2 set forth in SEQ ID NO: 26, the CDRH3 set forth in SEQ ID NO: 27, the CDRL1 set forth in SEQ ID NO: 28, the CDRL2 set forth in SEQ ID NO: 29 or 52, and the CDRL3 set forth in SEQ ID NO: 30; In some embodiments, a VH having at least 70% identity with any one of SEQ ID NO: 31, 33, and 34; and a VL having at least 70% identity with any one of SEQ ID NO: 32, 35, 36, and 54; wherein the CDRH1 set forth in SEQ ID NO: 25, the CDRH2 set forth in SEQ ID NO: 26, the CDRH3 set forth in SEQ ID NO: 27, the CDRL1 set forth in SEQ ID NO: 28, the CDRL2 set forth in SEQ ID NO: 29 or 52, and the CDRL3 set forth in SEQ ID NO: 30 are preferably maintained; For example, a VH as set forth in any one of SEQ ID NO: 31, 33, and 34; and a VL as set forth in any one of SEQ ID NO: 32, 35, 36, and 54.

[0209] More preferably, the multispecific antibody or multispecific antigen-binding fragment may be a tetravalent antibody or tetravalent antigen-binding fragment comprising: (i) an antigen-binding site comprising CDRH1 having at least 70% identity with SEQ ID NO: 1, CDRH2 having at least 70% identity with SEQ ID NO: 2, CDRH3 having at least 70% identity with SEQ ID NO: 3, CDRL1 having at least 70% identity with SEQ ID NO: 4, CDRL2 having at least 70% identity with SEQ ID NO: 5, and CDRL3 having at least 70% identity with SEQ ID NO: 6; in particular, CDRH1 as set forth in SEQ ID NO: 1, CDRH2 as set forth in SEQ ID NO: 2, CDRH3 as set forth in SEQ ID NO: 3, CDRL1 as set forth in SEQ ID NO: 4, CDRL2 as set forth in SEQ ID NO: 5, CDRL3 as set forth in SEQ ID NO: 6; (ii) an antigen-binding site comprising CDRH1 having at least 70% identity with SEQ ID NO: 9, CDRH2 having at least 70% identity with SEQ ID NO: 10, CDRH3 having at least 70% identity with SEQ ID NO: 11, CDRL1 having at least 70% identity with SEQ ID NO: 12, CDRL2 having at least 70% identity with SEQ ID NO: 13, and CDRL3 having at least 70% identity with SEQ ID NO: 14; in particular, CDRH1 as set forth in SEQ ID NO: 9, CDRH2 as set forth in SEQ ID NO: 10, CDRH3 as set forth in SEQ ID NO: 11, CDRL1 as set forth in SEQ ID NO: 12, CDRL2 as set forth in SEQ ID NO: 13, CDRL3 as set forth in SEQ ID NO: 14; (iii) an antigen-binding site comprising CDRH1 having at least 70% identity with SEQ ID NO: 17, CDRH2 having at least 70% identity with SEQ ID NO: 18, CDRH3 having at least 70% identity with SEQ ID NO: 51, CDRL1 having at least 70% identity with SEQ ID NO: 20, CDRL2 having at least 70% identity with SEQ ID NO: 21, and CDRL3 having at least 70% identity with SEQ ID NO: 22; in particular, CDRH1 as set forth in SEQ ID NO: 17, CDRH2 as set forth in SEQ ID NO: 18, CDRH3 as set forth in SEQ ID NO: 51, CDRL1 as set forth in SEQ ID NO: 20, CDRL2 as set forth in SEQ ID NO: 21, and CDRL3 as set forth in SEQ ID NO: 22; and, (iv) An antigen-binding site comprising a CDRH1 having at least 70% identity with SEQ ID NO: 25, a CDRH2 having at least 70% identity with SEQ ID NO: 26, a CDRH3 having at least 70% identity with SEQ ID NO: 27, a CDRL1 having at least 70% identity with SEQ ID NO: 28, a CDRL2 having at least 70% identity with SEQ ID NO: 29 or 52, and a CDRL3 having at least 70% identity with SEQ ID NO: 30; in particular, the CDRH1 described in SEQ ID NO: 25, the CDRH2 described in SEQ ID NO: 26, the CDRH3 described in SEQ ID NO: 27, the CDRL1 described in SEQ ID NO: 28, the CDRL2 described in SEQ ID NO: 29 or 52, and the CDRL3 described in SEQ ID NO: 30.

[0210] Even more preferably, the multispecific antibody or multispecific antigen-binding fragment may be a tetravalent specific antibody or tetravalent specific antigen-binding fragment comprising the following: (i) An antigen-binding site comprising a VH having at least 70% identity with SEQ ID NO: 45; and a VL having at least 70% identity with SEQ ID NO: 49; wherein the CDRH1 described in SEQ ID NO: 1, the CDRH2 described in SEQ ID NO: 2, the CDRH3 described in SEQ ID NO: 3, the CDRL1 described in SEQ ID NO: 4, the CDRL2 described in SEQ ID NO: 5, and the CDRL3 described in SEQ ID NO: 6 are preferably maintained; for example, the VH described in SEQ ID NO: 45, and the VL described in SEQ ID NO: 49; (ii) An antigen-binding site comprising a VH having at least 70% identity with SEQ ID NO: 38; and a VL having at least 70% identity with SEQ ID NO: 39; wherein the CDRH1 described in SEQ ID NO: 9, the CDRH2 described in SEQ ID NO: 10, the CDRH3 according to SEQ ID NO: 11, the CDRL1 according to SEQ ID NO: 12, the CDRL2 according to SEQ ID NO: 13, and the CDRL3 according to SEQ ID NO: 14 are preferably maintained; for example, the VH described in SEQ ID NO: 38, and the VL described in SEQ ID NO: 39; (iii) A VH having at least 70% identity with SEQ ID NO: 53; and an antigen-binding site comprising a VL having at least 70% identity with SEQ ID NO: 43; wherein the CDRH1 set forth in SEQ ID NO: 17, the CDRH2 set forth in SEQ ID NO: 18, the CDRH3 set forth in SEQ ID NO: 51, the CDRL1 set forth in SEQ ID NO: 20, the CDRL2 set forth in SEQ ID NO: 21, and the CDRL3 set forth in SEQ ID NO: 22 are preferably maintained; for example, the VH set forth in SEQ ID NO: 53 and the VL set forth in SEQ ID NO: 43; and, (iv) A VH having at least 70% identity with that set forth in SEQ ID NO: 34; and an antigen-binding site comprising a VL having at least 70% identity with SEQ ID NO: 35 or 54; wherein the CDRH1 set forth in SEQ ID NO: 25, the CDRH2 set forth in SEQ ID NO: 26, the CDRH3 set forth in SEQ ID NO: 27, the CDRL1 set forth in SEQ ID NO: 28, the CDRL2 set forth in SEQ ID NO: 29 or 52, and the CDRL3 set forth in SEQ ID NO: 30 are preferably maintained; for example, the VH set forth in SEQ ID NO: 34 and the VL set forth in SEQ ID NO: 35 or 54.

[0211] In other words, the antigen-binding site (paratope) of the multispecific antibody, or multispecific antigen-binding fragment, can be selected from the four different antibodies 17H9, 15E3, 2F8, and 7G6, or variants thereof, described above, particularly those shown in Tables 1 and 2.

[0212] In some embodiments, the multispecific antibody or multispecific antigen-binding fragment is bispecific and comprises two distinct antigen-binding sites selected from (i)-(iv). Such bispecific antibodies can, in use, be combined with a second antibody comprising one or both of the remaining antigen-binding sites selected from (i)-(iv) (i.e., one or both of the binding antigen-binding sites selected from (i)-(iv) not included in the (first) bispecific antibody). For example, two bispecific antibodies each comprising two distinct antigen-binding sites selected from (i)-(iv) can be combined such that the combination of the two bispecific antibodies comprises all four antigen-binding sites of (i)-(iv). Similarly, the bispecific antibody may be combined with one or two monospecific antibodies each comprising one of the remaining antigen-binding sites. When combined, the antibodies may be included in the same composition or in different compositions (provided they are administered in the context of a combination therapy schedule).

[0213] Preferably, the multispecific antibody or multispecific antigen-binding fragment is trispecific and comprises three distinct antigen-binding sites selected from (i)-(iv).

[0214] It is also preferred that the multispecific antibody or multispecific antigen-binding fragment is tetravalent and comprises the four distinct antigen-binding sites described in (i), (ii), (iii) and (iv).

[0215] [[Nucleic acid]] In another aspect, the invention also provides a nucleic acid molecule comprising a polynucleotide encoding an antibody or an antigen-binding fragment thereof according to the invention as described above.

[0216] In some embodiments, the nucleic acid molecule comprises one or more polynucleotides encoding an exemplary antibody in the present invention (e.g., the antibodies described above, particularly the antibodies described in Tables 1 and 2), or a sequence variant thereof described herein (e.g., a sequence variant having at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or more sequence identity).

[0217] Exemplary nucleic acid sequences encoding the CDR and VH / VL sequences of the exemplary antibodies described herein are shown in Table 3 below.

[0218]

Table 3

[0219] Examples of nucleic acid molecules and / or polynucleotides include, for example, recombinant polynucleotides, vectors, oligonucleotides, RNA molecules such as rRNA, mRNA, miRNA, siRNA, tRNA, or DNA molecules such as cDNA. The nucleic acid may encode the light and / or heavy chain of an antibody (or single-chain antibody). In other words, the light and heavy chains of the antibody may be encoded by the same nucleic acid molecule (e.g., in the case of a single-chain antibody, or in an expression cassette containing multiple ribosome entry sites such as a bicistronic antibody or IRES, where the heavy and light chains are separate). Alternatively, the light and heavy chains of the antibody may be encoded by separate nucleic acid molecules. Similarly, in the case of a multispecific antibody comprising two or more immunoglobulin chains, the different chains may be encoded by the same nucleic acid molecule (e.g., in a multi-cistronic manner or in an expression cassette containing two or more ribosome entry sites such as IRES). Alternatively, the different immunoglobulin chains of the multispecific antibody may be encoded by separate nucleic acid molecules.

[0220] Due to the redundancy of the genetic code, the present invention also includes sequence variants of nucleic acid sequences that encode the same amino acid sequence. The polynucleotide (or complete nucleic acid molecule) encoding the antibody can be optimized for antibody expression. For example, codon optimization of the nucleotide sequence can be used to improve translation efficiency in the expression system for antibody production. Furthermore, the nucleic acid molecule may contain heterologous elements (i.e., elements that are not naturally present on the same nucleic acid molecule as the coding sequence of the antibody (heavy or light chain)). For example, the nucleic acid molecule may contain a heterologous promoter, heterologous enhancer, heterologous UTR (e.g., for optimal translation / expression), heterologous Poly-A-tail, etc.

[0221] A nucleic acid molecule is a molecule that contains a nucleic acid component. The term nucleic acid molecule usually refers to a DNA or RNA molecule. The term nucleic acid molecule may be used as a synonym for "polynucleotide". That is, the nucleic acid molecule may be composed of a polynucleotide encoding an antibody. Alternatively, the nucleic acid molecule may contain additional elements in addition to the polynucleotide encoding the antibody. Typically, a nucleic acid molecule is a polymer containing or composed of nucleotide monomers covalently bonded to each other by phosphodiester bonds of the sugar / phosphate backbone. The term "nucleic acid molecule" also includes modified nucleic acid molecules, DNA, or RNA molecules such as base modifications, sugar modifications, backbone modifications, etc.

[0222] Generally, nucleic acid molecules can be modified to insert, delete, or alter a specific nucleic acid sequence. Changes by such modifications include, but are not limited to, changes for introducing restriction sites, changes for modifying codon usage, changes for adding or optimizing transcriptional and / or translational regulatory sequences, etc. It is also possible to change the nucleic acid to change the encoded amino acid. For example, it may be useful to introduce one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, etc.) amino acid substitutions, deletions, and / or insertions into the amino acid sequence of an antibody. Such point mutations can modify effector function, antigen-binding affinity, post-translational modification, immunogenicity, etc., can introduce amino acids for binding a covalent moiety (e.g., a label), or can introduce a tag (e.g., for purification purposes). Alternatively, a mutation in a nucleic acid sequence can be a “silent” mutation, i.e., a mutation that is not reflected in the amino acid sequence due to the redundancy of the genetic code. Generally, mutations may be introduced at specific sites, may be introduced randomly, or may be introduced through selection (e.g., molecular evolution). For example, one or more nucleic acids encoding either the light or heavy chain of an (exemplary) antibody can be mutated randomly or directionally to introduce different properties into the encoded amino acid. Such changes can be the result of an iterative process in which an initial change is retained and new changes are introduced at other nucleotide positions. Additionally, changes achieved in independent steps may be combined.

[0223] In some embodiments, the polynucleotide encoding the antibody, or antigen-binding fragment thereof (i.e., the (complete) nucleic acid molecule) can be codon-optimized. Those skilled in the art are aware that various tools for codon optimization are known to those skilled in the art and include, for example, those described in the following references: Ju Xin Chin, Bevan Kai-Sheng Chung, Dong-Yup Lee, Codon Optimization OnLine (COOL): a web-based multi-objective optimization platform for synthetic gene design, Bioinformatics, Volume 30, Issue 15, 1 August 2014, Pages 2210-2212; or in: Grote A, Hiller K, Scheer M, Munch R, Nortemann B, Hempel DC, Jahn D, JCat: a novel tool to adapt codon usage of a target gene to its potential expression host. Nucleic Acids Res. 2005 Jul 1;33(Web Server issue):W526-31; or, for example, the Genscript’s OptimumGene™ algorithm (disclosed in US2011 / 0091708A1).

[0224] For example, the nucleic acid molecule of the invention can include the nucleic acid sequence set forth in any one of SEQ ID NOs: 64 to 99; or a sequence variant thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 88%, at least 90%, at least 92%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% sequence identity. Thereby, the nucleic acid molecule can encode any one of the exemplary antibodies 17H9, 15E3, 2F8 and 7G6 (by combining the sequences as shown in Table 3), or sequence variants thereof as described herein.

[0225] The present invention also provides a plurality of nucleic acid molecules encoding the antibodies described herein, or antigen-binding fragments thereof. Each nucleic acid molecule (of the plurality of nucleic acid molecules) comprises a polynucleotide encoding an immunoglobulin chain of the antibody, or an antigen-binding fragment thereof. Thus, the plurality of nucleic acid molecules together encode the antibodies described herein, or all of the immunoglobulin chains of an antigen-binding fragment thereof. In some embodiments, the plurality of nucleic acid molecules encoding the antibodies described herein, or antigen-binding fragments thereof, may be a combination of a first and a second nucleic acid molecule, wherein the first nucleic acid molecule comprises a polynucleotide encoding the heavy chain of the antibody of the present invention, or an antigen-binding fragment thereof; the second nucleic acid molecule comprises a polynucleotide encoding the corresponding light chain of the same antibody, or the same antigen-binding fragment.

[0226] Generally, the above description regarding the (general) characteristics of the nucleic acid molecules of the present invention is also appropriately applicable to the nucleic acid molecules of the plurality of nucleic acid molecules. Thus, one or more of the polynucleotides encoding an immunoglobulin chain of the antibody, or an antigen-binding fragment thereof, may be codon-optimized. For example, the plurality may consist of a nucleic acid sequence set forth in any one of SEQ ID NOs: 64 to 99; or a sequence variant having at least 70%, at least 75%, at least 80%, at least 85%, at least 88%, at least 90%, at least 92%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% sequence identity thereto. Thereby, the plurality of nucleic acid molecules can encode any one of the exemplified antibodies 17H9, 15E3, 2F8 and 7G6 (by combining the sequences as shown in Table 3), or sequence variants as described herein thereof.

[0227] 〔Vector〕 Vectors containing the nucleic acid molecules according to the present invention or the plurality of nucleic acid molecules according to the present invention, such as expression vectors, are further included within the scope of the present invention. Usually, the vector contains nucleic acid molecules as described above.

[0228] The present invention also provides a plurality of vectors comprising a plurality of nucleic acid molecules according to the present invention as described above. Thereby, each vector of the plurality of vectors may comprise one or more nucleic acid molecules of the plurality of nucleic acid molecules according to the present invention as described above. In some embodiments, the plurality of vectors may be a combination of a first vector and a second vector, wherein the first vector comprises the first nucleic acid molecule described above (for the combination of nucleic acid molecules), and the second vector comprises the second nucleic acid molecule described above (for the combination of nucleic acid molecules).

[0229] A vector is typically a recombinant nucleic acid molecule, i.e., a nucleic acid molecule that does not exist in nature. Thus, a vector may contain heterologous elements (i.e., sequence elements that do not exist in nature). For example, a vector may contain a multiple cloning site, a heterologous promoter, a heterologous enhancer, a heterologous selection marker (for identifying cells that constitute the vector as compared to cells that do not), a heterologous origin of replication, a heterologous DNA insulator element, etc. In the context of the present invention, a vector is suitable for incorporating or carrying a desired nucleic acid sequence. Such a vector may be a storage vector, an expression vector, a cloning vector, a transfer vector, etc. A storage vector is a vector that enables convenient storage of nucleic acid molecules. Therefore, a vector can contain, for example, sequences corresponding to a desired antibody (heavy chain and / or light chain) according to the present invention. An expression vector can be used for the production of an expression product such as RNA, e.g., mRNA, or a peptide, polypeptide, or protein. For example, an expression vector may contain sequences necessary for transcription of the vector's sequence extension, such as a (heterologous) promoter sequence. A cloning vector is typically a vector that contains a cloning site that can be used to incorporate a nucleic acid sequence into the vector. A cloning vector can be, for example, a plasmid vector or a bacteriophage vector. A transfer vector is a vector suitable for transferring a nucleic acid molecule into a cell or an organism and can be, for example, a viral vector. A vector in the context of the present invention can be, for example, an RNA vector or a DNA vector. For example, a vector in the meaning of the present application contains a cloning site, a selection marker such as an antibiotic resistance factor, and sequences suitable for the propagation of the vector such as an origin of replication. A vector in the context of the present application can be a plasmid vector.

