Compositions and methods for treating and inhibiting allergic reactions

Abstract

Disclosed herein are antibodies, compositions and methods for treating allergic reactions. In some embodiments, the composition is a combination therapy of more than one antibody. In some embodiments, the antibodies bind to Ara h 2 and / or Ara h 6, and may be used to treat peanut allergy.

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims the benefit of U.S. Provisional Application No. 63 / 382,963, filed on November 9, 2022, which is incorporated herein by reference in its entirety. Summary of the Invention

[0003] Disclosed herein are compositions comprising a first binding domain that binds to Ara h 2 and Ara h 6, wherein the first binding domain comprises a heavy chain variable domain (VH) comprising complementarity determining regions (CDRs): HC-CDR1, HC-CDR2, HC-CDR3, wherein HC-CDR1, HC-CDR2, HC-CDR3 comprise an amino acid sequence according to HC-CDR1: SEQ ID NO: 1, HC-CDR2: SEQ ID NO: 2 or SEQ ID NO: 3, HC-CDR3: SEQ ID NO: 4 or SEQ ID NO: 5, and the first binding domain comprises a light chain variable (VL) domain comprising CDRs: LC-CDR1, LC-CDR2, LC-CDR3, wherein LC-CDR1, LC-CDR2, LC-CDR3 comprise an amino acid sequence according to LC-CDR1: SEQ ID NO: 6, LC-CDR2: SEQ ID NO: 7, LC-CDR3: SEQ ID NO: 8, wherein the composition comprises a heavy chain variable domain (VH) comprising complementarity determining regions (CDRs): HC-CDR1, HC-CDR2, HC-CDR3, wherein HC-CDR1, HC-CDR2, HC-CDR3 comprise an amino acid sequence according to LC-CDR1: SEQ ID NO: 6, LC-CDR2: SEQ ID NO: 7, LC-CDR3: SEQ ID NO: 8, wherein the composition comprises a heavy chain variable domain (VL) comprising CDRs: LC-CDR1, LC-CDR2, LC-CDR3 2 and Ara h 6, wherein the second binding domain comprises a VH comprising CDRs: HC-CDR1, HC-CDR2, HC-CDR3, wherein HC-CDR1, HC-CDR2, HC-CDR3 comprise the amino acid sequence according to HC-CDR1: SEQ ID NO: 18, HC-CDR2: SEQ ID NO: 19, HC-CDR-3: SEQ ID NO: 20 or SEQ ID NO: 21, and the second binding domain comprises a light chain variable (VL) domain comprising CDRs: LC-CDR1, LC-CDR2, LC-CDR3, wherein LC-CDR1, LC-CDR2, LC-CDR3 comprise the amino acid sequence according to LC-CDR1: SEQ ID NO: 22, LC-CDR2: SEQ ID NO: 23, LC-CDR-3: SEQ ID NO: 24, and wherein the composition comprises a VH comprising CDRs: HC-CDR1, HC-CDR2, HC-CDR3, wherein the VH comprising CDRs: LC-CDR1, LC-CDR2, LC-CDR3 comprise the amino acid sequence according to LC-CDR1: SEQ ID NO: 22, LC-CDR2: SEQ ID NO: 23, LC-CDR-3: SEQ ID NO: 24, and wherein the composition comprises a VL comprising CDRs: LC-CDR1, LC-CDR2, LC-CDR3 2, wherein the third binding domain comprises a VH comprising CDRs: HC-CDR1, HC-CDR2, HC-CDR3, wherein HC-CDR1, HC-CDR2, HC-CDR3 comprise the amino acid sequence according to HC-CDR1: SEQ ID NO: 35, HC-CDR2: SEQ ID NO: 36 or SEQ ID NO: 37, HC-CDR3: SEQ ID NO: 38, and the third binding domain comprises a light chain variable (VL) domain comprising CDRs: LC-CDR1, LC-CDR2, LC-CDR3,wherein LC-CDR1, LC-CDR2, and LC-CDR3 comprise the amino acid sequence according to LC-CDR1: SEQ ID NO: 39, LC-CDR2: SEQ ID NO: 40, and LC-CDR3: SEQ ID NO: 41. In some embodiments, the VH of the first binding domain comprises an amino acid sequence having at least 80%, 85%, 90%, 95%, 98%, 99%, or 100% sequence identity to SEQ ID NO: 9 or SEQ ID NO: 10. In some embodiments, the VL of the first binding domain comprises an amino acid sequence having at least 80%, 85%, 90%, 95%, 98%, 99%, or 100% sequence identity to SEQ ID NO: 11. In some embodiments, the VH of the first binding domain comprises an amino acid sequence having at least 80%, 85%, 90%, 95%, 98%, 99% or 100% sequence identity to SEQ ID NO: 9 or SEQ ID NO: 10, and wherein the VL of the first binding domain comprises an amino acid sequence having at least 80%, 85%, 90%, 95%, 98%, 99% or 100% sequence identity to SEQ ID NO: 11. In some embodiments, the first binding domain comprises a Fab, Fab', F(ab')2, or a single-chain variable fragment (scFv). In some embodiments, the first binding domain is a Fab, Fab', F(ab')2, or a single-chain variable fragment (scFv). In some embodiments, the first binding domain comprises an scFv. In some embodiments, the VH of the first binding domain and the VL of the first binding domain are connected by an scFv linker sequence. In some embodiments, the scFv linker sequence of the first binding domain comprises an amino acid sequence according to SEQ ID No: 12. In some embodiments, the scFv of the first binding domain comprises an amino acid sequence having at least 80%, 85%, 90%, 95%, 98%, 99% or 100% sequence identity to SEQ ID NO: 13 or SEQ ID NO: 14. In some embodiments, the first binding domain comprises a constant domain. In some embodiments, the constant domain of the first binding domain comprises a human IgG4 sequence. In some embodiments, the human IgG4 sequence of the first binding domain comprises an S228P point mutation, wherein the amino acid numbering follows the EU index as in Kabat et al. In some embodiments, the human IgG4 sequence of the first binding domain does not have a C-terminal lysine residue. In some embodiments, the constant domain of the first binding domain comprises a human IgG1 sequence. In some embodiments, the constant domain of the first binding domain comprises a C, H 1. C H 2. C H 3 or C L In some embodiments, the first binding domain comprises C H 1. CH 2. C H 3 and C LAmino acid sequence. In some embodiments, the first binding domain comprises an amino acid sequence having at least 80%, 85%, 90%, 95%, 98%, 99%, or 100% sequence identity to SEQ ID NO: 15, SEQ ID NO: 16, SEQ ID NO: 72, or SEQ ID NO: 73, and the first binding domain comprises an amino acid sequence having at least 80%, 85%, 90%, 95%, 98%, 99%, or 100% sequence identity to SEQ ID NO: 17. In some embodiments, the VH of the second binding domain comprises an amino acid sequence having at least 80%, 85%, 90%, 95%, 98%, 99%, or 100% sequence identity to SEQ ID NO: 25 or SEQ ID NO: 26. In some embodiments, the VL of the second binding domain comprises an amino acid sequence having at least 80%, 85%, 90%, 95%, 98%, 99%, or 100% sequence identity to SEQ ID NO: 27 or SEQ ID NO: 28. In some embodiments, the VH of the second binding domain comprises an amino acid sequence having at least 80%, 85%, 90%, 95%, 98%, 99% or 100% sequence identity to SEQ ID NO: 25 or SEQ ID NO: 26, and wherein the VL of the second binding domain comprises an amino acid sequence having at least 80%, 85%, 90%, 95%, 98%, 99% or 100% sequence identity to SEQ ID NO: 27 or SEQ ID NO: 28. In some embodiments, the second binding domain comprises a Fab, Fab', F(ab')2, or a single-chain variable fragment (scFv). In some embodiments, the second binding domain is a Fab, Fab', F(ab')2, or a single-chain variable fragment (scFv). In some embodiments, the second binding domain comprises an scFv. In some embodiments, the VH of the second binding domain and the VL of the second binding domain are connected by an scFv linker sequence. In some embodiments, the scFv linker sequence of the second binding domain comprises an amino acid sequence according to SEQ ID NO: 29. In some embodiments, the scFv of the second binding domain comprises an amino acid sequence that has at least 80%, 85%, 90%, 95%, 98%, 99%, or 100% sequence identity to SEQ ID NO: 30 or SEQ ID NO: 31. In some embodiments, the second binding domain comprises a constant domain. In some embodiments, the constant domain of the second binding domain comprises a human IgG4 sequence. In some embodiments, the human IgG4 sequence of the second binding domain comprises an S228P point mutation, wherein amino acid numbering follows the EU index as in Kabat et al. In some embodiments, the human IgG4 sequence of the second binding domain does not have a C-terminal lysine residue. In some embodiments, the constant domain of the second binding domain comprises a human IgG1 sequence.In some embodiments, the constant domain of the second binding domain comprises C. H 1. C H 2. C H 3 or C L In some embodiments, the second binding domain comprises C H 1. C H 2. C H 3 and C LAmino acid sequence. In some embodiments, the second binding domain comprises an amino acid sequence having at least 80%, 85%, 90%, 95%, 98%, 99% or 100% sequence identity to SEQ ID NO: 32, SEQ ID NO: 33, SEQ ID NO: 74 or SEQ ID NO: 75, and the isolated antibody comprises an amino acid sequence having at least 80%, 85%, 90%, 95%, 98%, 99% or 100% sequence identity to SEQ ID NO: 34 or SEQ ID NO: 76. In some embodiments, the VH of the third binding domain comprises an amino acid sequence having at least 80%, 85%, 90%, 95%, 98%, 99% or 100% sequence identity to SEQ ID NO: 42 or SEQ ID NO: 43. In some embodiments, the VL of the third binding domain comprises an amino acid sequence having at least 80%, 85%, 90%, 95%, 98%, 99% or 100% sequence identity to SEQ ID NO: 44. In some embodiments, the VH of the third binding domain comprises an amino acid sequence having at least 80%, 85%, 90%, 95%, 98%, 99% or 100% sequence identity to SEQ ID NO: 42 or SEQ ID NO: 43, and wherein the VL of the third binding domain comprises an amino acid sequence having at least 80%, 85%, 90%, 95%, 98%, 99% or 100% sequence identity to SEQ ID NO: 44. In some embodiments, the third binding domain comprises a Fab, Fab', F(ab')2, or a single-chain variable fragment (scFv). In some embodiments, the third binding domain is a Fab, Fab', F(ab')2, or a single-chain variable fragment (scFv). In some embodiments, the third binding domain comprises an scFv. In some embodiments, the VH of the third binding domain and the VL of the third binding domain are connected by an scFv linker sequence. In some embodiments, the scFv linker sequence of the third binding domain comprises an amino acid sequence according to SEQ ID NO: 45. In some embodiments, the scFv of the third binding domain comprises an amino acid sequence having at least 80%, 85%, 90%, 95%, 98%, 99% or 100% sequence identity to SEQ ID NO: 46 or SEQ ID NO: 47. In some embodiments, the third binding domain comprises a constant domain. In some embodiments, the constant domain of the third binding domain comprises a human IgG4 sequence. In some embodiments, the human IgG4 sequence of the third binding domain comprises an S228P point mutation, wherein the amino acid numbering follows the EU index in Kabat et al. In some embodiments, the human IgG4 sequence of the third binding domain does not have a C-terminal lysine residue. In some embodiments, the constant domain of the third binding domain comprises a human IgG1 sequence. In some embodiments, the constant domain of the third binding domain comprises a CH 1. C H 2. C H 3 or C L In some embodiments, the third binding domain comprises C H 1. C H 2. C H 3 and C L Amino acid sequence. In some embodiments, the third binding domain comprises an amino acid sequence having at least 80%, 85%, 90%, 95%, 98%, 99% or 100% sequence identity to SEQ ID NO: 48, SEQ ID NO: 49, SEQ ID NO: 77 or SEQ ID NO: 78, and the isolated antibody comprises an amino acid sequence having at least 80%, 85%, 90%, 95%, 98%, 99% or 100% sequence identity to SEQ ID NO: 50. In some embodiments, the first binding domain, the second binding domain, and the third binding domain are linked within the same molecule. In some embodiments, the first binding domain, the second binding domain, and the third binding domain belong to separate molecules. In some embodiments, the first binding domain and the second binding domain are within the same molecule, and the third binding domain belongs to a molecule separate from the molecule having the first binding domain and the second binding domain. In some embodiments, the first binding domain and the third binding domain are within the same molecule, and the second binding domain belongs to a molecule separate from the molecule having the first binding domain and the third binding domain. In some embodiments, the second binding domain and the third binding domain are in the same molecule, and the first binding domain is a separate molecule from the molecules having the second and third binding domains. In some embodiments, the first binding domain comprises an scFv, and the second binding domain comprises a C H 1. C H 2. C H 3 and C L In some embodiments, the second binding domain comprises an scFv and the first binding domain comprises a C H 1. C H 2. C H 3 and C L In some embodiments, the first binding domain and the second binding domain are connected by a connecting portion. In some embodiments, the connecting portion is an amino acid sequence. In some embodiments, the connecting portion is at least 4 amino acids long. In some embodiments, the length of the connecting portion is between 4 and 20 amino acids. In some embodiments, the connecting portion connects the C of the second binding domain to the C of the second binding domain. HIn some embodiments, the first and second binding domains comprise an amino acid sequence having at least 80%, 85%, 90%, 95%, 98%, 99%, or 100% sequence identity to SEQ ID NO: 53 and an amino acid sequence having at least 80%, 85%, 90%, 95%, 98%, 99%, or 100% sequence identity to SEQ ID NO: 52, and wherein the third binding domain comprises an amino acid sequence having at least 80%, 85%, 90%, 95%, 98%, 99%, or 100% sequence identity to SEQ ID NO: 48, SEQ ID NO: 49, SEQ ID NO: 77, or SEQ ID NO: 78, and the third binding domain comprises an amino acid sequence having at least 80%, 85%, 90%, 95%, 98%, 99%, or 100% sequence identity to SEQ ID NO: 50. In some embodiments, the first and second binding domains comprise an amino acid sequence having at least 80%, 85%, 90%, 95%, 98%, 99%, or 100% sequence identity to SEQ ID NO:55 and an amino acid sequence having at least 80%, 85%, 90%, 95%, 98%, 99%, or 100% sequence identity to SEQ ID NO:54, and wherein the third binding domain comprises an amino acid sequence having at least 80%, 85%, 90%, 95%, 98%, 99%, or 100% sequence identity to SEQ ID NO:48, SEQ ID NO:49, SEQ ID NO:77, or SEQ ID NO:78, and the third binding domain comprises an amino acid sequence having at least 80%, 85%, 90%, 95%, 98%, 99%, or 100% sequence identity to SEQ ID NO:50. In some embodiments, the first and second binding domains comprise an amino acid sequence having at least 80%, 85%, 90%, 95%, 98%, 99%, or 100% sequence identity to SEQ ID NO:65 and an amino acid sequence having at least 80%, 85%, 90%, 95%, 98%, 99%, or 100% sequence identity to SEQ ID NO:64, and wherein the third binding domain comprises an amino acid sequence having at least 80%, 85%, 90%, 95%, 98%, 99%, or 100% sequence identity to SEQ ID NO:48, SEQ ID NO:49, SEQ ID NO:77, or SEQ ID NO:78, and the third binding domain comprises an amino acid sequence having at least 80%, 85%, 90%, 95%, 98%, 99%, or 100% sequence identity to SEQ ID NO:50.In some embodiments, the first and second binding domains comprise an amino acid sequence having at least 80%, 85%, 90%, 95%, 98%, 99%, or 100% sequence identity to SEQ ID NO:67 and an amino acid sequence having at least 80%, 85%, 90%, 95%, 98%, 99%, or 100% sequence identity to SEQ ID NO:66, and wherein the third binding domain comprises an amino acid sequence having at least 80%, 85%, 90%, 95%, 98%, 99%, or 100% sequence identity to SEQ ID NO:48, SEQ ID NO:49, SEQ ID NO:77, or SEQ ID NO:78, and the third binding domain comprises an amino acid sequence having at least 80%, 85%, 90%, 95%, 98%, 99%, or 100% sequence identity to SEQ ID NO:50. In some embodiments, the first and second binding domains comprise an amino acid sequence having at least 80%, 85%, 90%, 95%, 98%, 99%, or 100% sequence identity to SEQ ID NO:69 and an amino acid sequence having at least 80%, 85%, 90%, 95%, 98%, 99%, or 100% sequence identity to SEQ ID NO:68, and wherein the third binding domain comprises an amino acid sequence having at least 80%, 85%, 90%, 95%, 98%, 99%, or 100% sequence identity to SEQ ID NO:48, SEQ ID NO:49, SEQ ID NO:77, or SEQ ID NO:78, and the third binding domain comprises an amino acid sequence having at least 80%, 85%, 90%, 95%, 98%, 99%, or 100% sequence identity to SEQ ID NO:50. In some embodiments, the first and second binding domains comprise an amino acid sequence having at least 80%, 85%, 90%, 95%, 98%, 99%, or 100% sequence identity to SEQ ID NO: 71 and an amino acid sequence having at least 80%, 85%, 90%, 95%, 98%, 99%, or 100% sequence identity to SEQ ID NO: 70, and wherein the third binding domain comprises an amino acid sequence having at least 80%, 85%, 90%, 95%, 98%, 99%, or 100% sequence identity to SEQ ID NO: 48, SEQ ID NO: 49, SEQ ID NO: 77, or SEQ ID NO: 78, and the third binding domain comprises an amino acid sequence having at least 80%, 85%, 90%, 95%, 98%, 99%, or 100% sequence identity to SEQ ID NO: 50. In some embodiments, the composition comprises a pharmaceutically acceptable excipient.

[0004] Disclosed herein is an isolated recombinant nucleic acid sequence encoding the amino acid sequence of the composition according to any one of the above embodiments.

[0005] Disclosed herein are vectors comprising the isolated recombinant nucleic acid sequence according to the above embodiments.

[0006] Disclosed herein are kits comprising at least one of the following: the composition of any one of the above embodiments; the vector of the above embodiments; or the nucleic acid molecule of the above embodiments.

[0007] Disclosed herein are methods of treating food allergy in a subject in need thereof, comprising administering to the subject a composition according to any of the above embodiments.

[0008] Disclosed herein are methods of treating food allergies in a subject in need thereof, comprising administering to the subject a composition according to any of the above embodiments. In some embodiments, the food allergy comprises peanut allergy. BRIEF DESCRIPTION OF THE DRAWINGS

[0009] The novel features of the present disclosure are set forth with particularity in the appended claims. A better understanding of the features and advantages of the present invention will be obtained by reference to the following detailed description of illustrative embodiments in which the principles of the present disclosure are utilized, and the accompanying drawings, in which:

[0010] Figure 1 The peanut antigen-specific distribution of mAbs found from peanut-allergic individuals is shown.

[0011] Figure 2 Epitope binning of Ara h 2-specific mAbs is shown.

[0012] Figure 3A Schematic representation of a simplified ELISA for assessing the ability of IgG mAbs to block the binding of allergic plasma IgE to tagged allergens.

[0013] Figure 3B Shown is the inhibition of recombinant Ara h 2 binding to peanut allergic plasma IgE by one or more molecule-2 mAbs.

[0014] Figure 3C The binding of Molecule-1 and Molecule-2 mAbs to recombinant Ara h 2 is shown.

[0015] Figure 3D The graph shows that Molecule-1 and Molecule-2 mAbs inhibit the binding of recombinant Ara h 2 to peanut allergic plasma IgE.

[0016] Figure 4A An overview of the Mast Cell Activation Test (MAT) is shown.

[0017] Figure 4B The percentage inhibition of peanut-mediated and Ara h 2-mediated mast cell activation by IgG1 and IgG4 mAbs alone or in combination is shown.

[0018] Figure 5A Combination-1 comprising two molecules is shown.

[0019] Figure 5B Graph depicts the blockade of recombinant Ara h 2 binding to peanut allergic plasma IgE by Combination-1.

[0020] Figure 5C Graph depicting the inhibition of peanut-mediated mast cell activation by Combination-1 and its components.

[0021] Figure 6A Schematic diagram of the protocol for the oral sensitization / oral peanut challenge mouse model of peanut allergy.

[0022] Figure 6B Graphed are the dose-dependent effects of Combination-1 and its components on hypothermic responses in peanut-allergic animals when challenged with 25 mg peanut protein delivered via oral gavage.

[0023] Figure 6C Graphed are the dose-dependent effects of Combination-1 and its components on serum MCPT-1 in peanut-allergic animals when challenged with 25 mg peanut protein delivered via oral gavage. DETAILED DESCRIPTION

[0024] Allergies are characterized by a variety of conditions caused by hypersensitivity of the immune system to substances in the environment that are often harmful. Generally speaking, an allergic reaction occurs when aspects of the immune system overreact to the presence of a substance (allergen) that would not cause a reaction if the allergy were not present. Foods, insect bites, and medications are common causes of severe allergic reactions. In addition, there are many important non-food allergies, including but not limited to pollens (e.g., ragweed, trees, and grasses), animals (e.g., animal dander), molds, metals, and latex.

[0025] As commonly understood, allergens are a class of antigens that produce an abnormally intense immune response, in which the immune system fights off a perceived threat that would otherwise be harmless. Technically, allergens are antigens that can stimulate a type I hypersensitivity reaction in atopic individuals through an immunoglobulin E (IgE) response. Most people only have a significant IgE response as a line of defense against parasitic infections. However, some individuals can respond to many common environmental antigens. This genetic predisposition is called atopy. In atopic individuals, non-parasitic antigens stimulate inappropriate IgE production, leading to type I hypersensitivity.

[0026] Some foods, such as peanuts (a legume), tree nuts, seafood, and shellfish, are the cause of severe allergies in many people. The U.S. Food and Drug Administration officially recognizes nine foods as common allergic reactions in the most sensitive population. These foods include peanuts, tree nuts, eggs, milk, shellfish, fish, sesame seeds, wheat and its derivatives, soy and its derivatives, and sulfites (chemical bases commonly found in flavorings and dyes in food).

[0027] An allergic reaction can be caused by any form of direct contact with an allergen—eating a food or drink to which a person is sensitive (ingestion), breathing in pollen, fragrances, or pet dander (inhalation), or rubbing a part of the body against an allergenic plant (direct contact). Extremely severe forms of allergic reactions are called anaphylaxis.

[0028] Immunoglobulin E (IgE) antibodies mediate allergic reactions. The antibodies bind to specific receptors on inflammatory immune cells, including mast cells in the mucosal tissues of the body surface and the lining of body cavities, as well as circulating basophils. These cells mediate allergic reactions triggered by specific antigens (allergens) recognized by IgE through the release of inflammatory molecules (such as histamine). The inflammatory response is the cause of many symptoms, such as sneezing, runny or stuffy nose, itchy eyes, difficulty breathing, and in extreme cases, anaphylactic shock and even death.

[0029] Food allergies are on the rise. The most common food allergens include soy products, tree nuts (almonds, cashews, walnuts, pecans, pistachios, Brazil nuts, macadamia nuts, etc.), peanuts, eggs, shellfish, fish, milk, sesame seeds, and wheat. Food allergies negatively impact quality of life and further result in a significant economic burden. For example, people with allergies need to be highly vigilant and may avoid situations that could trigger an allergic reaction, including socializing. In addition, the risk of severe reactions and anaphylaxis increases for people with multiple food allergies. For many allergies, there is currently no cure, and individuals must engage in lifelong avoidance. Treatment for allergies includes avoidance of known allergens and the use of medications such as steroids and antihistamines. In severe reactions, injectable epinephrine is recommended as emergency treatment. One treatment for allergies is immunotherapy. Immunotherapy involves repeated injections or exposure to allergen extracts to desensitize the patient to the allergen. However, immunotherapy is time-consuming, typically involving several years of treatment, and generally fails to achieve its goal of desensitizing the patient to the allergen. Furthermore, immunotherapy carries the risk of potentially serious adverse events, including anaphylaxis. Therefore, there is a need for improved therapies for treating allergic reactions.

[0030] Disclosed herein are compositions for preventing, treating, and inhibiting allergic reactions associated with specific allergens. These compositions provide high-affinity allergen-specific antibody preparations designed to reduce and / or prevent allergic reactions associated with specific allergens.

[0031] Composition

[0032] Antibodies that bind to Ara h 2 and Ara h 6

[0033] Disclosed herein are isolated antibodies that bind to Ara h 2 and Ara h 6, the antibodies comprising a heavy chain variable domain (VH) comprising complementarity determining regions (CDRs): HC-CDR1, HC-CDR2, HC-CDR3, wherein the HC-CDR1, HC-CDR2, HC-CDR3 comprise the amino acid sequence according to HC-CDR1: SEQ ID NO: 1, HC-CDR2: SEQ ID NO: 2 or SEQ ID NO: 3, HC-CDR-3: SEQ ID NO: 4 or SEQ ID NO: 5, and the isolated antibodies comprising a light chain variable (VL) domain comprising CDRs: LC-CDR1, LC-CDR2, LC-CDR3, wherein the LC-CDR1, LC-CDR2, LC-CDR3 comprise the amino acid sequence according to LC-CDR1: SEQ ID NO: 6, LC-CDR2: SEQ ID NO: 7, LC-CDR-3: SEQ ID NO: 8. Disclosed herein are isolated antibodies that bind to Ara h 2 and Arah 6, comprising a heavy chain variable domain (VH) comprising complementarity determining regions (CDRs): HC-CDR1, HC-CDR2, HC-CDR3, wherein HC-CDR1, HC-CDR2, HC-CDR3 comprise the amino acid sequence according to HC-CDR1: SEQ ID NO: 1, HC-CDR2: SEQ ID NO: 2, HC-CDR-3: SEQ ID NO: 4, and the isolated antibody comprises a light chain variable (VL) domain comprising CDRs: LC-CDR1, LC-CDR2, LC-CDR3, wherein LC-CDR1, LC-CDR2, LC-CDR3 comprise the amino acid sequence according to LC-CDR1: SEQ ID NO: 6, LC-CDR2: SEQ ID NO: 7, LC-CDR-3: SEQ ID NO: 8. In some embodiments, the VH comprises an amino acid sequence having at least 80%, 85%, 90%, 95%, 98%, 99%, or 100% sequence identity to SEQ ID NO: 9 or SEQ ID NO: 10. In some embodiments, the VL comprises an amino acid sequence having at least 80%, 85%, 90%, 95%, 98%, 99%, or 100% sequence identity to SEQ ID NO: 11. In some embodiments, the VH comprises an amino acid sequence having at least 80%, 85%, 90%, 95%, 98%, 99%, or 100% sequence identity to SEQ ID NO: 9 or SEQ ID NO: 10, and wherein the VL comprises an amino acid sequence having at least 80%, 85%, 90%, 95%, 98%, 99%, or 100% sequence identity to SEQ ID NO: 11.In some embodiments, the isolated antibody comprises Fab, Fab', F(ab')2, or a single-chain variable fragment (scFv). In some embodiments, the isolated antibody is Fab, Fab', F(ab')2, or a single-chain variable fragment (scFv). In some embodiments, the isolated antibody comprises an scFv. In some embodiments, VH and VL are connected by an scFv linker sequence. In some embodiments, the scFv linker sequence comprises an amino acid sequence according to SEQ ID No: 12. In some embodiments, the scFv comprises an amino acid sequence having at least 80%, 85%, 90%, 95%, 98%, 99%, or 100% sequence identity with SEQ ID NO: 13 or SEQ ID NO: 14. In some embodiments, the isolated antibody comprises a constant domain. In some embodiments, the constant domain comprises a human IgG4 sequence. In some embodiments, the human IgG4 sequence comprises an S228P point mutation, wherein the amino acid numbering follows the EU index in Kabat et al. In some embodiments, the human IgG4 sequence does not have a C-terminal lysine residue. In some embodiments, the constant domain comprises a human IgG1 sequence. In some embodiments, the constant domain comprises C. H 1. C H 2. C H 3 or C L In some embodiments, the isolated antibody comprises C H 1. C H 2. C H 3 and C L Amino acid sequences. In some embodiments, the isolated antibody comprises an amino acid sequence that has at least 80%, 85%, 90%, 95%, 98%, 99%, or 100% sequence identity to SEQ ID NO: 15, SEQ ID NO: 16, SEQ ID NO: 72, or SEQ ID NO: 73, and the isolated antibody comprises an amino acid sequence that has at least 80%, 85%, 90%, 95%, 98%, 99%, or 100% sequence identity to SEQ ID NO: 17.

[0034] Table 1. Amino acid sequences of antibodies that bind to Ara h 2 and Ara h 6; CDRs were determined using the IMGT domain system.