[0230] As used herein, the term "vector" can refer to, for example, a delivery vector for viral or non-viral delivery of the nucleic acids of the present invention. Alternatively, it can refer to a viral or non-viral delivery system. Thus, the present invention also provides a delivery vector / system comprising a nucleic acid molecule as described above (or comprising an expression vector as described above). The delivery vector / system can be viral or non-viral. Various examples of viral and non-viral delivery vectors / systems are known in the art and include, for example, those described in Nayerossadat N, Maedeh T, Ali PA. Viral and nonviral delivery systems for gene delivery. Adv Biomed Res. 2012;1:27. doi:10.4103 / 2277-9175.98152, which is incorporated herein by reference. Non-limiting examples of viral delivery vectors / systems include retroviral vectors; adenoviral vectors; adeno-associated virus (AAV) vectors including helper-dependent adenoviral vectors and hybrid adenoviral vectors; herpes simplex virus vectors; lentiviral vectors; poxvirus vectors and Epstein-Barr virus vectors. Among viral vectors, adenoviral vectors and adeno-associated virus (AAV) vectors are preferred. Non-limiting examples of non-viral delivery vectors / systems include chemical methods and non-chemical methods. Non-chemical delivery includes physical methods such as electroporation and other methods for transient penetration of cell membranes by mechanical, electrical, ultrasonic, hydrodynamic, or laser-based energy; naked DNA or RNA delivery; gene guns; hydrodynamic delivery; ultrasonic delivery and magnetofection. Chemical non-viral delivery systems include cationic particles, particularly cationic lipids / liposomes, cationic polymers, lipid / polymer systems. Among non-viral vectors / systems, cationic liposomes are preferred.

[0231] [Cell] In a further aspect, the invention also provides a (host) cell expressing an antibody according to the invention, or an antigen-binding fragment thereof; and / or a (host) cell comprising a vector (or vectors) according to the invention. The (host) cell can be an isolated cell that is not part of a human or animal body, such as a cell line or an artificial cell. This cell can recombinantly, e.g., heterologously, express the nucleic acid or vector of the invention (i.e., this cell / cell type does not naturally express the antibody or antigen-binding fragment).

[0232] Examples of such cells include, but are not limited to, eukaryotic cells such as yeast cells, animal cells, plant cells, etc. Other examples of such cells include, but are not limited to, prokaryotic cells such as Escherichia coli. In some embodiments, the cell is a mammalian cell such as a mammalian cell line. Examples include human cells, CHO cells, HEK293 cells, PER.C6 cells, NS0 cells, human hepatocytes, myeloma cells or hybridoma cells.

[0233] The cell may be transfected with a vector according to the invention, such as an expression vector. The term "transfection" refers to the introduction of a nucleic acid molecule, such as a DNA or RNA (e.g., mRNA) molecule, into a cell, such as a eukaryotic or prokaryotic cell. In the context of the present invention, the term "transfection" encompasses any method known to those skilled in the art for introducing a nucleic acid molecule into a cell such as a mammalian cell. Such methods include, for example, electroporation, lipofection based on cationic lipids and / or liposomes, calcium phosphate precipitation, nanoparticle-based transfection, virus-based transfection, or transfection based on cationic polymers such as DEAE-dextran or polyethyleneimine. In some embodiments, the introduction is non-viral.

[0234] Furthermore, the cells of the present invention may be stably or transiently transfected with the vectors of the present invention, for example, to express the antibodies according to the present invention. In some embodiments, the cells are stably transfected with the vectors of the present invention encoding the antibodies according to the present invention. In other embodiments, the cells are transiently transfected with the vectors of the present invention encoding the antibodies according to the present invention.

[0235] Accordingly, the present invention also provides recombinant host cells that heterologously express the antibodies of the present invention or antigen-binding fragments thereof. For example, the cells can be of a different species than the antibody (e.g., CHO cells expressing human antibodies). In some embodiments, the cell type of the cells does not naturally express (such) antibodies. Furthermore, the host cell can confer post-translational modifications (PTMs; e.g., glycosylation) to the antibody that do not exist in the native state. Such PTMs can result in functional differences (e.g., reduced immunogenicity). Accordingly, the antibodies of the present invention or antigen-binding fragments thereof can have post-translational modifications distinct from those of naturally produced antibodies (e.g., antibodies of the human immune response).

[0236] [Production of Antibodies] The antibodies according to the present invention can be produced by any method known in the art. For example, the general methodology for producing monoclonal antibodies using hybridoma technology is well known (Kohler, G. and Milstein, C., 1975; Kozbar et al. 1983).

[0237] Standard techniques of molecular biology can be used to prepare the DNA sequences encoding the antibodies or antigen-binding fragments of the present invention. The desired DNA sequence can be synthesized completely or partially, for example, using oligonucleotide synthesis techniques. Site-directed mutagenesis and polymerase chain reaction (PCR) techniques may be used as appropriate.

[0238] For the expression of the DNA sequence encoding the antibody molecule of the present invention, any suitable host cell / vector system can be used. Eukaryotic, for example mammalian host cell expression systems, can be used for the production of antibody molecules such as full antibody molecules. Suitable mammalian host cells include, but are not limited to, CHO, HEK293, PER.C6, NS0, myeloma or hybridoma cells. Also, prokaryotic, for example bacterial host cell expression systems, can be used for the production of antibody molecules such as full antibody molecules. Suitable bacterial host cells include, but are not limited to, E. coli cells.

[0239] Accordingly, the present invention provides a method for preparing an antibody, antigen-binding fragment or immunoglobulin chain according to the present invention, said method comprising (i) culturing a host cell as described above; and (ii) isolating the antibody or immunoglobulin chain from the culture.

[0240] In other words, the present invention also provides a method for producing an antibody molecule according to the present invention, which comprises culturing a (heterologous) host cell containing a vector encoding the nucleic acid of the present invention, particularly under conditions suitable for the expression of a protein from DNA encoding the antibody molecule of the present invention, to isolate the antibody molecule.

[0241] To produce an antibody containing both a heavy chain and a light chain, a host cell such as a cell line may be transfected with two vectors, for example, a first vector encoding a light chain polypeptide and a second vector encoding a heavy chain polypeptide, as described above. Alternatively, a single vector may be used, which vector contains sequences encoding a light chain polypeptide and a heavy chain polypeptide (e.g., in a single-chain antibody or bicistronic manner). Similarly, when expressing a multispecific antibody having two or more immunoglobulin chains, multiple vectors can also be used.

[0242] Accordingly, the present invention also provides a method for preparing a recombinant cell, comprising the following steps: (i) providing one or more nucleic acids encoding an antibody of the present invention; (ii) inserting the nucleic acid into an expression vector; and (iii) transfecting the vector into a (heterologous) host cell to enable expression of the antibody of interest in the host cell. The nucleic acid in step (i) can be manipulated, but is not essential, for introduction of restriction sites, alteration of codon usage, and / or optimization of transcriptional and / or translational regulatory sequences.

[0243] Furthermore, the present invention also provides a method for preparing a transfected host cell, comprising the step of transfecting a host cell with one or more nucleic acids encoding an antibody of interest. Thus, the procedure of first preparing the nucleic acid and then using it to transfect the host cell can be carried out by different people at different times in different locations (e.g., different countries).

[0244] Such recombinant cells of the present invention can be used for the purposes of expression and culture. In particular, they are useful for the expression of antibodies for large-scale pharmaceutical production. They can also be used as an active ingredient of a pharmaceutical composition. Any suitable culture technique can be used, including but not limited to static culture, roller bottle culture, ascites, hollow fiber type bioreactor cartridge, modular mini fermenter, stirred tank, microcarrier culture, ceramic core perfusion, etc.

[0245] The transfected host cells can be eukaryotic cells including yeast and animal cells, particularly mammalian cells (such as human cells like CHO cells, NS0 cells, PER.C6, HEK293 or HKB11 cells, myeloma cells, or human hepatocytes), as well as plant cells. In some embodiments, the transfected host cells are mammalian cells such as human cells. In some embodiments, the expression host can glycosylate the antibodies of the present invention with a sugar chain structure that is not immunogenic per se in humans. In some embodiments, the transfected host cells can be grown in serum-free medium. In further embodiments, the transfected host cells can be grown in culture in the absence of animal-derived products. The transfected host cells may be cultured to obtain cell lines.

[0246] The present invention also provides a method for preparing an antibody of interest, comprising culturing or subculturing a transfected host cell population, such as a stably transfected host cell population, under conditions in which the antibody of interest is expressed, and optionally purifying the antibody of interest. The transfected host cell population can be prepared by (i) providing a nucleic acid encoding the antibody of interest selected, (ii) inserting the nucleic acid into an expression vector, (iii) transfecting the vector into a host cell capable of expressing the antibody of interest, and (iv) culturing or subculturing the transfected host cells containing the inserted nucleic acid to produce the antibody of interest.

[0247] In some embodiments, the antibodies according to the present invention can be produced by (i) expressing the nucleic acid sequence according to the present invention in a host cell, for example, by using a vector (or host cell) according to the present invention, and (ii) isolating the expressed antibody product. Further, the method can include (iii) purifying the isolated antibody.

[0248] Thus, after production, the antibody can be further purified, if necessary, using various chromatography methods such as filtration, centrifugation, HPLC, and affinity chromatography. Techniques for purifying antibodies, such as monoclonal antibodies, are known in the art, including techniques for producing pharmaceutical-grade antibodies.

[0249] [Compositions and Kits] The present invention also provides a composition comprising one or more of the following: (i) an antibody of the invention or an antigen-binding fragment thereof; (ii) a nucleic acid or nucleic acids of the invention; (iii) a vector or vectors of the invention; or (iv) a cell expressing an antibody according to the invention, or a cell comprising a vector according to the invention.

[0250] The present composition can be used for therapeutic or diagnostic purposes. Thus, the composition can be a pharmaceutical composition or a diagnostic composition. The composition may comprise (pharmaceutically acceptable) excipients, diluents or carriers.

[0251] Thus, the present invention also provides a pharmaceutical composition comprising an antibody or an antigen-binding fragment thereof according to the invention, a nucleic acid or nucleic acids of the invention, a vector or vectors of the invention, and / or a cell according to the invention.

[0252] The pharmaceutical composition may optionally also comprise a pharmaceutically acceptable carrier, diluent and / or excipient. The carrier or excipient may facilitate administration, but should not itself induce the production of antibodies harmful to the individual to whom the composition is administered. Also, it should not be toxic. Suitable carriers can be large, slowly metabolized macromolecules such as proteins, polypeptides, liposomes, polysaccharides, polylactic acid, polyglycolic acid, polymeric amino acids, amino acid copolymers and inactivated virus particles. In some embodiments, the pharmaceutically acceptable carrier, diluent and / or excipient in the pharmaceutical composition is not an active ingredient related to peanut allergy.

[0253] Examples of pharmaceutically acceptable salts that can be used include mineral acid salts such as hydrochloride, hydrobromide, phosphate, sulfate, and organic acid salts such as acetate, propionate, malonate, benzoate, and the like.

[0254] The pharmaceutically acceptable carriers in the pharmaceutical composition may further contain liquids such as water, physiological saline, glycerol, ethanol, and the like. Further, auxiliary substances such as wetting agents or emulsifying agents or pH buffering substances may be present in such compositions. With such carriers, the pharmaceutical composition can be formulated into tablets, pills, dragees, capsules, solutions, gels, syrups, slurries, suspensions, etc. and administered to a subject.

[0255] The pharmaceutical composition can be prepared in various dosage forms. For example, the composition can be prepared as an injection as a liquid solution or suspension. It can also be prepared in a solid form suitable for dissolution or suspension in a liquid vehicle before injection (e.g., a lyophilized composition similar to Synagis (trademark) and Herceptin (registered trademark) and reconstituted with sterile water containing a preservative). The present composition can be prepared as, for example, an ointment, cream or powder for topical administration. The present composition can be prepared as, for example, a tablet or capsule, as a spray, or as a (optionally flavored) syrup for oral administration. The composition can be prepared, for example, as an inhaler for pulmonary administration using a fine powder or a spray. The composition can be prepared as a suppository or pessary. The composition can be prepared, for example, as a drop for nasal, ear or eye administration. The composition may be in the form of a kit and designed such that the combined composition is reconstituted immediately prior to administration to a subject. For example, a lyophilized antibody can be provided in kit form together with sterile water or sterile buffer.

[0256] In some embodiments, the (sole) active ingredient in the composition is the antibody described herein. As such, it may be prone to degradation in the gastrointestinal tract. Thus, when the composition is administered via the gastrointestinal tract route, the composition can include an agent that protects the antibody from degradation but releases the antibody upon absorption from the gastrointestinal tract.

[0257] A thorough discussion of pharmaceutically acceptable carriers can be found in Gennaro (2000) Remington: The Science and Practice of Pharmacy, 20th edition, ISBN: 0683306472.

[0258] The present invention also provides a method for preparing a pharmaceutical composition comprising the following steps: (i) preparing the antibody of the present invention; and (ii) mixing the purified antibody with one or more pharmaceutically acceptable excipients, diluents or carriers.

[0259] In other embodiments, the method for preparing a pharmaceutical composition includes the step of mixing an antibody with one or more pharmaceutically acceptable carriers, wherein the antibody is a monoclonal antibody.

[0260] The pharmaceutical composition can generally have a pH between 5.5 and 8.5, and in some embodiments, the pH can be between 6 and 8, for example, about 7. The composition can be sterile and / or pyrogen-free. The composition can be isotonic with respect to humans. In some embodiments, the pharmaceutical composition is supplied in a sealed container.

[0261] Compositions in several dosage forms are included within the scope of the present invention; the forms include, but are not limited to, forms suitable for parenteral administration, such as injection or infusion, such as bolus injection or continuous infusion. When the composition is for injection or infusion, it can take the form of a suspension, solution or emulsion in an oily or aqueous vehicle and can include formulation agents such as suspending agents, preservatives, stabilizers and / or dispersing agents. Alternatively, the antibody can be in a dry form that is reconstituted with a suitable sterile liquid before use.

[0262] The vehicle is typically understood to be a material suitable for storing, transporting, and / or administering a pharmaceutically active compound, particularly a compound such as the antibodies described herein. For example, the vehicle can be a physiologically acceptable liquid suitable for storing, transporting, and / or administering a pharmaceutically active compound, particularly the antibodies described herein. Once formulated, the composition can be administered directly to a subject. In some embodiments, the composition is adapted for administration to a mammalian, e.g., human subject.

[0263] The pharmaceutical composition can include an antibacterial agent, particularly when packaged in a form for multiple administrations. For example, it may contain a detergent such as Tween (polysorbate) such as Tween80. The detergent is generally present at a low level, e.g., less than 0.01%. The composition can also contain a sodium salt (e.g., sodium chloride) to provide tonicity. For example, a NaCl concentration of 10±2 mg / ml is typical.

[0264] Furthermore, the pharmaceutical composition can contain, for example, a sugar alcohol (e.g., mannitol) or a disaccharide (e.g., sucrose or trehalose) at about 15 - 30 mg / ml (e.g., 25 mg / ml), particularly when lyophilized or when containing a material reconstituted from a lyophilized material. The pH of the composition for lyophilization can be adjusted to 5 - 8, or 5.5 - 7, or around 6.1 before lyophilization.

[0265] The pharmaceutical composition can be administered by any number of routes including, but not limited to, oral, intravenous, intramuscular, intraarterial, intramedullary, intraperitoneal, intrathecal, intraventricular, percutaneous, transdermal, topical, subcutaneous, nasal, enteral, sublingual, intravaginal or rectal routes. Optionally, the pharmaceutical composition can be prepared, for example, as tablets, capsules, etc. for oral administration, or as liquid solutions or suspensions for topical administration or for injection. In some embodiments, the pharmaceutical composition is an injectable. Solid forms suitable for solutions or suspensions in a liquid vehicle prior to injection may also be included, for example, the pharmaceutical composition can be in lyophilized form.

[0266] In the case of injection, for example intravenous injection, skin injection, subcutaneous injection, or injection into the affected area, the active ingredient can be in the form of a parenterally acceptable aqueous solution that is pyrogen-free and has appropriate pH, isotonicity and stability. A person skilled in the art can prepare an appropriate solution using an isotonic vehicle such as, for example, sodium chloride injection solution, Ringer's injection solution, lactated Ringer's injection solution. Optionally, it can contain preservatives, stabilizers, buffers, antioxidants and / or other additives. Whether the individual is to be administered an antibody, peptide, nucleic acid molecule, or other pharmaceutically useful compound, the administration is usually carried out in an "effective amount", for example an "effectively prophylactic amount" or an "effectively therapeutic amount" (where appropriate), which is an amount sufficient to show benefit to the individual. The actual dosage, rate of administration and time of administration depend on the nature and severity of the subject to be treated. In the case of injection, the pharmaceutical composition can be provided, for example, in a pre-filled syringe.

[0267] The pharmaceutical composition can also be orally administered in any orally acceptable dosage form including, but not limited to, capsules, tablets, aqueous suspensions or solutions. In the case of tablets for oral use, commonly used carriers include lactose and corn starch. Lubricants such as magnesium stearate are also typically added. When orally administered in capsule form, useful diluents include lactose and dried corn starch. When an aqueous suspension is required for oral administration, the active ingredient, i.e., the antibody defined above, is used in combination with an emulsifying agent and a suspending agent. Optionally, certain sweetening, flavoring and coloring agents can also be added.

[0268] The pharmaceutical composition can also be topically administered, particularly when the treatment target is an accessible area or organ where topical administration is easy, such as an accessible epithelial tissue. Suitable topical formulations can be easily prepared for each of these areas or organs. The pharmaceutical composition can be formulated into a suitable ointment for topical administration by suspending or dissolving the pharmaceutical composition, particularly the components as defined above, in one or more carriers. Carriers for topical administration include, but are not limited to, mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene, polyoxypropylene compounds, emulsifying wax and water. Alternatively, the pharmaceutical composition can be formulated into a suitable lotion or cream. Suitable carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl ester wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water.