[0035]

[0036]

[0037]

[0038] Disclosed herein are antibodies that bind to Ara h 2 and Ara h 6, the antibodies comprising a heavy chain variable domain (VH) comprising complementarity determining regions (CDRs): HC-CDR1, HC-CDR2, HC-CDR3, wherein HC-CDR1, HC-CDR2, HC-CDR3 comprise the amino acid sequence according to HC-CDR1: SEQ ID NO: 18, HC-CDR2: SEQ ID NO: 19, HC-CDR-3: SEQ ID NO: 20, or SEQ ID NO: 21, and the isolated antibodies comprising a light chain variable (VL) domain comprising CDRs: LC-CDR1, LC-CDR2, LC-CDR3, wherein LC-CDR1, LC-CDR2, LC-CDR3 comprise the amino acid sequence according to LC-CDR1: SEQ ID NO: 22, LC-CDR2: SEQ ID NO: 23, LC-CDR-3: SEQ ID NO: 24. Disclosed herein are antibodies that bind to Ara h 2 and Ara h 6, comprising a heavy chain variable domain (VH) comprising complementarity determining regions (CDRs): HC-CDR1, HC-CDR2, HC-CDR3, wherein HC-CDR1, HC-CDR2, HC-CDR3 comprise the amino acid sequence according to HC-CDR1: SEQ ID NO: 18, HC-CDR2: SEQ ID NO: 19, HC-CDR-3: SEQ ID NO: 20, and an isolated antibody comprising a light chain variable (VL) domain comprising CDRs: LC-CDR1, LC-CDR2, LC-CDR3, wherein LC-CDR1, LC-CDR2, LC-CDR3 comprise the amino acid sequence according to LC-CDR1: SEQ ID NO: 22, LC-CDR2: SEQ ID NO: 23, LC-CDR-3: SEQ ID NO: 24. In some embodiments, the VH comprises an amino acid sequence having at least 80%, 85%, 90%, 95%, 98%, 99%, or 100% sequence identity to SEQ ID NO: 25 or SEQ ID NO: 26. In some embodiments, the VL comprises an amino acid sequence having at least 80%, 85%, 90%, 95%, 98%, 99%, or 100% sequence identity to SEQ ID NO: 27 or SEQ ID NO: 28. In some embodiments, the VH comprises an amino acid sequence having at least 80%, 85%, 90%, 95%, 98%, 99%, or 100% sequence identity to SEQ ID NO: 25 or SEQ ID NO: 26, and wherein the VL comprises an amino acid sequence having at least 80%, 85%, 90%, 95%, 98%, 99%, or 100% sequence identity to SEQ ID NO: 27 or SEQ ID NO: 28.In some embodiments, the isolated antibody comprises Fab, Fab', F(ab')2, or a single-chain variable fragment (scFv). In some embodiments, the isolated antibody is Fab, Fab', F(ab')2, or a single-chain variable fragment (scFv). In some embodiments, the isolated antibody comprises an scFv. In some embodiments, VH and VL are connected by an scFv linker sequence. In some embodiments, the scFv linker sequence comprises an amino acid sequence according to SEQ ID NO:29. In some embodiments, the scFv comprises an amino acid sequence having at least 80%, 85%, 90%, 95%, 98%, 99%, or 100% sequence identity with SEQ ID NO:30 or SEQ ID NO:31. In some embodiments, the isolated antibody comprises a constant domain. In some embodiments, the constant domain comprises a human IgG4 sequence. In some embodiments, the human IgG4 sequence comprises an S228P point mutation, wherein the amino acid numbering follows the EU index in Kabat et al. In some embodiments, the human IgG4 sequence does not have a C-terminal lysine residue. In some embodiments, the constant domain comprises a human IgG1 sequence. In some embodiments, the constant domain comprises C. H 1. C H 2. C H 3 or C L In some embodiments, the isolated antibody comprises C H 1. C H 2. C H 3 and C L Amino acid sequences. In some embodiments, the isolated antibody comprises an amino acid sequence that has at least 80%, 85%, 90%, 95%, 98%, 99%, or 100% sequence identity to SEQ ID NO: 32, SEQ ID NO: 33, SEQ ID NO: 74, or SEQ ID NO: 75, and the isolated antibody comprises an amino acid sequence that has at least 80%, 85%, 90%, 95%, 98%, 99%, or 100% sequence identity to SEQ ID NO: 34 or SEQ ID NO: 76.

[0039] Table 2. Amino acid sequences of antibodies that bind to Ara h 2 and Ara h 6; CDRs determined using the IMGT domain system.

[0040]

[0041]

[0042]

[0043]

[0044] Antibodies that bind to Ara h 2

[0045] Disclosed herein are isolated antibodies that bind to Ara h 2, the antibody comprising a heavy chain variable domain (VH) comprising complementarity determining regions (CDRs): HC-CDR1, HC-CDR2, HC-CDR3, wherein HC-CDR1, HC-CDR2, HC-CDR3 comprise the amino acid sequence according to HC-CDR1: SEQ ID NO: 35, HC-CDR2: SEQ ID NO: 36 or SEQ ID NO: 37, HC-CDR-3: SEQ ID NO: 38, and the isolated antibody comprises a light chain variable (VL) domain comprising CDRs: LC-CDR1, LC-CDR2, LC-CDR3, wherein LC-CDR1, LC-CDR2, LC-CDR3 comprise the amino acid sequence according to LC-CDR1: SEQ ID NO: 39, LC-CDR2: SEQ ID NO: 40, LC-CDR-3: SEQ ID NO: 41. Disclosed herein are isolated antibodies that bind to Ara h 2, the antibody comprising a heavy chain variable domain (VH) comprising complementarity determining regions (CDRs): HC-CDR1, HC-CDR2, HC-CDR3, wherein HC-CDR1, HC-CDR2, HC-CDR3 comprise the amino acid sequence according to HC-CDR1: SEQ ID NO: 35, HC-CDR2: SEQ ID NO: 36, HC-CDR-3: SEQ ID NO: 38, and the isolated antibody comprises a light chain variable (VL) domain comprising CDRs: LC-CDR1, LC-CDR2, LC-CDR3, wherein LC-CDR1, LC-CDR2, LC-CDR3 comprise the amino acid sequence according to LC-CDR1: SEQ ID NO: 39, LC-CDR2: SEQ ID NO: 40, LC-CDR-3: SEQ ID NO: 41. In some embodiments, the VH comprises an amino acid sequence having at least 80%, 85%, 90%, 95%, 98%, 99%, or 100% sequence identity to SEQ ID NO: 42 or SEQ ID NO: 43. In some embodiments, the VL comprises an amino acid sequence having at least 80%, 85%, 90%, 95%, 98%, 99%, or 100% sequence identity to SEQ ID NO: 44. In some embodiments, the VH comprises an amino acid sequence having at least 80%, 85%, 90%, 95%, 98%, 99%, or 100% sequence identity to SEQ ID NO: 42 or SEQ ID NO: 43, and wherein the VL comprises an amino acid sequence having at least 80%, 85%, 90%, 95%, 98%, 99%, or 100% sequence identity to SEQ ID NO: 44.In some embodiments, the isolated antibody comprises Fab, Fab', F(ab')2, or a single-chain variable fragment (scFv). In some embodiments, the isolated antibody is Fab, Fab', F(ab')2, or a single-chain variable fragment (scFv). In some embodiments, the isolated antibody comprises an scFv. In some embodiments, VH and VL are connected by an scFv linker sequence. In some embodiments, the scFv linker sequence comprises an amino acid sequence according to SEQ ID NO:45. In some embodiments, the scFv comprises an amino acid sequence having at least 80%, 85%, 90%, 95%, 98%, 99%, or 100% sequence identity with SEQ ID NO:46 or SEQ ID NO:47. In some embodiments, the isolated antibody comprises a constant domain. In some embodiments, the constant domain comprises a human IgG4 sequence. In some embodiments, the human IgG4 sequence comprises an S228P point mutation, wherein the amino acid numbering follows the EU index in Kabat et al. In some embodiments, the human IgG4 sequence does not have a C-terminal lysine residue. In some embodiments, the constant domain comprises a human IgG1 sequence. In some embodiments, the constant domain comprises C. H 1. C H 2. C H 3 or C L In some embodiments, the isolated antibody comprises C H 1. C H 2. C H 3 and C L Amino acid sequences. In some embodiments, the isolated antibody comprises an amino acid sequence that has at least 80%, 85%, 90%, 95%, 98%, 99%, or 100% sequence identity to SEQ ID NO:48, SEQ ID NO:49, SEQ ID NO:77, or SEQ ID NO:78, and the isolated antibody comprises an amino acid sequence that has at least 80%, 85%, 90%, 95%, 98%, 99%, or 100% sequence identity to SEQ ID NO:50.

[0046] Table 3. Amino acid sequences of antibodies that bind to Ara h 2; CDRs determined using the IMGT domain system.

[0047]

[0048]

[0049]

[0050] Antibodies having a first binding domain and a second binding domain

[0051] Disclosed herein are isolated antibodies comprising a first binding domain that binds to Ara h 2 and Ara h 6, wherein the first binding domain comprises a heavy chain variable domain (VH) comprising complementarity determining regions (CDRs): HC-CDR1, HC-CDR2, HC-CDR3, wherein HC-CDR1, HC-CDR2, HC-CDR3 comprise an amino acid sequence according to HC-CDR1: SEQ ID NO: 1, HC-CDR2: SEQ ID NO: 2 or SEQ ID NO: 3, HC-CDR-3: SEQ ID NO: 4 or SEQ ID NO: 5, and the first binding domain comprises a light chain variable (VL) domain comprising CDRs: LC-CDR1, LC-CDR2, LC-CDR3, wherein LC-CDR1, LC-CDR2, LC-CDR3 comprise an amino acid sequence according to LC-CDR1: SEQ ID NO: 6, LC-CDR2: SEQ ID NO: 7, LC-CDR-3: SEQ ID NO: 8, wherein the isolated antibody comprises a heavy chain variable domain (VH) comprising complementarity determining regions (CDRs): HC-CDR1, HC-CDR2, HC-CDR3, wherein HC-CDR1, HC-CDR2, HC-CDR3 comprise an amino acid sequence according to LC-CDR1: SEQ ID NO: 6, LC-CDR2: SEQ ID NO: 7, LC-CDR-3: SEQ ID NO: 8, 2 and Ara h 6, wherein the second binding domain comprises a VH comprising complementarity determining regions (CDRs): HC-CDR1, HC-CDR2, HC-CDR3, wherein HC-CDR1, HC-CDR2, HC-CDR3 comprise the amino acid sequence according to HC-CDR1: SEQ ID NO: 18, HC-CDR2: SEQ ID NO: 19, HC-CDR-3: SEQ ID NO: 20 or SEQ ID NO: 21, and the second binding domain comprises a light chain variable (VL) domain comprising CDRs: LC-CDR1, LC-CDR2, LC-CDR3, wherein LC-CDR1, LC-CDR2, LC-CDR3 comprise the amino acid sequence according to LC-CDR1: SEQ ID NO: 22, LC-CDR2: SEQ ID NO: 23, LC-CDR-3: SEQ ID NO: 24.Disclosed herein are isolated antibodies comprising a first binding domain that binds to Ara h 2 and Ara h 6, wherein the first binding domain comprises a heavy chain variable domain (VH) comprising complementarity determining regions (CDRs): HC-CDR1, HC-CDR2, HC-CDR3, wherein HC-CDR1, HC-CDR2, HC-CDR3 comprise the amino acid sequence according to HC-CDR1: SEQ ID NO: 1, HC-CDR2: SEQ ID NO: 2, HC-CDR3: SEQ ID NO: 4, and the first binding domain comprises a light chain variable (VL) domain comprising CDRs: LC-CDR1, LC-CDR2, LC-CDR3, wherein LC-CDR1, LC-CDR2, LC-CDR3 comprise the amino acid sequence according to LC-CDR1: SEQ ID NO: 6, LC-CDR2: SEQ ID NO: 7, LC-CDR3: SEQ ID NO: 8, wherein the isolated antibody comprises a first binding domain that binds to Ara h 2 and Ara h 6. 6, wherein the second binding domain comprises a VH comprising complementarity determining regions (CDRs): HC-CDR1, HC-CDR2, HC-CDR3, wherein HC-CDR1, HC-CDR2, HC-CDR3 comprise the amino acid sequence according to HC-CDR1: SEQ ID NO: 18, HC-CDR2: SEQ ID NO: 19, HC-CDR-3: SEQ ID NO: 20, and the second binding domain comprises a light chain variable (VL) domain comprising CDRs: LC-CDR1, LC-CDR2, LC-CDR3, wherein LC-CDR1, LC-CDR2, LC-CDR3 comprise the amino acid sequence according to LC-CDR1: SEQ ID NO: 22, LC-CDR2: SEQ ID NO: 23, LC-CDR-3: SEQ ID NO: 24. In some embodiments, the VH of the first binding domain comprises an amino acid sequence having at least 80%, 85%, 90%, 95%, 98%, 99%, or 100% sequence identity to SEQ ID NO: 9 or SEQ ID NO: 10. In some embodiments, the VL of the first binding domain comprises an amino acid sequence having at least 80%, 85%, 90%, 95%, 98%, 99%, or 100% sequence identity to SEQ ID NO: 11. In some embodiments, the VH of the first binding domain comprises an amino acid sequence having at least 80%, 85%, 90%, 95%, 98%, 99%, or 100% sequence identity to SEQ ID NO: 9 or SEQ ID NO: 10, and wherein the VL of the first binding domain comprises an amino acid sequence having at least 80%, 85%, 90%, 95%, 98%, 99%, or 100% sequence identity to SEQ ID NO: 11.In some embodiments, the first binding domain comprises a Fab, Fab', F(ab')2, or a single-chain variable fragment (scFv). In some embodiments, the first binding domain is a Fab, Fab', F(ab')2, or a single-chain variable fragment (scFv). In some embodiments, the first binding domain comprises an scFv. In some embodiments, the VH of the first binding domain and the VL of the first binding domain are connected by an scFv linker sequence. In some embodiments, the scFv linker sequence of the first binding domain comprises an amino acid sequence according to SEQ ID No: 12. In some embodiments, the scFv of the first binding domain comprises an amino acid sequence having at least 80%, 85%, 90%, 95%, 98%, 99%, or 100% sequence identity to SEQ ID NO: 13 or SEQ ID NO: 14. In some embodiments, the first binding domain comprises a constant domain. In some embodiments, the constant domain of the first binding domain comprises a human IgG4 sequence. In some embodiments, the human IgG4 sequence of the first binding domain comprises an S228P point mutation, wherein amino acid numbering follows the EU index as in Kabat et al. In some embodiments, the human IgG4 sequence of the first binding domain does not have a C-terminal lysine residue. In some embodiments, the constant domain of the first binding domain comprises a human IgG1 sequence. In some embodiments, the constant domain of the first binding domain comprises C. H 1. C H 2. C H 3 or C L In some embodiments, the first binding domain comprises C H 1. C H 2. C H 3 and C LAmino acid sequence. In some embodiments, the first binding domain comprises an amino acid sequence having at least 80%, 85%, 90%, 95%, 98%, 99%, or 100% sequence identity to SEQ ID NO: 15, SEQ ID NO: 16, SEQ ID NO: 72, or SEQ ID NO: 73, and the first binding domain comprises an amino acid sequence having at least 80%, 85%, 90%, 95%, 98%, 99%, or 100% sequence identity to SEQ ID NO: 17. In some embodiments, the VH of the second binding domain comprises an amino acid sequence having at least 80%, 85%, 90%, 95%, 98%, 99%, or 100% sequence identity to SEQ ID NO: 25 or SEQ ID NO: 26. In some embodiments, the VL of the second binding domain comprises an amino acid sequence having at least 80%, 85%, 90%, 95%, 98%, 99%, or 100% sequence identity to SEQ ID NO: 27 or SEQ ID NO: 28. In some embodiments, the VH of the second binding domain comprises an amino acid sequence having at least 80%, 85%, 90%, 95%, 98%, 99% or 100% sequence identity to SEQ ID NO: 25 or SEQ ID NO: 26, and wherein the VL of the second binding domain comprises an amino acid sequence having at least 80%, 85%, 90%, 95%, 98%, 99% or 100% sequence identity to SEQ ID NO: 27 or SEQ ID NO: 28. In some embodiments, the second binding domain comprises a Fab, Fab', F(ab')2, or a single-chain variable fragment (scFv). In some embodiments, the second binding domain is a Fab, Fab', F(ab')2, or a single-chain variable fragment (scFv). In some embodiments, the second binding domain comprises an scFv. In some embodiments, the VH of the second binding domain and the VL of the second binding domain are connected by an scFv linker sequence. In some embodiments, the scFv linker sequence of the second binding domain comprises an amino acid sequence according to SEQ ID NO: 29. In some embodiments, the scFv of the second binding domain comprises an amino acid sequence that has at least 80%, 85%, 90%, 95%, 98%, 99%, or 100% sequence identity to SEQ ID NO: 30 or SEQ ID NO: 31. In some embodiments, the second binding domain comprises a constant domain. In some embodiments, the constant domain of the second binding domain comprises a human IgG4 sequence. In some embodiments, the human IgG4 sequence of the second binding domain comprises an S228P point mutation, wherein amino acid numbering follows the EU index as in Kabat et al. In some embodiments, the human IgG4 sequence of the second binding domain does not have a C-terminal lysine residue. In some embodiments, the constant domain of the second binding domain comprises a human IgG1 sequence.In some embodiments, the constant domain of the second binding domain comprises C. H 1. C H 2. C H 3 or C L In some embodiments, the second binding domain comprises C H 1. C H 2. C H 3 and C L In some embodiments, the second binding domain comprises an amino acid sequence having at least 80%, 85%, 90%, 95%, 98%, 99% or 100% sequence identity to SEQ ID NO:32, SEQ ID NO:33, SEQ ID NO:74 or SEQ ID NO:75, and the isolated antibody comprises an amino acid sequence having at least 80%, 85%, 90%, 95%, 98%, 99% or 100% sequence identity to SEQ ID NO:34 or SEQ ID NO:76. In some embodiments, the first binding domain comprises an scFv and the second binding domain comprises a C H 1. C H 2. C H 3 and C L In some embodiments, the second binding domain comprises an scFv and the first binding domain comprises a C H 1. C H 2. C H 3 and C L In some embodiments, the first binding domain and the second binding domain are connected by a connecting portion. In some embodiments, the connecting portion is an amino acid sequence. In some embodiments, the connecting portion is at least 4 amino acids long. In some embodiments, the length of the connecting portion is between 4 and 20 amino acids. In some embodiments, the connecting portion connects the C of the second binding domain to the C of the second binding domain. HIn some embodiments, the connecting portion comprises an amino acid sequence of SEQ ID NO: 51. In some embodiments, the isolated antibody comprises an amino acid sequence having at least 80%, 85%, 90%, 95%, 98%, 99% or 100% sequence identity to SEQ ID NO: 53 and an amino acid sequence having at least 80%, 85%, 90%, 95%, 98%, 99% or 100% sequence identity to SEQ ID NO: 52. In some embodiments, the isolated antibody comprises an amino acid sequence having at least 80%, 85%, 90%, 95%, 98%, 99% or 100% sequence identity to SEQ ID NO: 55 and an amino acid sequence having at least 80%, 85%, 90%, 95%, 98%, 99% or 100% sequence identity to SEQ ID NO: 54. In some embodiments, the isolated antibody comprises an amino acid sequence having at least 80%, 85%, 90%, 95%, 98%, 99% or 100% sequence identity to SEQ ID NO: 65 and an amino acid sequence having at least 80%, 85%, 90%, 95%, 98%, 99% or 100% sequence identity to SEQ ID NO: 64. In some embodiments, the isolated antibody comprises an amino acid sequence having at least 80%, 85%, 90%, 95%, 98%, 99% or 100% sequence identity to SEQ ID NO: 67 and an amino acid sequence having at least 80%, 85%, 90%, 95%, 98%, 99% or 100% sequence identity to SEQ ID NO: 66. In some embodiments, the isolated antibody comprises an amino acid sequence having at least 80%, 85%, 90%, 95%, 98%, 99% or 100% sequence identity to SEQ ID NO: 69 and an amino acid sequence having at least 80%, 85%, 90%, 95%, 98%, 99% or 100% sequence identity to SEQ ID NO: 68. In some embodiments, the isolated antibody comprises an amino acid sequence having at least 80%, 85%, 90%, 95%, 98%, 99% or 100% sequence identity to SEQ ID NO: 71 and an amino acid sequence having at least 80%, 85%, 90%, 95%, 98%, 99% or 100% sequence identity to SEQ ID NO: 70.

[0052] Disclosed herein are isolated antibodies comprising a first binding domain that binds to Ara h 2 and Ara h 6, wherein the first binding domain comprises a heavy chain variable domain (VH) comprising complementarity determining regions (CDRs): HC-CDR1, HC-CDR2, HC-CDR3, wherein HC-CDR1, HC-CDR2, HC-CDR3 comprise an amino acid sequence according to HC-CDR1: SEQ ID NO: 1, HC-CDR2: SEQ ID NO: 2 or SEQ ID NO: 3, HC-CDR-3: SEQ ID NO: 4 or SEQ ID NO: 5, and the first binding domain comprises a light chain variable (VL) domain comprising CDRs: LC-CDR1, LC-CDR2, LC-CDR3, wherein LC-CDR1, LC-CDR2, LC-CDR3 comprise an amino acid sequence according to LC-CDR1: SEQ ID NO: 6, LC-CDR2: SEQ ID NO: 7, LC-CDR-3: SEQ ID NO: 8, wherein the isolated antibody comprises a heavy chain variable domain (VH) comprising complementarity determining regions (CDRs): HC-CDR1, HC-CDR2, HC-CDR3, wherein HC-CDR1, HC-CDR2, HC-CDR3 comprise an amino acid sequence according to LC-CDR1: SEQ ID NO: 6, LC-CDR2: SEQ ID NO: 7, LC-CDR-3: SEQ ID NO: 8, 2, wherein the second binding domain comprises a (VH) comprising complementarity determining regions (CDRs): HC-CDR1, HC-CDR2, HC-CDR3, wherein HC-CDR1, HC-CDR2, HC-CDR3 comprise the amino acid sequence according to HC-CDR1: SEQ ID NO:35, HC-CDR2: SEQ ID NO:36 or SEQ ID NO:37, HC-CDR-3: SEQ ID NO:38, and the isolated antibody comprises a light chain variable (VL) domain comprising CDRs: LC-CDR1, LC-CDR2, LC-CDR3, wherein LC-CDR1, LC-CDR2, LC-CDR3 comprise the amino acid sequence according to LC-CDR1: SEQ ID NO:39, LC-CDR2: SEQ ID NO:40, LC-CDR-3: SEQ ID NO:41.Disclosed herein are isolated antibodies comprising a first binding domain that binds to Ara h 2 and Ara h 6, wherein the first binding domain comprises a heavy chain variable domain (VH) comprising complementarity determining regions (CDRs): HC-CDR1, HC-CDR2, HC-CDR3, wherein HC-CDR1, HC-CDR2, HC-CDR3 comprise the amino acid sequence according to HC-CDR1: SEQ ID NO: 1, HC-CDR2: SEQ ID NO: 2, HC-CDR3: SEQ ID NO: 4, and the first binding domain comprises a light chain variable (VL) domain comprising CDRs: LC-CDR1, LC-CDR2, LC-CDR3, wherein LC-CDR1, LC-CDR2, LC-CDR3 comprise the amino acid sequence according to LC-CDR1: SEQ ID NO: 6, LC-CDR2: SEQ ID NO: 7, LC-CDR3: SEQ ID NO: 8, wherein the isolated antibody comprises a first binding domain that binds to Ara h 2 and Ara h 6, wherein the first binding domain comprises a heavy chain variable domain (VH) comprising complementarity determining regions (CDRs): HC-CDR1, HC-CDR2, HC-CDR3, wherein the HC-CDR1, HC-CDR2, HC-CDR3 comprise the amino acid sequence according to LC-CDR1: SEQ ID NO: 6, LC-CDR2: SEQ ID NO: 7, LC-CDR3: SEQ ID NO: 8, 2, wherein the second binding domain comprises a (VH) comprising complementarity determining regions (CDRs): HC-CDR1, HC-CDR2, HC-CDR3, wherein HC-CDR1, HC-CDR2, HC-CDR3 comprise the amino acid sequence according to HC-CDR1: SEQ ID NO: 35, HC-CDR2: SEQ ID NO: 36, HC-CDR-3: SEQ ID NO: 38, and the isolated antibody comprises a light chain variable (VL) domain comprising CDRs: LC-CDR1, LC-CDR2, LC-CDR3, wherein LC-CDR1, LC-CDR2, LC-CDR3 comprise the amino acid sequence according to LC-CDR1: SEQ ID NO: 39, LC-CDR2: SEQ ID NO: 40, LC-CDR-3: SEQ ID NO: 41. In some embodiments, the VH of the first binding domain comprises an amino acid sequence having at least 80%, 85%, 90%, 95%, 98%, 99%, or 100% sequence identity to SEQ ID NO: 9 or SEQ ID NO: 10. In some embodiments, the VL of the first binding domain comprises an amino acid sequence having at least 80%, 85%, 90%, 95%, 98%, 99%, or 100% sequence identity to SEQ ID NO: 11. In some embodiments, the VH of the first binding domain comprises an amino acid sequence having at least 80%, 85%, 90%, 95%, 98%, 99%, or 100% sequence identity to SEQ ID NO: 9 or SEQ ID NO: 10, and wherein the VL of the first binding domain comprises an amino acid sequence having at least 80%, 85%, 90%, 95%, 98%, 99%, or 100% sequence identity to SEQ ID NO: 11.In some embodiments, the first binding domain comprises a Fab, Fab', F(ab')2, or a single-chain variable fragment (scFv). In some embodiments, the first binding domain is a Fab, Fab', F(ab')2, or a single-chain variable fragment (scFv). In some embodiments, the first binding domain comprises an scFv. In some embodiments, the VH of the first binding domain and the VL of the first binding domain are connected by an scFv linker sequence. In some embodiments, the scFv linker sequence of the first binding domain comprises an amino acid sequence according to SEQ ID No: 12. In some embodiments, the scFv of the first binding domain comprises an amino acid sequence having at least 80%, 85%, 90%, 95%, 98%, 99%, or 100% sequence identity to SEQ ID NO: 13 or SEQ ID NO: 14. In some embodiments, the first binding domain comprises a constant domain. In some embodiments, the constant domain of the first binding domain comprises a human IgG4 sequence. In some embodiments, the human IgG4 sequence of the first binding domain comprises an S228P point mutation, wherein amino acid numbering follows the EU index as in Kabat et al. In some embodiments, the human IgG4 sequence of the first binding domain does not have a C-terminal lysine residue. In some embodiments, the constant domain of the first binding domain comprises a human IgG1 sequence. In some embodiments, the constant domain of the first binding domain comprises C. H 1. C H 2. C H 3 or C L In some embodiments, the first binding domain comprises C H 1. C H 2. C H 3 and C LAmino acid sequence. In some embodiments, the first binding domain comprises an amino acid sequence having at least 80%, 85%, 90%, 95%, 98%, 99%, or 100% sequence identity to SEQ ID NO: 15, SEQ ID NO: 16, SEQ ID NO: 72, or SEQ ID NO: 73, and the first binding domain comprises an amino acid sequence having at least 80%, 85%, 90%, 95%, 98%, 99%, or 100% sequence identity to SEQ ID NO: 17. In some embodiments, the VH of the second binding domain comprises an amino acid sequence having at least 80%, 85%, 90%, 95%, 98%, 99%, or 100% sequence identity to SEQ ID NO: 42 or SEQ ID NO: 43. In some embodiments, the VL of the second binding domain comprises an amino acid sequence having at least 80%, 85%, 90%, 95%, 98%, 99%, or 100% sequence identity to SEQ ID NO: 44. In some embodiments, the VH of the second binding domain comprises an amino acid sequence having at least 80%, 85%, 90%, 95%, 98%, 99% or 100% sequence identity to SEQ ID NO: 42 or SEQ ID NO: 43, and wherein the VL of the second binding domain comprises an amino acid sequence having at least 80%, 85%, 90%, 95%, 98%, 99% or 100% sequence identity to SEQ ID NO: 44. In some embodiments, the second binding domain comprises a Fab, Fab', F(ab')2, or a single-chain variable fragment (scFv). In some embodiments, the second binding domain is a Fab, Fab', F(ab')2, or a single-chain variable fragment (scFv). In some embodiments, the second binding domain comprises an scFv. In some embodiments, the VH of the second binding domain and the VL of the second binding domain are connected by an scFv linker sequence. In some embodiments, the scFv linker sequence of the second binding domain comprises an amino acid sequence according to SEQ ID NO: 45. In some embodiments, the scFv of the second binding domain comprises an amino acid sequence having at least 80%, 85%, 90%, 95%, 98%, 99% or 100% sequence identity to SEQ ID NO: 46 or SEQ ID NO: 47. In some embodiments, the second binding domain comprises a constant domain. In some embodiments, the constant domain of the second binding domain comprises a human IgG4 sequence. In some embodiments, the human IgG4 sequence of the second binding domain comprises an S228P point mutation, wherein the amino acid numbering follows the EU index as in Kabat et al. In some embodiments, the human IgG4 sequence of the second binding domain does not have a C-terminal lysine residue. In some embodiments, the constant domain of the second binding domain comprises a human IgG1 sequence. In some embodiments, the constant domain of the second binding domain comprises a C H 1. CH 2. C H 3 or C L In some embodiments, the second binding domain comprises C H 1. C H 2. C H 3 and C L In some embodiments, the second binding domain comprises an amino acid sequence having at least 80%, 85%, 90%, 95%, 98%, 99% or 100% sequence identity to SEQ ID NO:48, SEQ ID NO:49, SEQ ID NO:77 or SEQ ID NO:78, and the isolated antibody comprises an amino acid sequence having at least 80%, 85%, 90%, 95%, 98%, 99% or 100% sequence identity to SEQ ID NO:50. In some embodiments, the first binding domain comprises an scFv and the second binding domain comprises a C H 1. C H 2. C H 3 and C L In some embodiments, the second binding domain comprises an scFv and the first binding domain comprises a C H 1. C H 2. C H 3 and C L In some embodiments, the first binding domain and the second binding domain are connected by a connecting portion. In some embodiments, the connecting portion is an amino acid sequence. In some embodiments, the connecting portion is at least 4 amino acids long. In some embodiments, the length of the connecting portion is between 4 and 20 amino acids. In some embodiments, the connecting portion connects the C of the second binding domain to the C of the second binding domain. H In some embodiments, the connecting portion comprises an amino acid sequence of SEQ ID NO: 51. In some embodiments, the isolated antibody comprises an amino acid sequence having at least 80%, 85%, 90%, 95%, 98%, 99% or 100% sequence identity to SEQ ID NO: 57 and an amino acid sequence having at least 80%, 85%, 90%, 95%, 98%, 99% or 100% sequence identity to SEQ ID NO: 56. In some embodiments, the isolated antibody comprises an amino acid sequence having at least 80%, 85%, 90%, 95%, 98%, 99% or 100% sequence identity to SEQ ID NO: 59 and an amino acid sequence having at least 80%, 85%, 90%, 95%, 98%, 99% or 100% sequence identity to SEQ ID NO: 58.