[0269] The dosing regimen can be a single-dose schedule or a multiple-dose schedule. In a single-dose administration, for example, daily, weekly or monthly dosing, the amount of the antibody in the pharmaceutical composition does not exceed 1 g or 500 mg. In some embodiments, in a single-dose administration, the amount of the antibody in the pharmaceutical composition does not exceed 200 mg, or does not exceed 100 mg. For example, in the case of a single-dose administration, the amount of the antibody in the pharmaceutical composition does not exceed 50 mg.

[0270] In some embodiments, the composition may comprise an antibody of the invention, where the antibody may account for at least 50% by weight of the total protein in the composition (e.g., 60%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or more). In the composition, the antibody may be in a purified form.

[0271] Instead of delivering an antibody for therapeutic purposes, it is also possible to deliver to a subject a nucleic acid (typically DNA) encoding the monoclonal antibody of interest, such that the nucleic acid is expressed in situ within the subject to obtain the desired therapeutic effect. Suitable gene therapy and nucleic acid transfection vectors are known in the art.

[0272] A pharmaceutical composition typically comprises an “effective” amount of one or more of the antibodies described herein, i.e., an amount sufficient to treat, ameliorate, attenuate, reduce or prevent a desired disease or condition, or to exhibit a detectable therapeutic effect. Therapeutic effects also include reduction or attenuation of the effects of a pathogen or physical symptoms. The exact effective amount for a particular subject depends on the subject's physical characteristics, weight, health status, nature and extent of the medical condition, and the therapeutic agent or combination of therapeutic agents selected for administration. The effective amount for a given situation is determined by routine experimentation and is within the judgment of the clinician. The effective amount can generally be from about 0.005 to about 100 mg / kg, e.g., from about 0.0075 to about 50 mg / kg, or from about 0.01 to about 10 mg / kg. In some embodiments, the effective amount can be from about 0.02 to about 5 mg / kg in terms of the amount of antibody (e.g., the amount of antibody in the pharmaceutical composition) per unit body weight (e.g., in kg) of the individual to whom it is administered.

[0273] Furthermore, the pharmaceutical composition may comprise additional active ingredients, which may be additional antibodies or non-antibody components. In other embodiments, the pharmaceutical composition may not comprise additional active ingredients (in addition to the antibodies, nucleic acids, vectors or cells of the invention described above).

[0274] Accordingly, the pharmaceutical composition may comprise one or more additional active ingredients. The antibody of the present invention may be present in the same pharmaceutical composition as the additional active ingredient, or the antibody may be constituted by a first pharmaceutical composition and the additional active ingredient may be constituted by a second pharmaceutical composition different from the first pharmaceutical composition. Thus, when a plurality of additional active ingredients are envisaged, each additional active ingredient and the antibody may be constituted as different pharmaceutical compositions. Such different pharmaceutical compositions may be administered in combination / simultaneously, or at separate times or at separate locations (e.g., separate parts of the body), optionally by different routes of administration.

[0275] The antibody and the additional active ingredient may result in an additive therapeutic effect, such as a synergistic therapeutic effect. The term "synergistic effect" is used to denote that the combined effect of two or more active agents is greater than the sum of the individual effects of each active agent. Thus, when a "synergistic inhibition" of an activity or process is brought about by the combined effect of two or more agents, it is intended that the inhibition of the activity or process is greater than the sum of the inhibitory effects of the individual active agents. The term "synergistic therapeutic effect" is a therapeutic effect observed by the combination of two or more therapies, and means that the therapeutic effect (measured by some parameters) is greater than the sum of the individual therapeutic effects observed by the individual therapies.

[0276] Preferably, the composition comprises at least two distinct antibodies, or antigen-binding fragments thereof, that bind to distinct non-overlapping epitopes of Ara h 2. More preferably, the composition comprises exactly three distinct antibodies, or antigen-binding fragments thereof, that bind to distinct non-overlapping epitopes of Ara h 2. Even more preferably, the composition comprises exactly four distinct antibodies, or antigen-binding fragments thereof, that bind to distinct non-overlapping epitopes of Ara h 2. For this purpose, the antibodies included in the composition can be selected from, for example, the four distinct antibodies 17H9, 15E3, 2F8 and 7G6, or variants thereof, as described in Tables 1 and 2. As shown in the attached examples, 17H9, 15E3, 2F8 and 7G6 bind to distinct non-overlapping epitopes of Ara h 2.

[0277] Accordingly, the composition can comprise at least two of the following: (i) an antibody or antigen-binding fragment thereof that comprises, for 17H9, (a) the CDRH1, CDRH2, CDRH3, CDRL1, CDRL2 and CDRL3 sequences and / or (b) the VH and VL sequences, or sequence variants thereof as described above; (ii) an antibody or antigen-binding fragment thereof that comprises, for 15E3, (a) the CDRH1, CDRH2, CDRH3, CDRL1, CDRL2 and CDRL3 sequences and / or (b) the VH and VL sequences, or sequence variants thereof as described above; (iii) an antibody or antigen-binding fragment thereof that comprises, for 2F8, (a) the CDRH1, CDRH2, CDRH3, CDRL1, CDRL2 and CDRL3 sequences and / or (b) the VH and VL sequences, or sequence variants thereof as described above; and / or, (iv) an antibody or antigen-binding fragment thereof that comprises, for 7G6, (a) the CDRH1, CDRH2, CDRH3, CDRL1, CDRL2 and CDRL3 sequences as described above and / or (b) the VH and VL sequences, or sequence variants thereof as described above.

[0278] In some embodiments, the composition comprises the following (exactly) two distinct antibodies. The two distinct antibodies are: (i) an antibody or antigen-binding fragment thereof comprising (a) the CDRH1, CDRH2, CDRH3, CDRL1, CDRL2 and CDRL3 sequences and / or (b) the VH and VL sequences of 17H9, or sequence variants thereof as described above; and, (ii) an antibody or antigen-binding fragment thereof comprising (a) the CDRH1, CDRH2, CDRH3, CDRL1, CDRL2 and CDRL3 sequences and / or (b) the VH and VL sequences of 15E3, or sequence variants thereof as described above.

[0279] In some embodiments, the composition comprises the following (exactly) two distinct antibodies. The two distinct antibodies are: (i) an antibody or antigen-binding fragment thereof comprising (a) the CDRH1, CDRH2, CDRH3, CDRL1, CDRL2 and CDRL3 sequences and / or (b) the VH and VL sequences of 17H9, or sequence variants thereof as described above; and, (iii) an antibody or antigen-binding fragment thereof comprising (a) the CDRH1, CDRH2, CDRH3, CDRL1, CDRL2 and CDRL3 sequences and / or (b) the VH and VL sequences of 2F8, or sequence variants thereof as described above.

[0280] In some embodiments, the composition comprises the following (exactly) two distinct antibodies: (ii) an antibody or antigen-binding fragment thereof comprising (a) the CDRH1, CDRH2, CDRH3, CDRL1, CDRL2 and CDRL3 sequences and / or (b) the VH and VL sequences of 15E3, or sequence variants thereof as described above; and, (iv) An antibody or an antigen-binding fragment thereof comprising (a) the CDRH1, CDRH2, CDRH3, CDRL1, CDRL2 and CDRL3 sequences and / or (b) the VH and VL sequences of 7G6, or sequence variants thereof as described above.

[0281] In some embodiments, the composition comprises exactly two distinct antibodies as follows: (iii) The above antibody or an antigen-binding fragment thereof comprising (a) the CDRH1, CDRH2, CDRH3, CDRL1, CDRL2 and CDRL3 sequences and / or (b) the VH and VL sequences of 2F8, or sequence variants thereof as described above; and (iv) An antibody or an antigen-binding fragment thereof comprising (a) the CDRH1, CDRH2, CDRH3, CDRL1, CDRL2 and CDRL3 sequences and / or (b) the VH and VL sequences of 7G6, or sequence variants thereof as described above.

[0282] Preferably, the composition comprises exactly two distinct antibodies as follows: (ii) The above antibody or an antigen-binding fragment thereof comprising (a) the CDRH1, CDRH2, CDRH3, CDRL1, CDRL2 and CDRL3 sequences and / or (b) the VH and VL sequences of 15E3, or sequence variants thereof as described above; and (iii) An antibody or an antigen-binding fragment thereof comprising (a) the CDRH1, CDRH2, CDRH3, CDRL1, CDRL2 and CDRL3 sequences and / or (b) the VH and VL sequences of 2F8, or sequence variants thereof as described above.

[0283] More preferably, it comprises exactly two distinct antibodies as follows: (i) An antibody or an antigen-binding fragment thereof that comprises (a) the CDRH1, CDRH2, CDRH3, CDRL1, CDRL2, and CDRL3 sequences and / or (b) the VH and VL sequences of 17H9, or sequence variants thereof as described above; and, (iv) An antibody or an antigen-binding fragment thereof that comprises (a) the CDRH1, CDRH2, CDRH3, CDRL1, CDRL2, and CDRL3 sequences and / or (b) the VH and VL sequences of 7G6, or sequence variants thereof as described above.

[0284] Preferably, the composition comprises (exactly) three or four distinct antibodies, or antigen-binding fragments, that bind to distinct non-overlapping epitopes of Ara h 2, wherein the (exactly) three or four distinct antibodies, or antigen-binding fragments, are preferably selected from (i)-(iv) above.

[0285] In some embodiments, the composition comprises the following (exactly) three distinct antibodies. The three distinct antibodies are: (i) An antibody or an antigen-binding fragment thereof that comprises (a) the CDRH1, CDRH2, CDRH3, CDRL1, CDRL2, and CDRL3 sequences and / or (b) the VH and VL sequences of 17H9, or sequence variants thereof as described above; (ii) The above-mentioned antibody or an antigen-binding fragment thereof that comprises (a) the CDRH1, CDRH2, CDRH3, CDRL1, CDRL2, and CDRL3 sequences and / or (b) the VH and VL sequences of 15E3, or sequence variants thereof as described above; and, (iii) An antibody or an antigen-binding fragment thereof that comprises (a) the CDRH1, CDRH2, CDRH3, CDRL1, CDRL2, and CDRL3 sequences and / or (b) the VH and VL sequences of 2F8, or sequence variants thereof as described above.

[0286] In some embodiments, the composition comprises the following (exactly) three distinct antibodies. The three distinct antibodies are: (i) An antibody or an antigen-binding fragment thereof that comprises (a) the CDRH1, CDRH2, CDRH3, CDRL1, CDRL2, and CDRL3 sequences and / or (b) the VH and VL sequences of 17H9, or sequence variants thereof as described above. (iii) The above antibody or an antigen-binding fragment thereof that comprises (a) the CDRH1, CDRH2, CDRH3, CDRL1, CDRL2, and CDRL3 sequences and / or (b) the VH and VL sequences of 2F8, or sequence variants thereof as described above; and, (iv) An antibody or an antigen-binding fragment thereof that comprises (a) the CDRH1, CDRH2, CDRH3, CDRL1, CDRL2, and CDRL3 sequences and / or (b) the VH and VL sequences of 7G6, or sequence variants thereof as described above.

[0287] In some embodiments, the composition comprises the following (exactly) three distinct antibodies. The three distinct antibodies are: (ii) An antibody or an antigen-binding fragment thereof that comprises (a) the CDRH1, CDRH2, CDRH3, CDRL1, CDRL2, and CDRL3 sequences and / or (b) the VH and VL sequences of 15E3, or sequence variants thereof as described above. (iii) The above antibody or an antigen-binding fragment thereof that comprises (a) the CDRH1, CDRH2, CDRH3, CDRL1, CDRL2, and CDRL3 sequences and / or (b) the VH and VL sequences of 2F8, or sequence variants thereof as described above; and, (iv) An antibody or an antigen-binding fragment thereof that comprises (a) the CDRH1, CDRH2, CDRH3, CDRL1, CDRL2, and CDRL3 sequences and / or (b) the VH and VL sequences of 7G6, or sequence variants thereof as described above.

[0288] Preferably, the composition comprises the following (exactly) three distinct antibodies. The three distinct antibodies are: (i) An antibody or an antigen-binding fragment thereof comprising (a) the CDRH1, CDRH2, CDRH3, CDRL1, CDRL2 and CDRL3 sequences and / or (b) the VH and VL sequences of 17H9, or sequence variants thereof as described above; (ii) An antibody or an antigen-binding fragment thereof comprising (a) the CDRH1, CDRH2, CDRH3, CDRL1, CDRL2 and CDRL3 sequences and / or (b) the VH and VL sequences of 15E3, or sequence variants thereof as described above; and, (iv) An antibody or an antigen-binding fragment thereof comprising (a) the CDRH1, CDRH2, CDRH3, CDRL1, CDRL2 and CDRL3 sequences and / or (b) the VH and VL sequences of 7G6, or sequence variants thereof as described above.

[0289] Also, it is preferred that the composition contains (exactly) four distinct antibodies. The four distinct antibodies are: (i) An antibody or an antigen-binding fragment thereof comprising (a) the CDRH1, CDRH2, CDRH3, CDRL1, CDRL2 and CDRL3 sequences and / or (b) the VH and VL sequences of 17H9, or sequence variants thereof as described above; (ii) An antibody or an antigen-binding fragment thereof comprising (a) the CDRH1, CDRH2, CDRH3, CDRL1, CDRL2 and CDRL3 sequences and / or (b) the VH and VL sequences of 15E3, or sequence variants thereof as described above; (iii) An antibody or an antigen-binding fragment thereof comprising (a) the CDRH1, CDRH2, CDRH3, CDRL1, CDRL2 and CDRL3 sequences and / or (b) the VH and VL sequences of 2F8, or sequence variants thereof as described above; and, (iv) An antibody or an antigen-binding fragment thereof comprising (a) the CDRH1, CDRH2, CDRH3, CDRL1, CDRL2 and CDRL3 sequences and / or (b) the VH and VL sequences of 7G6, or sequence variants thereof as described above.

[0290] In some embodiments, the composition can include the following (i) and (ii): (i) an antibody or an antigen-binding fragment thereof that includes, for 17H9, (a) the CDRH1, CDRH2, CDRH3, CDRL1, CDRL2, and CDRL3 sequences and / or (b) the VH and VL sequences, or sequence variants thereof as described above; and (ii) an antibody or an antigen-binding fragment thereof that includes, for the (wild-type) 7G6 as described above, (a) the CDRH1, CDRH2, CDRH3, CDRL1, CDRL2, and CDRL3 sequences and / or (b) the VH and VL sequences, or sequence variants thereof described, for example, in Tables 1 and 2 herein. Optionally, such a composition can further include an antibody or an antigen-binding fragment thereof that includes the CDR and / or VH / VL sequences of 15E3 (or a sequence variant thereof), and / or an antibody or an antigen-binding fragment thereof that includes the CDR and / or VH / VL sequences of 2F8 (or a sequence variant thereof).

[0291] In some embodiments, the composition can include the following (i) and (ii): (i) an antibody or an antigen-binding fragment thereof that includes, for 17H9, (a) the CDRH1, CDRH2, CDRH3, CDRL1, CDRL2, and CDRL3 sequences and / or (b) the VH and VL sequences, or sequence variants thereof as described above; and (ii) an antibody or an antigen-binding fragment thereof that includes, for the (wild-type) 2F8 as described above, (a) the CDRH1, CDRH2, CDRH3, CDRL1, CDRL2, and CDRL3 sequences and / or (b) the VH and VL sequences, or sequence variants thereof described, for example, in Tables 1 and 2 herein. Optionally, such a composition can further include an antibody or an antigen-binding fragment thereof that includes the CDR and / or VH / VL sequences of 15E3 (or a sequence variant thereof), and / or an antibody or an antigen-binding fragment thereof that includes the CDR and / or VH / VL sequences of 7G6 (or a sequence variant thereof).

[0292] In some embodiments, the composition can include the following (i) and (ii): (i) an antibody or antigen-binding fragment thereof that includes, for 15E3, (a) the CDRH1, CDRH2, CDRH3, CDRL1, CDRL2, and CDRL3 sequences and / or (b) the VH and VL sequences, or sequence variants thereof as described above; and, (ii) an antibody or antigen-binding fragment thereof that includes, for the above-described (wild-type) 7G6, (a) the CDRH1, CDRH2, CDRH3, CDRL1, CDRL2, and CDRL3 sequences and / or (b) the VH and VL sequences, or sequence variants thereof as described, for example, in Tables 1 and 2 herein. Optionally, such a composition can further include an antibody or antigen-binding fragment thereof that includes the CDR and / or VH / VL sequences of 17H9 (or a sequence variant thereof), and / or an antibody or antigen-binding fragment thereof that includes the CDR and / or VH / VL sequences of 2F8 (or a sequence variant thereof).

[0293] In some embodiments, the composition can include the following (i) and (ii): (i) an antibody or antigen-binding fragment thereof that includes, for 15E3, (a) the CDRH1, CDRH2, CDRH3, CDRL1, CDRL2, and CDRL3 sequences and / or (b) the VH and VL sequences, or sequence variants thereof as described above; and, (ii) an antibody or antigen-binding fragment thereof that includes, for the (wild-type) 2F8, (a) the CDRH1, CDRH2, CDRH3, CDRL1, CDRL2, and CDRL3 sequences and / or (b) the VH and VL sequences, or sequence variants thereof as described, for example, in Tables 1 and 2 herein. Optionally, such a composition can further include an antibody or antigen-binding fragment thereof that includes the CDR and / or VH / VL sequences of 17H9 (or a sequence variant thereof), and / or an antibody or antigen-binding fragment thereof that includes the CDR and / or VH / VL sequences of 7G6 (or a sequence variant thereof).