[0053] Disclosed herein are isolated antibodies comprising a first binding domain that binds to Ara h 2 and Ara h 6, wherein the first binding domain comprises a heavy chain variable domain (VH) comprising complementarity determining regions (CDRs): HC-CDR1, HC-CDR2, HC-CDR3, wherein HC-CDR1, HC-CDR2, HC-CDR3 comprise the amino acid sequence according to HC-CDR1: SEQ ID NO: 18, HC-CDR2: SEQ ID NO: 19, HC-CDR-3: SEQ ID NO: 20 or SEQ ID NO: 21, and the first binding domain comprises a light chain variable (VL) domain comprising CDRs: LC-CDR1, LC-CDR2, LC-CDR3, wherein LC-CDR1, LC-CDR2, LC-CDR3 comprise the amino acid sequence according to LC-CDR1: SEQ ID NO: 22, LC-CDR2: SEQ ID NO: 23, LC-CDR-3: SEQ ID NO: 24, wherein the isolated antibody comprises a heavy chain variable domain (VH) comprising complementarity determining regions (CDRs): HC-CDR1, HC-CDR2, HC-CDR3, wherein the amino acid sequence according to LC-CDR1: SEQ ID NO: 24, LC-CDR2: SEQ ID NO: 25, LC-CDR3: SEQ ID NO: 26. h2 binds to a second binding domain, wherein the second binding domain comprises a (VH) comprising complementarity determining regions (CDRs): HC-CDR1, HC-CDR2, HC-CDR3, wherein HC-CDR1, HC-CDR2, HC-CDR3 comprise the amino acid sequence according to HC-CDR1: SEQ ID NO: 35, HC-CDR2: SEQ ID NO: 36 or SEQ ID NO: 37, HC-CDR-3: SEQ ID NO: 38, and the isolated antibody comprises a light chain variable (VL) domain comprising CDRs: LC-CDR1, LC-CDR2, LC-CDR3, wherein LC-CDR1, LC-CDR2, LC-CDR3 comprise the amino acid sequence according to LC-CDR1: SEQ ID NO: 39, LC-CDR2: SEQ ID NO: 40, LC-CDR-3: SEQ ID NO: 41.Disclosed herein are isolated antibodies comprising a first binding domain that binds to Ara h 2 and Ara h 6, wherein the first binding domain comprises a heavy chain variable domain (VH) comprising complementarity determining regions (CDRs): HC-CDR1, HC-CDR2, HC-CDR3, wherein HC-CDR1, HC-CDR2, HC-CDR3 comprise the amino acid sequence according to HC-CDR1: SEQ ID NO: 18, HC-CDR2: SEQ ID NO: 19, HC-CDR3: SEQ ID NO: 20, and the first binding domain comprises a light chain variable (VL) domain comprising CDRs: LC-CDR1, LC-CDR2, LC-CDR3, wherein LC-CDR1, LC-CDR2, LC-CDR3 comprise the amino acid sequence according to LC-CDR1: SEQ ID NO: 22, LC-CDR2: SEQ ID NO: 23, LC-CDR3: SEQ ID NO: 24, wherein the isolated antibody comprises a first binding domain that binds to Ara h 2 and Ara h 6, wherein the first binding domain comprises a heavy chain variable domain (VH) comprising complementarity determining regions (CDRs): HC-CDR1, HC-CDR2, HC-CDR3, wherein the HC-CDR1, HC-CDR2, HC-CDR3 comprise the amino acid sequence according to LC-CDR1: SEQ ID NO: 22, LC-CDR2: SEQ ID NO: 23, LC-CDR3: SEQ ID NO: 24. 2, wherein the second binding domain comprises a (VH) comprising complementarity determining regions (CDRs): HC-CDR1, HC-CDR2, HC-CDR3, wherein HC-CDR1, HC-CDR2, HC-CDR3 comprise the amino acid sequence according to HC-CDR1: SEQ ID NO: 35, HC-CDR2: SEQ ID NO: 36, HC-CDR-3: SEQ ID NO: 38, and the isolated antibody comprises a light chain variable (VL) domain comprising CDRs: LC-CDR1, LC-CDR2, LC-CDR3, wherein LC-CDR1, LC-CDR2, LC-CDR3 comprise the amino acid sequence according to LC-CDR1: SEQ ID NO: 39, LC-CDR2: SEQ ID NO: 40, LC-CDR-3: SEQ ID NO: 41. In some embodiments, the VH of the first binding domain comprises an amino acid sequence having at least 80%, 85%, 90%, 95%, 98%, 99%, or 100% sequence identity to SEQ ID NO: 25 or SEQ ID NO: 26. In some embodiments, the VL of the first binding domain comprises an amino acid sequence having at least 80%, 85%, 90%, 95%, 98%, 99%, or 100% sequence identity to SEQ ID NO: 27 or SEQ ID NO: 28.In some embodiments, the VH of the first binding domain comprises an amino acid sequence having at least 80%, 85%, 90%, 95%, 98%, 99% or 100% sequence identity to SEQ ID NO: 25 or SEQ ID NO: 26, and wherein the VL of the first binding domain comprises an amino acid sequence having at least 80%, 85%, 90%, 95%, 98%, 99% or 100% sequence identity to SEQ ID NO: 27 or SEQ ID NO: 28. In some embodiments, the first binding domain comprises a Fab, Fab', F(ab')2, or a single-chain variable fragment (scFv). In some embodiments, the first binding domain is a Fab, Fab', F(ab')2, or a single-chain variable fragment (scFv). In some embodiments, the first binding domain comprises an scFv. In some embodiments, the VH of the first binding domain and the VL of the first binding domain are connected by an scFv linker sequence. In some embodiments, the scFv linker sequence of the first binding domain comprises an amino acid sequence according to SEQ ID NO: 29. In some embodiments, the scFv of the first binding domain comprises an amino acid sequence that has at least 80%, 85%, 90%, 95%, 98%, 99%, or 100% sequence identity to SEQ ID NO: 30 or SEQ ID NO: 31. In some embodiments, the first binding domain comprises a constant domain. In some embodiments, the constant domain of the first binding domain comprises a human IgG4 sequence. In some embodiments, the human IgG4 sequence of the first binding domain comprises an S228P point mutation, wherein amino acid numbering follows the EU index as in Kabat et al. In some embodiments, the human IgG4 sequence of the first binding domain does not have a C-terminal lysine residue. In some embodiments, the constant domain of the first binding domain comprises a human IgG1 sequence. In some embodiments, the constant domain of the first binding domain comprises a C. H 1. C H 2. C H 3 or C L In some embodiments, the first binding domain comprises C H 1. C H 2. C H 3 and C LAmino acid sequence. In some embodiments, the first binding domain comprises an amino acid sequence having at least 80%, 85%, 90%, 95%, 98%, 99% or 100% sequence identity to SEQ ID NO: 32, SEQ ID NO: 33, SEQ ID NO: 74 or SEQ ID NO: 75, and the isolated antibody comprises an amino acid sequence having at least 80%, 85%, 90%, 95%, 98%, 99% or 100% sequence identity to SEQ ID NO: 34 or SEQ ID NO: 76. In some embodiments, the VH of the second binding domain comprises an amino acid sequence having at least 80%, 85%, 90%, 95%, 98%, 99% or 100% sequence identity to SEQ ID NO: 42 or SEQ ID NO: 43. In some embodiments, the VL of the second binding domain comprises an amino acid sequence having at least 80%, 85%, 90%, 95%, 98%, 99% or 100% sequence identity to SEQ ID NO: 44. In some embodiments, the VH of the second binding domain comprises an amino acid sequence having at least 80%, 85%, 90%, 95%, 98%, 99% or 100% sequence identity to SEQ ID NO: 42 or SEQ ID NO: 43, and wherein the VL of the second binding domain comprises an amino acid sequence having at least 80%, 85%, 90%, 95%, 98%, 99% or 100% sequence identity to SEQ ID NO: 44. In some embodiments, the second binding domain comprises a Fab, Fab', F(ab')2, or a single-chain variable fragment (scFv). In some embodiments, the second binding domain is a Fab, Fab', F(ab')2, or a single-chain variable fragment (scFv). In some embodiments, the second binding domain comprises an scFv. In some embodiments, the VH of the second binding domain and the VL of the second binding domain are connected by an scFv linker sequence. In some embodiments, the scFv linker sequence of the second binding domain comprises an amino acid sequence according to SEQ ID NO: 45. In some embodiments, the scFv of the second binding domain comprises an amino acid sequence having at least 80%, 85%, 90%, 95%, 98%, 99% or 100% sequence identity to SEQ ID NO: 46 or SEQ ID NO: 47. In some embodiments, the second binding domain comprises a constant domain. In some embodiments, the constant domain of the second binding domain comprises a human IgG4 sequence. In some embodiments, the human IgG4 sequence of the second binding domain comprises an S228P point mutation, wherein the amino acid numbering follows the EU index in Kabat et al. In some embodiments, the human IgG4 sequence of the second binding domain does not have a C-terminal lysine residue. In some embodiments, the constant domain of the second binding domain comprises a human IgG1 sequence. In some embodiments, the constant domain of the second binding domain comprises a CH 1. C H 2. C H 3 or C L In some embodiments, the second binding domain comprises C H 1. C H 2. C H 3 and C L In some embodiments, the second binding domain comprises an amino acid sequence having at least 80%, 85%, 90%, 95%, 98%, 99% or 100% sequence identity to SEQ ID NO:48, SEQ ID NO:49, SEQ ID NO:77 or SEQ ID NO:78, and the isolated antibody comprises an amino acid sequence having at least 80%, 85%, 90%, 95%, 98%, 99% or 100% sequence identity to SEQ ID NO:50. In some embodiments, the first binding domain comprises an scFv and the second binding domain comprises a C H 1. C H 2. C H 3 and C L In some embodiments, the second binding domain comprises an scFv and the first binding domain comprises a C H 1. C H 2. C H 3 and C L In some embodiments, the first binding domain and the second binding domain are connected by a connecting portion. In some embodiments, the connecting portion is an amino acid sequence. In some embodiments, the connecting portion is at least 4 amino acids long. In some embodiments, the length of the connecting portion is between 4 and 20 amino acids. In some embodiments, the connecting portion connects the C of the second binding domain to the C of the second binding domain. H In some embodiments, the connecting portion comprises an amino acid sequence of SEQ ID NO: 51. In some embodiments, the isolated antibody comprises an amino acid sequence having at least 80%, 85%, 90%, 95%, 98%, 99% or 100% sequence identity to SEQ ID NO: 61 and an amino acid sequence having at least 80%, 85%, 90%, 95%, 98%, 99% or 100% sequence identity to SEQ ID NO: 60. In some embodiments, the isolated antibody comprises an amino acid sequence having at least 80%, 85%, 90%, 95%, 98%, 99% or 100% sequence identity to SEQ ID NO: 63 and an amino acid sequence having at least 80%, 85%, 90%, 95%, 98%, 99% or 100% sequence identity to SEQ ID NO: 62.

[0054] Table 4. Amino acid sequences of antibodies having a first binding domain and a second binding domain

[0055]

[0056]

[0057]

[0058]

[0059]

[0060]

[0061]

[0062]

[0063] Composition having a first binding domain, a second binding domain and a third binding domain

[0064] Disclosed herein are compositions comprising a first binding domain that binds to Ara h 2 and Ara h 6, wherein the first binding domain comprises a heavy chain variable domain (VH) comprising complementarity determining regions (CDRs): HC-CDR1, HC-CDR2, HC-CDR3, wherein HC-CDR1, HC-CDR2, HC-CDR3 comprise an amino acid sequence according to HC-CDR1: SEQ ID NO: 1, HC-CDR2: SEQ ID NO: 2 or SEQ ID NO: 3, HC-CDR3: SEQ ID NO: 4 or SEQ ID NO: 5, and the first binding domain comprises a light chain variable (VL) domain comprising CDRs: LC-CDR1, LC-CDR2, LC-CDR3, wherein LC-CDR1, LC-CDR2, LC-CDR3 comprise an amino acid sequence according to LC-CDR1: SEQ ID NO: 6, LC-CDR2: SEQ ID NO: 7, LC-CDR3: SEQ ID NO: 8, wherein the composition comprises a heavy chain variable domain (VH) comprising complementarity determining regions (CDRs): HC-CDR1, HC-CDR2, HC-CDR3, wherein HC-CDR1, HC-CDR2, HC-CDR3 comprise an amino acid sequence according to LC-CDR1: SEQ ID NO: 6, LC-CDR2: SEQ ID NO: 7, LC-CDR3: SEQ ID NO: 8, wherein the composition comprises a heavy chain variable domain (VL) comprising CDRs: LC-CDR1, LC-CDR2, LC-CDR3 2 and Ara h 6, wherein the second binding domain comprises a VH comprising CDRs: HC-CDR1, HC-CDR2, HC-CDR3, wherein HC-CDR1, HC-CDR2, HC-CDR3 comprise the amino acid sequence according to HC-CDR1: SEQ ID NO: 18, HC-CDR2: SEQ ID NO: 19, HC-CDR-3: SEQ ID NO: 20 or SEQ ID NO: 21, and the second binding domain comprises a light chain variable (VL) domain comprising CDRs: LC-CDR1, LC-CDR2, LC-CDR3, wherein LC-CDR1, LC-CDR2, LC-CDR3 comprise the amino acid sequence according to LC-CDR1: SEQ ID NO: 22, LC-CDR2: SEQ ID NO: 23, LC-CDR-3: SEQ ID NO: 24, and wherein the composition comprises a VH comprising CDRs: HC-CDR1, HC-CDR2, HC-CDR3, wherein the VH comprising CDRs: LC-CDR1, LC-CDR2, LC-CDR3 comprise the amino acid sequence according to LC-CDR1: SEQ ID NO: 22, LC-CDR2: SEQ ID NO: 23, LC-CDR-3: SEQ ID NO: 24, and wherein the composition comprises a VL comprising CDRs: LC-CDR1, LC-CDR2, LC-CDR3 2, wherein the third binding domain comprises a VH comprising CDRs: HC-CDR1, HC-CDR2, HC-CDR3, wherein HC-CDR1, HC-CDR2, HC-CDR3 comprise the amino acid sequence according to HC-CDR1: SEQ ID NO: 35, HC-CDR2: SEQ ID NO: 36 or SEQ ID NO: 37, HC-CDR3: SEQ ID NO: 38, and the third binding domain comprises a light chain variable (VL) domain comprising CDRs: LC-CDR1, LC-CDR2, LC-CDR3,Wherein LC-CDR1, LC-CDR2, and LC-CDR3 comprise the amino acid sequences according to LC-CDR1: SEQ ID NO: 39, LC-CDR2: SEQ ID NO: 40, and LC-CDR-3: SEQ ID NO: 41. Disclosed herein are compositions comprising a first binding domain that binds to Ara h 2 and Ara h 6, wherein the first binding domain comprises a heavy chain variable domain (VH) comprising complementarity determining regions (CDRs): HC-CDR1, HC-CDR2, HC-CDR3, wherein HC-CDR1, HC-CDR2, HC-CDR3 comprise the amino acid sequence according to HC-CDR1: SEQ ID NO: 1, HC-CDR2: SEQ ID NO: 2, HC-CDR3: SEQ ID NO: 4, and the first binding domain comprises a light chain variable (VL) domain comprising CDRs: LC-CDR1, LC-CDR2, LC-CDR3, wherein LC-CDR1, LC-CDR2, LC-CDR3 comprise the amino acid sequence according to LC-CDR1: SEQ ID NO: 6, LC-CDR2: SEQ ID NO: 7, LC-CDR3: SEQ ID NO: 8, wherein the composition comprises proteins that bind to Ara h 2 and Ara h 6. 6, wherein the second binding domain comprises a VH comprising CDRs: HC-CDR1, HC-CDR2, HC-CDR3, wherein HC-CDR1, HC-CDR2, HC-CDR3 comprise the amino acid sequence according to HC-CDR1: SEQ ID NO: 18, HC-CDR2: SEQ ID NO: 19, HC-CDR-3: SEQ ID NO: 20, and the second binding domain comprises a light chain variable (VL) domain comprising CDRs: LC-CDR1, LC-CDR2, LC-CDR3, wherein LC-CDR1, LC-CDR2, LC-CDR3 comprise the amino acid sequence according to LC-CDR1: SEQ ID NO: 22, LC-CDR2: SEQ ID NO: 23, LC-CDR-3: SEQ ID NO: 24, and wherein the composition comprises a VH comprising CDRs: HC-CDR1, HC-CDR2, HC-CDR3, wherein the VH comprising CDRs: LC-CDR1, LC-CDR2, LC-CDR3 comprise the amino acid sequence according to LC-CDR1: SEQ ID NO: 22, LC-CDR2: SEQ ID NO: 23, LC-CDR-3: SEQ ID NO: 24, and wherein the composition comprises a VH comprising CDRs: HC-CDR1, HC-CDR2, HC-CDR3, wherein the VH comprising CDRs: LC-CDR1, LC-CDR2, LC-CDR3 2, wherein the third binding domain comprises a VH comprising CDRs: HC-CDR1, HC-CDR2, HC-CDR3, wherein HC-CDR1, HC-CDR2, HC-CDR3 comprise the amino acid sequence according to HC-CDR1: SEQ ID NO: 35, HC-CDR2: SEQ ID NO: 36, HC-CDR-3: SEQ ID NO: 38, and the third binding domain comprises a light chain variable (VL) domain comprising CDRs: LC-CDR1, LC-CDR2, LC-CDR3,wherein LC-CDR1, LC-CDR2, and LC-CDR3 comprise the amino acid sequence according to LC-CDR1: SEQ ID NO: 39, LC-CDR2: SEQ ID NO: 40, and LC-CDR3: SEQ ID NO: 41. In some embodiments, the VH of the first binding domain comprises an amino acid sequence having at least 80%, 85%, 90%, 95%, 98%, 99%, or 100% sequence identity to SEQ ID NO: 9 or SEQ ID NO: 10. In some embodiments, the VL of the first binding domain comprises an amino acid sequence having at least 80%, 85%, 90%, 95%, 98%, 99%, or 100% sequence identity to SEQ ID NO: 11. In some embodiments, the VH of the first binding domain comprises an amino acid sequence having at least 80%, 85%, 90%, 95%, 98%, 99% or 100% sequence identity to SEQ ID NO: 9 or SEQ ID NO: 10, and wherein the VL of the first binding domain comprises an amino acid sequence having at least 80%, 85%, 90%, 95%, 98%, 99% or 100% sequence identity to SEQ ID NO: 11. In some embodiments, the first binding domain comprises a Fab, Fab', F(ab')2, or a single-chain variable fragment (scFv). In some embodiments, the first binding domain is a Fab, Fab', F(ab')2, or a single-chain variable fragment (scFv). In some embodiments, the first binding domain comprises an scFv. In some embodiments, the VH of the first binding domain and the VL of the first binding domain are connected by an scFv linker sequence. In some embodiments, the scFv linker sequence of the first binding domain comprises an amino acid sequence according to SEQ ID No: 12. In some embodiments, the scFv of the first binding domain comprises an amino acid sequence having at least 80%, 85%, 90%, 95%, 98%, 99% or 100% sequence identity to SEQ ID NO: 13 or SEQ ID NO: 14. In some embodiments, the first binding domain comprises a constant domain. In some embodiments, the constant domain of the first binding domain comprises a human IgG4 sequence. In some embodiments, the human IgG4 sequence of the first binding domain comprises an S228P point mutation, wherein the amino acid numbering follows the EU index as in Kabat et al. In some embodiments, the human IgG4 sequence of the first binding domain does not have a C-terminal lysine residue. In some embodiments, the constant domain of the first binding domain comprises a human IgG1 sequence. In some embodiments, the constant domain of the first binding domain comprises a C, H 1. C H 2. C H 3 or C L In some embodiments, the first binding domain comprises C H 1. CH 2. C H 3 and C LAmino acid sequence. In some embodiments, the first binding domain comprises an amino acid sequence having at least 80%, 85%, 90%, 95%, 98%, 99%, or 100% sequence identity to SEQ ID NO: 15, SEQ ID NO: 16, SEQ ID NO: 72, or SEQ ID NO: 73, and the first binding domain comprises an amino acid sequence having at least 80%, 85%, 90%, 95%, 98%, 99%, or 100% sequence identity to SEQ ID NO: 17. In some embodiments, the VH of the second binding domain comprises an amino acid sequence having at least 80%, 85%, 90%, 95%, 98%, 99%, or 100% sequence identity to SEQ ID NO: 25 or SEQ ID NO: 26. In some embodiments, the VL of the second binding domain comprises an amino acid sequence having at least 80%, 85%, 90%, 95%, 98%, 99%, or 100% sequence identity to SEQ ID NO: 27 or SEQ ID NO: 28. In some embodiments, the VH of the second binding domain comprises an amino acid sequence having at least 80%, 85%, 90%, 95%, 98%, 99% or 100% sequence identity to SEQ ID NO: 25 or SEQ ID NO: 26, and wherein the VL of the second binding domain comprises an amino acid sequence having at least 80%, 85%, 90%, 95%, 98%, 99% or 100% sequence identity to SEQ ID NO: 27 or SEQ ID NO: 28. In some embodiments, the second binding domain comprises a Fab, Fab', F(ab')2, or a single-chain variable fragment (scFv). In some embodiments, the second binding domain is a Fab, Fab', F(ab')2, or a single-chain variable fragment (scFv). In some embodiments, the second binding domain comprises an scFv. In some embodiments, the VH of the second binding domain and the VL of the second binding domain are connected by an scFv linker sequence. In some embodiments, the scFv linker sequence of the second binding domain comprises an amino acid sequence according to SEQ ID NO: 29. In some embodiments, the scFv of the second binding domain comprises an amino acid sequence that has at least 80%, 85%, 90%, 95%, 98%, 99%, or 100% sequence identity to SEQ ID NO: 30 or SEQ ID NO: 31. In some embodiments, the second binding domain comprises a constant domain. In some embodiments, the constant domain of the second binding domain comprises a human IgG4 sequence. In some embodiments, the human IgG4 sequence of the second binding domain comprises an S228P point mutation, wherein amino acid numbering follows the EU index as in Kabat et al. In some embodiments, the human IgG4 sequence of the second binding domain does not have a C-terminal lysine residue. In some embodiments, the constant domain of the second binding domain comprises a human IgG1 sequence.In some embodiments, the constant domain of the second binding domain comprises C. H 1. C H 2. C H 3 or C L In some embodiments, the second binding domain comprises C H 1. C H 2. C H 3 and C LAmino acid sequence. In some embodiments, the second binding domain comprises an amino acid sequence having at least 80%, 85%, 90%, 95%, 98%, 99% or 100% sequence identity to SEQ ID NO: 32, SEQ ID NO: 33, SEQ ID NO: 74 or SEQ ID NO: 75, and the isolated antibody comprises an amino acid sequence having at least 80%, 85%, 90%, 95%, 98%, 99% or 100% sequence identity to SEQ ID NO: 34 or SEQ ID NO: 76. In some embodiments, the VH of the third binding domain comprises an amino acid sequence having at least 80%, 85%, 90%, 95%, 98%, 99% or 100% sequence identity to SEQ ID NO: 42 or SEQ ID NO: 43. In some embodiments, the VL of the third binding domain comprises an amino acid sequence having at least 80%, 85%, 90%, 95%, 98%, 99% or 100% sequence identity to SEQ ID NO: 44. In some embodiments, the VH of the third binding domain comprises an amino acid sequence having at least 80%, 85%, 90%, 95%, 98%, 99% or 100% sequence identity to SEQ ID NO: 42 or SEQ ID NO: 43, and wherein the VL of the third binding domain comprises an amino acid sequence having at least 80%, 85%, 90%, 95%, 98%, 99% or 100% sequence identity to SEQ ID NO: 44. In some embodiments, the third binding domain comprises a Fab, Fab', F(ab')2, or a single-chain variable fragment (scFv). In some embodiments, the third binding domain is a Fab, Fab', F(ab')2, or a single-chain variable fragment (scFv). In some embodiments, the third binding domain comprises an scFv. In some embodiments, the VH of the third binding domain and the VL of the third binding domain are connected by an scFv linker sequence. In some embodiments, the scFv linker sequence of the third binding domain comprises an amino acid sequence according to SEQ ID NO: 45. In some embodiments, the scFv of the third binding domain comprises an amino acid sequence having at least 80%, 85%, 90%, 95%, 98%, 99% or 100% sequence identity to SEQ ID NO: 46 or SEQ ID NO: 47. In some embodiments, the third binding domain comprises a constant domain. In some embodiments, the constant domain of the third binding domain comprises a human IgG4 sequence. In some embodiments, the human IgG4 sequence of the third binding domain comprises an S228P point mutation, wherein the amino acid numbering follows the EU index in Kabat et al. In some embodiments, the human IgG4 sequence of the third binding domain does not have a C-terminal lysine residue. In some embodiments, the constant domain of the third binding domain comprises a human IgG1 sequence. In some embodiments, the constant domain of the third binding domain comprises a CH 1. C H 2. C H 3 or C L In some embodiments, the third binding domain comprises C H 1. C H 2. C H 3 and C L Amino acid sequence. In some embodiments, the third binding domain comprises an amino acid sequence having at least 80%, 85%, 90%, 95%, 98%, 99% or 100% sequence identity to SEQ ID NO: 48, SEQ ID NO: 49, SEQ ID NO: 77 or SEQ ID NO: 78, and the isolated antibody comprises an amino acid sequence having at least 80%, 85%, 90%, 95%, 98%, 99% or 100% sequence identity to SEQ ID NO: 50. In some embodiments, the first binding domain, the second binding domain, and the third binding domain are linked within the same molecule. In some embodiments, the first binding domain, the second binding domain, and the third binding domain belong to separate molecules. In some embodiments, the first binding domain and the second binding domain are within the same molecule, and the third binding domain belongs to a molecule separate from the molecule having the first binding domain and the second binding domain. In some embodiments, the first binding domain and the third binding domain are within the same molecule, and the second binding domain belongs to a molecule separate from the molecule having the first binding domain and the third binding domain. In some embodiments, the second binding domain and the third binding domain are in the same molecule, and the first binding domain is a separate molecule from the molecules having the second and third binding domains. In some embodiments, the first binding domain comprises an scFv, and the second binding domain comprises a C H 1. C H 2. C H 3 and C L In some embodiments, the second binding domain comprises an scFv and the first binding domain comprises a C H 1. C H 2. C H 3 and C L In some embodiments, the first binding domain and the second binding domain are connected by a connecting portion. In some embodiments, the connecting portion is an amino acid sequence. In some embodiments, the connecting portion is at least 4 amino acids long. In some embodiments, the length of the connecting portion is between 4 and 20 amino acids. In some embodiments, the connecting portion connects the C of the second binding domain to the C of the second binding domain. HIn some embodiments, the first and second binding domains comprise an amino acid sequence having at least 80%, 85%, 90%, 95%, 98%, 99%, or 100% sequence identity to SEQ ID NO: 53 and an amino acid sequence having at least 80%, 85%, 90%, 95%, 98%, 99%, or 100% sequence identity to SEQ ID NO: 52, and wherein the third binding domain comprises an amino acid sequence having at least 80%, 85%, 90%, 95%, 98%, 99%, or 100% sequence identity to SEQ ID NO: 48, SEQ ID NO: 49, SEQ ID NO: 77, or SEQ ID NO: 78, and the third binding domain comprises an amino acid sequence having at least 80%, 85%, 90%, 95%, 98%, 99%, or 100% sequence identity to SEQ ID NO: 50. In some embodiments, the first and second binding domains comprise an amino acid sequence having at least 80%, 85%, 90%, 95%, 98%, 99%, or 100% sequence identity to SEQ ID NO:55 and an amino acid sequence having at least 80%, 85%, 90%, 95%, 98%, 99%, or 100% sequence identity to SEQ ID NO:54, and wherein the third binding domain comprises an amino acid sequence having at least 80%, 85%, 90%, 95%, 98%, 99%, or 100% sequence identity to SEQ ID NO:48, SEQ ID NO:49, SEQ ID NO:77, or SEQ ID NO:78, and the third binding domain comprises an amino acid sequence having at least 80%, 85%, 90%, 95%, 98%, 99%, or 100% sequence identity to SEQ ID NO:50. In some embodiments, the first and second binding domains comprise an amino acid sequence having at least 80%, 85%, 90%, 95%, 98%, 99%, or 100% sequence identity to SEQ ID NO:65 and an amino acid sequence having at least 80%, 85%, 90%, 95%, 98%, 99%, or 100% sequence identity to SEQ ID NO:64, and wherein the third binding domain comprises an amino acid sequence having at least 80%, 85%, 90%, 95%, 98%, 99%, or 100% sequence identity to SEQ ID NO:48, SEQ ID NO:49, SEQ ID NO:77, or SEQ ID NO:78, and the third binding domain comprises an amino acid sequence having at least 80%, 85%, 90%, 95%, 98%, 99%, or 100% sequence identity to SEQ ID NO:50.In some embodiments, the first and second binding domains comprise an amino acid sequence having at least 80%, 85%, 90%, 95%, 98%, 99%, or 100% sequence identity to SEQ ID NO:67 and an amino acid sequence having at least 80%, 85%, 90%, 95%, 98%, 99%, or 100% sequence identity to SEQ ID NO:66, and wherein the third binding domain comprises an amino acid sequence having at least 80%, 85%, 90%, 95%, 98%, 99%, or 100% sequence identity to SEQ ID NO:48, SEQ ID NO:49, SEQ ID NO:77, or SEQ ID NO:78, and the third binding domain comprises an amino acid sequence having at least 80%, 85%, 90%, 95%, 98%, 99%, or 100% sequence identity to SEQ ID NO:50. In some embodiments, the first and second binding domains comprise an amino acid sequence having at least 80%, 85%, 90%, 95%, 98%, 99%, or 100% sequence identity to SEQ ID NO:69 and an amino acid sequence having at least 80%, 85%, 90%, 95%, 98%, 99%, or 100% sequence identity to SEQ ID NO:68, and wherein the third binding domain comprises an amino acid sequence having at least 80%, 85%, 90%, 95%, 98%, 99%, or 100% sequence identity to SEQ ID NO:48, SEQ ID NO:49, SEQ ID NO:77, or SEQ ID NO:78, and the third binding domain comprises an amino acid sequence having at least 80%, 85%, 90%, 95%, 98%, 99%, or 100% sequence identity to SEQ ID NO:50. In some embodiments, the first and second binding domains comprise an amino acid sequence having at least 80%, 85%, 90%, 95%, 98%, 99%, or 100% sequence identity to SEQ ID NO:71 and an amino acid sequence having at least 80%, 85%, 90%, 95%, 98%, 99%, or 100% sequence identity to SEQ ID NO:70, and wherein the third binding domain comprises an amino acid sequence having at least 80%, 85%, 90%, 95%, 98%, 99%, or 100% sequence identity to SEQ ID NO:48, SEQ ID NO:49, SEQ ID NO:77, or SEQ ID NO:78, and the third binding domain comprises an amino acid sequence having at least 80%, 85%, 90%, 95%, 98%, 99%, or 100% sequence identity to SEQ ID NO:50.

[0065] Disclosed herein are compositions comprising a first molecule comprising a first binding domain that binds to Ara h 2 and Ara h 6 and a second binding domain that binds to Ara h 2 and Ara h 6, wherein the first binding domain comprises an scFv, and the second binding domain comprises a heavy chain variable domain, a light chain variable domain, and a constant domain, and the scFv of the first binding domain is linked to the constant domain of the second binding domain by a linker, and the composition comprises a second molecule comprising a third binding domain that binds to Ara h 2.In some embodiments, the first binding domain comprises a heavy chain variable domain (VH) comprising complementarity determining regions (CDRs): HC-CDR1, HC-CDR2, HC-CDR3, wherein HC-CDR1, HC-CDR2, HC-CDR3 comprise the amino acid sequences according to HC-CDR1: SEQ ID NO: 1, HC-CDR2: SEQ ID NO: 2 or SEQ ID NO: 3, HC-CDR-3: SEQ ID NO: 4 or SEQ ID NO: 5, and the first binding domain comprises a light chain variable (VL) domain comprising CDRs: LC-CDR1, LC-CDR2, LC-CDR3, wherein LC-CDR1, LC-CDR2, LC-CDR3 comprise the amino acid sequences according to LC-CDR1: SEQ ID NO: 6, LC-CDR2: SEQ ID NO: 7, LC-CDR-3: SEQ ID NO: 8. NO:8, wherein the second binding domain comprises a VH comprising CDRs: HC-CDR1, HC-CDR2, HC-CDR3, wherein HC-CDR1, HC-CDR2, HC-CDR3 comprise the amino acid sequence according to HC-CDR1: SEQ ID NO:18, HC-CDR2: SEQ ID NO:19, HC-CDR-3: SEQ ID NO:20 or SEQ ID NO:21, and the second binding domain comprises a light chain variable (VL) domain comprising CDRs: LC-CDR1, LC-CDR2, LC-CDR3, wherein LC-CDR1, LC-CDR2, LC-CDR3 comprise the amino acid sequence according to LC-CDR1: SEQ ID NO:22, LC-CDR2: SEQ ID NO:23, LC-CDR-3: SEQ ID NO:24. NO:24, and wherein the third binding domain comprises a VH comprising CDRs: HC-CDR1, HC-CDR2, HC-CDR3, wherein HC-CDR1, HC-CDR2, HC-CDR3 comprise the amino acid sequence according to HC-CDR1: SEQ ID NO:35, HC-CDR2: SEQ ID NO:36 or SEQ ID NO:37, HC-CDR-3: SEQ ID NO:38, and the third binding domain comprises a light chain variable (VL) domain comprising CDRs: LC-CDR1, LC-CDR2, LC-CDR3, wherein LC-CDR1, LC-CDR2, LC-CDR3 comprise the amino acid sequence according to LC-CDR1: SEQ ID NO:39, LC-CDR2: SEQ ID NO:40, LC-CDR-3: SEQ ID NO:41.In some embodiments, the first binding domain comprises a heavy chain variable domain (VH) comprising complementarity determining regions (CDRs): HC-CDR1, HC-CDR2, HC-CDR3, wherein HC-CDR1, HC-CDR2, HC-CDR3 comprise amino acid sequences according to HC-CDR1: SEQ ID NO: 1, HC-CDR2: SEQ ID NO: 2, HC-CDR-3: SEQ ID NO: 4, and the first binding domain comprises a light chain variable (VL) domain comprising CDRs: LC-CDR1, LC-CDR2, LC-CDR3, wherein LC-CDR1, LC-CDR2, LC-CDR3 comprise amino acid sequences according to LC-CDR1: SEQ ID NO: 6, LC-CDR2: SEQ ID NO: 7, LC-CDR-3: SEQ ID NO: 8. NO:8, wherein the second binding domain comprises a VH comprising CDRs: HC-CDR1, HC-CDR2, HC-CDR3, wherein HC-CDR1, HC-CDR2, HC-CDR3 comprise the amino acid sequences according to HC-CDR1: SEQ ID NO:18, HC-CDR2: SEQ ID NO:19, HC-CDR-3: SEQ ID NO:20, and the second binding domain comprises a light chain variable (VL) domain comprising CDRs: LC-CDR1, LC-CDR2, LC-CDR3, wherein LC-CDR1, LC-CDR2, LC-CDR3 comprise the amino acid sequences according to LC-CDR1: SEQ ID NO:22, LC-CDR2: SEQ ID NO:23, LC-CDR-3: SEQ ID NO:24, and wherein the third binding domain comprises a VH comprising CDRs: HC-CDR1, HC-CDR2, HC-CDR3, wherein HC-CDR1, HC-CDR2, HC-CDR3 comprise the amino acid sequence according to HC-CDR1: SEQ ID NO:35, HC-CDR2: SEQ ID NO:36, HC-CDR-3: SEQ ID NO:38, and the third binding domain comprises a light chain variable (VL) domain comprising CDRs: LC-CDR1, LC-CDR2, LC-CDR3, wherein LC-CDR1, LC-CDR2, LC-CDR3 comprise the amino acid sequence according to LC-CDR1: SEQ ID NO:39, LC-CDR2: SEQ ID NO:40, LC-CDR-3: SEQ ID NO:41. In some embodiments, the VH of the first binding domain comprises an amino acid sequence having at least 80%, 85%, 90%, 95%, 98%, 99%, or 100% sequence identity to SEQ ID NO:9 or SEQ ID NO:10.In some embodiments, the VL of the first binding domain comprises an amino acid sequence having at least 80%, 85%, 90%, 95%, 98%, 99%, or 100% sequence identity to SEQ ID NO: 11. In some embodiments, the VH of the first binding domain comprises an amino acid sequence having at least 80%, 85%, 90%, 95%, 98%, 99%, or 100% sequence identity to SEQ ID NO: 9 or SEQ ID NO: 10, and wherein the VL of the first binding domain comprises an amino acid sequence having at least 80%, 85%, 90%, 95%, 98%, 99%, or 100% sequence identity to SEQ ID NO: 11. In some embodiments, the VH of the first binding domain and the VL of the first binding domain are connected by an scFv linker sequence. In some embodiments, the scFv linker sequence of the first binding domain comprises an amino acid sequence according to SEQ ID NO: 12. In some embodiments, the scFv of the first binding domain comprises an amino acid sequence having at least 80%, 85%, 90%, 95%, 98%, 99%, or 100% sequence identity to SEQ ID NO: 13 or SEQ ID NO: 14. In some embodiments, the VH of the second binding domain comprises an amino acid sequence having at least 80%, 85%, 90%, 95%, 98%, 99%, or 100% sequence identity to SEQ ID NO: 25 or SEQ ID NO: 26. In some embodiments, the VL of the second binding domain comprises an amino acid sequence having at least 80%, 85%, 90%, 95%, 98%, 99%, or 100% sequence identity to SEQ ID NO: 27 or SEQ ID NO: 28. In some embodiments, the VH of the second binding domain comprises an amino acid sequence having at least 80%, 85%, 90%, 95%, 98%, 99%, or 100% sequence identity to SEQ ID NO: 25 or SEQ ID NO: 26, and wherein the VL of the second binding domain comprises an amino acid sequence having at least 80%, 85%, 90%, 95%, 98%, 99%, or 100% sequence identity to SEQ ID NO: 27 or SEQ ID NO: 28. In some embodiments, the second binding domain comprises a Fab, Fab', or F(ab')2. In some embodiments, the second binding domain is a Fab, Fab', or F(ab')2. In some embodiments, the constant domain of the second binding domain comprises a human IgG4 sequence. In some embodiments, the human IgG4 sequence of the second binding domain comprises an S228P point mutation, wherein amino acid numbering follows the EU index as in Kabat et al. In some embodiments, the human IgG4 sequence of the second binding domain does not have a C-terminal lysine residue. In some embodiments, the constant domain of the second binding domain comprises a human IgG1 sequence. In some embodiments, the constant domain of the second binding domain comprises C.H 1. C H 2. C H 3 or C L In some embodiments, the second binding domain comprises C H 1. C H 2. C H 3 and C LAmino acid sequence. In some embodiments, the second binding domain comprises an amino acid sequence having at least 80%, 85%, 90%, 95%, 98%, 99% or 100% sequence identity to SEQ ID NO: 32, SEQ ID NO: 33, SEQ ID NO: 74 or SEQ ID NO: 75, and the isolated antibody comprises an amino acid sequence having at least 80%, 85%, 90%, 95%, 98%, 99% or 100% sequence identity to SEQ ID NO: 34 or SEQ ID NO: 76. In some embodiments, the VH of the third binding domain comprises an amino acid sequence having at least 80%, 85%, 90%, 95%, 98%, 99% or 100% sequence identity to SEQ ID NO: 42 or SEQ ID NO: 43. In some embodiments, the VL of the third binding domain comprises an amino acid sequence having at least 80%, 85%, 90%, 95%, 98%, 99% or 100% sequence identity to SEQ ID NO: 44. In some embodiments, the VH of the third binding domain comprises an amino acid sequence having at least 80%, 85%, 90%, 95%, 98%, 99% or 100% sequence identity to SEQ ID NO: 42 or SEQ ID NO: 43, and wherein the VL of the third binding domain comprises an amino acid sequence having at least 80%, 85%, 90%, 95%, 98%, 99% or 100% sequence identity to SEQ ID NO: 44. In some embodiments, the third binding domain comprises a Fab, Fab', F(ab')2, or a single-chain variable fragment (scFv). In some embodiments, the third binding domain is a Fab, Fab', F(ab')2, or a single-chain variable fragment (scFv). In some embodiments, the third binding domain comprises an scFv. In some embodiments, the VH of the third binding domain and the VL of the third binding domain are connected by an scFv linker sequence. In some embodiments, the scFv linker sequence of the third binding domain comprises an amino acid sequence according to SEQ ID NO: 45. In some embodiments, the scFv of the third binding domain comprises an amino acid sequence having at least 80%, 85%, 90%, 95%, 98%, 99% or 100% sequence identity to SEQ ID NO: 46 or SEQ ID NO: 47. In some embodiments, the third binding domain comprises a constant domain. In some embodiments, the constant domain of the third binding domain comprises a human IgG4 sequence. In some embodiments, the human IgG4 sequence of the third binding domain comprises an S228P point mutation, wherein the amino acid numbering follows the EU index as in Kabat et al. In some embodiments, the human IgG4 sequence of the third binding domain does not have a C-terminal lysine residue. In some embodiments, the constant domain of the third binding domain comprises a human IgG1 sequence. In some embodiments, the constant domain of the third binding domain comprises a CH 1. C H 2. C H 3 or C L In some embodiments, the third binding domain comprises C H 1. C H 2. C H 3 and C L amino acid sequence. In some embodiments, the third binding domain comprises an amino acid sequence having at least 80%, 85%, 90%, 95%, 98%, 99% or 100% sequence identity to SEQ ID NO:48, SEQ ID NO:49, SEQ ID NO:77 or SEQ ID NO:78, and the isolated antibody comprises an amino acid sequence having at least 80%, 85%, 90%, 95%, 98%, 99% or 100% sequence identity to SEQ ID NO:50. In some embodiments, the first binding domain and the second binding domain are connected by a connecting portion. In some embodiments, the connecting portion is an amino acid sequence. In some embodiments, the connecting portion is at least 4 amino acids long. In some embodiments, the length of the connecting portion is between 4-20 amino acids. In some embodiments, the connecting portion connects the C of the second binding domain to the C of the second binding domain. HIn some embodiments, the first and second binding domains comprise an amino acid sequence having at least 80%, 85%, 90%, 95%, 98%, 99%, or 100% sequence identity to SEQ ID NO: 53 and an amino acid sequence having at least 80%, 85%, 90%, 95%, 98%, 99%, or 100% sequence identity to SEQ ID NO: 52, and wherein the third binding domain comprises an amino acid sequence having at least 80%, 85%, 90%, 95%, 98%, 99%, or 100% sequence identity to SEQ ID NO: 48, SEQ ID NO: 49, SEQ ID NO: 77, or SEQ ID NO: 78, and the third binding domain comprises an amino acid sequence having at least 80%, 85%, 90%, 95%, 98%, 99%, or 100% sequence identity to SEQ ID NO: 50. In some embodiments, the first and second binding domains comprise an amino acid sequence having at least 80%, 85%, 90%, 95%, 98%, 99%, or 100% sequence identity to SEQ ID NO:65 and an amino acid sequence having at least 80%, 85%, 90%, 95%, 98%, 99%, or 100% sequence identity to SEQ ID NO:64, and wherein the third binding domain comprises an amino acid sequence having at least 80%, 85%, 90%, 95%, 98%, 99%, or 100% sequence identity to SEQ ID NO:48, SEQ ID NO:49, SEQ ID NO:77, or SEQ ID NO:78, and the third binding domain comprises an amino acid sequence having at least 80%, 85%, 90%, 95%, 98%, 99%, or 100% sequence identity to SEQ ID NO:50. In some embodiments, the first and second binding domains comprise an amino acid sequence having at least 80%, 85%, 90%, 95%, 98%, 99%, or 100% sequence identity to SEQ ID NO:67 and an amino acid sequence having at least 80%, 85%, 90%, 95%, 98%, 99%, or 100% sequence identity to SEQ ID NO:66, and wherein the third binding domain comprises an amino acid sequence having at least 80%, 85%, 90%, 95%, 98%, 99%, or 100% sequence identity to SEQ ID NO:48, SEQ ID NO:49, SEQ ID NO:77, or SEQ ID NO:78, and the third binding domain comprises an amino acid sequence having at least 80%, 85%, 90%, 95%, 98%, 99%, or 100% sequence identity to SEQ ID NO:50.

[0066] Pharmaceutical composition

[0067] In some embodiments, disclosed herein are pharmaceutical compositions comprising: (a) an antibody and composition as disclosed herein; and (b) a pharmaceutically acceptable excipient.

[0068] In some embodiments, the antibody further comprises a detectable label, a therapeutic agent, or a pharmacokinetic modifying moiety. In some embodiments, the detectable label comprises a fluorescent label, a radiolabel, an enzyme, a nucleic acid probe, or a contrast agent.

[0069] In order to be applied to a subject, antibodies as disclosed herein can be provided in a pharmaceutical composition together with one or more pharmaceutically acceptable carriers or excipients. The term "pharmaceutically acceptable carrier" includes, but is not limited to, any carrier that does not interfere with the effectiveness of the biological activity of the component and is nontoxic to the patient to which it is applied. Examples of suitable pharmaceutical carriers are well known in the art and include phosphate buffered saline solutions, water, emulsions (such as oil / water emulsions), various types of wetting agents, sterile solutions, etc. Such carriers can be prepared by conventional methods and can be applied to a subject in a suitable dosage. Preferably, the composition is sterile. These compositions can also contain adjuvants, such as preservatives, emulsifiers, and dispersants. The effects of microorganisms can be prevented by including various antibacterial and antifungal agents.

[0070] The pharmaceutical composition can be in any suitable form, (depending on the desired method of administration). It can be provided in unit dosage form, can be provided in a sealed container, and can be provided as part of a kit. Such a kit can include instructions for use. It can include a plurality of said unit dosage forms.

[0071] The pharmaceutical composition can be suitable for administration by any appropriate route, including parenteral (e.g., subcutaneous, intramuscular or intravenous) routes. Such compositions can be prepared by any method known in the pharmaceutical art, for example, by mixing the active ingredient with a carrier or excipient under aseptic conditions.

[0072] The dosage of the substances of the present disclosure may vary between wide limits, depending on the condition to be treated, the age and condition of the individual to be treated, etc., and the physician will ultimately decide the appropriate dosage to use.

[0073] Antibody production

[0074] In some embodiments, the polypeptides described herein (e.g., antibodies and binding fragments thereof) are produced using any method known in the art for synthesizing polypeptides (e.g., antibodies), in particular by chemical synthesis or by recombinant expression, and preferably by recombinant expression technology.

[0075] In some cases, the antibody or its binding fragment is expressed recombinantly and the nucleic acid encoding the antibody or its binding fragment is assembled from chemically synthesized oligonucleotides (e.g., as described in Kutmeier et al., 1994, BioTechniques 17:242), which involves the synthesis of overlapping oligonucleotides containing portions of the antibody coding sequence, annealing and ligation of those oligonucleotides, and subsequent PCR amplification of the ligated oligonucleotides.

[0076] Alternatively, nucleic acid molecules encoding the antibody are optionally generated from a suitable source (e.g., an antibody cDNA library or a cDNA library generated from any tissue or cell that expresses immunoglobulins) by PCR amplification using synthetic primers that hybridize to the 3' and 5' ends of the sequence or by cloning using oligonucleotide probes specific for a particular gene sequence.

[0077] In some cases, the antibody or its binding partner is optionally generated by immunizing an animal (such as a rabbit) to produce a polyclonal antibody, or more preferably, by generating a monoclonal antibody, e.g., as described by Kohler and Milstein (1975, Nature 256:495-497), or as described by Kozbor et al. (1983, Immunology Today 4:72), or Cole et al. (1985, Monoclonal Antibodies and Cancer Therapy, Alan R. Liss, Inc., pp. 77-96). Alternatively, clones encoding at least the Fab portion of an antibody are optionally obtained by screening a Fab expression library (e.g., as described in Huse et al., 1989, Science 246: 1275-1281) for clones that bind to a specific antigen or by screening antibody libraries (see, e.g., Clackson et al., 1991, Nature 352: 624; Hane et al., 1997 Proc. Natl. Acad. Sci. USA 94: 4937).

[0078] In some embodiments, a technique developed for producing "chimeric antibodies" by splicing together genes from a mouse antibody molecule with the appropriate antigenic specificity with genes from a human antibody molecule with the appropriate biological activity (Morrison et al., 1984, Proc. Natl. Acad. Sci. 81:851-855; Neuberger et al., 1984, Nature 312:604-608; Takeda et al., 1985, Nature 314:452-454) is used. A chimeric antibody is a molecule in which different portions are derived from different animal species, such as those having variable regions derived from a murine monoclonal antibody and human immunoglobulin constant regions.

[0079] In some embodiments, the technology described for producing single-chain antibodies (U.S. Patent No. 4,694,778; Bird, 1988, Science 242: 423-42; Huston et al., 1988, Proc. Natl. Acad. Sci. USA 85: 5879-5883; and Ward et al., 1989, Nature 334: 544-54) is applicable to the production of single-chain antibodies. Single-chain antibodies are formed by connecting the heavy chain and light chain fragments of the Fv region via an amino acid bridge to produce a single-chain polypeptide. Technology (Skerra et al., 1988, Science 242: 1038-1041) for assembling functional Fv fragments in Escherichia coli (E. coli) is also optionally used.

[0080] In some embodiments, an expression vector comprising the nucleotide sequence of the antibody or the nucleotide sequence of the antibody is transferred to a host cell by conventional techniques (e.g., electroporation, liposome transfection, and calcium phosphate precipitation), and the transfected cells are then cultured by conventional techniques to produce the antibody. In specific embodiments, the expression of the antibody is regulated by a constitutive promoter, an inducible promoter, or a tissue-specific promoter.

[0081] In some embodiments, a variety of host expression vector systems are utilized to express the antibodies or their binding fragments described herein. Such host expression systems represent vehicles by which antibody coding sequences are produced and subsequently purified, and also represent cells that express antibodies or their binding fragments in situ when transformed or transfected with appropriate nucleotide coding sequences. These include, but are not limited to, microorganisms such as bacteria (e.g., Escherichia coli and Bacillus subtilis (B. subtilis)) transformed with recombinant phage DNA, plasmid DNA, or cosmid DNA expression vectors containing antibody or its binding fragment coding sequences; yeast (e.g., Saccharomyces, Pichia) transformed with recombinant yeast expression vectors containing antibody or its binding fragment coding sequences; insect cell systems infected with recombinant viral expression vectors (e.g., baculovirus) containing antibody or its binding fragment coding sequences; insect cell systems infected with recombinant viral expression vectors (e.g., cauliflower mosaic virus (CaMV) and tobacco mosaic virus (tobacco mosaic virus)). virus, TMV)) or transformed with a recombinant plasmid expression vector (e.g., Ti plasmid) containing the antibody or its binding fragment coding sequence; or a mammalian cell system (e.g., COS, CHO, BH, 293, 293T, 3T3 cells) carrying a recombinant expression construct containing a promoter derived from the genome of a mammalian cell (e.g., a metallothionein promoter) or a promoter derived from a mammalian virus (e.g., adenovirus late promoter; vaccinia virus 7.5K promoter).

[0082] For the long-term high yield production of recombinant protein, stably expressed is preferred.In some cases, the cell line of stably expressed antibody is optionally by through engineering approaches.With by the DNA and the selectable marker transformed host cell of suitable expression control element (for example, promotor, enhancer, sequence, transcription terminator, polyadenylation site etc.) control, and do not use the expression vector containing viral replication origin.After introducing foreign DNA, make the cell of through engineering approaches grow 1-2 days in enrichment medium subsequently, and switch to selective medium subsequently.The selectable marker in the recombinant plasmid gives the resistance to selection, and allows cell stably to be integrated into its chromosome by plasmid and grow to form cell focus (foci), and these cell focus are then cloned and expanded into cell line.This method can be advantageously used for the cell line through engineering approaches making expression antibody or its binding fragment.

[0083] In some cases, multiple selection systems are used, including but not limited to the herpes simplex virus thymidine kinase (Wigler et al., 1977, Cell 11:223), hypoxanthine-guanine phosphoribosyltransferase (Szybalska & Szybalski, 192, Proc. Natl. Acad. Sci. USA 48:202), and adenine phosphoribosyltransferase (Lowy et al., 1980, Cell 22:817) genes in tk-, hgprt-, or aprt- cells, respectively. In addition, antimetabolite resistance has been used as the basis for selection for the following genes: dhfr, which confers resistance to methotrexate (Wigler et al., 1980, Proc. Natl. Acad. Sci. USA 77:357; O'Hare et al., 1981, Proc. Natl. Acad. Sci. USA 78:1527); gpt, which confers resistance to mycophenolic acid (Mulligan & Berg, 1981, Proc. Natl. Acad. Sci. USA 78:2072); neo, which confers resistance to the aminoglycoside G-418 (Clinical Pharmacy 12:488-505; Wu and Wu, 1991, Biotherapy 78: 3:87-95; Tolstoshev, 1993, Ann. Rev. Pharmacol. Toxicol. 32:573-596; Mulligan, 1993, Science 260:926-932; and Morgan and Anderson, 1993, Ann. Rev. Biochem. 62:191-217; May 1993, TIB TECH 11(5):155-215) and hygro, which confers resistance to hygromycin (Santerre et al., 1984, Gene 30:147). Methods well known in the art of recombinant DNA technology that can be used are described in Ausubel et al. (eds., 1993, Current Protocols in Molecular Biology, John Wiley & Sons, NY; Kriegler, 1990, Gene Transfer and Expression, A Laboratory Manual, Stockton Press, NY; and Dracopoli et al. (eds.), 1994, Current Protocols in Human Genetics, John Wiley & Sons, NY., Chapters 12 and 13; Colberre-Garapin et al., 1981, J. Mol. Biol. 150: 1).

[0084] In some cases, the expression level of the antibody is increased by vector amplification (for review, see Bebbington and Hentschel, the use of vectors based on gene amplification for the expression of cloned genes in mammalian cells in DNA cloning, Volume 3 (Academic Press, New York, 1987)). When the marker in the vector system expressing the antibody is amplifiable, an increase in the level of inhibitors present in the host cell culture will increase the copy number of the marker gene. Since the amplified region is related to the nucleotide sequence of the antibody, the production of the antibody will also increase (Crouse et al., 1983, Mol. Cell Biol. 3: 257).

[0085] In some cases, any method known in the art for antibody purification is used, for example, by chromatography (e.g., ion exchange chromatography, affinity chromatography (particularly by affinity for specific antigens following protein A), and sizing column chromatography), centrifugation, differential solubility, or by any other standard technique for protein purification.

[0086] expression vector

[0087] In some embodiments, the vector includes any suitable vector derived from a eukaryotic or prokaryotic source. In some cases, the vector is obtained from bacteria (e.g., Escherichia coli), insects, yeast (e.g., Pichia pastoris), algae, or mammalian sources. Exemplary bacterial vectors include pACYC177, pASK75, pBAD vector series, pBADM vector series, pET vector series, pETM vector series, pGEX vector series, pHAT, pHAT2, pMal-c2, pMal-p2, pQE vector series, pRSET A, pRSET B, pRSET C, pTrcHis2 series, pZA31-Luc, pZE21-MCS-1, pFLAG ATS, pFLAG CTS, pFLAG MAC, pFLAG Shift-12c, pTAC-MAT-1, pFLAG CTC, or pTAC-MAT-2.

[0088] Exemplary insect vectors include pFastBac1, pFastBac DUAL, pFastBac ET, pFastBac HTa, pFastBac HTb, pFastBac HTc, pFastBac M30a, pFastBac M30b, pFastBac, M30c, pVL1392, pVL1393, pVL1393 M10, pVL1393M11, pVL1393 M12, a FLAG vector (such as pPolh-FLAG1 or pPolh-MAT 2), or a MAT vector (such as pPolh-MAT1 or pPolh-MAT2).

[0089] In some cases, the yeast carrier comprises pDEST TM 14 carriers, pDEST TM 15 carriers, pDEST TM 17 carriers, pDEST TM 24 carriers, pYES-DEST52 vector, pBAD-DEST49 Destination vector, pAO815 Pichia vector, pFLD1 Pichia pastoris vector, pGAPZA, B&C Pichia pastoris vector, pPIC3.5K Pichia vector, pPIC6 A, B&C Pichia vector, pPIC9K Pichia vector, pTEF1 / Zeo, pYES2 yeast vector, pYES2 / CT yeast vector, pYES2 / NTA, B&C yeast vector, or pYES3 / CT yeast vector.

[0090] Exemplary algal vectors include pChlamy-4 vectors or MCS vectors.

[0091] Examples of mammalian vectors include transient expression vectors or stable expression vectors. Mammalian transient expression vectors can include pRK5, p3xFLAG-CMV 8, pFLAG-Myc-CMV 19, pFLAG-Myc-CMV 23, pFLAG-CMV 2, pFLAG-CMV 6a, b, c, pFLAG-CMV 5.1, pFLAG-CMV 5a, b, c, p3xFLAG-CMV 7.1, pFLAG-CMV 20, p3xFLAG-Myc-CMV 24, pCMV-FLAG-MAT1, pCMV-FLAG-MAT2, pBICEP-CMV 3, pcDNA3.4, or pBICEP-CMV 4. Mammalian stable expression vectors can include pFLAG-CMV 3, p3xFLAG-CMV 9, p3xFLAG-CMV 13, pFLAG-Myc-CMV 21, p3xFLAG-Myc-CMV 25, pFLAG-CMV 4, p3xFLAG-CMV 10, p3xFLAG-CMV 14, pFLAG-Myc-CMV 22, p3xFLAG-Myc-CMV 26, pBICEP-CMV 1, or pBICEP-CMV2.

[0092] In some cases, the cell-free system is a mixture of cytoplasmic and / or nuclear components from cells and is used for in vitro nucleic acid synthesis. In some cases, the cell-free system utilizes prokaryotic cell components or eukaryotic cell components. Sometimes, nucleic acid synthesis is obtained in a cell-free system based on, for example, Drosophila cells, Xenopus eggs, or HeLa cells. Exemplary cell-free systems include, but are not limited to, E. coli S30 extract systems, E. coli T7 S30 systems, or

[0093] host cells

[0094] In some embodiments, the host cell includes any suitable cell, such as a cell of natural origin or a genetically modified cell. In some cases, the host cell is a production host cell. In some cases, the host cell is a eukaryotic cell. In other cases, the host cell is a prokaryotic cell. In some cases, the eukaryotic cell includes a fungus (e.g., a yeast cell), an animal cell, or a plant cell. In some cases, the prokaryotic cell is a bacterial cell. Examples of bacterial cells include gram-positive bacteria or gram-negative bacteria. Sometimes gram-negative bacteria are anaerobic bacteria, rod-shaped bacteria, or both.