[0294] The present invention also provides a composition comprising at least three different antibodies, or antigen-binding fragments thereof. Here, the three different antibodies or antigen-binding fragments bind to different non-overlapping epitopes of Ara h 2. Here, the composition comprises at least three of the following (i) to (iv): (i) An antibody or an antigen-binding fragment thereof comprising a CDRH1 having at least 70% identity with SEQ ID NO: 1, a CDRH2 having at least 70% identity with SEQ ID NO: 2, a CDRH3 having at least 70% identity with SEQ ID NO: 3, a CDRL1 having at least 70% identity with SEQ ID NO: 4, a CDRL2 having at least 70% identity with SEQ ID NO: 5, and a CDRL3 having at least 70% identity with SEQ ID NO: 6; (ii) An antibody or an antigen-binding fragment thereof comprising a CDRH1 having at least 70% identity with SEQ ID NO: 9, a CDRH2 having at least 70% identity with SEQ ID NO: 10, a CDRH3 having at least 70% identity with SEQ ID NO: 11, a CDRL1 having at least 70% identity with SEQ ID NO: 12, a CDRL2 having at least 70% identity with SEQ ID NO: 13, and a CDRL3 having at least 70% identity with SEQ ID NO: 14; (iii) An antibody or an antigen-binding fragment thereof comprising a CDRH1 having at least 70% identity with SEQ ID NO: 17, a CDRH2 having at least 70% identity with SEQ ID NO: 18, a CDRH3 having at least 70% identity with SEQ ID NO: 19 or 51, a CDRL1 having at least 70% identity with SEQ ID NO: 20, a CDRL2 having at least 70% identity with SEQ ID NO: 21, and a CDRL3 having at least 70% identity with SEQ ID NO: 22; (iv) An antibody or an antigen-binding fragment thereof comprising a CDRH1 having at least 70% identity with SEQ ID NO: 25, a CDRH2 having at least 70% identity with SEQ ID NO: 26, a CDRH3 having at least 70% identity with SEQ ID NO: 27, a CDRL1 having at least 70% identity with SEQ ID NO: 28, a CDRL2 having at least 70% identity with SEQ ID NO: 29 or 52, and a CDRL3 having at least 70% identity with SEQ ID NO: 30.

[0295] Preferably, the composition comprises at least three of the following: (i) An antibody or an antigen-binding fragment thereof comprising CDRH1 set forth in SEQ ID NO: 1, CDRH2 set forth in SEQ ID NO: 2, CDRH3 set forth in SEQ ID NO: 3, CDRL1 set forth in SEQ ID NO: 4, CDRL2 set forth in SEQ ID NO: 5, and CDRL3 set forth in SEQ ID NO: 6; (ii) An antibody or an antigen-binding fragment thereof comprising CDRH1 set forth in SEQ ID NO: 9, CDRH2 set forth in SEQ ID NO: 10, CDRH3 set forth in SEQ ID NO: 11, CDRL1 set forth in SEQ ID NO: 12, CDRL2 set forth in SEQ ID NO: 13, and CDRL3 set forth in SEQ ID NO: 14; (iii) An antibody or an antigen-binding fragment thereof comprising CDRH1 set forth in SEQ ID NO: 17, CDRH2 set forth in SEQ ID NO: 18, CDRH3 set forth in SEQ ID NO: 19 or 51, CDRL1 set forth in SEQ ID NO: 20, CDRL2 set forth in SEQ ID NO: 21, and CDRL3 set forth in SEQ ID NO: 22; (iv) An antibody or an antigen-binding fragment thereof comprising CDRH1 set forth in SEQ ID NO: 25, CDRH2 set forth in SEQ ID NO: 26, CDRH3 set forth in SEQ ID NO: 27, CDRL1 set forth in SEQ ID NO: 28, CDRL2 set forth in SEQ ID NO: 29 or 52, and CDRL3 set forth in SEQ ID NO: 30.

[0296] More preferably, the composition comprises at least three of the following: (i) An antibody or an antigen-binding fragment thereof comprising a VH having at least 70% identity with any one of SEQ ID NOs: 7, 44, and 45; and a VL having at least 70% identity with any one of SEQ ID NOs: 8, 46, 47, 48, and 49; (ii) An antibody or an antigen-binding fragment thereof comprising a VH having at least 70% identity with any one of SEQ ID NOs: 15, 37, and 38; and a VL having at least 70% identity with any one of SEQ ID NOs: 16, 39, and 40; (iii) A VH having at least 70% identity with any one of SEQ ID NOs: 23, 41, 50 and 53; and a VL having at least 70% identity with any one of SEQ ID NOs: 24, 42 and 43, or an antigen-binding fragment thereof; (iv) A VH having at least 70% identity with any one of SEQ ID NOs: 31, 33 and 34; and a VL having at least 70% identity with any one of SEQ ID NOs: 32, 35, 36 and 54, or an antigen-binding fragment thereof.

[0297] Even more preferably, the composition comprises at least three of the following: (i) An antibody or an antigen-binding fragment thereof comprising a VH as set forth in any one of SEQ ID NOs: 7, 44 and 45 and a VL as set forth in any one of SEQ ID NOs: 8, 46, 47, 48 and 49; (ii) An antibody or an antigen-binding fragment thereof comprising a VH according to any one of SEQ ID NOs: 15, 37 and 38 and a VL as set forth in any one of SEQ ID NOs: 16, 39 and 40; (iii) An antibody or an antigen-binding fragment thereof comprising a VH as set forth in any one of SEQ ID NOs: 23, 41, 50 and 53 and a VL as set forth in any one of SEQ ID NOs: 24, 42 and 43; (iv) An antibody or an antigen-binding fragment thereof comprising a VH according to any one of SEQ ID NOs: 31, 33 and 34 and a VL according to any one of SEQ ID NOs: 32, 35, 36 and 54.

[0298] In some embodiments, the composition comprises: (i) An antibody or an antigen-binding fragment thereof comprising: CDRH1 having at least 70% identity with SEQ ID NO: 1, CDRH2 having at least 70% identity with SEQ ID NO: 2, CDRH3 having at least 70% identity with SEQ ID NO: 3, CDRL1 having at least 70% identity with SEQ ID NO: 4, CDRL2 having at least 70% identity with SEQ ID NO: 5, and CDRL3 having at least 70% identity with SEQ ID NO: 6; In particular, CDRH1 set forth in SEQ ID NO: 1, CDRH2 set forth in SEQ ID NO: 2, CDRH3 set forth in SEQ ID NO: 3, CDRL1 set forth in SEQ ID NO: 4, CDRL2 set forth in SEQ ID NO: 5, and CDRL3 set forth in SEQ ID NO: 6; In some embodiments, a VH having at least 70% identity with any one of SEQ ID NOs: 7, 44, and 45; and a VL having at least 70% identity with any one of SEQ ID NOs: 8, 46, 47, 48, and 49; wherein CDRH1 according to SEQ ID NO: 1, CDRH2 set forth in SEQ ID NOs: 1 and 2, CDRH3 set forth in SEQ ID NO: 3, CDRL1 set forth in SEQ ID NO: 4, CDRL2 set forth in SEQ ID NO: 5, and CDRL3 set forth in SEQ ID NO: 6 are preferably maintained; For example, a VH by any one of SEQ ID NOs: 7, 44, and 45; and a VL by any one of SEQ ID NOs: 8, 46, 47, 48, and 49, etc.; (ii) An antibody or an antigen-binding fragment thereof comprising the following: CDRH1 having at least 70% identity with SEQ ID NO: 9, CDRH2 having at least 70% identity with SEQ ID NO: 10, CDRH3 having at least 70% identity with SEQ ID NO: 11, CDRL1 having at least 70% identity with SEQ ID NO: 12, CDRL2 having at least 70% identity with SEQ ID NO: 13, and CDRL3 having at least 70% identity with SEQ ID NO: 14; In particular, CDRH1 set forth in SEQ ID NO: 9, CDRH2 set forth in SEQ ID NO: 10, CDRH3 set forth in SEQ ID NO: 11, CDRL1 set forth in SEQ ID NO: 12, CDRL2 set forth in SEQ ID NO: 13, and CDRL3 set forth in SEQ ID NO: 14; In some embodiments, a VH having at least 70% identity with any one of SEQ ID NOs: 15, 37, and 38; and a VL having at least 70% identity with any one of SEQ ID NOs: 16, 39, and 40; wherein CDRH1 set forth in SEQ ID NO: 9, CDRH2 set forth in SEQ ID NOs: 9 and 10, CDRH3 set forth in SEQ ID NO: 11, CDRL1 set forth in SEQ ID NO: 12, CDRL2 set forth in SEQ ID NO: 13, and CDRL3 set forth in SEQ ID NO: 14 are preferably maintained; VH as described in any one of SEQ ID NOs: 15, 37, and 38; and VL as described in any one of SEQ ID NOs: 16, 39, and 40; and, (iii) an antibody or an antigen-binding fragment thereof comprising: CDRH1 having at least 70% identity with SEQ ID NO: 17, CDRH2 having at least 70% identity with SEQ ID NO: 18, CDRH3 having at least 70% identity with SEQ ID NO: 19 or 51, CDRL1 having at least 70% identity with SEQ ID NO: 20, CDRL2 having at least 70% identity with SEQ ID NO: 21, and CDRL3 having at least 70% identity with SEQ ID NO: 22; In particular, CDRH1 as described in SEQ ID NO: 17, CDRH2 as described in SEQ ID NO: 18, CDRH3 as described in SEQ ID NO: 19 or 51, CDRL1 as described in SEQ ID NO: 20, CDRL2 as described in SEQ ID NO: 21, and CDRL3 as described in SEQ ID NO: 22; In some embodiments, VH having at least 70% identity with any one of SEQ ID NOs: 23, 41, 50, and 53; and VL having at least 70% identity with any one of SEQ ID NOs: 24, 42, and 43; wherein CDRH1 as described in SEQ ID NO: 17, CDRH3 as described in SEQ ID NO: 18 or 51, CDRL1 as described in SEQ ID NO: 20, CDRL2 as described in SEQ ID NO: 20, SEQ ID NO: 17, CDRH2 as described in SEQ ID NO: 18, CDRH3 as described in SEQ ID NO: 19 or 51, CDRL1 as described in SEQ ID NO: 20, CDRL2 as described in SEQ ID NO: 21, and CDRL3 as described in SEQ ID NO: 22 are preferably maintained; For example, VH as described in any one of SEQ ID NOs: 23, 41, 50, and 53; and VL as described in any one of SEQ ID NOs: 24, 42, and 43.

[0299] In some embodiments, the composition comprises: (i) an antibody or an antigen-binding fragment thereof, comprising: CDRH1 having at least 70% identity with SEQ ID NO: 1, CDRH2 having at least 70% identity with SEQ ID NO: 2, CDRH3 having at least 70% identity with SEQ ID NO: 3, CDRL1 having at least 70% identity with SEQ ID NO: 4, CDRL2 having at least 70% identity with SEQ ID NO: 5, and CDRL3 having at least 70% identity with SEQ ID NO: 6; In particular, CDRH1 as set forth in SEQ ID NO: 1, CDRH2 as set forth in SEQ ID NO: 2, CDRH3 as set forth in SEQ ID NO: 3, CDRL1 as set forth in SEQ ID NO: 4, CDRL2 as set forth in SEQ ID NO: 5, and CDRL3 as set forth in SEQ ID NO: 6; In some embodiments, VH having at least 70% identity with any one of SEQ ID NOs: 7, 44, and 45; and VL having at least 70% identity with any one of SEQ ID NOs: 8, 46, 47, 48, and 49; wherein CDRH1 as set forth in SEQ ID NO: 1, SEQ ID NO: 1, CDRH2 as set forth in SEQ ID NO: 2, CDRH3 as set forth in SEQ ID NO: 3, CDRL1 as set forth in SEQ ID NO: 4, CDRL2 as set forth in SEQ ID NO: 5, and CDRL3 as set forth in SEQ ID NO: 6 are preferably maintained; For example, VH as set forth in any one of SEQ ID NOs: 7, 44, and 45; and VL as set forth in any one of SEQ ID NOs: 8, 46, 47, 48, and 49, etc.; (iii) An antibody or an antigen-binding fragment thereof comprising: CDRH1 having at least 70% identity with SEQ ID NO: 17, CDRH2 having at least 70% identity with SEQ ID NO: 18, CDRH3 having at least 70% identity with SEQ ID NO: 19 or 51, CDRL1 having at least 70% identity with SEQ ID NO: 20, CDRL2 having at least 70% identity with SEQ ID NO: 21, and CDRL3 having at least 70% identity with SEQ ID NO: 22; In particular, CDRH1 as set forth in SEQ ID NO: 17, CDRH2 as set forth in SEQ ID NO: 18, CDRH3 as set forth in SEQ ID NO: 19 or 51, CDRL1 as set forth in SEQ ID NO: 20, CDRL2 as set forth in SEQ ID NO: 21, and CDRL3 as set forth in SEQ ID NO: 22; In some embodiments, a VH having at least 70% identity to any one of SEQ ID NO: 23, 41, 50, and 53; and a VL having at least 70% identity to any one of SEQ ID NO: 24, 42, and 43; wherein CDRH1 as set forth in SEQ ID NO: 17, CDRH3 as set forth in SEQ ID NO: 18 or 51, CDRL1 as set forth in SEQ ID NO: 20, CDRL2 as set forth in SEQ ID NO: 20, CDRH2 as set forth in SEQ ID NO: 17, SEQ ID NO: 18, CDRH3 as set forth in SEQ ID NO: 19 or 51, CDRL1 as set forth in SEQ ID NO: 20, CDRL2 as set forth in SEQ ID NO: 21, and CDRL3 as set forth in SEQ ID NO: 22 are preferably maintained; A VH as set forth in any one of SEQ ID NO: 23, 41, 50, and 53; and a VL as set forth in any one of SEQ ID NO: 24, 42, and 43; and, (iv) an antibody or an antigen-binding fragment thereof comprising: CDRH1 having at least 70% identity to SEQ ID NO: 25, CDRH2 having at least 70% identity to SEQ ID NO: 26, CDRH3 having at least 70% identity to SEQ ID NO: 27, CDRL1 having at least 70% identity to SEQ ID NO: 28, CDRL2 having at least 70% identity to SEQ ID NO: 29 or 52, and CDRL3 having at least 70% identity to SEQ ID NO: 30; In particular, CDRH1 as set forth in SEQ ID NO: 25, CDRH2 as set forth in SEQ ID NO: 26, CDRH3 as set forth in SEQ ID NO: 27, CDRL1 as set forth in SEQ ID NO: 28, CDRL2 as set forth in SEQ ID NO: 29 or 52, and CDRL3 as set forth in SEQ ID NO: 30; In some embodiments, a VH having at least 70% identity to any one of SEQ ID NO: 31, 33, and 34; and a VL having at least 70% identity to any one of SEQ ID NO: 32, 35, 36, and 54; wherein CDRH1 as set forth in SEQ ID NO: 25, CDRH2 as set forth in SEQ ID NO: 26, CDRH3 as set forth in SEQ ID NO: 27, CDRL1 as set forth in SEQ ID NO: 28, CDRL2 as set forth in SEQ ID NO: 29 or 52, and CDRL3 as set forth in SEQ ID NO: 30 are preferably maintained; For example, VH described in any one of SEQ ID NOs: 31, 33, and 34; and VL described in any one of SEQ ID NOs: 32, 35, 36, and 54.

[0300] In some embodiments, the composition comprises: (ii) an antibody or an antigen-binding fragment thereof comprising: CDRH1 having at least 70% identity with SEQ ID NO: 9, CDRH2 having at least 70% identity with SEQ ID NO: 10, CDRH3 having at least 70% identity with SEQ ID NO: 11, CDRL1 having at least 70% identity with SEQ ID NO: 12, CDRL2 having at least 70% identity with SEQ ID NO: 13, and CDRL3 having at least 70% identity with SEQ ID NO: 14; In particular, CDRH1 described in SEQ ID NO: 9, CDRH2 described in SEQ ID NO: 10, CDRH3 described in SEQ ID NO: 11, CDRL1 described in SEQ ID NO: 12, CDRL2 described in SEQ ID NO: 13, and CDRL3 described in SEQ ID NO: 14; In some embodiments, VH having at least 70% identity with any one of SEQ ID NOs: 15, 37, and 38; and VL having at least 70% identity with any one of SEQ ID NOs: 16, 39, and 40; wherein CDRH1 described in SEQ ID NO: 9, CDRH2 described in SEQ ID NOs: 9 and 10, CDRH3 described in SEQ ID NO: 11, CDRL1 described in SEQ ID NO: 12, CDRL2 described in SEQ ID NO: 13, and CDRL3 described in SEQ ID NO: 14 are preferably maintained; For example, VH described in any one of SEQ ID NOs: 15, 37, and 38; and VL described in any one of SEQ ID NOs: 16, 39, and 40; (iii) an antibody or an antigen-binding fragment thereof comprising: CDRH1 having at least 70% identity with SEQ ID NO: 17, CDRH2 having at least 70% identity with SEQ ID NO: 18, CDRH3 having at least 70% identity with SEQ ID NO: 19 or 51, CDRL1 having at least 70% identity with SEQ ID NO: 20, CDRL2 having at least 70% identity with SEQ ID NO: 21, and CDRL3 having at least 70% identity with SEQ ID NO: 22; In particular, CDRH1 as described in SEQ ID NO: 17, CDRH2 as described in SEQ ID NO: 18, CDRH3 as described in SEQ ID NO: 19 or 51, CDRL1 as described in SEQ ID NO: 20, CDRL2 as described in SEQ ID NO: 21, and CDRL3 as described in SEQ ID NO: 22; In some embodiments, VH having at least 70% identity with any one of SEQ ID NOs: 23, 41, 50, and 53; and VL having at least 70% identity with any one of SEQ ID NOs: 24, 42, and 43; wherein CDRH1 as described in SEQ ID NO: 17, CDRH3 as described in SEQ ID NO: 18 or 51, CDRL1 as described in SEQ ID NO: 20, CDRL2 as described in SEQ ID NO: 20, SEQ ID NO: 17, CDRH2 as described in SEQ ID NO: 18, CDRH3 as described in SEQ ID NO: 19 or 51, CDRL1 as described in SEQ ID NO: 20, CDRL2 as described in SEQ ID NO: 21, and CDRL3 as described in SEQ ID NO: 22 are preferably maintained; VH as described in any one of SEQ ID NOs: 23, 41, 50, and 53; and VL as described in any one of SEQ ID NOs: 24, 42, and 43; and, (iv) an antibody or an antigen-binding fragment thereof comprising: CDRH1 having at least 70% identity with SEQ ID NO: 25, CDRH2 having at least 70% identity with SEQ ID NO: 26, CDRH3 having at least 70% identity with SEQ ID NO: 27, CDRL1 having at least 70% identity with SEQ ID NO: 28, CDRL2 having at least 70% identity with SEQ ID NO: 29 or 52, and CDRL3 having at least 70% identity with SEQ ID NO: 30; Particularly, CDRH1 set forth in SEQ ID NO: 25, CDRH2 set forth in SEQ ID NO: 26, CDRH3 set forth in SEQ ID NO: 27, CDRL1 set forth in SEQ ID NO: 28, CDRL2 set forth in SEQ ID NO: 29 or 52, and CDRL3 set forth in SEQ ID NO: 30; In some embodiments, a VH having at least 70% identity to any one of SEQ ID NOs: 31, 33, and 34; and a VL having at least 70% identity to any one of SEQ ID NOs: 32, 35, 36, and 54; wherein the CDRH1 set forth in SEQ ID NO: 25, CDRH2 set forth in SEQ ID NO: 26, CDRH3 set forth in SEQ ID NO: 27, CDRL1 set forth in SEQ ID NO: 28, CDRL2 set forth in SEQ ID NO: 29 or 52, and CDRL3 set forth in SEQ ID NO: 30 are preferably maintained; For example, a VH by any one of SEQ ID NOs: 31, 33, and 34; and a VL by any one of SEQ ID NOs: 32, 35, 36, and 54.