[0095] In some cases, Gram-positive bacteria include Actinobacteria, Firmicutes, or Tenericutes. In some cases, Gram-negative bacteria include Aquificae, Deinococcus-Thermus, Fibrobacteres-Chlorobi / Bacteroidetes (FCB group), Fusobacteria, Gemmatimonadetes, Nitrospirae, Planctomycetes-Verrucomicrobia / Chlamydiae (PVC group), Proteobacteria, Spirochaetes, or Synergistetes. The other bacteria may be from the phyla Acidobacteria, Chloroflexi, Chrysiogenetes, Cyanobacteria, Deferribacteres, Dictyoglomi, Thermodesulfobacteria, or Thermotogae. The bacterial cell may be Escherichia coli, Clostridium botulinum, or Colibacilli.

[0096] Exemplary prokaryotic host cells include, but are not limited to, BL21, Mach1 TM DH10B TM 、TOP10、DH5α、DH10Bac TM 、OmniMax TM 、MegaX TM DH12S TM , INV110, TOP10F', INVαF, TOP10 / P3, ccdB Survival, PIR1, PIR2, Stbl2 TM 、Stbl3 TM or Stbl4 TM .

[0097] In some cases, animal cells include cells from vertebrates or from invertebrates. In some cases, animal cells include cells from marine invertebrates, fish, insects, amphibians, reptiles, or mammals. In some cases, fungal cells include yeast cells, such as brewer's yeast, baker's yeast, or wine yeast.

[0098] In some cases, yeast includes Ascomycetes, such as yeast, mold, filamentous fungi, Basidiomycetes or Zygomycetes. In some cases, yeast includes Ascomycota or Basidiomycota. In some cases, Ascomycota includes Saccharomycotina (true yeast, such as Saccharomyces cerevisiae (beer yeast)) or Taphrinomycotina (e.g., Schizosaccharomycetes (fission yeast)). In some cases, Basidiomycota includes Agaricomycota (e.g., Tremellomycetes) or Pucciniomycotina (e.g., Microbotryomycetes).

[0099] Exemplary yeasts or filamentous fungi include, for example, the genera Saccharomyces, Schizosaccharomyces, Candida, Pichia, Hansenula, Kluyveromyces, Zygosaccharomyces, Yarrowia, Trichosporon, Rhodosporidi, Aspergillus, Fusarium, or Trichoderma.Exemplary yeasts or filamentous fungi include, for example, the following species: Saccharomyces cerevisiae, Schizosaccharomyces pombe, Candida utilis, Candida boidini, Candida albicans, Candida tropicalis, Candida stellatoidea, Candida glabrata, Candida krusei, Candida parapsilosis, Candida guilliermondii, Candida viswanathii, Candida lusitaniae, Rhodotorula mucilaginosa, Pichia metanolica, Pichia angusta, Pichia pastoris, Pichia anomala, and Pichia spp. anomala), Hansenula polymorpha, Kluyveromyces lactis, Zygosaccharomyces rouxii, Yarrowia lipolytica, Trichosporon pullulans, Rhodosporidium toru-Aspergillus niger, Aspergillus nidulans, Aspergillus awamori, Aspergillus oryzae, Trichoderma reesei, Yarrowia lipolytica, Brettanomyces bruxellensis, Candida stellata, Schizosaccharomyces pombe, Torulaspora delbrueckii delbrueckii), Zygosaccharomyces bailii, Cryptococcus neoformans, Cryptococcus gattii, or Saccharomyces boulardii.

[0100] Exemplary yeast host cells include, but are not limited to, Pichia pastoris yeast strains such as GS115, KM71H, SMD1168, SMD1168H, and X-33; and Saccharomyces cerevisiae yeast strains such as INVSc1.

[0101] In some cases, additional animal cells include cells obtained from molluscs, arthropods, annelids, or sponges. In some cases, additional animal cells are mammalian cells, such as from primates, apes, horses, cattle, pigs, dogs, cats, or rodents. In some cases, rodents include mice, rats, hamsters, gerbils, hamsters, chinchillas, squirrels, or guinea pigs.

[0102] Exemplary mammalian host cells include, but are not limited to, 293A cell line, 293FT cell line, 293F cells, 293H cells, CHO DG44 cells, CHO-S cells, CHO-K1 cells, FUT8 KO CHO-K1, Expi293F cells, TM cells, Flp-In TM T-REx TM 293 cell line, Flp-In TM -293 cell line, Flp-In TM -3T3 cell line, Flp-In TM -BHK cell line, Flp-In TM -CHO cell lines, Flp-In TM -CV-1 cell line, Flp-In TM -Jurkat cell line, FreeStyle TM 293-F cells, FreeStyle TM CHO-S cells, GripTite TM 293MSR cell line, GS-CHO cell line, HepaRG TM cells, T-REx TM Jurkat cell line, Per.C6 cells, T-REx TM -293 cell line, T-REx TM -CHO cell lines and T-REx TM -HeLa cell line.

[0103] In some cases, the mammalian host cell is a stable cell line, or a cell line that has incorporated the genetic material of interest into its own genome and has the ability to express the product of that genetic material after many generations of cell division. In some cases, the mammalian host cell is a "transient cell line," or a cell line that has not incorporated the genetic material of interest into its own genome and does not have the ability to express the product of that genetic material after many generations of cell division.

[0104] Exemplary insect host cells include, but are not limited to, Drosophila S2 cells, Sf9 cells, Sf21 cells, High Five TM Cells and cell.

[0105] In some cases, the plant cell comprises a cell from algae.Exemplary algal cell lines include, but are not limited to, strains from Chlamydomonas reinhardtii 137c or Synechococcuse longatus PPC 7942.

[0106] Treatment

[0107] Disclosed herein are methods of treating food allergies in a subject in need thereof, comprising administering to the subject an isolated antibody and / or composition disclosed herein. In some embodiments, the food allergy comprises peanut allergy. In some embodiments, the subject exhibits symptoms of peanut allergy. In some embodiments, the symptoms of peanut allergy comprise hives, vomiting, abdominal pain, coughing, wheezing, or anaphylaxis. In some embodiments, the isolated antibody or composition administered to the subject is administered intravenously (IV), intramuscularly (IM), or subcutaneously.

[0108] In some embodiments, the composition comprises a first binding domain that binds to Ara h 2 and Ara h 6, wherein the first binding domain comprises a heavy chain variable domain (VH) comprising the complementarity determining regions (CDRs): HC-CDR1, HC-CDR2, HC-CDR3, wherein the HC-CDR1, HC-CDR2, HC-CDR3 comprise the amino acid sequence according to HC-CDR1: SEQ ID NO: 1, HC-CDR2: SEQ ID NO: 2, HC-CDR3: SEQ ID NO: 4, and the first binding domain comprises a light chain variable (VL) domain comprising the CDRs: LC-CDR1, LC-CDR2, LC-CDR3, wherein the LC-CDR1, LC-CDR2, LC-CDR3 comprise the amino acid sequence according to LC-CDR1: SEQ ID NO: 6, LC-CDR2: SEQ ID NO: 7, LC-CDR3: SEQ ID NO: 8, wherein the composition comprises a first binding domain that binds to Ara h 2 and Ara h 6, wherein the first binding domain comprises a heavy chain variable domain (VH) comprising the complementarity determining regions (CDRs): HC-CDR1, HC-CDR2, HC-CDR3, wherein the HC-CDR1, HC-CDR2, HC-CDR3 comprise the amino acid sequence according to LC-CDR1: SEQ ID NO: 6, LC-CDR2: SEQ ID NO: 7, LC-CDR3: SEQ ID NO: 8, 6, wherein the second binding domain comprises a VH comprising CDRs: HC-CDR1, HC-CDR2, HC-CDR3, wherein HC-CDR1, HC-CDR2, HC-CDR3 comprise the amino acid sequence according to HC-CDR1: SEQ ID NO: 18, HC-CDR2: SEQ ID NO: 19, HC-CDR-3: SEQ ID NO: 20, and the second binding domain comprises a light chain variable (VL) domain comprising CDRs: LC-CDR1, LC-CDR2, LC-CDR3, wherein LC-CDR1, LC-CDR2, LC-CDR3 comprise the amino acid sequence according to LC-CDR1: SEQ ID NO: 22, LC-CDR2: SEQ ID NO: 23, LC-CDR-3: SEQ ID NO: 24, and wherein the composition comprises a VH comprising CDRs: HC-CDR1, HC-CDR2, HC-CDR3, wherein the VH comprising CDRs: LC-CDR1, LC-CDR2, LC-CDR3 comprise the amino acid sequence according to LC-CDR1: SEQ ID NO: 22, LC-CDR2: SEQ ID NO: 23, LC-CDR-3: SEQ ID NO: 24, and wherein the composition comprises a VH comprising CDRs: HC-CDR1, HC-CDR2, HC-CDR3, wherein the VH comprising CDRs: LC-CDR1, LC-CDR2, LC-CDR3 2, wherein the third binding domain comprises a VH comprising CDRs: HC-CDR1, HC-CDR2, HC-CDR3, wherein HC-CDR1, HC-CDR2, HC-CDR3 comprise the amino acid sequence according to HC-CDR1: SEQ ID NO:35, HC-CDR2: SEQ ID NO:36, HC-CDR-3: SEQ ID NO:38, and the third binding domain comprises a light chain variable (VL) domain comprising CDRs: LC-CDR1, LC-CDR2, LC-CDR3, wherein LC-CDR1, LC-CDR2, LC-CDR3 comprise the amino acid sequence according to LC-CDR1: SEQ ID NO:39, LC-CDR2: SEQ ID NO:40, LC-CDR-3: SEQ ID NO:41.In some embodiments, the first binding domain and the second binding domain are within the same molecule and the third binding domain belongs to a separate molecule from the molecules having the first and second binding domains. In some embodiments, the first binding domain comprises an scFv and the second binding domain comprises a C. H 1. C H 2. C H 3 and C L amino acid sequence, and the first binding domain and the second binding domain are connected by a connecting portion to the Fc region of the second binding domain. In some embodiments, the third binding domain, which is a molecule separate from the first binding domain and the second binding domain, is a monoclonal antibody. In some embodiments, the molecules containing the first binding domain and the second binding domain are administered to the subject before the molecules containing the third binding domain. In some embodiments, the molecules containing the first binding domain and the second binding domain are administered to the subject simultaneously with the molecules containing the third binding domain. In some embodiments, the molecules containing the first binding domain and the second binding domain are administered to the subject after the molecules containing the third binding domain.

[0109] Products

[0110] In another aspect of the present disclosure, a product containing materials that can be used for the treatment, prevention and / or diagnosis of the above-mentioned conditions is provided. The product includes a container and a label or drug package insert on or associated with the container. Suitable containers include, for example, bottles, vials, syringes, IV solution bags, etc. The container can be formed from various materials, such as glass or plastic. The container holds a composition that is effective for treating, preventing and / or diagnosing the condition by itself or in combination with another composition, and can have a sterile access port (for example, the container can be an intravenous solution bag or a vial with a stopper that can be pierced by a hypodermic needle). At least one active agent in the composition is an antibody that specifically binds to Ara h 2 and / or Ara h 6.

[0111] The label or package insert indicates that the composition is used to treat a selected condition. Additionally, the article of manufacture may include (a) a first container containing a composition, wherein the composition comprises a bispecific antibody of the present disclosure; and (b) a second container containing a composition, wherein the composition comprises a further cytotoxic agent or other therapeutic agent. The article of manufacture in this embodiment of the present disclosure may further include a package insert indicating that the composition can be used to treat a specific condition.

[0112] Alternatively or additionally, the article of manufacture may further comprise a second (or third) container comprising a pharmaceutically acceptable buffer, such as bacteriostatic water for injection (BWFI), phosphate-buffered saline, Ringer's solution, and dextrose solution. It may further include other materials desirable from a commercial and user standpoint, including other buffers, diluents, filters, needles, and syringes.

[0113] definition

[0114] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as those commonly understood by those skilled in the art to which the claimed subject matter belongs. It should be understood that the foregoing general description and the following detailed description are merely exemplary and explanatory and do not limit any subject matter claimed. The section headings used herein are only for organizational purposes and are not to be construed as limiting the described subject matter. In this application, unless otherwise specifically stated, the use of the singular includes the plural. It should be noted that, as used in this specification and the appended claims, unless the context clearly dictates otherwise, the singular forms "a", "an", and "the" include plural references. In this application, unless otherwise stated, the use of "or" means "and / or". In addition, the use of the term "including" ("including" and other forms, such as "include", "includes", and "included") is not restrictive.

[0115] As used herein, ranges and amounts can be expressed as "about" a particular value or range. About also includes the exact amount. Thus, "about 5 μL" means "about 5 μL" as well as "5 μL." In general, the term "about" includes amounts that are expected to be within the range of experimental error.

[0116] The section headings used herein are for organizational purposes only and are not to be construed as limiting the subject matter described.

[0117] "Antibodies" and "immunoglobulins" (Ig) are glycoproteins with the same structural characteristics. The two terms are used synonymously. In some cases, the antigenic specificity of an immunoglobulin is known.

[0118] The term "antibody" is used in its broadest sense and encompasses fully assembled antibodies, antibody fragments that can bind to an antigen (e.g., Fab, F(ab')2, Fv, single-chain antibodies, single-chain variable fragments (scFv), diabodies, antibody chimeras, hybrid antibodies, bispecific antibodies, etc.), and recombinant peptides comprising the foregoing. "Antibody" may refer to a monospecific antibody, a bispecific antibody, or a multispecific antibody.

[0119] The terms "monoclonal antibody" and "mAb" as used herein refer to an antibody obtained from a population of substantially homogeneous antibodies, ie, the individual antibodies comprising the population are identical except for possible naturally occurring mutations that may be present in minor amounts.

[0120] "Native antibodies" and "natural immunoglobulins" are typically heterotetrameric glycoproteins of about 150,000 daltons, consisting of two identical light (L) chains and two identical heavy (H) chains. Each light chain is linked to a heavy chain by one covalent disulfide bond, however the number of disulfide linkages varies between the heavy chains of different immunoglobulin isotypes. Each heavy and light chain also has regularly spaced intrachain disulfide bonds. Each heavy chain has a variable domain (VH) at one end, followed by multiple constant domains. Each light chain has a variable domain (VL) at one end and a constant domain at its other end; the constant domain of the light chain is aligned with the first constant domain of the heavy chain, and the light chain variable domain is aligned with the variable domain of the heavy chain. Specific amino acid residues are believed to form the interface between the light and heavy chain variable domains.

[0121] The term "variable" refers to the fact that certain parts of the variable domain have huge sequence differences between antibodies. The variable region confers antigen binding specificity. However, variability is not evenly distributed throughout the entire variable domain of the antibody. It is concentrated in three segments called complementary determining regions (CDRs) or hypervariable regions in both the light and heavy chain variable domains. The more highly conserved parts of the variable domain are separated by framework (FR) regions. The variable domains of native heavy and light chains each contain four FR regions, which mainly adopt a β-pleated structure and are connected by three CDRs, which form a loop connecting the β-pleated structure (and in some cases forming a part of the β-pleated structure). The CDRs in each chain are kept together in close proximity by the FR region and contribute to the formation of the antigen binding site of the antibody with the CDRs in the other chain (see Kabat et al. (1991) NIH PubL. No. 91-3242, Vol. 1, pp. 647-669). The constant domains are not involved directly in binding an antibody to an antigen, but exhibit various effector functions, such as Fc receptor (FcR) binding, participation of the antibody in antibody-dependent cellular cytotoxicity, initiation of complement-dependent cytotoxicity, and mast cell degranulation.

[0122] As used herein, the term "hypervariable region" refers to the amino acid residues in an antibody that are responsible for antigen binding. The hypervariable region comprises amino acid residues from the "complementarity determining region" or "CDR" (i.e., residues 24-34 (L1), 50-56 (L2), and 89-97 (L3) in the light chain variable domain and 31-35 (H1), 50-65 (H2), and 95-102 (H3) in the heavy chain variable domain; Kabat et al. (1991) Sequences of Proteins of Immunological Interest, 5th ed., Public Health Service, National Institutes of Health, Bethesda, Md.) and / or those residues from the "hypervariable loops" (i.e., residues 26-32 (L1), 50-52 (L2), and 91-96 (L3) in the light chain variable domain and (H1), 53-55 (H2), and 96-101 (I3) in the heavy chain variable domain; Clothia and Lesk, (1987) J. Mol. Biol., 196:901-917). As considered herein, "framework" or "FR" residues are those variable domain residues other than the hypervariable region residues.

[0123] "Fv" is the smallest antibody fragment containing a complete antigen recognition and binding site. This region is composed of a dimer of a heavy chain variable domain and a light chain variable domain that are tightly non-covalently associated. The three CDRs of each variable domain interact in this configuration and define the antigen binding site on the surface of the VH-VL dimer. The six CDRs collectively confer antigen binding specificity to the antibody. However, even a single variable domain (or only half an Fv comprising three CDRs specific for an antigen) has the ability to recognize and bind to an antigen, but the affinity is lower than that of a complete binding site.

[0124] Fab fragments also contain the constant domain of the light chain and the first constant domain (CH1) of the heavy chain. Fab fragments differ from Fab' fragments by the addition of several residues to the carboxyl terminus of the heavy chain CH1 domain, including one or more cysteines from the antibody hinge region. Fab'-SH is the designation herein for Fab' in which the cysteine residues in the constant domains bear free thiol groups. Fab' fragments are produced by reducing the heavy chain disulfide bonds of the F(ab')2 fragment. Other chemical couplings of antibody fragments are also known.

[0125] The "light chains" of antibodies (immunoglobulins) from any vertebrate species can be assigned to one of two clearly distinct types, called kappa (κ) and lambda (λ), based on the amino acid sequences of their constant domains.

[0126] "Single-chain variable fragment" or "scFv" refers to a fusion protein of a light chain variable region and a heavy chain variable region. The light chain variable region can be N-terminal to the heavy chain variable region, or the heavy chain variable region can be N-terminal to the light chain variable region.

[0127] The heavy chain constant domains of immunoglobulins are categorized into different classes. Depending on the amino acid sequence of their heavy chain constant domains, immunoglobulins can be classified into different classes. There are five major classes of human immunoglobulins: IgA, IgD, IgE, IgG, and IgM, and several of these can be further divided into subclasses (isotypes), for example, IgG1, IgG2, IgG3, IgG4, IgA1, and IgA2. The heavy chain constant domains corresponding to different classes of immunoglobulins are referred to as α, δ, ε, γ, and μ, respectively. Different classes of immunoglobulin subunit structures and three-dimensional configurations are well known. Different isotypes have different effector functions. For example, human IgG1 and IgG3 isotypes have ADCC (antibody-dependent cell-mediated cytotoxicity) activity.

[0128] In some cases, the CDRs of an antibody are identified according to: (i) the Kabat numbering system (Kabat et al. (197) Ann. NY Acad. Sci. 190:382-391 and Kabat et al. (1991) Sequences of Proteins of Immunological Interest, 5th ed., U.S. Department of Health and Human Services, NIH Publication No. 91-3242); or (ii) the Chothia numbering scheme, which will be referred to herein as "Chothia CDRs" (see, e.g., Chothia and Lesk, 1987, J. Mol. Biol., 196:901-917; Al-Lazikani et al., 1997, J. Mol. Biol., 273:927-948; Chothia et al., 1992, J. Mol. Biol., 227:799-817; Tramontano et al., 1993, J. Mol. Biol., 234:817-821). A et al., 1990, J. Mol. Biol. 215(1):175-82; and U.S. Patent No. 7,709,226); or (iii) the ImMunoGeneTics (IMGT) numbering system, e.g., as described in Lefranc, M.-P., 1999, The Immunologist, 7:132-136 and Lefranc, M.-P. et al., 1999, Nucleic Acids Res., 27:209-212 ("IMGT CDRs"); or (iv) MacCallum et al., 1996, J. Mol. Biol., 262:732-745. See also, e.g., Martin, A., "Protein Sequence and Structure Analysis of Antibody Variable Domains," in Antibody Engineering, Kontermann and Diibel, eds., Chapter 31, pp. 422-439, Springer-Verlag, Berlin (2001).

[0129] With respect to the Kabat numbering system, the CDRs within an antibody heavy chain molecule are typically present at amino acid positions 31 to 35 (which may optionally include one or two additional amino acids after 35 (referred to as 35A and 35B in the Kabat numbering scheme)) (CDR1), amino acid positions 50 to 65 (CDR2), and amino acid positions 95 to 102 (CDR3). Using the Kabat numbering system, the CDRs within an antibody light chain molecule are typically present at amino acid positions 24 to 34 (CDR1), amino acid positions 50 to 56 (CDR2), and amino acid positions 89 to 97 (CDR3). As is well known to those skilled in the art, when using the Kabat numbering system, the actual linear amino acid sequence of an antibody variable domain may contain fewer or additional amino acids due to shortening or lengthening of FRs and / or CDRs, and thus the Kabat number of an amino acid is not necessarily the same as its linear amino acid number.

[0130] The term "chimeric" antibody refers to an antibody in which a portion of the heavy and / or light chain is derived from a particular source or species, while the remainder of the heavy and / or light chain is derived from a different source or species.

[0131] As used herein, the term "recombinant human antibody" is intended to include all human antibodies prepared, expressed, generated or isolated by recombinant means, such as antibodies isolated from host cells such as NSO or CHO cells or from animals (e.g., mice) transgenic for human immunoglobulin genes, or antibodies expressed using recombinant expression vectors transfected into host cells. Such recombinant human antibodies have variable and constant regions in rearranged form. In some cases, the recombinant human antibodies have been subjected to somatic hypermutation in vivo. Therefore, although the amino acid sequences of the VH and VL regions of the recombinant antibodies are derived from and related to human germline VH and VL sequences, they may not naturally occur within the human antibody germline repertoire in vivo.

[0132] The terms "individual," "subject," and "patient" are used interchangeably herein and refer to any mammal. In some embodiments, the mammal is a human. In some embodiments, the mammal is a non-human. None of these terms require or are limited to situations characterized by supervision (e.g., continuous or intermittent) by a health care worker (e.g., a physician, registered nurse, licensed practical nurse, physician assistant, nursing assistant, or hospice worker).

[0133] As used herein, the term " amino acid sequence identity percentage (%) " with regard to sequence is defined as after the comparison sequences and introducing gap (if necessary) to realize maximum sequence identity percentage and any conservative substitution is not considered as a part for sequence identity, the percentage of the amino acid residue identical with the amino acid residue in the particular sequence in the candidate sequence. The comparison that is purpose to determine amino acid sequence identity percentage can be realized in the whole range of ways within the skill in the art, for example, using publicly available computer software to realize, such as EMBOSS MATCHER, EMBOSS WATER, EMBOSS STRETCHER, EMBOSS NEEDLE, EMBOSS LALIGN, BLAST, BLAST-2, ALIGN or Megalign (DNASTAR) software. Those skilled in the art can determine to be used to measure the appropriate parameters for comparison, are included in and reach maximum comparison required any algorithm on the compared sequence full length.

[0134] In the case of amino acid sequence comparisons using ALIGN-2, the % amino acid sequence identity of a given amino acid sequence A to a given amino acid sequence B, and a given amino acid sequence B, or as compared to a given amino acid sequence B (or alternatively, it can be phrased as a given amino acid sequence A having or comprising a certain % amino acid sequence identity to a given amino acid sequence B, and a given amino acid sequence B, or as compared to a given amino acid sequence B) is calculated as follows: 100 multiplied by the fraction X / Y, where X is the number of amino acid residues scored as identical matches by the sequence alignment program ALIGN-2 when the program aligns A and B, and where Y is the total number of amino acid residues in B. It will be understood that where the length of amino acid sequence A is not equal to the length of amino acid sequence B, the % amino acid sequence identity of A to B will not be equal to the % amino acid sequence identity of B to A. Unless specifically stated otherwise, all % amino acid sequence identity values used herein are obtained using the ALIGN-2 computer program as described in the preceding paragraph.

[0135] As used herein, "treatment" (and grammatical variations such as "treat" or "treating") refers to clinical intervention made to alter the natural course of the individual being treated, and can be performed for prevention or during the course of clinical pathology. Desirable therapeutic effects include, but are not limited to, preventing the occurrence or recurrence of allergic reactions, allergic reaction relief, allergic reaction. Any direct or indirect pathological consequences, prevention of metastasis, reduction of allergic reaction rate, amelioration or alleviation of allergic reactions, and alleviation or improvement of prognosis. In some embodiments, the molecules of the present disclosure are used to delay disease progression or slow down allergic reactions.

[0136] Implementation Plan

[0137] Embodiment A1. An isolated antibody that binds to Ara h 2 and Ara h 6, the isolated antibody comprising a heavy chain variable domain (VH) comprising the complementarity determining regions (CDRs): HC-CDR1, HC-CDR2, HC-CDR3, wherein the HC-CDR1, HC-CDR2, HC-CDR3 comprise the amino acid sequence according to HC-CDR1: SEQ ID NO: 1, HC-CDR2: SEQ ID NO: 2 or SEQ ID NO: 3, HC-CDR-3: SEQ ID NO: 4 or SEQ ID NO: 5, and the isolated antibody comprises a light chain variable (VL) domain comprising the CDRs: LC-CDR1, LC-CDR2, LC-CDR3, wherein the LC-CDR1, LC-CDR2, LC-CDR3 comprise the amino acid sequence according to LC-CDR1: SEQ ID NO: 6, LC-CDR2: SEQ ID NO: 7, LC-CDR-3: SEQ ID NO: 8.

[0138] Embodiment A2. The isolated antibody of Embodiment A1, wherein the VH comprises an amino acid sequence having at least 80%, 85%, 90%, 95%, 98%, 99% or 100% sequence identity to SEQ ID NO: 9 or SEQ ID NO: 10.

[0139] Embodiment A3. The isolated antibody of Embodiment A1 or A2, wherein the VL comprises an amino acid sequence having at least 80%, 85%, 90%, 95%, 98%, 99% or 100% sequence identity to SEQ ID NO: 11.

[0140] Embodiment A4. An isolated antibody according to any one of Embodiments A1-A3, wherein the VH comprises an amino acid sequence having at least 80%, 85%, 90%, 95%, 98%, 99% or 100% sequence identity to SEQ ID NO: 9 or SEQ ID NO: 10, and wherein the VL comprises an amino acid sequence having at least 80%, 85%, 90%, 95%, 98%, 99% or 100% sequence identity to SEQ ID NO: 11.

[0141] Embodiment A5. The isolated antibody of any one of Embodiments A1-A4, wherein the isolated antibody comprises a Fab, a Fab', a F(ab')2, or a single-chain variable fragment (scFv).

[0142] Embodiment A6. The isolated antibody of any one of Embodiments A1-A5, wherein the isolated antibody is a Fab, Fab', F(ab')2, or a single-chain variable fragment (scFv).

[0143] Embodiment A7. The isolated antibody of Embodiment A5 or A6, wherein the isolated antibody comprises the scFv.

[0144] Embodiment A8. The isolated antibody of any one of Embodiments A1-A7, wherein the VH and VL are connected by a scFv linker sequence.

[0145] Embodiment A9. The isolated antibody of Embodiment A8, wherein the scFv linker sequence comprises the amino acid sequence according to SEQ ID No: 12.

[0146] Embodiment A10. The isolated antibody of any one of Embodiments A5-A9, wherein the scFv comprises an amino acid sequence having at least 80%, 85%, 90%, 95%, 98%, 99% or 100% sequence identity to SEQ ID NO: 13 or SEQ ID NO: 14.

[0147] Embodiment A11. The isolated antibody of any one of Embodiments A1-A6, wherein the isolated antibody comprises a constant domain.

[0148] Embodiment A12. The isolated antibody of Embodiment A11, wherein the constant domain comprises a human IgG4 sequence.

[0149] Embodiment A13. The isolated antibody of Embodiment A12, wherein the human IgG4 sequence comprises an S228P point mutation, wherein amino acid numbering follows the EU index as in Kabat et al.

[0150] Embodiment A14. The isolated antibody of Embodiment A12 or A13, wherein the human IgG4 sequence does not have a C-terminal lysine residue.

[0151] Embodiment A15. The isolated antibody of any one of Embodiments A11-A14, wherein the constant domain comprises a human IgG1 sequence.

[0152] Embodiment A16. The isolated antibody of any one of Embodiments A11-A15, wherein the constant domain comprises C H 1. C H 2. C H 3 or C L Amino acid sequence.

[0153] Embodiment A17. The isolated antibody of any one of Embodiments A1-A15, wherein the isolated antibody comprises C H 1. C H 2. C H 3 and C L Amino acid sequence.

[0154] Embodiment A18. The isolated antibody of any one of Embodiments A1 to A17, wherein the isolated antibody comprises an amino acid sequence that has at least 80%, 85%, 90%, 95%, 98%, 99% or 100% sequence identity to SEQ ID NO: 15, SEQ ID NO: 16, SEQ ID NO: 72 or SEQ ID NO: 73, and the isolated antibody comprises an amino acid sequence that has at least 80%, 85%, 90%, 95%, 98%, 99% or 100% sequence identity to SEQ ID NO: 17.

[0155] Embodiment A19. An isolated recombinant nucleic acid sequence encoding the amino acid sequence of the isolated antibody according to any one of embodiments A1-A18.

[0156] Embodiment A20. A vector comprising the isolated recombinant nucleic acid sequence according to embodiment A19.

[0157] Embodiment A21. A pharmaceutical composition comprising: (a) the isolated antibody of any one of Embodiments A1-A18; and (b) a pharmaceutically acceptable excipient.