[0301] Preferably, the composition comprises: (i) An antibody or an antigen-binding fragment thereof comprising: CDRH1 having at least 70% identity to SEQ ID NO: 1, CDRH2 having at least 70% identity to SEQ ID NO: 2, CDRH3 having at least 70% identity to SEQ ID NO: 3, CDRL1 having at least 70% identity to SEQ ID NO: 4, CDRL2 having at least 70% identity to SEQ ID NO: 5, and CDRL3 having at least 70% identity to SEQ ID NO: 6; Particularly, CDRH1 set forth in SEQ ID NO: 1, CDRH2 set forth in SEQ ID NO: 2, CDRH3 set forth in SEQ ID NO: 3, CDRL1 set forth in SEQ ID NO: 4, CDRL2 set forth in SEQ ID NO: 5, and CDRL3 set forth in SEQ ID NO: 6; In some embodiments, a VH having at least 70% identity to any one of SEQ ID NO: 7, 44, and 45; and a VL having at least 70% identity to any one of SEQ ID NO: 8, 46, 47, 48, and 49; wherein the CDRH1 set forth in SEQ ID NO: 1, the CDRH2 set forth in SEQ ID NO: 2, the CDRH3 set forth in SEQ ID NO: 3, the CDRL1 set forth in SEQ ID NO: 4, the CDRL2 set forth in SEQ ID NO: 5, and the CDRL3 set forth in SEQ ID NO: 6 are preferably maintained; For example, a VH set forth in any one of SEQ ID NO: 7, 44, and 45; and a VL set forth in any one of SEQ ID NO: 8, 46, 47, 48, and 49, etc.; (ii) An antibody or an antigen-binding fragment thereof comprising: A CDRH1 having at least 70% identity to SEQ ID NO: 9, a CDRH2 having at least 70% identity to SEQ ID NO: 10, a CDRH3 having at least 70% identity to SEQ ID NO: 11, a CDRL1 having at least 70% identity to SEQ ID NO: 12, a CDRL2 having at least 70% identity to SEQ ID NO: 13, and a CDRL3 having at least 70% identity to SEQ ID NO: 14; In particular, the CDRH1 set forth in SEQ ID NO: 9, the CDRH2 set forth in SEQ ID NO: 10, the CDRH3 set forth in SEQ ID NO: 11, the CDRL1 set forth in SEQ ID NO: 12, the CDRL2 set forth in SEQ ID NO: 13, and the CDRL3 set forth in SEQ ID NO: 14; In some embodiments, a VH having at least 70% identity to any one of SEQ ID NO: 15, 37, and 38; and a VL having at least 70% identity to any one of SEQ ID NO: 16, 39, and 40; wherein the CDRH1 set forth in SEQ ID NO: 9, the CDRH2 set forth in SEQ ID NO: 9, SEQ ID NO: 10, the CDRH3 set forth in SEQ ID NO: 11, the CDRL1 set forth in SEQ ID NO: 12, the CDRL2 set forth in SEQ ID NO: 13, and the CDRL3 set forth in SEQ ID NO: 14 are preferably maintained; A VH set forth in any one of SEQ ID NO: 15, 37, and 38; and a VL set forth in any one of SEQ ID NO: 16, 39, and 40; and, (iv) An antibody or an antigen-binding fragment thereof comprising: CDRH1 having at least 70% identity with SEQ ID NO: 25, CDRH2 having at least 70% identity with SEQ ID NO: 26, CDRH3 having at least 70% identity with SEQ ID NO: 27, CDRL1 having at least 70% identity with SEQ ID NO: 28, CDRL2 having at least 70% identity with SEQ ID NO: 29 or 52, and CDRL3 having at least 70% identity with SEQ ID NO: 30; In particular, CDRH1 as set forth in SEQ ID NO: 25, CDRH2 as set forth in SEQ ID NO: 26, CDRH3 as set forth in SEQ ID NO: 27, CDRL1 as set forth in SEQ ID NO: 28, CDRL2 as set forth in SEQ ID NO: 29 or 52, and CDRL3 as set forth in SEQ ID NO: 30; In some embodiments, VH having at least 70% identity with any one of SEQ ID NOs: 31, 33, and 34; and VL having at least 70% identity with any one of SEQ ID NOs: 32, 35, 36, and 54; wherein CDRH1 as set forth in SEQ ID NO: 25, CDRH2 as set forth in SEQ ID NO: 26, CDRH3 as set forth in SEQ ID NO: 27, CDRL1 as set forth in SEQ ID NO: 28, CDRL2 as set forth in SEQ ID NO: 29 or 52, and CDRL3 as set forth in SEQ ID NO: 30 are preferably maintained; For example, VH as set forth in any one of SEQ ID NOs: 31, 33, and 34; and VL as set forth in any one of SEQ ID NOs: 32, 35, 36, and 54.

[0302] Preferably, the composition comprises an antibody that binds to four distinct non-overlapping epitopes on Ara h 2. Thus, the composition may comprise four distinct antibodies, or antigen-binding fragments, by (i), (ii), (iii), and (iv).

[0303] Preferably, the composition comprises: (i) An antibody or an antigen-binding fragment thereof comprising: CDRH1 having at least 70% identity with SEQ ID NO: 1, CDRH2 having at least 70% identity with SEQ ID NO: 2, CDRH3 having at least 70% identity with SEQ ID NO: 3, CDRL1 having at least 70% identity with SEQ ID NO: 4, CDRL2 having at least 70% identity with SEQ ID NO: 5, and CDRL3 having at least 70% identity with SEQ ID NO: 6; In particular, CDRH1 as set forth in SEQ ID NO: 1, CDRH2 as set forth in SEQ ID NO: 2, CDRH3 as set forth in SEQ ID NO: 3, CDRL1 as set forth in SEQ ID NO: 4, CDRL2 as set forth in SEQ ID NO: 5, and CDRL3 as set forth in SEQ ID NO: 6; In some embodiments, VH having at least 70% identity with any one of SEQ ID NOs: 7, 44, and 45; and VL having at least 70% identity with any one of SEQ ID NOs: 8, 46, 47, 48, and 49; wherein CDRH1 as set forth in SEQ ID NO: 1, CDRH2 as set forth in SEQ ID NO: 2, CDRH3 as set forth in SEQ ID NO: 3, CDRL1 as set forth in SEQ ID NO: 4, CDRL2 as set forth in SEQ ID NO: 5, and CDRL3 as set forth in SEQ ID NO: 6 are preferably maintained; For example, VH by any one of SEQ ID NOs: 7, 44, and 45; and VL by any one of SEQ ID NOs: 8, 46, 47, 48, and 49; (ii) An antibody or an antigen-binding fragment thereof comprising: CDRH1 having at least 70% identity with SEQ ID NO: 9, CDRH2 having at least 70% identity with SEQ ID NO: 10, CDRH3 having at least 70% identity with SEQ ID NO: 11, CDRL1 having at least 70% identity with SEQ ID NO: 12, CDRL2 having at least 70% identity with SEQ ID NO: 13, and CDRL3 having at least 70% identity with SEQ ID NO: 14; In particular, CDRH1 as set forth in SEQ ID NO: 9, CDRH2 as set forth in SEQ ID NO: 10, CDRH3 as set forth in SEQ ID NO: 11, CDRL1 as set forth in SEQ ID NO: 12, CDRL2 as set forth in SEQ ID NO: 13, and CDRL3 as set forth in SEQ ID NO: 14; In some embodiments, a VH having at least 70% identity to any one of SEQ ID NOs: 15, 37, and 38; and a VL having at least 70% identity to any one of SEQ ID NOs: 16, 39, and 40; wherein the CDRH1 set forth in SEQ ID NO: 9, the CDRH2 set forth in SEQ ID NO: 10, the CDRH3 set forth in SEQ ID NO: 11, the CDRL1 set forth in SEQ ID NO: 12, the CDRL2 set forth in SEQ ID NO: 13, and the CDRL3 set forth in SEQ ID NO: 14 are preferably maintained; For example, a VH by any one of SEQ ID NOs: 15, 37, and 38; and a VL by any one of SEQ ID NOs: 16, 39, and 40; (iii) An antibody or an antigen-binding fragment thereof comprising: A CDRH1 having at least 70% identity to SEQ ID NO: 17, a CDRH2 having at least 70% identity to SEQ ID NO: 18, a CDRH3 having at least 70% identity to SEQ ID NO: 19 or 51, a CDRL1 having at least 70% identity to SEQ ID NO: 20, a CDRL2 having at least 70% identity to SEQ ID NO: 21, and a CDRL3 having at least 70% identity to SEQ ID NO: 22; In particular, the CDRH1 set forth in SEQ ID NO: 17, the CDRH2 set forth in SEQ ID NO: 18, the CDRH3 set forth in SEQ ID NO: 19 or 51, the CDRL1 set forth in SEQ ID NO: 20, the CDRL2 set forth in SEQ ID NO: 21, and the CDRL3 set forth in SEQ ID NO: 22; In some embodiments, a VH having at least 70% identity to any one of SEQ ID NOs: 23, 41, 50, and 53; and a VL having at least 70% identity to any one of SEQ ID NOs: 24, 42, and 43; wherein the CDRH1 set forth in SEQ ID NO: 17, the CDRH2 set forth in SEQ ID NO: 18, the CDRH3 set forth in SEQ ID NO: 19 or 51, the CDRL1 set forth in SEQ ID NO: 20, the CDRL2 set forth in SEQ ID NO: 21, and the CDRL3 set forth in SEQ ID NO: 22 are preferably maintained; For example, a VH by any one of SEQ ID NOs: 23, 41, 50, and 53; and a VL by any one of SEQ ID NOs: 24, 42, and 43; and, (iv) An antibody or antigen-binding fragment thereof comprising: CDRH1 having at least 70% identity with SEQ ID NO: 25, CDRH2 having at least 70% identity with SEQ ID NO: 26, CDRH3 having at least 70% identity with SEQ ID NO: 27, CDRL1 having at least 70% identity with SEQ ID NO: 28, CDRL2 having at least 70% identity with SEQ ID NO: 29 or 52, and CDRL3 having at least 70% identity with SEQ ID NO: 30; In particular, CDRH1 as set forth in SEQ ID NO: 25, CDRH2 as set forth in SEQ ID NO: 26, CDRH3 as set forth in SEQ ID NO: 27, CDRL1 as set forth in SEQ ID NO: 28, CDRL2 as set forth in SEQ ID NO: 29 or 52, and CDRL3 as set forth in SEQ ID NO: 30; In some embodiments, VH having at least 70% identity with any one of SEQ ID NOs: 31, 33, and 34; and VL having at least 70% identity with any one of SEQ ID NOs: 32, 35, 36, and 54; wherein CDRH1 as set forth in SEQ ID NO: 25, CDRH2 as set forth in SEQ ID NO: 26, CDRH3 as set forth in SEQ ID NO: 27, CDRL1 as set forth in SEQ ID NO: 28, CDRL2 as set forth in SEQ ID NO: 29 or 52, and CDRL3 as set forth in SEQ ID NO: 30 are preferably maintained; For example, VH by any one of SEQ ID NOs: 31, 33, and 34; and VL by any one of SEQ ID NOs: 32, 35, 36, and 54.

[0304] More preferably, the composition comprises: (i) comprising a CDRH1 having at least 70% identity with SEQ ID NO: 1, a CDRH2 having at least 70% identity with SEQ ID NO: 2, a CDRH3 having at least 70% identity with SEQ ID NO: 3, a CDRL1 having at least 70% identity with SEQ ID NO: 4, a CDRL2 having at least 70% identity with SEQ ID NO: 5, and a CDRL3 having at least 70% identity with SEQ ID NO: 6; in particular, an antibody or an antigen-binding fragment thereof comprising the CDRH1 described in SEQ ID NO: 1, the CDRH2 described in SEQ ID NO: 2, the CDRH3 described in SEQ ID NO: 3, the CDRL1 described in SEQ ID NO: 4, the CDRL2 described in SEQ ID NO: 5, and the CDRL3 described in SEQ ID NO: 6; (ii) comprising a CDRH1 having at least 70% identity with SEQ ID NO: 9, a CDRH2 having at least 70% identity with SEQ ID NO: 10, a CDRH3 having at least 70% identity with SEQ ID NO: 11, a CDRL1 having at least 70% identity with SEQ ID NO: 12, a CDRL2 having at least 70% identity with SEQ ID NO: 13, and a CDRL3 having at least 70% identity with SEQ ID NO: 14; in particular, an antibody or an antigen-binding fragment thereof comprising the CDRH1 described in SEQ ID NO: 9, the CDRH2 described in SEQ ID NO: 10, the CDRH3 described in SEQ ID NO: 11, the CDRL1 described in SEQ ID NO: 12, the CDRL2 described in SEQ ID NO: 13, and the CDRL3 described in SEQ ID NO: 14; (iii) comprising a CDRH1 having at least 70% identity with SEQ ID NO: 17, a CDRH2 having at least 70% identity with SEQ ID NO: 18, a CDRH3 having at least 70% identity with SEQ ID NO: 51, a CDRL1 having at least 70% identity with SEQ ID NO: 20, a CDRL2 having at least 70% identity with SEQ ID NO: 21, and a CDRL3 having at least 70% identity with SEQ ID NO: 22; in particular, an antibody or an antigen-binding fragment thereof comprising the CDRH1 described in SEQ ID NO: 17, the CDRH2 described in SEQ ID NO: 18, the CDRH3 described in SEQ ID NO: 51, the CDRL1 described in SEQ ID NO: 20, the CDRL2 described in SEQ ID NO: 21, and the CDRL3 described in SEQ ID NO: 22; and, (iv) a CDRH1 having at least 70% identity with SEQ ID NO: 25, a CDRH2 having at least 70% identity with SEQ ID NO: 26, a CDRH3 having at least 70% identity with SEQ ID NO: 27, a CDRL1 having at least 70% identity with SEQ ID NO: 28, a CDRL2 having at least 70% identity with SEQ ID NO: 29 or 52, and a CDRL3 having at least 70% identity with SEQ ID NO: 30; in particular, an antibody or an antigen-binding fragment thereof comprising a CDRH1 as set forth in SEQ ID NO: 25, a CDRH2 as set forth in SEQ ID NO: 26, a CDRH3 as set forth in SEQ ID NO: 27, a CDRL1 as set forth in SEQ ID NO: 28, a CDRL2 as set forth in SEQ ID NO: 29 or 52, and a CDRL3 as set forth in SEQ ID NO: 30.

[0305] More preferably, the composition comprises the following: (i) a VH having at least 70% identity with SEQ ID NO: 45; and a VL having at least 70% identity with SEQ ID NO: 49; wherein the CDRH1 as set forth in SEQ ID NO: 1, the CDRH2 as set forth in SEQ ID NO: 2, the CDRH3 as set forth in SEQ ID NO: 3, the CDRL1 as set forth in SEQ ID NO: 4, the CDRL2 as set forth in SEQ ID NO: 5, and the CDRL3 as set forth in SEQ ID NO: 6 are preferably maintained; for example, an antibody or an antigen-binding fragment thereof which is a VH according to SEQ ID NO: 45 and a VL according to SEQ ID NO: 49; (ii) a VH having at least 70% identity with SEQ ID NO: 38; and a VL having at least 70% identity with SEQ ID NO: 39; wherein the CDRH1 as set forth in SEQ ID NO: 9, the CDRH2 as set forth in SEQ ID NO: 10, the CDRH3 as set forth in SEQ ID NO: 11, the CDRL1 as set forth in SEQ ID NO: 12, the CDRL2 as set forth in SEQ ID NO: 13, and the CDRL3 as set forth in SEQ ID NO: 14 are preferably maintained; for example, an antibody or an antigen-binding fragment thereof which is a VH according to SEQ ID NO: 38 and a VL according to SEQ ID NO: 39; (iii) a VH having at least 70% identity with SEQ ID NO: 53; and a VL having at least 70% identity with SEQ ID NO: 43; wherein the CDRH1 set forth in SEQ ID NO: 17, the CDRH2 set forth in SEQ ID NO: 18, the CDRH3 set forth in SEQ ID NO: 51, the CDRL1 set forth in SEQ ID NO: 20, the CDRL2 set forth in SEQ ID NO: 21, and the CDRL3 set forth in SEQ ID NO: 22 are preferably maintained; for example, an antibody or an antigen-binding fragment thereof that is the VH according to SEQ ID NO: 53 and the VL according to SEQ ID NO: 43; and, (iv) a VH having at least 70% identity with SEQ ID NO: 34; and a VL having at least 70% identity with SEQ ID NO: 35 or 54; wherein the CDRH1 set forth in SEQ ID NO: 25, the CDRH2 set forth in SEQ ID NO: 26, the CDRH3 set forth in SEQ ID NO: 27, the CDRL1 set forth in SEQ ID NO: 28, the CDRL2 set forth in SEQ ID NO: 29 or 52, and the CDRL3 set forth in SEQ ID NO: 30 are preferably maintained; for example, an antibody or an antigen-binding fragment thereof that is the VH according to SEQ ID NO: 34 and the VL according to SEQ ID NO: 35 or 54.