[0158] Embodiment A22. A method of treating food allergy in a subject in need thereof, comprising administering to the subject the isolated antibody of any one of embodiments A1-A18.

[0159] Embodiment A23. The method of embodiment A22, wherein the food allergy comprises peanut allergy.

[0160] Embodiment B1. An isolated antibody that binds to Ara h 2 and Ara h 6, the isolated antibody comprising a heavy chain variable domain (VH) comprising the complementarity determining regions (CDRs): HC-CDR1, HC-CDR2, HC-CDR3, wherein the HC-CDR1, HC-CDR2, HC-CDR3 comprise the amino acid sequence according to HC-CDR1: SEQ ID NO: 18, HC-CDR2: SEQ ID NO: 19, HC-CDR-3: SEQ ID NO: 20 or SEQ ID NO: 21, and the isolated antibody comprises a light chain variable (VL) domain comprising the CDRs: LC-CDR1, LC-CDR2, LC-CDR3, wherein the LC-CDR1, LC-CDR2, LC-CDR3 comprise the amino acid sequence according to LC-CDR1: SEQ ID NO: 22, LC-CDR2: SEQ ID NO: 23, LC-CDR-3: SEQ ID NO: 24.

[0161] Embodiment B2. The isolated antibody of Embodiment B1, wherein the VH comprises an amino acid sequence having at least 80%, 85%, 90%, 95%, 98%, 99% or 100% sequence identity to SEQ ID NO: 25 or SEQ ID NO: 26.

[0162] Embodiment B3. The isolated antibody of Embodiment B1 or B2, wherein the VL comprises an amino acid sequence having at least 80%, 85%, 90%, 95%, 98%, 99% or 100% sequence identity to SEQ ID NO: 27 or SEQ ID NO: 28.

[0163] Embodiment B4. An isolated antibody according to any one of Embodiments B1-B3, wherein the VH comprises an amino acid sequence having at least 80%, 85%, 90%, 95%, 98%, 99% or 100% sequence identity to SEQ ID NO: 25 or SEQ ID NO: 26, and wherein the VL comprises an amino acid sequence having at least 80%, 85%, 90%, 95%, 98%, 99% or 100% sequence identity to SEQ ID NO: 27 or SEQ ID NO: 28.

[0164] Embodiment B5. The isolated antibody of any one of Embodiments B1-B4, wherein the isolated antibody comprises a Fab, a Fab', a F(ab')2, or a single-chain variable fragment (scFv).

[0165] Embodiment B6. The isolated antibody of any one of Embodiments B1-B5, wherein the isolated antibody is a Fab, Fab', F(ab')2, or a single-chain variable fragment (scFv).

[0166] Embodiment B7. The isolated antibody of Embodiment B6 or B7, wherein the isolated antibody comprises the scFv.

[0167] Embodiment B8. The isolated antibody of any one of Embodiments B1-B7, wherein the VH and VL are connected by a scFv linker sequence.

[0168] Embodiment B9. The isolated antibody of Embodiment B8, wherein the scFv linker sequence comprises the amino acid sequence according to SEQ ID NO: 29.

[0169] Embodiment B10. The isolated antibody of any one of Embodiments B5-B9, wherein the scFv comprises an amino acid sequence having at least 80%, 85%, 90%, 95%, 98%, 99% or 100% sequence identity to SEQ ID NO: 30 or SEQ ID NO: 31.

[0170] Embodiment B11. The isolated antibody of any one of Embodiments B1-B6, wherein the isolated antibody comprises a constant domain.

[0171] Embodiment B12. The isolated antibody of Embodiment B11, wherein the constant domain comprises a human IgG4 sequence.

[0172] Embodiment B13. The isolated antibody of Embodiment B12, wherein the human IgG4 sequence comprises an S228P point mutation, wherein amino acid numbering follows the EU index as in Kabat et al.

[0173] Embodiment B14. The isolated antibody of Embodiment B12 or B13, wherein the human IgG4 sequence does not have a C-terminal lysine residue.

[0174] Embodiment B15. The isolated antibody of any one of Embodiments B11-B14, wherein the constant domain comprises a human IgG1 sequence.

[0175] Embodiment B16. The isolated antibody of any one of Embodiments B11-B15, wherein the constant domain comprises C H 1. C H 2. C H 3 or C L Amino acid sequence.

[0176] Embodiment B17. The isolated antibody of any one of Embodiments B1-B15, wherein the isolated antibody comprises C H 1. C H 2. C H 3 and C L Amino acid sequence.

[0177] Embodiment B18. The isolated antibody of any one of Embodiments B1 to B17, wherein the isolated antibody comprises an amino acid sequence that has at least 80%, 85%, 90%, 95%, 98%, 99% or 100% sequence identity to SEQ ID NO: 32, SEQ ID NO: 33, SEQ ID NO: 74 or SEQ ID NO: 75, and the isolated antibody comprises an amino acid sequence that has at least 80%, 85%, 90%, 95%, 98%, 99% or 100% sequence identity to SEQ ID NO: 34 or SEQ ID NO: 76.

[0178] Embodiment B19. An isolated recombinant nucleic acid sequence encoding the amino acid sequence of the isolated antibody according to any one of Embodiments B1-B18.

[0179] Embodiment B20. A vector comprising the isolated recombinant nucleic acid sequence according to embodiment B19.

[0180] Embodiment B21. A pharmaceutical composition comprising: (a) the isolated antibody of any one of Embodiments B1-B18; and (b) a pharmaceutically acceptable excipient.

[0181] Embodiment B22. A method of treating food allergy in a subject in need thereof, comprising administering to the subject the isolated antibody of any one of Embodiments B1-B18.

[0182] Embodiment B23. The method of embodiment B22, wherein the food allergy comprises peanut allergy.

[0183] Embodiment C1. An isolated antibody that binds to Ara h 2, the isolated antibody comprising a heavy chain variable domain (VH) comprising the complementarity determining regions (CDRs): HC-CDR1, HC-CDR2, HC-CDR3, wherein the HC-CDR1, HC-CDR2, HC-CDR3 comprise the amino acid sequence according to HC-CDR1: SEQ ID NO: 35, HC-CDR2: SEQ ID NO: 36 or SEQ ID NO: 37, HC-CDR-3: SEQ ID NO: 38, and the isolated antibody comprises a light chain variable (VL) domain comprising the CDRs: LC-CDR1, LC-CDR2, LC-CDR3, wherein the LC-CDR1, LC-CDR2, LC-CDR3 comprise the amino acid sequence according to LC-CDR1: SEQ ID NO: 39, LC-CDR2: SEQ ID NO: 40, LC-CDR-3: SEQ ID NO: 41.

[0184] Embodiment C2. The isolated antibody of Embodiment C1, wherein the VH comprises an amino acid sequence having at least 80%, 85%, 90%, 95%, 98%, 99% or 100% sequence identity to SEQ ID NO:42 or SEQ ID NO:43.

[0185] Embodiment C3. The isolated antibody of Embodiment C1 or C2, wherein the VL comprises an amino acid sequence having at least 80%, 85%, 90%, 95%, 98%, 99% or 100% sequence identity to SEQ ID NO:44.

[0186] Embodiment C4. An isolated antibody according to any one of embodiments C1-C3, wherein the VH comprises an amino acid sequence having at least 80%, 85%, 90%, 95%, 98%, 99% or 100% sequence identity to SEQ ID NO:42 or SEQ ID NO:43, and wherein the VL comprises an amino acid sequence having at least 80%, 85%, 90%, 95%, 98%, 99% or 100% sequence identity to SEQ ID NO:44.

[0187] Embodiment C5. The isolated antibody of any one of Embodiments C1-C4, wherein the isolated antibody comprises a Fab, a Fab', a F(ab')2, or a single-chain variable fragment (scFv).

[0188] Embodiment C6. The isolated antibody of any one of Embodiments C1-C5, wherein the isolated antibody is a Fab, Fab', F(ab')2, or a single-chain variable fragment (scFv).

[0189] Embodiment C7. The isolated antibody of Embodiment C5 or C6, wherein the isolated antibody comprises the scFv.

[0190] Embodiment C8. The isolated antibody of any one of Embodiments C1-C7, wherein the VH and VL are connected by a scFv linker sequence.

[0191] Embodiment C9. The isolated antibody of embodiment C8, wherein the scFv linker sequence comprises the amino acid sequence according to SEQ ID NO:45.

[0192] Embodiment C10. The isolated antibody of any one of Embodiments C5-C9, wherein the scFv comprises an amino acid sequence having at least 80%, 85%, 90%, 95%, 98%, 99% or 100% sequence identity to SEQ ID NO:46 or SEQ ID NO:47.

[0193] Embodiment C11. The isolated antibody of any one of Embodiments C1-C6, wherein the isolated antibody comprises a constant domain.

[0194] Embodiment C12. The isolated antibody of Embodiment C11, wherein the constant domain comprises a human IgG4 sequence.

[0195] Embodiment C13. The isolated antibody of embodiment C12, wherein the human IgG4 sequence comprises an S228P point mutation, wherein the amino acid numbering follows the EU index as in Kabat et al.

[0196] Embodiment C14. The isolated antibody of Embodiment C12 or C13, wherein the human IgG4 sequence does not have a C-terminal lysine residue.

[0197] Embodiment C15. The isolated antibody of any one of Embodiments C11-C14, wherein the constant domain comprises a human IgG1 sequence.

[0198] Embodiment C16. The isolated antibody of any one of embodiments C11-C15, wherein the constant domain comprises C H 1. C H 2. C H 3 or C L Amino acid sequence.

[0199] Embodiment C17. The isolated antibody of any one of Embodiments C1-C16, wherein the isolated antibody comprises C H 1. C H2. C H 3 and C L Amino acid sequence.

[0200] Embodiment C18. The isolated antibody of any one of Embodiments C1-C17, wherein the isolated antibody comprises an amino acid sequence that has at least 80%, 85%, 90%, 95%, 98%, 99% or 100% sequence identity to SEQ ID NO:48, SEQ ID NO:49, SEQ ID NO:77 or SEQ ID NO:78, and the isolated antibody comprises an amino acid sequence that has at least 80%, 85%, 90%, 95%, 98%, 99% or 100% sequence identity to SEQ ID NO:50.

[0201] Embodiment C19. An isolated recombinant nucleic acid sequence encoding the amino acid sequence of the isolated antibody according to any one of embodiments C1-C18.

[0202] Embodiment C20. A vector comprising the isolated recombinant nucleic acid sequence according to embodiment C19.

[0203] Embodiment C21. A pharmaceutical composition comprising: (a) the isolated antibody of any one of Embodiments C1-C18; and (b) a pharmaceutically acceptable excipient.

[0204] Embodiment C22. A method of treating food allergy in a subject in need thereof, comprising administering to the subject the isolated antibody of any one of Embodiments C1-C18.

[0205] Embodiment C23. The method of embodiment C22, wherein the food allergy comprises peanut allergy.

[0206] Embodiment D1. An isolated antibody comprising a first binding domain that binds to Ara h 2 and Ara h 6, wherein the first binding domain comprises a heavy chain variable domain (VH) comprising the complementarity determining regions (CDRs): HC-CDR1, HC-CDR2, HC-CDR3, wherein the HC-CDR1, HC-CDR2, HC-CDR3 comprise the amino acid sequence according to HC-CDR1: SEQ ID NO: 1, HC-CDR2: SEQ ID NO: 2 or SEQ ID NO: 3, HC-CDR-3: SEQ ID NO: 4 or SEQ ID NO: 5, and the first binding domain comprises a light chain variable (VL) domain comprising the CDRs: LC-CDR1, LC-CDR2, LC-CDR3, wherein the LC-CDR1, LC-CDR2, LC-CDR3 comprise the amino acid sequence according to LC-CDR1: SEQ ID NO: 6, LC-CDR2: SEQ ID NO: 7, LC-CDR-3: SEQ ID NO: 8. NO:8, wherein the isolated antibody comprises a second binding domain that binds to Ara h 2 and Ara h 6, wherein the second binding domain comprises a VH comprising complementarity determining regions (CDRs): HC-CDR1, HC-CDR2, HC-CDR3, wherein the HC-CDR1, HC-CDR2, HC-CDR3 comprise the amino acid sequence according to HC-CDR1: SEQ ID NO:18, HC-CDR2: SEQ ID NO:19, HC-CDR-3: SEQ ID NO:20 or SEQ ID NO:21, and the second binding domain comprises a light chain variable (VL) domain comprising CDRs: LC-CDR1, LC-CDR2, LC-CDR3, wherein the LC-CDR1, LC-CDR2, LC-CDR3 comprise the amino acid sequence according to LC-CDR1: SEQ ID NO:22, LC-CDR2: SEQ ID NO:23, LC-CDR-3: SEQ ID NO:24.

[0207] Embodiment D2. An isolated antibody according to embodiment D1, wherein the VH of the first binding domain comprises an amino acid sequence having at least 80%, 85%, 90%, 95%, 98%, 99% or 100% sequence identity to SEQ ID NO:9 or SEQ ID NO:10.

[0208] Embodiment D3. An isolated antibody according to embodiment D1 or D2, wherein the VL of the first binding domain comprises an amino acid sequence having at least 80%, 85%, 90%, 95%, 98%, 99% or 100% sequence identity to SEQ ID NO: 11.

[0209] Embodiment D4. An isolated antibody according to any one of embodiments D1-D3, wherein the VH of the first binding domain comprises an amino acid sequence having at least 80%, 85%, 90%, 95%, 98%, 99% or 100% sequence identity to SEQ ID NO: 9 or SEQ ID NO: 10, and wherein the VL of the first binding domain comprises an amino acid sequence having at least 80%, 85%, 90%, 95%, 98%, 99% or 100% sequence identity to SEQ ID NO: 11.

[0210] Embodiment D5. The isolated antibody of any one of Embodiments D1-D4, wherein the first binding domain comprises a Fab, Fab', F(ab')2, or a single-chain variable fragment (scFv).

[0211] Embodiment D6. The isolated antibody of any one of Embodiments D1-D5, wherein the first binding domain is a Fab, Fab', F(ab')2, or a single-chain variable fragment (scFv).

[0212] Embodiment D7. The isolated antibody of Embodiment D5 or D6, wherein the first binding domain comprises the scFv.

[0213] Embodiment D8. The isolated antibody of any one of Embodiments D1-D7, wherein the VH of the first binding domain and the VL of the first binding domain are connected by a scFv linker sequence.

[0214] Embodiment D9. The isolated antibody of embodiment D8, wherein the scFv linker sequence of the first binding domain comprises the amino acid sequence according to SEQ ID No:12.

[0215] Embodiment D10. The isolated antibody of any one of Embodiments D5-D9, wherein the scFv of the first binding domain comprises an amino acid sequence having at least 80%, 85%, 90%, 95%, 98%, 99% or 100% sequence identity to SEQ ID NO: 13 or SEQ ID NO: 14.

[0216] Embodiment D11. The isolated antibody of any one of Embodiments D1-D6, wherein the first binding domain comprises a constant domain.

[0217] Embodiment D12. The isolated antibody of Embodiment D11, wherein the constant domain of the first binding domain comprises a human IgG4 sequence.

[0218] Embodiment D13. The isolated antibody of embodiment D12, wherein the human IgG4 sequence of the first binding domain comprises an S228P point mutation, wherein amino acid numbering follows the EU index as in Kabat et al.

[0219] Embodiment D14. The isolated antibody of Embodiment D12 or D13, wherein the human IgG4 sequence of the first binding domain does not have a C-terminal lysine residue.

[0220] Embodiment D15. The isolated antibody of any one of Embodiments D11-D14, wherein the constant domain of the first binding domain comprises a human IgG1 sequence.

[0221] Embodiment D16. The isolated antibody of any one of Embodiments D11-D15, wherein the constant domain of the first binding domain comprises C H 1. C H 2. C H 3 or C L Amino acid sequence.

[0222] Embodiment D17. An isolated antibody according to any one of embodiments D1-D15, wherein the first binding domain comprises C H 1. C H 2. C H 3 and C L Amino acid sequence.

[0223] Embodiment D18. An isolated antibody according to any one of embodiments D1 to D17, wherein the first binding domain comprises an amino acid sequence having at least 80%, 85%, 90%, 95%, 98%, 99% or 100% sequence identity to SEQ ID NO: 15, SEQ ID NO: 16, SEQ ID NO: 72 or SEQ ID NO: 73, and the first binding domain comprises an amino acid sequence having at least 80%, 85%, 90%, 95%, 98%, 99% or 100% sequence identity to SEQ ID NO: 17.

[0224] Embodiment D19. An isolated antibody according to any one of embodiments D1-D18, wherein the VH of the second binding domain comprises an amino acid sequence having at least 80%, 85%, 90%, 95%, 98%, 99% or 100% sequence identity to SEQ ID NO:25 or SEQ ID NO:26.

[0225] Embodiment D20. An isolated antibody according to any one of embodiments D1-D19, wherein the VL of the second binding domain comprises an amino acid sequence having at least 80%, 85%, 90%, 95%, 98%, 99% or 100% sequence identity to SEQ ID NO: 27 or SEQ ID NO: 28.

[0226] Embodiment D21. An isolated antibody according to any one of embodiments D1-D20, wherein the VH of the second binding domain comprises an amino acid sequence having at least 80%, 85%, 90%, 95%, 98%, 99% or 100% sequence identity to SEQ ID NO: 25 or SEQ ID NO: 26, and wherein the VL of the second binding domain comprises an amino acid sequence having at least 80%, 85%, 90%, 95%, 98%, 99% or 100% sequence identity to SEQ ID NO: 27 or SEQ ID NO: 28.

[0227] Embodiment D22. The isolated antibody of any one of Embodiments D1-D21, wherein the second binding domain comprises a Fab, Fab', F(ab')2, or a single-chain variable fragment (scFv).

[0228] Embodiment D23. The isolated antibody of any one of Embodiments D1-D22, wherein the second binding domain is a Fab, Fab', F(ab')2, or a single-chain variable fragment (scFv).

[0229] Embodiment D24. The isolated antibody of Embodiment D22 or D23, wherein the second binding domain comprises the scFv.

[0230] Embodiment D25. The isolated antibody of any one of Embodiments D1-D24, wherein the VH of the second binding domain and the VL of the second binding domain are connected by a scFv linker sequence.

[0231] Embodiment D26. The isolated antibody of Embodiment D25, wherein the scFv linker sequence of the second binding domain comprises the amino acid sequence according to SEQ ID NO:29.

[0232] Embodiment D27. An isolated antibody according to any one of Embodiments D1-D26, wherein the scFv of the second binding domain comprises an amino acid sequence having at least 80%, 85%, 90%, 95%, 98%, 99% or 100% sequence identity to SEQ ID NO:30 or SEQ ID NO:31.

[0233] Embodiment D28. The isolated antibody of any one of Embodiments D1-D27, wherein the second binding domain comprises a constant domain.

[0234] Embodiment D29. The isolated antibody of Embodiment D28, wherein the constant domain of the second binding domain comprises a human IgG4 sequence.

[0235] Embodiment D30. The isolated antibody of Embodiment D29, wherein the human IgG4 sequence of the second binding domain comprises an S228P point mutation, wherein the amino acid numbering follows the EU index in Kabat et al.

[0236] Embodiment D31. The isolated antibody of Embodiment D29 or D30, wherein the human IgG4 sequence of the second binding domain does not have a C-terminal lysine residue.

[0237] Embodiment D32. The isolated antibody of any one of Embodiments D28-D31, wherein the constant domain of the second binding domain comprises a human IgG1 sequence.

[0238] Embodiment D33. An isolated antibody according to any one of embodiments D28-D32, wherein the constant domain of the second binding domain comprises C H 1. C H 2. C H 3 or C L Amino acid sequence.

[0239] Embodiment D34. An isolated antibody according to any one of embodiments D1-D32, wherein the second binding domain comprises C H 1. C H 2. C H 3 and C L Amino acid sequence.

[0240] Embodiment D35. An isolated antibody according to any one of embodiments D1-D34, wherein the second binding domain comprises an amino acid sequence having at least 80%, 85%, 90%, 95%, 98%, 99% or 100% sequence identity to SEQ ID NO:32, SEQ ID NO:33, SEQ ID NO:74 or SEQ ID NO:75, and the isolated antibody comprises an amino acid sequence having at least 80%, 85%, 90%, 95%, 98%, 99% or 100% sequence identity to SEQ ID NO:34 or SEQ ID NO:76.

[0241] Embodiment D36. The isolated antibody of any one of Embodiments D1-D35, wherein the first binding domain comprises the scFv and the second binding domain comprises C H 1. C H 2. C H 3 and C L Amino acid sequence.

[0242] Embodiment D37. The isolated antibody of any one of Embodiments D1-D35, wherein the second binding domain comprises the scFv and the first binding domain comprises C H 1. C H 2. C H 3 and C L Amino acid sequence.

[0243] Embodiment D38. The isolated antibody of any one of Embodiments D1-D37, wherein the first binding domain and the second binding domain are connected by a linking moiety.

[0244] Embodiment D39. An isolated antibody according to embodiment D38, wherein the linking moiety is an amino acid sequence.

[0245] Embodiment D40. The isolated antibody of Embodiment D38 or D39, wherein the linking moiety is at least 4 amino acids in length.

[0246] Embodiment D41. The isolated antibody of any one of Embodiments D38-D40, wherein the linking moiety is between 4-20 amino acids in length.

[0247] Embodiment D42. An isolated antibody according to any one of embodiments D38-D41, wherein the linking moiety connects the C of the second binding domain to the H 3 amino acid sequence connected to the scFv of the first binding domain.

[0248] Embodiment D43. The isolated antibody of any one of Embodiments D38-D42, wherein the linking moiety comprises the amino acid sequence of SEQ ID NO: 51.

[0249] Embodiment D44. The isolated antibody of any one of Embodiments D1-D43, wherein the isolated antibody comprises an amino acid sequence having at least 80%, 85%, 90%, 95%, 98%, 99% or 100% sequence identity to SEQ ID NO: 53 and an amino acid sequence having at least 80%, 85%, 90%, 95%, 98%, 99% or 100% sequence identity to SEQ ID NO: 52.

[0250] Embodiment D45. The isolated antibody of any one of Embodiments D1-D43, wherein the isolated antibody comprises an amino acid sequence having at least 80%, 85%, 90%, 95%, 98%, 99% or 100% sequence identity to SEQ ID NO:55 and an amino acid sequence having at least 80%, 85%, 90%, 95%, 98%, 99% or 100% sequence identity to SEQ ID NO:54.

[0251] Embodiment D46. The isolated antibody of any one of Embodiments D1-D43, wherein the isolated antibody comprises an amino acid sequence having at least 80%, 85%, 90%, 95%, 98%, 99% or 100% sequence identity to SEQ ID NO: 65 and an amino acid sequence having at least 80%, 85%, 90%, 95%, 98%, 99% or 100% sequence identity to SEQ ID NO: 64.

[0252] Embodiment D47. The isolated antibody of any one of Embodiments D1-D43, wherein the isolated antibody comprises an amino acid sequence having at least 80%, 85%, 90%, 95%, 98%, 99% or 100% sequence identity to SEQ ID NO: 67 and an amino acid sequence having at least 80%, 85%, 90%, 95%, 98%, 99% or 100% sequence identity to SEQ ID NO: 66.

[0253] Embodiment D48. The isolated antibody of any one of Embodiments D1-D43, wherein the isolated antibody comprises an amino acid sequence having at least 80%, 85%, 90%, 95%, 98%, 99% or 100% sequence identity to SEQ ID NO: 69 and an amino acid sequence having at least 80%, 85%, 90%, 95%, 98%, 99% or 100% sequence identity to SEQ ID NO: 68.

[0254] Embodiment D49. The isolated antibody of any one of Embodiments D1-D43, wherein the isolated antibody comprises an amino acid sequence having at least 80%, 85%, 90%, 95%, 98%, 99% or 100% sequence identity to SEQ ID NO:71 and an amino acid sequence having at least 80%, 85%, 90%, 95%, 98%, 99% or 100% sequence identity to SEQ ID NO:70.

[0255] Embodiment D50. An isolated recombinant nucleic acid sequence encoding the amino acid sequence of the isolated antibody according to any one of embodiments D1-D49.

[0256] Embodiment D51. A vector comprising the isolated recombinant nucleic acid sequence according to embodiment D50.

[0257] Embodiment D52. A pharmaceutical composition comprising: (a) the isolated antibody of any one of Embodiments D1-D49; and (b) a pharmaceutically acceptable excipient.

[0258] Embodiment D53. A method of treating food allergy in a subject in need thereof, comprising administering to the subject the isolated antibody of any one of embodiments D1-D49.

[0259] Embodiment D54. The method of embodiment D53, wherein the food allergy comprises peanut allergy.

[0260] Embodiment E1. An isolated antibody comprising a first binding domain that binds to Ara h 2 and Ara h 6, wherein the first binding domain comprises a heavy chain variable domain (VH) comprising complementarity determining regions (CDRs): HC-CDR1, HC-CDR2, HC-CDR3, wherein the HC-CDR1, HC-CDR2, HC-CDR3 comprise the amino acid sequence according to HC-CDR1: SEQ ID NO: 1, HC-CDR2: SEQ ID NO: 2 or SEQ ID NO: 3, HC-CDR-3: SEQ ID NO: 4 or SEQ ID NO: 5, and the first binding domain comprises a light chain variable (VL) domain comprising CDRs: LC-CDR1, LC-CDR2, LC-CDR3, wherein the LC-CDR1, LC-CDR2, LC-CDR3 comprise the amino acid sequence according to LC-CDR1: SEQ ID NO: 6, LC-CDR2: SEQ ID NO: 7, LC-CDR-3: SEQ ID NO: 8. NO:8, wherein the isolated antibody comprises a second binding domain that binds to Ara h 2, wherein the second binding domain comprises a (VH) comprising complementarity determining regions (CDRs): HC-CDR1, HC-CDR2, HC-CDR3, wherein the HC-CDR1, HC-CDR2, HC-CDR3 comprise the amino acid sequence according to HC-CDR1: SEQ ID NO:35, HC-CDR2: SEQ ID NO:36 or SEQ ID NO:37, HC-CDR-3: SEQ ID NO:38, and the isolated antibody comprises a light chain variable (VL) domain comprising CDRs: LC-CDR1, LC-CDR2, LC-CDR3, wherein the LC-CDR1, LC-CDR2, LC-CDR3 comprise the amino acid sequence according to LC-CDR1: SEQ ID NO:39, LC-CDR2: SEQ ID NO:40, LC-CDR-3: SEQ ID NO:41.

[0261] Embodiment E2. The isolated antibody of Embodiment E1, wherein the VH of the first binding domain comprises an amino acid sequence having at least 80%, 85%, 90%, 95%, 98%, 99% or 100% sequence identity to SEQ ID NO: 9 or SEQ ID NO: 10.

[0262] Embodiment E3. An isolated antibody according to Embodiment E1 or E2, wherein the VL of the first binding domain comprises an amino acid sequence having at least 80%, 85%, 90%, 95%, 98%, 99% or 100% sequence identity to SEQ ID NO: 11.

[0263] Embodiment E4. An isolated antibody according to any one of embodiments E1 to E3, wherein the VH of the first binding domain comprises an amino acid sequence having at least 80%, 85%, 90%, 95%, 98%, 99% or 100% sequence identity to SEQ ID NO: 9 or SEQ ID NO: 10, and wherein the VL of the first binding domain comprises an amino acid sequence having at least 80%, 85%, 90%, 95%, 98%, 99% or 100% sequence identity to SEQ ID NO: 11.

[0264] Embodiment E5. The isolated antibody of any one of Embodiments E1-E4, wherein the first binding domain comprises a Fab, Fab', F(ab')2, or a single-chain variable fragment (scFv).

[0265] Embodiment E6. The isolated antibody of any one of Embodiments E1 to E5, wherein the first binding domain is a Fab, Fab', F(ab')2, or a single-chain variable fragment (scFv).

[0266] Embodiment E7. The isolated antibody of Embodiment E5 or E6, wherein the first binding domain comprises the scFv.

[0267] Embodiment E8. The isolated antibody of any one of Embodiments E1-E7, wherein the VH of the first binding domain and the VL of the first binding domain are connected by a scFv linker sequence.

[0268] Embodiment E9. The isolated antibody of Embodiment E8, wherein the scFv linker sequence of the first binding domain comprises the amino acid sequence according to SEQ ID No: 12.

[0269] Embodiment E10. The isolated antibody of Embodiment E7, wherein the scFv of the first binding domain comprises an amino acid sequence having at least 80%, 85%, 90%, 95%, 98%, 99% or 100% sequence identity to SEQ ID NO: 13 or SEQ ID NO: 14.

[0270] Embodiment E11. The isolated antibody of any one of Embodiments E1-E6, wherein the first binding domain comprises a constant domain.

[0271] Embodiment E12. The isolated antibody of Embodiment E11, wherein the constant domain of the first binding domain comprises a human IgG4 sequence.

[0272] Embodiment E13. The isolated antibody of Embodiment E12, wherein the human IgG4 sequence of the first binding domain comprises an S228P point mutation, wherein amino acid numbering follows the EU index as in Kabat et al.

[0273] Embodiment E14. The isolated antibody of Embodiment E12 or E13, wherein the human IgG4 sequence of the first binding domain does not have a C-terminal lysine residue.

[0274] Embodiment E15. The isolated antibody of any one of Embodiments E11-E14, wherein the constant domain of the first binding domain comprises a human IgG1 sequence.

[0275] Embodiment E16. The isolated antibody of any one of Embodiments E11-E15, wherein the constant domain of the first binding domain comprises C H 1. C H 2. C H 3 or C L Amino acid sequence.

[0276] Embodiment E17. An isolated antibody according to any one of Embodiments E1 to E15, wherein the first binding domain comprises C H 1. C H 2. C H 3 and C L Amino acid sequence.

[0277] Embodiment E18. An isolated antibody according to any one of embodiments E1 to E17, wherein the first binding domain comprises an amino acid sequence having at least 80%, 85%, 90%, 95%, 98%, 99% or 100% sequence identity to SEQ ID NO: 15, SEQ ID NO: 16, SEQ ID NO: 72 or SEQ ID NO: 73, and the first binding domain comprises an amino acid sequence having at least 80%, 85%, 90%, 95%, 98%, 99% or 100% sequence identity to SEQ ID NO: 17.

[0278] Embodiment E19. An isolated antibody according to any one of Embodiments E1 to E18, wherein the VH of the second binding domain comprises an amino acid sequence having at least 80%, 85%, 90%, 95%, 98%, 99% or 100% sequence identity to SEQ ID NO:42 or SEQ ID NO:43.

[0279] Embodiment E20. An isolated antibody according to any one of Embodiments E1-E19, wherein the VL of the second binding domain comprises an amino acid sequence having at least 80%, 85%, 90%, 95%, 98%, 99% or 100% sequence identity to SEQ ID NO:44.

[0280] Embodiment E21. An isolated antibody according to any one of embodiments E1 to E20, wherein the VH of the second binding domain comprises an amino acid sequence having at least 80%, 85%, 90%, 95%, 98%, 99% or 100% sequence identity to SEQ ID NO:42 or SEQ ID NO:43, and wherein the VL of the second binding domain comprises an amino acid sequence having at least 80%, 85%, 90%, 95%, 98%, 99% or 100% sequence identity to SEQ ID NO:44.

[0281] Embodiment E22. The isolated antibody of any one of Embodiments E1 to E21, wherein the second binding domain comprises a Fab, Fab', F(ab')2, or a single-chain variable fragment (scFv).

[0282] Embodiment E23. The isolated antibody of any one of Embodiments E1 to E22, wherein the second binding domain is a Fab, Fab', F(ab')2, or a single-chain variable fragment (scFv).

[0283] Embodiment E24. The isolated antibody of Embodiment E22 or E23, wherein the second binding domain comprises the scFv.

[0284] Embodiment E25. The isolated antibody of any one of Embodiments E1-E24, wherein the VH of the second binding domain and the VL of the second binding domain are connected by a scFv linker sequence.

[0285] Embodiment E26. The isolated antibody of Embodiment E25, wherein the scFv linker sequence of the second binding domain comprises the amino acid sequence according to SEQ ID NO:45.

[0286] Embodiment E27. An isolated antibody according to any one of Embodiments E1 to E26, wherein the scFv of the second binding domain comprises an amino acid sequence having at least 80%, 85%, 90%, 95%, 98%, 99% or 100% sequence identity to SEQ ID NO: 46 or SEQ ID NO: 47.

[0287] Embodiment E28. The isolated antibody of any one of Embodiments E1-E23, wherein the second binding domain comprises a constant domain.

[0288] Embodiment E29. The isolated antibody of Embodiment E28, wherein the constant domain of the second binding domain comprises a human IgG4 sequence.

[0289] Embodiment E30. The isolated antibody of Embodiment E29, wherein the human IgG4 sequence of the second binding domain comprises an S228P point mutation, wherein the amino acid numbering follows the EU index in Kabat et al.

[0290] Embodiment E31. The isolated antibody of Embodiment E28 or E29, wherein the human IgG4 sequence of the second binding domain does not have a C-terminal lysine residue.

[0291] Embodiment E32. The isolated antibody of any one of Embodiments E28-E31, wherein the constant domain of the second binding domain comprises a human IgG1 sequence.

[0292] Embodiment E33. An isolated antibody according to any one of Embodiments E28-E32, wherein the constant domain of the second binding domain comprises C H 1. C H 2. C H 3 or C L Amino acid sequence.

[0293] Embodiment E34. An isolated antibody according to any one of Embodiments E1-E32, wherein the second binding domain comprises C H 1. C H 2. C H 3 and C L Amino acid sequence.

[0294] Embodiment E35. An isolated antibody according to any one of Embodiments E1 to E34, wherein the second binding domain comprises an amino acid sequence having at least 80%, 85%, 90%, 95%, 98%, 99% or 100% sequence identity to SEQ ID NO:48, SEQ ID NO:49, SEQ ID NO:77 or SEQ ID NO:78, and the isolated antibody comprises an amino acid sequence having at least 80%, 85%, 90%, 95%, 98%, 99% or 100% sequence identity to SEQ ID NO:50.

[0295] Embodiment E36. An isolated antibody according to any one of Embodiments E1 to E35, wherein the first binding domain comprises the scFv and the second binding domain comprises C H 1. C H 2. C H 3 and C L Amino acid sequence.

[0296] Embodiment E37. An isolated antibody according to any one of Embodiments E1 to E35, wherein the second binding domain comprises the scFv and the first binding domain comprises C H 1. C H 2. C H 3 and C L Amino acid sequence.

[0297] Embodiment E38. An isolated antibody according to any one of Embodiments E1 to E37, wherein the first binding domain and the second binding domain are connected by a linking moiety.

[0298] Embodiment E39. The isolated antibody of Embodiment E38, wherein the linking moiety is an amino acid sequence.

[0299] Embodiment E40. The isolated antibody of Embodiment E38 or E39, wherein the linking moiety is at least 4 amino acids in length.

[0300] Embodiment E41. The isolated antibody of any one of Embodiments E38-E41, wherein the linking moiety is between 4-20 amino acids in length.

[0301] Embodiment E42. An isolated antibody according to any one of Embodiments E38-E41, wherein the linking moiety connects the C H 3 amino acid sequence connected to the scFv of the first binding domain.

[0302] Embodiment E43. The isolated antibody of any one of Embodiments E38-E42, wherein the linking moiety comprises the amino acid sequence of SEQ ID NO: 51.

[0303] Embodiment E44. An isolated antibody according to any one of Embodiments E1 to E43, wherein the isolated antibody comprises an amino acid sequence having at least 80%, 85%, 90%, 95%, 98%, 99% or 100% sequence identity to SEQ ID NO: 57 and an amino acid sequence having at least 80%, 85%, 90%, 95%, 98%, 99% or 100% sequence identity to SEQ ID NO: 56.

[0304] Embodiment E45. An isolated antibody according to any one of Embodiments E1 to E43, wherein the isolated antibody comprises an amino acid sequence having at least 80%, 85%, 90%, 95%, 98%, 99% or 100% sequence identity to SEQ ID NO:59 and an amino acid sequence having at least 80%, 85%, 90%, 95%, 98%, 99% or 100% sequence identity to SEQ ID NO:58.

[0305] Embodiment E46. An isolated recombinant nucleic acid sequence encoding the amino acid sequence of the isolated antibody according to any one of embodiments E1 to E45.

[0306] Embodiment E47. A vector comprising the isolated recombinant nucleic acid sequence according to embodiment E46.

[0307] Embodiment E48. A pharmaceutical composition comprising: (a) the isolated antibody of any one of Embodiments E1-E45; and (b) a pharmaceutically acceptable excipient.

[0308] Embodiment E49. A method of treating food allergy in a subject in need thereof, comprising administering to the subject the isolated antibody of any one of embodiments E1-E45.

[0309] Embodiment E50. The method of embodiment E49, wherein the food allergy comprises peanut allergy.

[0310] Embodiment F1. An isolated antibody comprising a first binding domain that binds to Ara h 2 and Ara h 6, wherein the first binding domain comprises a heavy chain variable domain (VH) comprising the complementarity determining regions (CDRs): HC-CDR1, HC-CDR2, HC-CDR3, wherein the HC-CDR1, HC-CDR2, HC-CDR3 comprise the amino acid sequence according to HC-CDR1: SEQ ID NO: 18, HC-CDR2: SEQ ID NO: 19, HC-CDR-3: SEQ ID NO: 20 or SEQ ID NO: 21, and the first binding domain comprises a light chain variable (VL) domain comprising the CDRs: LC-CDR1, LC-CDR2, LC-CDR3, wherein the LC-CDR1, LC-CDR2, LC-CDR3 comprise the amino acid sequence according to LC-CDR1: SEQ ID NO: 22, LC-CDR2: SEQ ID NO: 23, LC-CDR-3: SEQ ID NO: 24. NO:24, wherein the isolated antibody comprises a second binding domain that binds to Ara h 2, wherein the second binding domain comprises a (VH) comprising complementarity determining regions (CDRs): HC-CDR1, HC-CDR2, HC-CDR3, wherein the HC-CDR1, HC-CDR2, HC-CDR3 comprise the amino acid sequence according to HC-CDR1: SEQ ID NO:35, HC-CDR2: SEQ ID NO:36 or SEQ ID NO:37, HC-CDR-3: SEQ ID NO:38, and the isolated antibody comprises a light chain variable (VL) domain comprising CDRs: LC-CDR1, LC-CDR2, LC-CDR3, wherein the LC-CDR1, LC-CDR2, LC-CDR3 comprise the amino acid sequence according to LC-CDR1: SEQ ID NO:39, LC-CDR2: SEQ ID NO:40, LC-CDR-3: SEQ ID NO:41.

[0311] Embodiment F2. The isolated antibody of Embodiment F1, wherein the VH of the first binding domain comprises an amino acid sequence having at least 80%, 85%, 90%, 95%, 98%, 99% or 100% sequence identity to SEQ ID NO:25 or SEQ ID NO:26.

[0312] Embodiment F3. The isolated antibody of Embodiment F1 or F2, wherein the VL of the first binding domain comprises an amino acid sequence having at least 80%, 85%, 90%, 95%, 98%, 99% or 100% sequence identity to SEQ ID NO:27 or SEQ ID NO:28.

[0313] Embodiment F4. The isolated antibody of any one of Embodiments F1-F3, wherein the VH of the first binding domain comprises an amino acid sequence having at least 80%, 85%, 90%, 95%, 98%, 99% or 100% sequence identity to SEQ ID NO: 25 or SEQ ID NO: 26, and wherein the VL of the first binding domain comprises an amino acid sequence having at least 80%, 85%, 90%, 95%, 98%, 99% or 100% sequence identity to SEQ ID NO: 27 or SEQ ID NO: 28.

[0314] Embodiment F5. The isolated antibody of any one of Embodiments F1-F4, wherein the first binding domain comprises a Fab, Fab', F(ab')2, or a single-chain variable fragment (scFv).

[0315] Embodiment F6. The isolated antibody of any one of Embodiments F1-F5, wherein the first binding domain is a Fab, Fab', F(ab')2, or a single-chain variable fragment (scFv).

[0316] Embodiment F7. The isolated antibody of Embodiment F5 or F6, wherein the first binding domain comprises the scFv.

[0317] Embodiment F8. The isolated antibody of any one of Embodiments F1-F7, wherein the VH of the first binding domain and the VL of the first binding domain are connected by a scFv linker sequence.

[0318] Embodiment F9. The isolated antibody of Embodiment F8, wherein the scFv linker sequence of the first binding domain comprises the amino acid sequence according to SEQ ID NO:29.

[0319] Embodiment F10. The isolated antibody of any one of Embodiments F1-F9, wherein the scFv of the first binding domain comprises an amino acid sequence having at least 80%, 85%, 90%, 95%, 98%, 99% or 100% sequence identity to SEQ ID NO:30 or SEQ ID NO:31.

[0320] Embodiment F11. The isolated antibody of any one of Embodiments F1-F6, wherein the first binding domain comprises a constant domain.

[0321] Embodiment F12. The isolated antibody of Embodiment F11, wherein the constant domain of the first binding domain comprises a human IgG4 sequence.

[0322] Embodiment F13. The isolated antibody of Embodiment F12, wherein the human IgG4 sequence of the first binding domain comprises an S228P point mutation, wherein amino acid numbering follows the EU index as in Kabat et al.

[0323] Embodiment F14. The isolated antibody of Embodiment F12 or F13, wherein the human IgG4 sequence of the first binding domain does not have a C-terminal lysine residue.

[0324] Embodiment F15. The isolated antibody of any one of Embodiments F11-F14, wherein the constant domain of the first binding domain comprises a human IgG1 sequence.

[0325] Embodiment F16. The isolated antibody of any one of Embodiments F11-F15, wherein the constant domain of the first binding domain comprises C H 1. C H 2. C H 3 or C L Amino acid sequence.

[0326] Embodiment F17. The isolated antibody of any one of Embodiments F1-F15, wherein the first binding domain comprises C H 1. C H 2. C H 3 and C L Amino acid sequence.

[0327] Embodiment F18. The isolated antibody of any one of Embodiments F1 to F17, wherein the first binding domain comprises an amino acid sequence that has at least 80%, 85%, 90%, 95%, 98%, 99% or 100% sequence identity to SEQ ID NO: 32, SEQ ID NO: 33, SEQ ID NO: 74 or SEQ ID NO: 75, and the isolated antibody comprises an amino acid sequence that has at least 80%, 85%, 90%, 95%, 98%, 99% or 100% sequence identity to SEQ ID NO: 34 or SEQ ID NO: 76.

[0328] Embodiment F19. An isolated antibody according to any one of Embodiments F1-F18, wherein the VH of the second binding domain comprises an amino acid sequence having at least 80%, 85%, 90%, 95%, 98%, 99% or 100% sequence identity to SEQ ID NO:42 or SEQ ID NO:43.

[0329] Embodiment F20. An isolated antibody according to any one of Embodiments F1-F19, wherein the VL of the second binding domain comprises an amino acid sequence having at least 80%, 85%, 90%, 95%, 98%, 99% or 100% sequence identity to SEQ ID NO:44.

[0330] Embodiment F21. An isolated antibody according to any one of Embodiments F1 to F20, wherein the VH of the second binding domain comprises an amino acid sequence having at least 80%, 85%, 90%, 95%, 98%, 99% or 100% sequence identity to SEQ ID NO:42 or SEQ ID NO:43, and wherein the VL of the second binding domain comprises an amino acid sequence having at least 80%, 85%, 90%, 95%, 98%, 99% or 100% sequence identity to SEQ ID NO:44.

[0331] Embodiment F22. The isolated antibody of any one of Embodiments F1-F21, wherein the second binding domain comprises a Fab, Fab', F(ab')2, or a single-chain variable fragment (scFv).

[0332] Embodiment F23. The isolated antibody of any one of Embodiments F1-F22, wherein the second binding domain is a Fab, Fab', F(ab')2, or a single-chain variable fragment (scFv).

[0333] Embodiment F24. The isolated antibody of Embodiment F22 or F23, wherein the second binding domain comprises the scFv.

[0334] Embodiment F25. The isolated antibody of any one of Embodiments F1-F24, wherein the VH of the second binding domain and the VL of the second binding domain are connected by a scFv linker sequence.

[0335] Embodiment F26. The isolated antibody of Embodiment F25, wherein the scFv linker sequence of the second binding domain comprises the amino acid sequence according to SEQ ID NO:45.

[0336] Embodiment F27. The isolated antibody of any one of Embodiments F1-F26, wherein the scFv of the second binding domain comprises an amino acid sequence having at least 80%, 85%, 90%, 95%, 98%, 99% or 100% sequence identity to SEQ ID NO:46 or SEQ ID NO:47.

[0337] Embodiment F28. The isolated antibody of any one of Embodiments F1-F23, wherein the second binding domain comprises a constant domain.

[0338] Embodiment F29. The isolated antibody of Embodiment F28, wherein the constant domain of the second binding domain comprises a human IgG4 sequence.

[0339] Embodiment F30. The isolated antibody of Embodiment F29, wherein the human IgG4 sequence of the second binding domain comprises an S228P point mutation, wherein the amino acid numbering follows the EU index in Kabat et al.

[0340] Embodiment F31. The isolated antibody of Embodiment F29 or F30, wherein the human IgG4 sequence of the second binding domain does not have a C-terminal lysine residue.

[0341] Embodiment F32. The isolated antibody of any one of Embodiments F28-F31, wherein the constant domain of the second binding domain comprises a human IgG1 sequence.

[0342] Embodiment F33. The isolated antibody of any one of Embodiments F28-F32, wherein the constant domain of the second binding domain comprises C H 1. C H 2. C H 3 or C L Amino acid sequence.

[0343] Embodiment F34. An isolated antibody according to any one of Embodiments F1-F32, wherein the second binding domain comprises C H 1. C H 2. C H 3 and C L Amino acid sequence.

[0344] Embodiment F35. The isolated antibody of any one of Embodiments F1-F34, wherein the second binding domain comprises an amino acid sequence that has at least 80%, 85%, 90%, 95%, 98%, 99% or 100% sequence identity to SEQ ID NO:48, SEQ ID NO:49, SEQ ID NO:77 or SEQ ID NO:78, and the isolated antibody comprises an amino acid sequence that has at least 80%, 85%, 90%, 95%, 98%, 99% or 100% sequence identity to SEQ ID NO:50.

[0345] Embodiment F36. An isolated antibody according to any one of Embodiments F1 to F35, wherein the first binding domain comprises the scFv and the second binding domain comprises C H 1. C H 2. C H 3 and C L Amino acid sequence.

[0346] Embodiment F37. The isolated antibody of any one of Embodiments F1-F35, wherein the second binding domain comprises the scFv and the first binding domain comprises C H 1. C H 2. C H 3 and C L Amino acid sequence.

[0347] Embodiment F38. The isolated antibody of any one of Embodiments F1-F37, wherein the first binding domain and the second binding domain are connected by a linking moiety.

[0348] Embodiment F39. The isolated antibody of Embodiment F38, wherein the linking moiety is an amino acid sequence.

[0349] Embodiment F40. The isolated antibody of Embodiment F38 or F39, wherein the linking moiety is at least 4 amino acids in length.

[0350] Embodiment F41. The isolated antibody of any one of Embodiments F38-F40, wherein the linking moiety is between 4-20 amino acids in length.

[0351] Embodiment F42. An isolated antibody according to any one of Embodiments F38-F41, wherein the linking moiety connects the C H 3 amino acid sequence connected to the scFv of the first binding domain.

[0352] Embodiment F43. The isolated antibody of any one of Embodiments F38-F42, wherein the linking moiety comprises the amino acid sequence of SEQ ID NO:51.

[0353] Embodiment F44. The isolated antibody of any one of Embodiments F1-F43, wherein the isolated antibody comprises an amino acid sequence having at least 80%, 85%, 90%, 95%, 98%, 99% or 100% sequence identity to SEQ ID NO:61 and an amino acid sequence having at least 80%, 85%, 90%, 95%, 98%, 99% or 100% sequence identity to SEQ ID NO:60.

[0354] Embodiment F45. The isolated antibody of any one of Embodiments F1-F43, wherein the isolated antibody comprises an amino acid sequence having at least 80%, 85%, 90%, 95%, 98%, 99% or 100% sequence identity to SEQ ID NO: 63 and an amino acid sequence having at least 80%, 85%, 90%, 95%, 98%, 99% or 100% sequence identity to SEQ ID NO: 62.

[0355] Embodiment F46. An isolated recombinant nucleic acid sequence encoding the amino acid sequence of the isolated antibody according to any one of Embodiments F1-F45.

[0356] Embodiment F47. A vector comprising the isolated recombinant nucleic acid sequence according to embodiment F46.

[0357] Embodiment F48. A pharmaceutical composition comprising: (a) the isolated antibody of any one of Embodiments F1-F47; and (b) a pharmaceutically acceptable excipient.

[0358] Embodiment F49. A method of treating food allergy in a subject in need thereof, comprising administering to the subject the isolated antibody of any one of Embodiments F1-F47.

[0359] Embodiment F50. The method of embodiment F49, wherein the food allergy comprises peanut allergy.

[0360] Embodiment G1. A composition comprising a first binding domain that binds to Ara h 2 and Ara h 6, wherein the first binding domain comprises a heavy chain variable domain (VH) comprising complementarity determining regions (CDRs): HC-CDR1, HC-CDR2, HC-CDR3, wherein the HC-CDR1, HC-CDR2, HC-CDR3 comprise the amino acid sequence according to HC-CDR1: SEQ ID NO: 1, HC-CDR2: SEQ ID NO: 2 or SEQ ID NO: 3, HC-CDR-3: SEQ ID NO: 4 or SEQ ID NO: 5, and the first binding domain comprises a light chain variable (VL) domain comprising CDRs: LC-CDR1, LC-CDR2, LC-CDR3, wherein the LC-CDR1, LC-CDR2, LC-CDR3 comprise the amino acid sequence according to LC-CDR1: SEQ ID NO: 6, LC-CDR2: SEQ ID NO: 7, LC-CDR-3: SEQ ID NO: 8, wherein the composition comprises a heavy chain variable domain (VH) comprising complementarity determining regions (CDRs): HC-CDR1, HC-CDR2, HC-CDR3, wherein the HC-CDR1, HC-CDR2, HC-CDR3 comprise the amino acid sequence according to LC-CDR1: SEQ ID NO: 6, LC-CDR2: SEQ ID NO: 7, LC-CDR-3: SEQ ID NO: 8, wherein the composition comprises a heavy chain variable domain (VL) comprising CDRs: LC-CDR1, LC-CDR2, LC-CDR3 2 and Ara h 6, wherein the second binding domain comprises a VH comprising CDRs: HC-CDR1, HC-CDR2, HC-CDR3, wherein the HC-CDR1, HC-CDR2, HC-CDR3 comprise the amino acid sequence according to HC-CDR1: SEQ ID NO: 18, HC-CDR2: SEQ ID NO: 19, HC-CDR-3: SEQ ID NO: 20 or SEQ ID NO: 21, and the second binding domain comprises a light chain variable (VL) domain comprising CDRs: LC-CDR1, LC-CDR2, LC-CDR3, wherein the LC-CDR1, LC-CDR2, LC-CDR3 comprise the amino acid sequence according to LC-CDR1: SEQ ID NO: 22, LC-CDR2: SEQ ID NO: 23, LC-CDR-3: SEQ ID NO: 24, and wherein the composition comprises a VH comprising CDRs: HC-CDR1, HC-CDR2, HC-CDR3, wherein the VH comprising CDRs: LC-CDR1, LC-CDR2, LC-CDR3 2, wherein the third binding domain comprises a VH comprising CDRs: HC-CDR1, HC-CDR2, HC-CDR3, wherein the HC-CDR1, HC-CDR2, HC-CDR3 comprise the amino acid sequence according to HC-CDR1: SEQ ID NO: 35, HC-CDR2: SEQ ID NO: 36 or SEQ ID NO: 37, HC-CDR3: SEQ ID NO: 38, and the third binding domain comprises a light chain variable (VL) domain comprising CDRs: LC-CDR1, LC-CDR2, LC-CDR3,wherein the LC-CDR1, LC-CDR2, and LC-CDR3 comprise the amino acid sequences of LC-CDR1: SEQ ID NO: 39, LC-CDR2: SEQ ID NO: 40, and LC-CDR-3: SEQ ID NO: 41.

[0361] Embodiment G2. A composition according to embodiment G1, wherein the VH of the first binding domain comprises an amino acid sequence having at least 80%, 85%, 90%, 95%, 98%, 99% or 100% sequence identity to SEQ ID NO:9 or SEQ ID NO:10.

[0362] Embodiment G3. A composition according to embodiment G1 or G2, wherein the VL of the first binding domain comprises an amino acid sequence having at least 80%, 85%, 90%, 95%, 98%, 99% or 100% sequence identity to SEQ ID NO: 11.

[0363] Embodiment G4. A composition according to any of embodiments G1-G3, wherein the VH of the first binding domain comprises an amino acid sequence having at least 80%, 85%, 90%, 95%, 98%, 99% or 100% sequence identity to SEQ ID NO:9 or SEQ ID NO:10, and wherein the VL of the first binding domain comprises an amino acid sequence having at least 80%, 85%, 90%, 95%, 98%, 99% or 100% sequence identity to SEQ ID NO:11.

[0364] Embodiment G5. The composition of any one of Embodiments G1-G4, wherein the first binding domain comprises a Fab, a Fab', a F(ab')2, or a single-chain variable fragment (scFv).

[0365] Embodiment G6. A composition according to any one of Embodiments G1-G5, wherein the first binding domain is a Fab, Fab', F(ab')2, or a single-chain variable fragment (scFv).

[0366] Embodiment G7. A composition according to Embodiment G5 or G6, wherein the first binding domain comprises the scFv.

[0367] Embodiment G8. A composition according to any one of embodiments G1-G7, wherein the VH of the first binding domain and the VL of the first binding domain are connected by a scFv linker sequence.

[0368] Embodiment G9. A composition according to embodiment G8, wherein the scFv linker sequence of the first binding domain comprises an amino acid sequence according to SEQ ID No:12.

[0369] Embodiment G10. A composition according to any of Embodiments G5-G9, wherein the scFv of the first binding domain comprises an amino acid sequence having at least 80%, 85%, 90%, 95%, 98%, 99% or 100% sequence identity to SEQ ID NO: 13 or SEQ ID NO: 14.

[0370] Embodiment G11. The composition of any one of Embodiments G1-G6, wherein the first binding domain comprises a constant domain.

[0371] Embodiment G12. A composition according to Embodiment G11, wherein the constant domain of the first binding domain comprises a human IgG4 sequence.

[0372] Embodiment G13. A composition according to Embodiment G12, wherein the human IgG4 sequence of the first binding domain comprises an S228P point mutation, wherein the amino acid numbering follows the EU index in Kabat et al.

[0373] Embodiment G14. A composition according to Embodiment G12 or G13, wherein the human IgG4 sequence of the first binding domain does not have a C-terminal lysine residue.

[0374] Embodiment G15. A composition according to any one of Embodiments G11-G14, wherein the constant domain of the first binding domain comprises a human IgG1 sequence.

[0375] Embodiment G16. A composition according to any one of Embodiments G11 to G15, wherein the constant domain of the first binding domain comprises C H 1. C H 2. C H 3 or C L Amino acid sequence.

[0376] Embodiment G17. A composition according to any one of Embodiments G1-G15, wherein the first binding domain comprises C H 1. C H 2. C H 3 and C L Amino acid sequence.

[0377] Embodiment G18. A composition according to any of embodiments G1-G17, wherein the first binding domain comprises an amino acid sequence having at least 80%, 85%, 90%, 95%, 98%, 99% or 100% sequence identity to SEQ ID NO: 15, SEQ ID NO: 16, SEQ ID NO: 72 or SEQ ID NO: 73, and the first binding domain comprises an amino acid sequence having at least 80%, 85%, 90%, 95%, 98%, 99% or 100% sequence identity to SEQ ID NO: 17.

[0378] Embodiment G19. A composition according to any of Embodiments G1-G18, wherein the VH of the second binding domain comprises an amino acid sequence having at least 80%, 85%, 90%, 95%, 98%, 99% or 100% sequence identity to SEQ ID NO:25 or SEQ ID NO:26.

[0379] Embodiment G20. A composition according to any of embodiments G1-G19, wherein the VL of the second binding domain comprises an amino acid sequence having at least 80%, 85%, 90%, 95%, 98%, 99% or 100% sequence identity to SEQ ID NO:27 or SEQ ID NO:28.

[0380] Embodiment G21. A composition according to any of embodiments G1-G20, wherein the VH of the second binding domain comprises an amino acid sequence having at least 80%, 85%, 90%, 95%, 98%, 99% or 100% sequence identity to SEQ ID NO:25 or SEQ ID NO:26, and wherein the VL of the second binding domain comprises an amino acid sequence having at least 80%, 85%, 90%, 95%, 98%, 99% or 100% sequence identity to SEQ ID NO:27 or SEQ ID NO:28.

[0381] Embodiment G22. The composition of any one of Embodiments G1-G21, wherein the second binding domain comprises a Fab, a Fab', a F(ab')2, or a single-chain variable fragment (scFv).

[0382] Embodiment G23. A composition according to any one of Embodiments G1-G22, wherein the second binding domain is a Fab, Fab', F(ab')2, or a single chain variable fragment (scFv).

[0383] Embodiment G24. A composition according to Embodiment G22 or G23, wherein the second binding domain comprises the scFv.

[0384] Embodiment G25. A composition according to any one of Embodiments G1-G24, wherein the VH of the second binding domain and the VL of the second binding domain are connected by a scFv linker sequence.

[0385] Embodiment G26. A composition according to Embodiment G25, wherein the scFv linker sequence of the second binding domain comprises an amino acid sequence according to SEQ ID NO:29.

[0386] Embodiment G27. A composition according to any of Embodiments G22-G26, wherein the scFv of the second binding domain comprises an amino acid sequence having at least 80%, 85%, 90%, 95%, 98%, 99% or 100% sequence identity to SEQ ID NO:30 or SEQ ID NO:31.

[0387] Embodiment G28. The composition of any one of Embodiments G1-G23, wherein the second binding domain comprises a constant domain.

[0388] Embodiment G29. A composition according to Embodiment G28, wherein the constant domain of the second binding domain comprises a human IgG4 sequence.

[0389] Embodiment G30. A composition according to Embodiment G29, wherein the human IgG4 sequence of the second binding domain comprises an S228P point mutation, wherein the amino acid numbering follows the EU index in Kabat et al.

[0390] Embodiment G31. A composition according to embodiment G29 or G30, wherein the human IgG4 sequence of the second binding domain does not have a C-terminal lysine residue.

[0391] Embodiment G32. A composition according to any one of Embodiments G28-G31, wherein the constant domain of the second binding domain comprises a human IgG1 sequence.

[0392] Embodiment G33. A composition according to any one of Embodiments G28-G32, wherein the constant domain of the second binding domain comprises C H 1. C H 2. C H 3 or C L Amino acid sequence.

[0393] Embodiment G34. A composition according to any one of Embodiments G1-G32, wherein the second binding domain comprises C H 1. C H 2. C H3 and C L Amino acid sequence.