[0306] As described above, the composition of the present invention preferably comprises antibodies that bind to at least three, preferably four, distinct and non-overlapping epitopes of Ara h 2. The antibodies or antigen-binding fragments thereof contained in the composition can be selected from the four different antibodies 17H9, 15E3, 2F8 and 7G6, or variants thereof, as described above, particularly shown in Tables 1 and 2. Preferably, therefore, the composition comprises three or four (monospecific) antibodies selected from the four different antibodies 17H9, 15E3, 2F8 and 7G6, or variants thereof, as described herein, particularly as described above, particularly shown in Tables 1 and 2. In some embodiments, the composition comprises multispecific antibodies, particularly as described herein.

[0307] In a composition comprising three distinct antigen-binding sites, in particular, binding to three distinct epitopes of Ara h 2 can be obtained by a composition comprising: (i) Three separate monoclonal antibodies, or antigen-binding fragments thereof, that bind to three separate epitopes of Ara h 2, selected particularly as shown in Tables 1 and 2, particularly selected from 17H9, 15E3, 2F8 and 7G6 or variants thereof; (ii) (1) A bispecific antibody, or bispecific antigen-binding fragment, having two specificities, selected particularly as shown in Tables 1 and 2, particularly selected from 17H9, 15E3, 2F8 and 7G6, or variants thereof, and (2) an additional monoclonal antibody that binds to another epitope on Ara h 2, selected particularly as shown in Tables 1 and 2, particularly selected from 17H9, 15E3, 2F8 and 7G6, or variants thereof; or, (iii) A trispecific antibody, or trispecific antigen-binding fragment, having three specificities, selected particularly as shown in Tables 1 and 2, particularly selected from 17H9, 15E3, 2F8 and 7G6, or variants thereof.

[0308] In a composition comprising four separate antigen-binding sites, particularly, binding to four different epitopes of Ara h 2 can be obtained by a composition comprising: (i) Four separate monoclonal antibodies, or antigen-binding fragments thereof, that bind to three separate epitopes of Ara h 2, selected particularly as shown in Tables 1 and 2, particularly selected from 17H9, 15E3, 2F8 and 7G6 or variants thereof; (ii) (1) A bispecific antibody, or bispecific antigen-binding fragment, having two specificities, selected particularly as shown in Tables 1 and 2, particularly selected from 17H9, 15E3, 2F8 and 7G6, or variants thereof, and (2) two additional monoclonal antibodies that bind to further separate epitopes on Ara h 2, selected particularly as shown in Tables 1 and 2, particularly selected from 17H9, 15E3, 2F8 and 7G6, or variants thereof; (iii) Two separate bispecific antibodies, or bispecific antigen-binding fragments, wherein each of the bispecific antibodies or bispecific antigen-binding fragments has two separate specificities selected from, in particular, 17H9, 15E3, 2F8 and 7G6, or variants thereof, as described above, in particular as shown in Tables 1 and 2; (iv) (1) A trispecific antibody, or trispecific antigen-binding fragment, having three specificities selected from, in particular, 17H9, 15E3, 2F8 and 7G6, or variants thereof, as described above, in particular as shown in Tables 1 and 2, and (2) an additional monospecific antibody that binds to another epitope on Ara h 2, selected from, in particular, 17H9, 15E3, 2F8 and 7G6, or variants thereof, as described above, in particular as shown in Tables 1 and 2; or (v) A tetravalent antibody, or tetravalent antigen-binding fragment, having four specificities selected from, in particular, 17H9, 15E3, 2F8 and 7G6, or variants thereof, as described above, in particular as shown in Tables 1 and 2.

[0309] Alternatively or additionally, the composition may further comprise at least one additional agent useful for treating peanut allergy. Additional agents useful for treating peanut allergy may be selected from the group consisting of β - adrenergic agonists (such as epinephrine), antihistamines, corticosteroids, anti-IgE antibodies, anti-IgE antibody fragments, peptide vaccines, and additional antibodies capable of binding to peanut allergens. In some embodiments, the composition comprises a β - adrenergic agonist such as epinephrine.

[0310] In some embodiments, the composition comprises a peanut allergen. The peanut allergen may be untreated peanuts or processed peanuts such as peanut powder, roasted peanuts or peanut butter. In some embodiments, the peanut allergen may be a commercial product such as Palforzia (defatted peanut powder). The peanut allergen may be a peanut protein such as Ara h 1, Ara h 2, Ara h 3, Ara h 4, Ara h 5, Ara h 6 / 7, Ara h 8, Ara h 9 and Ara h 10 / 11. In certain embodiments, the peanut protein may be selected in particular from Ara h 2, Ara h 3 and Ara h 6, or combinations thereof. The peanut allergen may be of peanut origin, recombinantly expressed or a synthetic peanut peptide. In some embodiments, the anti-peanut allergen antibody or antigen-binding fragment thereof described herein may be pre-incubated with the peanut allergen and administered to a subject as a mixture.

[0311] Preferably, a combination of a peanut allergen selected from the group consisting of Ara h 1, Ara h 2, Ara h 3, Ara h 4, Ara h 5, Ara h 6 / 7, Ara h 8, Ara h 9 and Ara h 10 / 11 or mixtures thereof, or more preferably a peanut allergen selected from the group consisting of Ara h1, Ara h2, Ara h3 and Ara h6 or mixtures thereof, and the antibody of the present invention enhances the safety of allergen administration (e.g., in desensitization). Furthermore, without being bound by any theory, the inventors assume that the combination of an antibody and each allergen (targeted by the antibody), i.e., the combination of passive (antibody) immunity and active (allergen) immunity, has a synergistic effect. The components, i.e., the allergen component and the antibody component, may be administered simultaneously or at staggered times, for example, separately from each other within 15 minutes, 30 minutes, 60 minutes or 90 minutes.

[0312] The present invention also provides a diagnostic composition comprising an antibody according to the present invention, a nucleic acid according to the present invention, a vector according to the present invention, and / or a cell according to the present invention. The diagnostic composition may optionally comprise suitable means for detection, such as reagents conventionally used in immunological or nucleic acid-based diagnostic methods.

[0313] The antibodies described herein are, for example, suitable for diagnostic purposes. Thus, they can be used in immunoassays, where they can be utilized in solution phase or bound to a solid support. Such immunoassays can be competitive or non-competitive immunoassays, and can be in direct or indirect formats. Examples of such immunoassays include, but are not limited to, radioimmunoassay (RIA), enzyme-linked immunosorbent assay (ELISA), sandwich (immunometric assay), immunohistochemistry, flow cytometry, and Western blot assay. For this purpose, the antibodies can be labeled, for example, as described above.

[0314] In a further aspect, the present invention also provides a kit comprising one or more of the following: (i) an antibody according to the present invention or an antigen-binding fragment thereof, as described above, (ii) a nucleic acid molecule (or nucleic acid molecules) according to the present invention, as described above, (iii) a vector (or vectors) according to the present invention, as described above, (iv) a cell according to the present invention, as described above, and / or (v) a composition according to the present invention, as described above.

[0315] Furthermore, the kit can include an antibody or antigen-binding fragment thereof according to the invention, a nucleic acid according to the invention, a vector according to the invention, a cell according to the invention, or means for administering a pharmaceutical composition according to the invention, such as a syringe or container, a leaflet, and / or a co-agent to be administered as described herein. For example, the kit may include a leaflet consisting of, for example, instructions for use. Additionally or alternatively, the kit may include one or more reagents for use, for example, in an appropriate diagnostic assay. In some examples, the kit may include a reference agent or control. In some embodiments, the compositions of the invention can be provided in the form of a kit designed such that, for example, the combined composition is reconstituted immediately prior to administration to a subject. For example, a lyophilized antibody can be provided in kit form (e.g., in a separate container) with sterile water or a sterile buffer.

[0316] In some embodiments, the kit comprises at least two distinct antibodies (or nucleic acids encoding such antibodies or compositions comprising such antibodies), where the distinct antibodies can be provided in separate containers. Preferably, the kit comprises at least two distinct antibodies, or antigen-binding fragments thereof (or nucleic acids encoding such antibodies or compositions comprising such antibodies), that bind to distinct non-overlapping epitopes of Ara h 2. More preferably, the kit comprises (exactly) three distinct antibodies or antigen-binding fragments thereof (or nucleic acids encoding such antibodies or compositions comprising such antibodies) that bind to distinct non-overlapping epitopes of Ara h 2. Even more preferably, the kit comprises (exactly) four distinct antibodies, or antigen-binding fragments thereof (or nucleic acids encoding such antibodies or compositions comprising such antibodies) that bind to distinct non-overlapping epitopes of Ara h 2. For this purpose, the antibodies contained in the kit can be selected from the above four different antibodies 17H9, 15E3, 2F8, and 7G6, or variants thereof, as described above, for example, as described in Tables 1 and 2. As shown in the attached examples, 17H9, 15E3, 2F8, and 7G6 bind to distinct non-overlapping epitopes of Ara h 2.

[0317] Accordingly, the kit may comprise: (i) at least two distinct antibodies or antigen-binding fragments thereof that bind to different non-overlapping epitopes of Ara h 2, according to any of the present invention as described above; (ii) a nucleic acid molecule encoding at least two distinct antibodies or antigen-binding fragments thereof that bind to different non-overlapping epitopes of Ara h 2, according to any of the present invention as described above; or (iii) a composition comprising (i) or (ii).

[0318] In the following description, reference is made to kits containing separate antibodies or antigen-binding fragments thereof, although the kits may equally well comprise (separate) nucleic acids encoding said antibodies or antigen-binding fragments; or (separate) compositions comprising said antibodies or antigen-binding fragments or said nucleic acids.

[0319] In particular, the kit may comprise at least two of the following: (i) an antibody or antigen-binding fragment thereof comprising, for 17H9, (a) the CDRH1, CDRH2, CDRH3, CDRL1, CDRL2 and CDRL3 sequences and / or (b) the VH and VL sequences, or sequence variants thereof as described above; (ii) an antibody or antigen-binding fragment thereof comprising, for 15E3, (a) the CDRH1, CDRH2, CDRH3, CDRL1, CDRL2 and CDRL3 sequences and / or (b) the VH and VL sequences, or sequence variants thereof as described above; (iii) an antibody or antigen-binding fragment thereof comprising, for 2F8, (a) the CDRH1, CDRH2, CDRH3, CDRL1, CDRL2 and CDRL3 sequences and / or (b) the VH and VL sequences, or sequence variants thereof as described above; and / or, (iv) an antibody or antigen-binding fragment thereof comprising, for 7G6, (a) the CDRH1, CDRH2, CDRH3, CDRL1, CDRL2 and CDRL3 sequences and / or (b) the VH and VL sequences, or sequence variants thereof as described above.

[0320] In some embodiments, the kit comprises (exactly) two separate antibodies, namely: (i) an antibody or antigen-binding fragment thereof comprising, for 17H9, (a) the CDRH1, CDRH2, CDRH3, CDRL1, CDRL2 and CDRL3 sequences and / or (b) the VH and VL sequences, or sequence variants thereof as described above; and, (ii) An antibody or antigen-binding fragment thereof comprising, for 15E3, (a) the CDRH1, CDRH2, CDRH3, CDRL1, CDRL2, and CDRL3 sequences and / or (b) the VH and VL sequences, or sequence variants thereof as described above.

[0321] In some embodiments, the kit comprises (exactly) two distinct antibodies, namely: (i) An antibody or antigen-binding fragment thereof comprising, for 17H9, (a) the CDRH1, CDRH2, CDRH3, CDRL1, CDRL2, and CDRL3 sequences and / or (b) the VH and VL sequences, or sequence variants thereof as described above; and, (iii) An antibody or antigen-binding fragment thereof comprising, for 2F8, (a) the CDRH1, CDRH2, CDRH3, CDRL1, CDRL2, and CDRL3 sequences and / or (b) the VH and VL sequences, or sequence variants thereof as described above.

[0322] In some embodiments, the kit comprises (exactly) two distinct antibodies, namely: (ii) An antibody or antigen-binding fragment thereof comprising, for 15E3, (a) the CDRH1, CDRH2, CDRH3, CDRL1, CDRL2, and CDRL3 sequences and / or (b) the VH and VL sequences, or sequence variants thereof as described above; and, (iv) An antibody or antigen-binding fragment thereof comprising, for 7G6, (a) the CDRH1, CDRH2, CDRH3, CDRL1, CDRL2, and CDRL3 sequences and / or (b) the VH and VL sequences, or sequence variants thereof as described above.

[0323] In some embodiments, the kit comprises (exactly) two distinct antibodies, namely: (iii) An antibody or antigen-binding fragment thereof comprising (a) the CDRH1, CDRH2, CDRH3, CDRL1, CDRL2, and CDRL3 sequences and / or (b) the VH and VL sequences of 2F8, or sequence variants thereof as described above; and, (iv) An antibody or antigen-binding fragment thereof comprising (a) the CDRH1, CDRH2, CDRH3, CDRL1, CDRL2, and CDRL3 sequences and / or (b) the VH and VL sequences of 7G6, or sequence variants thereof as described above.

[0324] Preferably, the kit comprises (exactly) two distinct antibodies, namely: (ii) An antibody or antigen-binding fragment thereof comprising (a) the CDRH1, CDRH2, CDRH3, CDRL1, CDRL2, and CDRL3 sequences and / or (b) the VH and VL sequences of 15E3, or sequence variants thereof as described above; and, (iii) An antibody or antigen-binding fragment thereof comprising (a) the CDRH1, CDRH2, CDRH3, CDRL1, CDRL2, and CDRL3 sequences and / or (b) the VH and VL sequences of 2F8, or sequence variants thereof as described above.

[0325] More preferably, the kit comprises (exactly) two distinct antibodies, namely: (i) An antibody or antigen-binding fragment thereof comprising (a) the CDRH1, CDRH2, CDRH3, CDRL1, CDRL2, and CDRL3 sequences and / or (b) the VH and VL sequences of 17H9, or seq...

Claims

**Claim 1** An antibody or an antigen-binding fragment thereof that specifically binds to Ara h 2 (Arachis hypogaea allergen 2). **Claim 2** The antibody or the antigen-binding fragment thereof according to claim 1, wherein the antibody or the antigen-binding fragment thereof further specifically binds to Ara h 3 or Ara h 6. **Claim 3** The antibody or the antigen-binding fragment thereof according to claim 1 or 2, wherein the antibody or the antigen-binding fragment thereof comprises CDRH1 having at least 70% identity with SEQ ID NO: 1, CDRH2 having at least 70% identity with SEQ ID NO: 2, CDRH3 having at least 70% identity with SEQ ID NO: 3, CDRL1 having at least 70% identity with SEQ ID NO: 4, CDRL2 having at least 70% identity with SEQ ID NO: 5, and CDRL3 having at least 70% identity with SEQ ID NO:

6. **Claim 4** The antibody or the antigen-binding fragment thereof according to any one of the above claims, wherein the antibody or the antigen-binding fragment thereof comprises CDRH1 described in SEQ ID NO: 1, CDRH2 described in SEQ ID NO: 2, CDRH3 described in SEQ ID NO: 3, CDRL1 described in SEQ ID NO: 4, CDRL2 described in SEQ ID NO: 5, and CDRL3 described in SEQ ID NO:

6. **Claim 5** The antibody or the antigen-binding fragment thereof, wherein VH having at least 70% identity with any one of SEQ ID NOs: 7, 44, and 45; and VL having at least 70% identity with any one of SEQ ID NOs: 8, 46, 47, 48, and 49, the antibody or the antigen-binding fragment thereof according to any one of the above claims. **Claim 6** The antibody or the antigen-binding fragment thereof, wherein VH described in any one of SEQ ID NOs: 7, 44, and 45; and VL described in any one of SEQ ID NOs: 8, 46, 47, 48, and 49, the antibody or the antigen-binding fragment thereof according to any one of the above claims. **Claim 7** The antibody or antigen-binding fragment thereof according to claim 1 or 2, wherein the antibody or antigen-binding fragment thereof comprises CDRH1 having at least 70% identity with SEQ ID NO: 9, CDRH2 having at least 70% identity with SEQ ID NO: 10, CDRH3 having at least 70% identity with SEQ ID NO: 11, CDRL1 having at least 70% identity with SEQ ID NO: 12, CDRL2 having at least 70% identity with SEQ ID NO: 13, and CDRL3 having at least 70% identity with SEQ ID NO:

14.

8. The antibody or antigen-binding fragment thereof according to any one of claims 1, 2, and 7, wherein the antibody or antigen-binding fragment thereof comprises CDRH1 set forth in SEQ ID NO: 9, CDRH2 set forth in SEQ ID NO: 10, CDRH3 set forth in SEQ ID NO: 11, CDRL1 set forth in SEQ ID NO: 12, CDRL2 set forth in SEQ ID NO: 13, and CDRL3 set forth in SEQ ID NO:

14.

9. The antibody or antigen-binding fragment thereof is VH having at least 70% identity with any one of SEQ ID NOs: 15, 37, and 38; and The antibody or antigen-binding fragment thereof according to any one of claims 1, 2, 7, and 8, comprising VL having at least 70% identity with any one of SEQ ID NOs: 16, 39, and 40.

10. The antibody or antigen-binding fragment thereof is VH set forth in any one of SEQ ID NOs: 15, 37, and 38; and The antibody or antigen-binding fragment thereof according to any one of claims 1, 2, and 7 to 9, comprising VL set forth in any one of SEQ ID NOs: 16, 39, and 40.

11. The antibody or antigen-binding fragment thereof according to claim 1 or 2, wherein the antibody or antigen-binding fragment thereof comprises CDRH1 having at least 70% identity with SEQ ID NO: 17, CDRH2 having at least 70% identity with SEQ ID NO: 18, CDRH3 having at least 70% identity with SEQ ID NO: 51, CDRL1 having at least 70% identity with SEQ ID NO: 20, CDRL2 having at least 70% identity with SEQ ID NO: 21, and CDRL3 having at least 70% identity with SEQ ID NO:

22.

12. The antibody or antigen-binding fragment thereof according to any one of claims 1, 2, and 11, wherein the antibody or antigen-binding fragment thereof comprises CDRH1 set forth in SEQ ID NO: 17, CDRH2 set forth in SEQ ID NO: 18, CDRH3 set forth in SEQ ID NO: 51, CDRL1 set forth in SEQ ID NO: 20, CDRL2 set forth in SEQ ID NO: 21, and CDRL3 set forth in SEQ ID NO:

22.

13. The antibody or antigen-binding fragment thereof, VH having at least 70% identity with SEQ ID NO: 53; and VL having at least 70% identity with any one of SEQ ID NOs: 24, 42, and 43, the antibody or antigen-binding fragment thereof according to any one of claims 1, 2, 11, and 12.

14. The antibody or antigen-binding fragment thereof, VH set forth in SEQ ID NO: 53; and VL set forth in any one of SEQ ID NOs: 24, 42, and 43, the antibody or antigen-binding fragment thereof according to any one of claims 1, 2, and 11 to 13.

15. The antibody or antigen-binding fragment thereof, VH having at least 70% identity with any one of SEQ ID NOs: 41, 50, and 53; and VL having at least 70% identity with SEQ ID NO: 42 or 43, the antibody or antigen-binding fragment thereof according to claim 1 or 2.

16. The antibody or antigen-binding fragment thereof, VH set forth in any one of SEQ ID NOs: 41, 50, and 53; and VL set forth in SEQ ID NO: 42 or 43, the antibody or antigen-binding fragment thereof according to claim 15.

17. The antibody or antigen-binding fragment thereof, CDRH1 having at least 70% identity with SEQ ID NO: 25, CDRH2 having at least 70% identity with SEQ ID NO: 26, CDRH3 having at least 70% identity with SEQ ID NO: 27, CDRL1 having at least 70% identity with SEQ ID NO: 28, CDRL2 having at least 70% identity with SEQ ID NO: 52, and CDRL3 having at least 70% identity with SEQ ID NO: 30, the antibody or antigen-binding fragment thereof according to claim 1 or 2.

18. The antibody or antigen-binding fragment thereof according to any one of claims 1, 2, and 17, wherein the antibody or antigen-binding fragment thereof comprises CDRH1 set forth in SEQ ID NO: 25, CDRH2 set forth in SEQ ID NO: 26, CDRH3 set forth in SEQ ID NO: 27, CDRL1 set forth in SEQ ID NO: 28, CDRL2 set forth in SEQ ID NO: 52, and CDRL3 set forth in SEQ ID NO:

30.

19. The antibody or antigen-binding fragment thereof, wherein VH having at least 70% identity with any one of SEQ ID NOs: 31, 33, and 34; and VL having at least 70% identity with SEQ ID NO: 54, the antibody or antigen-binding fragment thereof according to any one of claims 1, 2, 17, and 18.

20. The antibody or antigen-binding fragment thereof, wherein VH set forth in any one of SEQ ID NOs: 31, 33, and 34; and VL set forth in SEQ ID NO: 54, the antibody or antigen-binding fragment thereof according to any one of claims 1, 2, and 17 to 19.

21. The antibody or antigen-binding fragment thereof, wherein VH having at least 70% identity with SEQ ID NO: 33 or 34; and VL having at least 70% identity with any one of SEQ ID NOs: 35, 36, and 54, the antibody or antigen-binding fragment thereof according to claim 1 or 2.

22. The antibody or antigen-binding fragment thereof, wherein VH set forth in SEQ ID NO: 33 or 34; and VL set forth in any one of SEQ ID NOs: 35, 36, and 54, the antibody or antigen-binding fragment thereof according to claim 21.

23. The antibody or antigen-binding fragment thereof according to any one of the above claims, wherein the CDR or variable region of the antibody or antigen-binding fragment thereof is a human CDR or variable region sequence or is derived from a human CDR or variable region sequence.

24. The antibody or antigen-binding fragment thereof according to any one of the above claims, wherein the antibody or antigen-binding fragment thereof is a human antibody.

25. The antibody or antigen-binding fragment thereof according to any one of the above claims, wherein the antibody or antigen-binding fragment thereof is a monoclonal antibody.

26. The antibody according to any one of the above claims, wherein the antibody comprises an Fc partial structure.

27. The antibody according to any one of the above claims, wherein the antibody is of the IgG type or IgA type.

28. The antibody according to claim 27, wherein the antibody is of the IgG1 type or IgG4 type.

29. The antibody according to any one of the above claims, wherein the variable region or the CDR is derived from an IgE antibody and grafted onto the scaffold of an IgG or IgA antibody.

30. The antibody or antigen-binding fragment thereof according to any one of the above claims, wherein the antibody or antigen-binding fragment thereof is purified.

31. The antibody or antigen-binding fragment thereof according to any one of the above claims, wherein the antibody or antigen-binding fragment thereof is a single-chain antibody.

32. The antibody or antigen-binding fragment thereof according to claim 24, wherein the antibody or antigen-binding fragment thereof is a scFv.

33. The antibody or antigen-binding fragment thereof according to any one of claims 1 to 23, wherein the antibody or antigen-binding fragment thereof is selected from Fab, Fab’, F(ab’)2 and Fv.

34. The antibody or antigen-binding fragment thereof according to any one of the above claims, wherein the antibody or antigen-binding fragment thereof is a multispecific antibody or multispecific antigen-binding fragment.

35. The antibody or antigen-binding fragment thereof according to claim 34, wherein the antibody or antigen-binding fragment thereof binds to distinct non-overlapping epitopes of Ara h 2.

36. The antibody or antigen-binding fragment thereof according to claim 34, wherein the antibody or antigen-binding fragment thereof comprises at least two of the following: (i) an antigen-binding site comprising (a) CDRH1, CDRH2, CDRH3, CDRL1, CDRL2 and CDRL3 sequences and / or (b) VH and VL sequences, as defined in any one of claims 3 to 6; (ii) an antigen-binding site comprising (a) CDRH1, CDRH2, CDRH3, CDRL1, CDRL2 and CDRL3 sequences and / or (b) VH and VL sequences, as defined in any one of claims 7 to 10; (iii) an antigen-binding site comprising (a) CDRH1, CDRH2, CDRH3, CDRL1, CDRL2 and CDRL3 sequences and / or (b) VH and VL sequences, as defined in any one of claims 11 to 16. An antigen-binding site defined by any one of claims 17 to 22 and comprising (a) CDRH1, CDRH2, CDRH3, CDRL1, CDRL2 and CDRL3 sequences and / or (b) VH and VL sequences. **Claim 37** A multispecific antibody or multispecific antigen-binding fragment, which binds to distinct non-overlapping epitopes of Ara h 2, wherein said antibody or antigen-binding fragment comprises at least two of the following: a multispecific antibody or multispecific antigen-binding fragment: (i) an antigen-binding site comprising a CDRH1 having at least 70% identity to SEQ ID NO: 1, a CDRH2 having at least 70% identity to SEQ ID NO: 2, a CDRH3 having at least 70% identity to SEQ ID NO: 3, a CDRL1 having at least 70% identity to SEQ ID NO: 4, a CDRL2 having at least 70% identity to SEQ ID NO: 5, and a CDRL3 having at least 70% identity to SEQ ID NO: 6; (ii) an antigen-binding site comprising a CDRH1 having at least 70% identity to SEQ ID NO: 9, a CDRH2 having at least 70% identity to SEQ ID NO: 10, a CDRH3 having at least 70% identity to SEQ ID NO: 11, a CDRL1 having at least 70% identity to SEQ ID NO: 12, a CDRL2 having at least 70% identity to SEQ ID NO: 13, and a CDRL3 having at least 70% identity to SEQ ID NO: 14; (iii) an antigen-binding site comprising a CDRH1 having at least 70% identity to SEQ ID NO: 17, a CDRH2 having at least 70% identity to SEQ ID NO: 18, a CDRH3 having at least 70% identity to SEQ ID NO: 19 or 51, a CDRL1 having at least 70% identity to SEQ ID NO: 20, a CDRL2 having at least 70% identity to SEQ ID NO: 21, and a CDRL3 having at least 70% identity to SEQ ID NO: 22; (iv) an antigen-binding site comprising a CDRH1 having at least 70% identity to SEQ ID NO: 25, a CDRH2 having at least 70% identity to SEQ ID NO: 26, a CDRH3 having at least 70% identity to SEQ ID NO: 27, a CDRL1 having at least 70% identity to SEQ ID NO: 28, a CDRL2 having at least 70% identity to SEQ ID NO: 29 or 52, and a CDRL3 having at least 70% identity to SEQ ID NO:

30. **Claim 38** The antibody or antigen-binding fragment according to claim 37, wherein the antibody or antigen-binding fragment comprises at least two of the following: (i) an antigen-binding site comprising CDRH1 set forth in SEQ ID NO: 1, CDRH2 set forth in SEQ ID NO: 2, CDRH3 set forth in SEQ ID NO: 3, CDRL1 set forth in SEQ ID NO: 4, CDRL2 set forth in SEQ ID NO: 5, and CDRL3 set forth in SEQ ID NO: 6; (ii) an antigen-binding site comprising CDRH1 set forth in SEQ ID NO: 9, CDRH2 set forth in SEQ ID NO: 10, CDRH3 set forth in SEQ ID NO: 11, CDRL1 set forth in SEQ ID NO: 12, CDRL2 set forth in SEQ ID NO: 13, and CDRL3 set forth in SEQ ID NO: 14; (iii) an antigen-binding site comprising CDRH1 set forth in SEQ ID NO: 17, CDRH2 set forth in SEQ ID NO: 18, CDRH3 set forth in SEQ ID NO: 19 or 51, CDRL1 set forth in SEQ ID NO: 20, CDRL2 set forth in SEQ ID NO: 21, and CDRL3 set forth in SEQ ID NO: 22; (iv) an antigen-binding site comprising CDRH1 set forth in SEQ ID NO: 25, CDRH2 set forth in SEQ ID NO: 26, CDRH3 set forth in SEQ ID NO: 27, CDRL1 set forth in SEQ ID NO: 28, CDRL2 set forth in SEQ ID NO: 29 or 52, and CDRL3 set forth in SEQ ID NO:

30.

39. The antibody or antigen-binding fragment according to claim 37 or 38, wherein the antibody or antigen-binding fragment comprises at least two of the following: (i) a VH having at least 70% identity to any one of SEQ ID NOs: 7, 44, and 45; and a VL having at least 70% identity to any one of SEQ ID NOs: 8, 46, 47, 48, and 49, comprising an antigen-binding site; (ii) a VH having at least 70% identity to any one of SEQ ID NOs: 15, 37, and 38; and a VL having at least 70% identity to any one of SEQ ID NOs: 16, 39, and 40, comprising an antigen-binding site; (iii) a VH having at least 70% identity to any one of SEQ ID NOs: 23, 41, 50, and 53; and a VL having at least 70% identity to any one of SEQ ID NOs: 24, 42, and 43, comprising an antigen-binding site; (iv) a VH having at least 70% identity to any one of SEQ ID NOs: 31, 33, and 34; and a VL having at least 70% identity to any one of SEQ ID NOs: 32, 35, 36, and 54, comprising an antigen-binding site.

40. The antibody or antigen-binding fragment according to any one of claims 37 to 39, wherein the antibody or antigen-binding fragment comprises at least two of the following: (i) a VH as set forth in any one of SEQ ID NOs: 7, 44, and 45; and an antigen-binding site comprising a VL as set forth in any one of SEQ ID NOs: 8, 46, 47, 48, and 49; (ii) a VH as set forth in any one of SEQ ID NOs: 15, 37, and 38; and an antigen-binding site comprising a VL as set forth in any one of SEQ ID NOs: 16, 39, and 40; (iii) a VH as set forth in any one of SEQ ID NOs: 23, 41, 50, and 53; and an antigen-binding site comprising a VL as set forth in any one of SEQ ID NOs: 24, 42, and 43; (iv) a VH as set forth in any one of SEQ ID NOs: 31, 33, and 34; and an antigen-binding site comprising a VL as set forth in any one of SEQ ID NOs: 32, 35, 36, and 54.

41. The antibody or antigen-binding fragment according to any one of claims 36 to 39, wherein the antibody or antigen-binding fragment is trispecific and comprises three distinct antigen-binding sites selected from (i) to (iv).

42. The antibody or antigen-binding fragment according to any one of claims 36 to 39, wherein the antibody or antigen-binding fragment is quadrispecific and comprises four distinct antigen-binding sites described in (i), (ii), (iii), and (iv).

43. The CDRH1, CDRH2, and CDRH3 sequences are The antibody or antigen-binding fragment according to claim 3 or 4, comprising a human variable light chain framework region VH chain selected from the group consisting of amino acids encoded by genes IGHV1-18, IGHV1-2, IGHV1-24, IGHV1-3, IGHV1-45, IGHV1-46, IGHV1-58, IGHV1-69, IGHV1-69-2, IGHV1-69D, IGHV1-8, IGHV2-26, IGHV2-5, IGHV2-70, IGHV2-70D, IGHV3-11, IGHV3-13, IGHV3-15, IGHV3-20, IGHV3-21, IGHV3-23, IGHV3-23D, IGHV3-30, IGHV3-30-3, IGHV3-30-5, IGHV3-33, IGHV3-35, IGHV3-43, IGHV3-43D, IGHV3-48, IGHV3-49, IGHV3-53, IGHV3-62, IGHV3-64, IGHV3-64D, IGHV3-66, IGHV3-7, IGHV3-72, IGHV3-73, IGHV3-74, IGHV3-9, IGHV3-NL1, IGHV4-28, IGHV4-30-1, IGHV4-30-2, IGHV4-30-4, IGHV4-31, IGHV4-34 and IGHV4-38-2.

44. The CDRL1, CDRL2 and CDRL3 sequences are The antibody or antigen-binding fragment according to claim 3, 4 or 43, comprising a human variable light chain framework region VL chain selected from the group consisting of amino acid sequences encoded by genes IGLV1-36, IGLV1-40, IGLV1-44, IGLV1-47, IGLV1-51, IGLV10-54, IGLV2-11, IGLV2-14, IGLV2-18, IGLV2-23, IGLV2-8, IGLV3-1, IGLV3-10, IGLV3-12, IGLV3-16, IGLV3-19, IGLV3-21, IGLV3-22, IGLV3-25, IGLV3-27, IGLV3-9, IGLV4-3, IGLV4-60, IGLV4-69, IGLV5-37, IGLV5-39, IGLV5-45, IGLV5-52, IGLV6-57, IGLV7-43, IGLV7-46, IGLV8-61 and IGLV9-49.

45. The CDRL1, CDRL2 and CDRL3 sequences are The antibody or antigen-binding fragment according to claim 3, 4 or 43, comprising a human variable light chain framework region VK chain selected from the group consisting of amino acid sequences encoded by genes IGKV1-12, IGKV1-13, IGKV1-16, IGKV1-17, IGKV1-27, IGKV1-33, IGKV1-39, IGKV1-5, IGKV1-6, IGKV1-8, IGKV1-9, IGKV1-NL1, IGKV1D-12, IGKV1D-13, IGKV1D-16, IGKV1D-17, IGKV1D-33, IGKV1D-39, IGKV1D-43, IGKV1D-8, IGKV2-24, IGKV2-28, IGKV2-29, IGKV2-30, IGKV2-40, IGKV2D-26, IGKV2D-28, IGKV2D-29, IGKV2D-30, IGKV2D-40, IGKV3-11, IGKV3-15, IGKV3-20, IGKV3D-11, IGKV3D-15, IGKV3D-20, IGKV3D-7, IGKV4-1, IGKV5-2, IGKV6-21 and IGKV6D-21.

46. The antibody or antigen-binding fragment thereof according to any one of the above claims, for use as a medicament.

47. The antibody or antigen-binding fragment thereof according to claim 46, for use in the prevention or treatment of peanut allergy.

48. A nucleic acid molecule comprising a polynucleotide encoding the antibody or antigen-binding fragment thereof according to any one of claims 1 to 45.

49. The nucleic acid molecule according to claim 48, comprising the nucleic acid sequence recited in any one of SEQ ID NOs: 64 to 99; or a sequence variant thereof having at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 88%, at least 90%, at least 92%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% sequence identity.

50. A plurality of nucleic acid molecules encoding the antibody or antigen-binding fragment thereof according to any one of claims 1 to 45, wherein each nucleic acid molecule comprises a polynucleotide encoding an immunoglobulin chain of the antibody or antigen-binding fragment thereof.

51. The nucleic acid sequence according to any one of SEQ ID NOs: 64 to 99; or a sequence variant thereof having at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 88%, at least 90%, at least 92%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% sequence identity, a combination of nucleic acid molecules according to claim 50.

52. A vector comprising the nucleic acid molecule according to claim 48 or 49, or a plurality of nucleic acid molecules according to claim 50 or 51.

53. A plurality of vectors comprising a plurality of nucleic acid molecules according to claim 50 or 51.

54. A host cell expressing the antibody or antigen-binding fragment thereof according to any one of claims 1 to 45, or comprising a combination of the vector according to claim 52 or the vectors according to claim 53.

55. (i) culturing the host cell according to claim 54; and (ii) isolating the antibody or its immunoglobulin chain from the culture A method for preparing the antibody or antigen-binding fragment thereof according to any one of claims 1 to 45 or their immunoglobulin chains, comprising:

56. A composition comprising the antibody or antigen-binding fragment thereof according to any one of claims 1 to 45, the nucleic acid or plurality of nucleic acids according to any one of claims 48 to 51, the vector or plurality of vectors according to claim 52 or 53, or the cell according to claim 54.

57. The composition according to claim 56, further comprising a pharmaceutically acceptable excipient, diluent or carrier.

58. The composition according to claim 56 or 57, wherein the composition comprises at least two distinct antibodies or antigen-binding fragments thereof that bind to distinct non-overlapping epitopes of Ara h 2.

59. The composition according to claim 58, wherein the composition comprises at least two of the following: (i) the antibody or antigen-binding fragment thereof according to any one of claims 3 to 6; (ii) the antibody or antigen-binding fragment thereof according to any one of claims 7 to 10; (iii) the antibody or antigen-binding fragment thereof according to any one of claims 11 to 16; (iv)An antibody or an antigen-binding fragment thereof according to any one of claims 17 to 22.

60. Comprising (exactly) three or four distinct antibodies or antigen-binding fragments that bind to distinct, non-overlapping epitopes of Ara h 2, The composition according to claim 58 or 59, wherein the (exactly) three or four distinct antibodies or antigen-binding fragments are preferably selected from (i) to (iv) of claim 59.

61. A composition comprising at least three distinct antibodies or antigen-binding fragments thereof, Wherein the three distinct antibodies or antigen-binding fragments bind to distinct, non-overlapping epitopes of Ara h 2, The composition comprising at least three of the following: (i) An antibody or an antigen-binding fragment thereof comprising a CDRH1 having at least 70% identity with SEQ ID NO: 1, a CDRH2 having at least 70% identity with SEQ ID NO: 2, a CDRH3 having at least 70% identity with SEQ ID NO: 3, a CDRL1 having at least 70% identity with SEQ ID NO: 4, a CDRL2 having at least 70% identity with SEQ ID NO: 5, and a CDRL3 having at least 70% identity with SEQ ID NO: 6; (ii) An antibody or an antigen-binding fragment thereof comprising a CDRH1 having at least 70% identity with SEQ ID NO: 9, a CDRH2 having at least 70% identity with SEQ ID NO: 10, a CDRH3 having at least 70% identity with SEQ ID NO: 11, a CDRL1 having at least 70% identity with SEQ ID NO: 12, a CDRL2 having at least 70% identity with SEQ ID NO: 13, and a CDRL3 having at least 70% identity with SEQ ID NO: 14; (iii) An antibody or an antigen-binding fragment thereof comprising a CDRH1 having at least 70% identity with SEQ ID NO: 17, a CDRH2 having at least 70% identity with SEQ ID NO: 18, a CDRH3 having at least 70% identity with SEQ ID NO: 19 or 51, a CDRL1 having at least 70% identity with SEQ ID NO: 20, a CDRL2 having at least 70% identity with SEQ ID NO: 21, and a CDRL3 having at least 70% identity with SEQ ID NO: 22; An antibody or an antigen-binding fragment thereof comprising CDRH1 having at least 70% identity with SEQ ID NO: 25, CDRH2 having at least 70% identity with SEQ ID NO: 26, CDRH3 having at least 70% identity with SEQ ID NO: 27, CDRL1 having at least 70% identity with SEQ ID NO: 28, CDRL2 having at least 70% identity with SEQ ID NO: 29 or 52, and CDRL3 having at least 70% identity with SEQ ID NO:

30.

62. The composition according to claim 61, wherein the composition comprises at least three of the following: (i) An antibody or an antigen-binding fragment thereof comprising CDRH1 set forth in SEQ ID NO: 1, CDRH2 set forth in SEQ ID NO: 2, CDRH3 set forth in SEQ ID NO: 3, CDRL1 set forth in SEQ ID NO: 4, CDRL2 set forth in SEQ ID NO: 5, and CDRL3 set forth in SEQ ID NO: 6; (ii) An antibody or an antigen-binding fragment thereof comprising CDRH1 set forth in SEQ ID NO: 9, CDRH2 set forth in SEQ ID NO: 10, CDRH3 set forth in SEQ ID NO: 11, CDRL1 set forth in SEQ ID NO: 12, CDRL2 set forth in SEQ ID NO: 13, and CDRL3 set forth in SEQ ID NO: 14; (iii) An antibody or an antigen-binding fragment thereof comprising CDRH1 set forth in SEQ ID NO: 17, CDRH2 set forth in SEQ ID NO: 18, CDRH3 set forth in SEQ ID NO: 19 or 51, CDRL1 set forth in SEQ ID NO: 20, CDRL2 set forth in SEQ ID NO: 21, and CDRL3 set forth in SEQ ID NO: 22; (iv) An antibody or an antigen-binding fragment thereof comprising CDRH1 set forth in SEQ ID NO: 25, CDRH2 set forth in SEQ ID NO: 26, CDRH3 set forth in SEQ ID NO: 27, CDRL1 set forth in SEQ ID NO: 28, CDRL2 set forth in SEQ ID NO: 29 or 52, and CDRL3 set forth in SEQ ID NO:

30.

63. The composition according to claim 61 or 62, wherein the composition comprises at least three of the following: (i) An antibody or an antigen-binding fragment thereof comprising VH having at least 70% identity with any one of SEQ ID NOs: 7, 44, and 45; and VL having at least 70% identity with any one of SEQ ID NOs: 8, 46, 47, 48, and 49; (ii)a VH having at least 70% identity with any one of SEQ ID NOs: 15, 37, and 38; and an antibody or an antigen-binding fragment thereof comprising a VL having at least 70% identity with any one of SEQ ID NOs: 16, 39, and 40; (iii)a VH having at least 70% identity with any one of SEQ ID NOs: 23, 41, 50, and 53; and an antibody or an antigen-binding fragment thereof comprising a VL having at least 70% identity with any one of SEQ ID NOs: 24, 42, and 43; (iv)a VH having at least 70% identity with any one of SEQ ID NOs: 31, 33, and 34; and an antibody or an antigen-binding fragment thereof comprising a VL having at least 70% identity with any one of SEQ ID NOs: 32, 35, 36, and 54.

64. The composition according to any one of claims 61 to 63, wherein the composition comprises at least three of the following: (i)an antibody or an antigen-binding fragment thereof comprising a VH set forth in any one of SEQ ID NOs: 7, 44, and 45; and a VL set forth in any one of SEQ ID NOs: 8, 46, 47, 48, and 49; (ii)an antibody or an antigen-binding fragment thereof comprising a VH set forth in any one of SEQ ID NOs: 15, 37, and 38; and a VL set forth in any one of SEQ ID NOs: 16, 39, and 40; (iii)an antibody or an antigen-binding fragment thereof comprising a VH set forth in any one of SEQ ID NOs: 23, 41, 50, and 53; and a VL set forth in any one of SEQ ID NOs: 24, 42, and 43; (iv)an antibody or an antigen-binding fragment thereof comprising a VH set forth in any one of SEQ ID NOs: 31, 33, and 34; and a VL set forth in any one of SEQ ID NOs: 32, 35, 36, and 54.

65. The composition according to any one of claims 59 to 64, wherein the composition comprises the four distinct antibodies or antigen-binding fragments described in (i), (ii), (iii), and (iv).

66. The composition according to any one of claims 56 to 64, wherein the composition further comprises at least one additional agent useful for treating peanut allergy.

67. The composition according to claim 66, wherein the additional agent useful for treating peanut allergy is selected from the group consisting of β - adrenergic agonists, epinephrine, antihistamines, corticosteroids, anti - IgE antibodies, anti - IgE antibody - binding fragments, peptide vaccines, and additional antibodies capable of binding to peanut allergens.

68. The composition according to any one of claims 56 - 67, further comprising a peanut allergen, wherein the composition is preferably selected from the group consisting of Ara h1, Ara h2, Ara h3 and Ara h6 or a mixture thereof.

69. (i)An antibody or an antigen - binding fragment thereof according to any one of claims 1 - 45; (ii)A nucleic acid molecule according to any one of claims 48 - 51; (iii)A vector according to claim 52 or 53; (iv)A cell according to claim 54; and / or (v)A composition according to any one of claims 56 - 68 A kit comprising one or more of the above.

70. The kit, (i)At least two distinct antibodies or antigen - binding fragments thereof according to any one of claims 1 - 45, which bind to distinct non - overlapping epitopes of Ara h 2; (ii)A nucleic acid molecule encoding at least two distinct antibodies or antigen - binding fragments thereof according to any one of claims 1 - 45, which bind to distinct non - overlapping epitopes of Ara h 2; or (iii)A composition comprising (i) or (ii) The kit according to claim 69.

71. The kit according to claim 70, comprising three or four distinct antibodies or antigen - binding fragments thereof according to any one of claims 1 - 45, which bind to distinct non - overlapping epitopes of Ara h 2; or a nucleic acid encoding the above antibodies or a composition comprising the above antibodies.

72. A kit comprising at least three distinct antibodies or antigen - binding fragments thereof, wherein the three distinct antibodies or antigen - binding fragments bind to distinct non - overlapping epitopes of Ara h 2, and the kit comprises at least three of the following: (i)An antibody or an antigen-binding fragment thereof comprising CDRH1 having at least 70% identity with SEQ ID NO: 1, CDRH2 having at least 70% identity with SEQ ID NO: 2, CDRH3 having at least 70% identity with SEQ ID NO: 3, CDRL1 having at least 70% identity with SEQ ID NO: 4, CDRL2 having at least 70% identity with SEQ ID NO: 5, and CDRL3 having at least 70% identity with SEQ ID NO: 6; (ii)An antibody or an antigen-binding fragment thereof comprising CDRH1 having at least 70% identity with SEQ ID NO: 9, CDRH2 having at least 70% identity with SEQ ID NO: 10, CDRH3 having at least 70% identity with SEQ ID NO: 11, CDRL1 having at least 70% identity with SEQ ID NO: 12, CDRL2 having at least 70% identity with SEQ ID NO: 13, and CDRL3 having at least 70% identity with SEQ ID NO: 14; (iii)An antibody or an antigen-binding fragment thereof comprising CDRH1 having at least 70% identity with SEQ ID NO: 17, CDRH2 having at least 70% identity with SEQ ID NO: 18, CDRH3 having at least 70% identity with SEQ ID NO: 19 or 51, CDRL1 having at least 70% identity with SEQ ID NO: 20, CDRL2 having at least 70% identity with SEQ ID NO: 21, and CDRL3 having at least 70% identity with SEQ ID NO: 22; (iv)An antibody or an antigen-binding fragment thereof comprising CDRH1 having at least 70% identity with SEQ ID NO: 25, CDRH2 having at least 70% identity with SEQ ID NO: 26, CDRH3 having at least 70% identity with SEQ ID NO: 27, CDRL1 having at least 70% identity with SEQ ID NO: 28, CDRL2 having at least 70% identity with SEQ ID NO: 29 or 52, and CDRL3 having at least 70% identity with SEQ ID NO:

30.

73. The kit according to claim 72, wherein the kit comprises at least three of the following: (i)An antibody or an antigen-binding fragment thereof comprising CDRH1 set forth in SEQ ID NO: 1, CDRH2 set forth in SEQ ID NO: 2, CDRH3 set forth in SEQ ID NO: 3, CDRL1 set forth in SEQ ID NO: 4, CDRL2 set forth in SEQ ID NO: 5, and CDRL3 set forth in SEQ ID NO: 6; (ii) An antibody or an antigen-binding fragment thereof comprising CDRH1 set forth in SEQ ID NO: 9, CDRH2 set forth in SEQ ID NO: 10, CDRH3 set forth in SEQ ID NO: 11, CDRL1 set forth in SEQ ID NO: 12, CDRL2 set forth in SEQ ID NO: 13, and CDRL3 set forth in SEQ ID NO: 14; (iii) An antibody or an antigen-binding fragment thereof comprising CDRH1 set forth in SEQ ID NO: 17, CDRH2 set forth in SEQ ID NO: 18, CDRH3 set forth in SEQ ID NO: 19 or 51, CDRL1 set forth in SEQ ID NO: 20, CDRL2 set forth in SEQ ID NO: 21, and CDRL3 set forth in SEQ ID NO: 22; (iv) An antibody or an antigen-binding fragment thereof comprising CDRH1 set forth in SEQ ID NO: 25, CDRH2 set forth in SEQ ID NO: 26, CDRH3 set forth in SEQ ID NO: 27, CDRL1 set forth in SEQ ID NO: 28, CDRL2 set forth in SEQ ID NO: 29 or 52, and CDRL3 set forth in SEQ ID NO:

30.

74. The kit according to claim 72 or 73, wherein the kit comprises at least three of the following: (i) An antibody or an antigen-binding fragment thereof comprising a VH having at least 70% identity with any one of SEQ ID NOs: 7, 44, and 45; and a VL having at least 70% identity with any one of SEQ ID NOs: 8, 46, 47, 48, and 49; (ii) An antibody or an antigen-binding fragment thereof comprising a VH having at least 70% identity with any one of SEQ ID NOs: 15, 37, and 38; and a VL having at least 70% identity with any one of SEQ ID NOs: 16, 39, and 40; (iii) An antibody or an antigen-binding fragment thereof comprising a VH having at least 70% identity with any one of SEQ ID NOs: 23, 41, 50, and 53; and a VL having at least 70% identity with any one of SEQ ID NOs: 24, 42, and 43; (iv) An antibody or an antigen-binding fragment thereof comprising a VH having at least 70% identity with any one of SEQ ID NOs: 31, 33, and 34; and a VL having at least 70% identity with any one of SEQ ID NOs: 32, 35, 36, and 54.

75. The kit according to any one of claims 72 to 74, wherein the kit comprises at least three of the following: (i) an antibody or an antigen-binding fragment thereof comprising a VH as set forth in any one of SEQ ID NOs: 7, 44, and 45; and a VL as set forth in any one of SEQ ID NOs: 8, 46, 47, 48, and 49; (ii) an antibody or an antigen-binding fragment thereof comprising a VH as set forth in any one of SEQ ID NOs: 15, 37, and 38; and a VL as set forth in any one of SEQ ID NOs: 16, 39, and 40; (iii) an antibody or an antigen-binding fragment thereof comprising a VH as set forth in any one of SEQ ID NOs: 23, 41, 50, and 53; and a VL as set forth in any one of SEQ ID NOs: 24, 42, and 43; (iv) an antibody or an antigen-binding fragment thereof comprising a VH as set forth in any one of SEQ ID NOs: 31, 33, and 34; and a VL as set forth in any one of SEQ ID NOs: 32, 35, 36, and 54.

76. The kit according to any one of claims 72 to 75, wherein the kit comprises four separate antibodies or antigen-binding fragments as described in (i), (ii), (iii), and (iv).

77. The kit according to any one of claims 69 to 76, wherein the kit further comprises at least one additional agent useful for the treatment of peanut allergy.

78. The kit according to any one of claims 69 to 77, wherein the kit further comprises a peanut allergen.

79. An antibody or an antigen-binding fragment thereof according to any one of claims 1 to 45, a nucleic acid or a plurality of nucleic acids according to any one of claims 48 to 51, a vector or a plurality of vectors according to claim 52 or 53, a cell according to claim 54, a composition according to any one of claims 56 to 68, or a kit according to any one of claims 69 to 78, for use as a medicament.

80. An antibody or an antigen-binding fragment thereof according to any one of claims 1 to 45, a nucleic acid or a plurality of nucleic acids according to any one of claims 48 to 51, a vector or a plurality of vectors according to claim 52 or 53, a cell according to claim 54, a composition according to any one of claims 56 to 68, or a kit according to any one of claims 69 to 78, for use in the prevention or treatment of peanut allergy.

81. At least two, three, or four distinct antibodies or antigen-binding fragments thereof that bind to distinct, non-overlapping epitopes of Ara h 2; or a nucleic acid or vector encoding said distinct antibodies; or an antibody or antigen-binding fragment thereof, nucleic acid or plurality of nucleic acids, vector or plurality of vectors, cell, or composition as described in claim 80, wherein said distinct antibody-containing composition is administered.

82. The administration of an antibody or antigen-binding fragment thereof, nucleic acid or plurality of nucleic acids, vector or plurality of vectors, cell, or composition as described in claim 80 or 81, wherein said administration is preferably combined with the administration of a peanut allergen selected from the group consisting of Ara h1, Ara h2, Ara h3, and Ara h6 or mixtures thereof.

83. The antibody or antigen-binding fragment thereof or composition as described in claim 82, wherein the antibody or antigen-binding fragment thereof or composition is administered before or during treatment for desensitization to a peanut allergen.

84. Use of an antibody or antigen-binding fragment thereof as described in any one of claims 1 to 45, a composition as described in any one of claims 56 to 68, or a kit as described in any one of claims 69 to 78 for the (in vitro) diagnosis of peanut allergy.

85. Use of an antibody or antigen-binding fragment thereof as described in any one of claims 1 to 45 or any one of claims 56 to 68, or a kit as described in any one of claims 69 to 78 in a method for detecting a peanut allergen.

86. Use of an antibody or antigen-binding fragment thereof as described in any one of claims 1 to 45, a nucleic acid or plurality of nucleic acids as described in any one of claims 48 to 51, a vector or plurality of vectors as described in claim 52 or 53, a cell as described in claim 54, a composition as described in any one of claims 56 to 68, or a kit as described in any one of claims 69 to 78 in the manufacture of a medicament for the prevention, treatment, or attenuation of peanut allergy.

87. A method for treating, ameliorating or reducing peanut allergy, or a method for reducing the risk of a peanut allergy reaction or anaphylactic reaction, comprising: administering to a subject in need thereof a therapeutically effective amount of the antibody or antigen-binding fragment thereof according to any one of claims 1 to 45, the nucleic acid or plurality of nucleic acids according to any one of claims 48 to 51, the vector or plurality of vectors according to claim 52 or 53, the cell according to claim 54, the composition according to any one of claims 56 to 68, or the kit according to any one of claims 69 to 78.

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