[0394] Embodiment G35. A composition according to any of Embodiments G1-G34, wherein the second binding domain comprises an amino acid sequence having at least 80%, 85%, 90%, 95%, 98%, 99% or 100% sequence identity to SEQ ID NO:32, SEQ ID NO:33, SEQ ID NO:74 or SEQ ID NO:75, and the isolated antibody comprises an amino acid sequence having at least 80%, 85%, 90%, 95%, 98%, 99% or 100% sequence identity to SEQ ID NO:34 or SEQ ID NO:76.

[0395] Embodiment G36. A composition according to any of Embodiments G1-G35, wherein the VH of the third binding domain comprises an amino acid sequence having at least 80%, 85%, 90%, 95%, 98%, 99% or 100% sequence identity to SEQ ID NO:42 or SEQ ID NO:43.

[0396] Embodiment G37. A composition according to any of Embodiments G1-G36, wherein the VL of the third binding domain comprises an amino acid sequence having at least 80%, 85%, 90%, 95%, 98%, 99% or 100% sequence identity to SEQ ID NO:44.

[0397] Embodiment G38. A composition according to any of embodiments G1-G37, wherein the VH of the third binding domain comprises an amino acid sequence having at least 80%, 85%, 90%, 95%, 98%, 99% or 100% sequence identity to SEQ ID NO:42 or SEQ ID NO:43, and wherein the VL of the third binding domain comprises an amino acid sequence having at least 80%, 85%, 90%, 95%, 98%, 99% or 100% sequence identity to SEQ ID NO:44.

[0398] Embodiment G39. A composition according to any one of Embodiments G1-G38, wherein the third binding domain comprises a Fab, a Fab', a F(ab')2, or a single-chain variable fragment (scFv).

[0399] Embodiment G40. A composition according to any one of Embodiments G1-G39, wherein the third binding domain is a Fab, Fab', F(ab')2, or a single-chain variable fragment (scFv).

[0400] Embodiment G41. A composition according to Embodiment G39 or G40, wherein the third binding domain comprises the scFv.

[0401] Embodiment G42. A composition according to any one of Embodiments G1-G41, wherein the VH of the third binding domain and the VL of the third binding domain are connected by a scFv linker sequence.

[0402] Embodiment G43. A composition according to Embodiment G42, wherein the scFv linker sequence of the third binding domain comprises an amino acid sequence according to SEQ ID NO:45.

[0403] Embodiment G44. A composition according to any of Embodiments G39-G43, wherein the scFv of the third binding domain comprises an amino acid sequence having at least 80%, 85%, 90%, 95%, 98%, 99% or 100% sequence identity to SEQ ID NO:46 or SEQ ID NO:47.

[0404] Embodiment G45. A composition according to any of Embodiments G1-G40, wherein the third binding domain comprises a constant domain.

[0405] Embodiment G46. A composition according to Embodiment G45, wherein the constant domain of the third binding domain comprises a human IgG4 sequence.

[0406] Embodiment G47. A composition according to Embodiment G46, wherein the human IgG4 sequence of the third binding domain comprises an S228P point mutation, wherein the amino acid numbering follows the EU index in Kabat et al.

[0407] Embodiment G48. A composition according to Embodiment G46 or G47, wherein the human IgG4 sequence of the third binding domain does not have a C-terminal lysine residue.

[0408] Embodiment G49. A composition according to any one of Embodiments G45-G48, wherein the constant domain of the third binding domain comprises a human IgG1 sequence.

[0409] Embodiment G50. A composition according to any one of Embodiments G45-G49, wherein the constant domain of the third binding domain comprises C H 1. C H 2. C H 3 or C L Amino acid sequence.

[0410] Embodiment G51. A composition according to any one of Embodiments G1-G49, wherein the third binding domain comprises C H 1. C H 2. C H 3 and C L Amino acid sequence.

[0411] Embodiment G52. A composition according to any of Embodiments G1-G51, wherein the third binding domain comprises an amino acid sequence having at least 80%, 85%, 90%, 95%, 98%, 99% or 100% sequence identity to SEQ ID NO:48, SEQ ID NO:49, SEQ ID NO:77 or SEQ ID NO:78, and the isolated antibody comprises an amino acid sequence having at least 80%, 85%, 90%, 95%, 98%, 99% or 100% sequence identity to SEQ ID NO:50.

[0412] Embodiment G53. A composition according to any one of Embodiments G1-G52, wherein the first binding domain, the second binding domain, and the third binding domain are linked within the same molecule.

[0413] Embodiment G54. The composition of any one of Embodiments G1-G52, wherein the first binding domain, the second binding domain, and the third binding domain are separate molecules.

[0414] Embodiment G55. A composition according to any of embodiments G1-G52, wherein the first binding domain and the second binding domain are in the same molecule and the third binding domain belongs to a molecule separate from the molecule having the first binding domain and the second binding domain.

[0415] Embodiment G56. A composition according to any of embodiments G1-G52, wherein the first binding domain and the third binding domain are in the same molecule and the second binding domain belongs to a molecule separate from the molecule having the first binding domain and the third binding domain.

[0416] Embodiment G57. A composition according to any of embodiments G1-G52, wherein the second binding domain and the third binding domain are in the same molecule and the first binding domain belongs to a molecule separate from the molecule having the second binding domain and the third binding domain.

[0417] Embodiment G58. A composition according to any one of Embodiments G5-G57, wherein the first binding domain comprises the scFv and the second binding domain comprises C H 1. C H 2. CH 3 and C L Amino acid sequence.

[0418] Embodiment G59. A composition according to any one of Embodiments G22-G58, wherein the second binding domain comprises the scFv and the first binding domain comprises C H 1. C H 2. C H 3 and C L Amino acid sequence.

[0419] Embodiment G60. A composition according to any of Embodiments G1-G59, wherein the first binding domain and the second binding domain are connected by a linking moiety.

[0420] Embodiment G61. A composition according to embodiment G60, wherein the linking moiety is an amino acid sequence.

[0421] Embodiment G62. A composition according to embodiment G60 or G61, wherein the linking portion is at least 4 amino acids in length.

[0422] Embodiment G63. A composition according to any one of embodiments G60-G62, wherein the length of the linking portion is between 4-20 amino acids.

[0423] Embodiment G64. A composition according to any one of embodiments G60-G63, wherein the linking moiety connects the C H 3 amino acid sequence connected to the scFv of the first binding domain.

[0424] Embodiment G65. A composition according to any one of embodiments G60-G64, wherein the linking moiety comprises the amino acid sequence of SEQ ID NO:51.

[0425] Embodiment G66. A composition according to any of embodiments G1-G65, wherein the first binding domain and the second binding domain comprise an amino acid sequence having at least 80%, 85%, 90%, 95%, 98%, 99% or 100% sequence identity to SEQ ID NO:53 and an amino acid sequence having at least 80%, 85%, 90%, 95%, 98%, 99% or 100% sequence identity to SEQ ID NO:52, and wherein the third binding domain comprises an amino acid sequence having at least 80%, 85%, 90%, 95%, 98%, 99% or 100% sequence identity to SEQ ID NO:48, SEQ ID NO:49, SEQ ID NO:77 or SEQ ID NO:78, and the third binding domain comprises an amino acid sequence having at least 80%, 85%, 90%, 95%, 98%, 99% or 100% sequence identity to SEQ ID NO:50.

[0426] Embodiment G67. A composition according to any of embodiments G1-G65, wherein the first binding domain and the second binding domain comprise an amino acid sequence having at least 80%, 85%, 90%, 95%, 98%, 99% or 100% sequence identity to SEQ ID NO:55 and an amino acid sequence having at least 80%, 85%, 90%, 95%, 98%, 99% or 100% sequence identity to SEQ ID NO:54, and wherein the third binding domain comprises an amino acid sequence having at least 80%, 85%, 90%, 95%, 98%, 99% or 100% sequence identity to SEQ ID NO:48, SEQ ID NO:49, SEQ ID NO:77 or SEQ ID NO:78, and the third binding domain comprises an amino acid sequence having at least 80%, 85%, 90%, 95%, 98%, 99% or 100% sequence identity to SEQ ID NO:50.

[0427] Embodiment G68. A composition according to any of embodiments G1-G65, wherein the first binding domain and the second binding domain comprise an amino acid sequence having at least 80%, 85%, 90%, 95%, 98%, 99% or 100% sequence identity to SEQ ID NO:65 and an amino acid sequence having at least 80%, 85%, 90%, 95%, 98%, 99% or 100% sequence identity to SEQ ID NO:64, and wherein the third binding domain comprises an amino acid sequence having at least 80%, 85%, 90%, 95%, 98%, 99% or 100% sequence identity to SEQ ID NO:48, SEQ ID NO:49, SEQ ID NO:77 or SEQ ID NO:78, and the third binding domain comprises an amino acid sequence having at least 80%, 85%, 90%, 95%, 98%, 99% or 100% sequence identity to SEQ ID NO:50.

[0428] Embodiment G69. A composition according to any of embodiments G1-G65, wherein the first binding domain and the second binding domain comprise an amino acid sequence having at least 80%, 85%, 90%, 95%, 98%, 99% or 100% sequence identity to SEQ ID NO:67 and an amino acid sequence having at least 80%, 85%, 90%, 95%, 98%, 99% or 100% sequence identity to SEQ ID NO:66, and wherein the third binding domain comprises an amino acid sequence having at least 80%, 85%, 90%, 95%, 98%, 99% or 100% sequence identity to SEQ ID NO:48, SEQ ID NO:49, SEQ ID NO:77 or SEQ ID NO:78, and the third binding domain comprises an amino acid sequence having at least 80%, 85%, 90%, 95%, 98%, 99% or 100% sequence identity to SEQ ID NO:50.

[0429] Embodiment G70. A composition according to any of embodiments G1-G65, wherein the first binding domain and the second binding domain comprise an amino acid sequence having at least 80%, 85%, 90%, 95%, 98%, 99% or 100% sequence identity to SEQ ID NO:69 and an amino acid sequence having at least 80%, 85%, 90%, 95%, 98%, 99% or 100% sequence identity to SEQ ID NO:68, and wherein the third binding domain comprises an amino acid sequence having at least 80%, 85%, 90%, 95%, 98%, 99% or 100% sequence identity to SEQ ID NO:48, SEQ ID NO:49, SEQ ID NO:77 or SEQ ID NO:78, and the third binding domain comprises an amino acid sequence having at least 80%, 85%, 90%, 95%, 98%, 99% or 100% sequence identity to SEQ ID NO:50.

[0430] Embodiment G71. A composition according to any of embodiments G1-G65, wherein the first binding domain and the second binding domain comprise an amino acid sequence having at least 80%, 85%, 90%, 95%, 98%, 99% or 100% sequence identity to SEQ ID NO:71 and an amino acid sequence having at least 80%, 85%, 90%, 95%, 98%, 99% or 100% sequence identity to SEQ ID NO:70, and wherein the third binding domain comprises an amino acid sequence having at least 80%, 85%, 90%, 95%, 98%, 99% or 100% sequence identity to SEQ ID NO:48, SEQ ID NO:49, SEQ ID NO:77 or SEQ ID NO:78, and the third binding domain comprises an amino acid sequence having at least 80%, 85%, 90%, 95%, 98%, 99% or 100% sequence identity to SEQ ID NO:50.

[0431] Embodiment G72. A composition according to any one of Embodiments G1-G71, wherein the composition comprises a pharmaceutically acceptable excipient.

[0432] Embodiment G73. An isolated recombinant nucleic acid sequence encoding the amino acid sequence of the composition of any one of Embodiments G1-G71.

[0433] Embodiment G74. A vector comprising the isolated recombinant nucleic acid sequence according to embodiment G73.

[0434] Embodiment G75. A kit comprising at least one of: (a) a composition according to any one of embodiments G1-G72; (b) a vector according to embodiment G74; or (b) a nucleic acid molecule according to embodiment G73.

[0435] Embodiment G76. A method of treating food allergy in a subject in need thereof, comprising administering to the subject a composition according to any one of Embodiments G1-G72.

[0436] Embodiment G77. The method of embodiment G76, wherein the food allergy comprises peanut allergy.

[0437] Embodiment H1. A composition comprising a first molecule comprising a first binding domain that binds to Ara h 2 and Ara h 6 and a second binding domain that binds to Ara h 2 and Ara h 6, wherein the first binding domain comprises an scFv, and the second binding domain comprises a heavy chain variable domain, a light chain variable domain, and a constant domain, and the scFv of the first binding domain and the constant domain of the second binding domain are linked by a linker, and the composition comprises a second molecule comprising a third binding domain that binds to Ara h 2.

[0438] Embodiment H2. A composition according to embodiment H1, wherein the first binding domain comprises a heavy chain variable domain (VH) comprising complementarity determining regions (CDRs): HC-CDR1, HC-CDR2, HC-CDR3, wherein the HC-CDR1, HC-CDR2, HC-CDR3 comprise an amino acid sequence according to HC-CDR1: SEQ ID NO: 1, HC-CDR2: SEQ ID NO: 2 or SEQ ID NO: 3, HC-CDR-3: SEQ ID NO: 4 or SEQ ID NO: 5, and the first binding domain comprises a light chain variable (VL) domain comprising CDRs: LC-CDR1, LC-CDR2, LC-CDR3, wherein the LC-CDR1, LC-CDR2, LC-CDR3 comprise an amino acid sequence according to LC-CDR1: SEQ ID NO: 6, LC-CDR2: SEQ ID NO: 7, LC-CDR-3: SEQ ID NO: 8. NO:8, wherein the second binding domain comprises a VH comprising CDRs: HC-CDR1, HC-CDR2, HC-CDR3, wherein the HC-CDR1, HC-CDR2, HC-CDR3 comprise the amino acid sequence according to HC-CDR1: SEQ ID NO:18, HC-CDR2: SEQ ID NO:19, HC-CDR-3: SEQ ID NO:20 or SEQ ID NO:21, and the second binding domain comprises a light chain variable (VL) domain comprising CDRs: LC-CDR1, LC-CDR2, LC-CDR3, wherein the LC-CDR1, LC-CDR2, LC-CDR3 comprise the amino acid sequence according to LC-CDR1: SEQ ID NO:22, LC-CDR2: SEQ ID NO:23, LC-CDR-3: SEQ ID NO:24. NO:24, and wherein the third binding domain comprises a VH comprising CDRs: HC-CDR1, HC-CDR2, HC-CDR3, wherein the HC-CDR1, HC-CDR2, HC-CDR3 comprise the amino acid sequence according to HC-CDR1: SEQ ID NO:35, HC-CDR2: SEQ ID NO:36 or SEQ ID NO:37, HC-CDR-3: SEQ ID NO:38, and the third binding domain comprises a light chain variable (VL) domain comprising CDRs: LC-CDR1, LC-CDR2, LC-CDR3, wherein the LC-CDR1, LC-CDR2, LC-CDR3 comprise the amino acid sequence according to LC-CDR1: SEQ ID NO:39, LC-CDR2: SEQ ID NO:40, LC-CDR-3: SEQ ID NO:41.

[0439] Embodiment H3. A composition according to embodiment H2, wherein the VH of the first binding domain comprises an amino acid sequence having at least 80%, 85%, 90%, 95%, 98%, 99% or 100% sequence identity to SEQ ID NO:9 or SEQ ID NO:10.

[0440] Embodiment H4. A composition according to any of Embodiments H2 or H3, wherein the VL of the first binding domain comprises an amino acid sequence having at least 80%, 85%, 90%, 95%, 98%, 99% or 100% sequence identity to SEQ ID NO: 11.

[0441] Embodiment H5. A composition according to any of embodiments H2-H4, wherein the VH of the first binding domain comprises an amino acid sequence having at least 80%, 85%, 90%, 95%, 98%, 99% or 100% sequence identity to SEQ ID NO:9 or SEQ ID NO:10, and wherein the VL of the first binding domain comprises an amino acid sequence having at least 80%, 85%, 90%, 95%, 98%, 99% or 100% sequence identity to SEQ ID NO:11.

[0442] Embodiment H6. A composition according to any one of embodiments H2-H5, wherein the VH of the first binding domain and the VL of the first binding domain are connected by a scFv linker sequence.

[0443] Embodiment H7. A composition according to embodiment H6, wherein the scFv linker sequence of the first binding domain comprises an amino acid sequence according to SEQ ID No: 12.

[0444] Embodiment H8. A composition according to any of Embodiments H1-H7, wherein the scFv of the first binding domain comprises an amino acid sequence having at least 80%, 85%, 90%, 95%, 98%, 99% or 100% sequence identity to SEQ ID NO: 13 or SEQ ID NO: 14.

[0445] Embodiment H9. A composition according to any one of embodiments H2-H8, wherein the VH of the second binding domain comprises an amino acid sequence having at least 80%, 85%, 90%, 95%, 98%, 99% or 100% sequence identity to SEQ ID NO:25 or SEQ ID NO:26.

[0446] Embodiment H10. A composition according to any one of embodiments H2-H9, wherein the VL of the second binding domain comprises an amino acid sequence having at least 80%, 85%, 90%, 95%, 98%, 99% or 100% sequence identity to SEQ ID NO:27 or SEQ ID NO:28.

[0447] Embodiment H11. A composition according to any of embodiments H1-H10, wherein the VH of the second binding domain comprises an amino acid sequence having at least 80%, 85%, 90%, 95%, 98%, 99% or 100% sequence identity to SEQ ID NO:25 or SEQ ID NO:26, and wherein the VL of the second binding domain comprises an amino acid sequence having at least 80%, 85%, 90%, 95%, 98%, 99% or 100% sequence identity to SEQ ID NO:27 or SEQ ID NO:28.

[0448] Embodiment H12. The composition of any one of Embodiments H1-H11, wherein the second binding domain comprises a Fab, Fab', or F(ab')2.

[0449] Embodiment H13. The composition of any one of Embodiments H1-H12, wherein the second binding domain is Fab, Fab', or F(ab')2.

[0450] Embodiment H14. A composition according to any one of Embodiments H1-H13, wherein the constant domain of the second binding domain comprises a human IgG4 sequence.

[0451] Embodiment H15. A composition according to embodiment H14, wherein the human IgG4 sequence of the second binding domain comprises an S228P point mutation, wherein the amino acid numbering follows the EU index in Kabat et al.

[0452] Embodiment H16. A composition according to Embodiment H14 or H15, wherein the human IgG4 sequence of the second binding domain does not have a C-terminal lysine residue.

[0453] Embodiment H17. The composition of any one of Embodiments H1-H16, wherein the constant domain of the second binding domain comprises a human IgG1 sequence.

[0454] Embodiment H18. A composition according to any one of Embodiments H1 to H17, wherein the constant domain of the second binding domain comprises C H 1. C H 2. C H 3 or CL Amino acid sequence.

[0455] Embodiment H19. A composition according to any one of Embodiments H1-H18, wherein the second binding domain comprises C H 1. C H 2. C H 3 and C L Amino acid sequence.

[0456] Embodiment H20. A composition according to any one of Embodiments H1-H19, wherein the second binding domain comprises an amino acid sequence having at least 80%, 85%, 90%, 95%, 98%, 99% or 100% sequence identity to SEQ ID NO:32, SEQ ID NO:33, SEQ ID NO:74 or SEQ ID NO:75, and the isolated antibody comprises an amino acid sequence having at least 80%, 85%, 90%, 95%, 98%, 99% or 100% sequence identity to SEQ ID NO:34 or SEQ ID NO:76.

[0457] Embodiment H21. A composition according to any of Embodiments H2-H20, wherein the VH of the third binding domain comprises an amino acid sequence having at least 80%, 85%, 90%, 95%, 98%, 99% or 100% sequence identity to SEQ ID NO:42 or SEQ ID NO:43.

[0458] Embodiment H22. A composition according to any of Embodiments H2-H21, wherein the VL of the third binding domain comprises an amino acid sequence having at least 80%, 85%, 90%, 95%, 98%, 99% or 100% sequence identity to SEQ ID NO:44.

[0459] Embodiment H23. A composition according to any of Embodiments H2-H22, wherein the VH of the third binding domain comprises an amino acid sequence having at least 80%, 85%, 90%, 95%, 98%, 99% or 100% sequence identity to SEQ ID NO:42 or SEQ ID NO:43, and wherein the VL of the third binding domain comprises an amino acid sequence having at least 80%, 85%, 90%, 95%, 98%, 99% or 100% sequence identity to SEQ ID NO:44.

[0460] Embodiment H24. A composition according to any one of Embodiments H1 to H23, wherein the third binding domain comprises a Fab, a Fab', a F(ab')2, or a single-chain variable fragment (scFv).

[0461] Embodiment H25. A composition according to any one of Embodiments H1 to H24, wherein the third binding domain is a Fab, Fab', F(ab')2, or a single-chain variable fragment (scFv).

[0462] Embodiment H26. A composition according to Embodiment H24 or H25, wherein the third binding domain comprises the scFv.

[0463] Embodiment H27. A composition according to any one of Embodiments H2-H26, wherein the VH of the third binding domain and the VL of the third binding domain are connected by a scFv linker sequence.

[0464] Embodiment H28. A composition according to Embodiment H27, wherein the scFv linker sequence of the third binding domain comprises an amino acid sequence according to SEQ ID NO:45.

[0465] Embodiment H29. A composition according to embodiment H26, wherein the scFv of the third binding domain comprises an amino acid sequence having at least 80%, 85%, 90%, 95%, 98%, 99% or 100% sequence identity to SEQ ID NO:46 or SEQ ID NO:47.

[0466] Embodiment H30. A composition according to any of Embodiments H1-H25, wherein the third binding domain comprises a constant domain.

[0467] Embodiment H31. A composition according to Embodiment H30, wherein the constant domain of the third binding domain comprises a human IgG4 sequence.

[0468] Embodiment H32. A composition according to Embodiment H31, wherein the human IgG4 sequence of the third binding domain comprises an S228P point mutation, wherein the amino acid numbering follows the EU index in Kabat et al.

[0469] Embodiment H33. A composition according to Embodiment H31 or H32, wherein the human IgG4 sequence of the third binding domain does not have a C-terminal lysine residue.

[0470] Embodiment H34. A composition according to any one of Embodiments H30-H33, wherein the constant domain of the third binding domain comprises a human IgG1 sequence.

[0471] Embodiment H35. A composition according to any one of Embodiments H30-H34, wherein the constant domain of the third binding domain comprises C H 1. CH 2. C H 3 or C L Amino acid sequence.

[0472] Embodiment H36. A composition according to any one of Embodiments H1-H35, wherein the third binding domain comprises C H 1. C H 2. C H 3 and C L Amino acid sequence.

[0473] Embodiment H37. A composition according to any of Embodiments H1-H36, wherein the third binding domain comprises an amino acid sequence having at least 80%, 85%, 90%, 95%, 98%, 99% or 100% sequence identity to SEQ ID NO:48, SEQ ID NO:49, SEQ ID NO:77 or SEQ ID NO:78, and the isolated antibody comprises an amino acid sequence having at least 80%, 85%, 90%, 95%, 98%, 99% or 100% sequence identity to SEQ ID NO:50.

[0474] Embodiment H38. A composition according to any of Embodiments H1-H37, wherein the first binding domain and the second binding domain are connected by a linking moiety.

[0475] Embodiment H39. A composition according to embodiment H38, wherein the linking portion is an amino acid sequence.

[0476] Embodiment H40. A composition according to embodiment H38 or H39, wherein the linking portion is at least 4 amino acids in length.

[0477] Embodiment H41. A composition according to any one of Embodiments H38-H40, wherein the length of the linking portion is between 4-20 amino acids.

[0478] Embodiment H42. A composition according to any one of Embodiments H38-H41, wherein the linking moiety connects the C H 3 amino acid sequence connected to the scFv of the first binding domain.

[0479] Embodiment H43. A composition according to any one of Embodiments H38-H42, wherein the linking moiety comprises the amino acid sequence of SEQ ID NO:51.

[0480] Embodiment H44. A composition according to any of embodiments H1 to H43, wherein the first binding domain and the second binding domain comprise an amino acid sequence having at least 80%, 85%, 90%, 95%, 98%, 99% or 100% sequence identity to SEQ ID NO:53 and an amino acid sequence having at least 80%, 85%, 90%, 95%, 98%, 99% or 100% sequence identity to SEQ ID NO:52, and wherein the third binding domain comprises an amino acid sequence having at least 80%, 85%, 90%, 95%, 98%, 99% or 100% sequence identity to SEQ ID NO:48, SEQ ID NO:49, SEQ ID NO:77 or SEQ ID NO:78, and the third binding domain comprises an amino acid sequence having at least 80%, 85%, 90%, 95%, 98%, 99% or 100% sequence identity to SEQ ID NO:50.

[0481] Embodiment H45. A composition according to any of embodiments H1 to H43, wherein the first binding domain and the second binding domain comprise an amino acid sequence having at least 80%, 85%, 90%, 95%, 98%, 99% or 100% sequence identity to SEQ ID NO:65 and an amino acid sequence having at least 80%, 85%, 90%, 95%, 98%, 99% or 100% sequence identity to SEQ ID NO:64, and wherein the third binding domain comprises an amino acid sequence having at least 80%, 85%, 90%, 95%, 98%, 99% or 100% sequence identity to SEQ ID NO:48, SEQ ID NO:49, SEQ ID NO:77 or SEQ ID NO:78, and the third binding domain comprises an amino acid sequence having at least 80%, 85%, 90%, 95%, 98%, 99% or 100% sequence identity to SEQ ID NO:50.

[0482] Embodiment H46. A composition according to any of embodiments H1 to H43, wherein the first binding domain and the second binding domain comprise an amino acid sequence having at least 80%, 85%, 90%, 95%, 98%, 99% or 100% sequence identity to SEQ ID NO:67 and an amino acid sequence having at least 80%, 85%, 90%, 95%, 98%, 99% or 100% sequence identity to SEQ ID NO:66, and wherein the third binding domain comprises an amino acid sequence having at least 80%, 85%, 90%, 95%, 98%, 99% or 100% sequence identity to SEQ ID NO:48, SEQ ID NO:49, SEQ ID NO:77 or SEQ ID NO:78, and the third binding domain comprises an amino acid sequence having at least 80%, 85%, 90%, 95%, 98%, 99% or 100% sequence identity to SEQ ID NO:50.

[0483] Embodiment H47. The composition of any one of Embodiments H1-H46, wherein the composition comprises a pharmaceutically acceptable excipient.

[0484] Embodiment H48. An isolated recombinant nucleic acid sequence encoding the amino acid sequence of the isolated antibody according to any one of Embodiments H1-H46.

[0485] Embodiment H49. A vector comprising the isolated recombinant nucleic acid sequence according to embodiment H48.

[0486] Embodiment H50. A kit comprising at least one of the following: (a) a composition according to any one of Embodiments H1-H47; (b) a vector according to Embodiment H49; or (b) a nucleic acid molecule according to Embodiment H48.

[0487] Embodiment H51. A method of treating food allergy in a subject in need thereof, comprising administering to the subject a composition according to any one of Embodiments H1-H47.

[0488] Embodiment H52. The method of embodiment H51, wherein the food allergy comprises peanut allergy.

[0489] Example

[0490] Example 1. Discovery of IgE monoclonal antibodies from peanut-allergic individuals.

[0491] In an Institutional Review Board (IRB)-approved observational study, blood was collected from dozens of highly peanut-allergic individuals (peanut-specific IgE > 15 kU / A) across the United States with informed consent. Sequencing was then performed using the SEQ SIFTER™ single-cell sorting and transcriptomics software in an unbiased manner. TM The platform was applied to capture extremely rare circulating IgE-producing B cells (Croote et al. "High affinity allergen-specific human antibodies cloned from single IgE B cell transcriptomes," Science 362.6420(2018):1306-1309). A high-throughput cloud-based bioinformatics pipeline was then used to reassemble the full-length paired heavy and light chain sequences that constitute monoclonal IgE antibodies, providing insights into the IgE repertoire of allergic individuals.

[0492] IgE variable region sequences discovered from peanut-allergic individuals were recombinantly expressed with IgG4 (rather than IgE) constant regions. In this way, monoclonal antibodies (mAbs) with the specificity of the original IgE antibodies were generated, which now blocked rather than triggered the allergic cascade. Since the discovery process was unbiased with respect to the specificity of IgE antibodies produced by circulating B cells, the distribution of Ara h allergen specificity naturally reflected the repertoire of circulating IgE-producing B cells. The majority of peanut-specific antibodies were found to be specific for Ara h 2 and / or the cognate allergen Ara h 6 ( Figure 1 It is clear that although there are several mAbs discovered against Ara h 1, these mAbs are mainly derived from a single individual and have lower affinity relative to mAbs specific for Ara h 2 and Ara h 6, with only 13% of Ara h 1-specific mAbs being in the subnanomolar range. This has led to a focus on Ara h 2. Figure 1 The specificity distribution of 158 mAbs discovered in an unbiased manner from 27 peanut-allergic individuals is shown. "Other" includes mAbs specific for Ara h 3, Ara h 8, and Ara h 9, as well as mAbs that did not have detectable binding to Ara h 1, Ara h 2, Ara h 3, Ara h 6, Ara h 8, or Ara h 9 on ImmunoCAP.

[0493] Example 2. Measurement of monoclonal antibody affinity and epitope binning.

[0494] The Carterra LSA is an instrument that utilizes surface plasmon resonance (SPR) for both antibody affinity measurement and epitope binning (a pairwise competition assay that groups antibodies according to the epitope to which they bind). The goal is to understand the number of epitopes (linear and / or conformational) on an antigen recognized by monoclonal IgE antibodies (expressed as IgG4), as well as to understand the distribution of monoclonal antibody epitope specificity (i.e., is there a bias towards immunodominant epitopes?). Antibodies are then grouped according to epitope bins, which, when combined with affinity data, allows the monoclonal antibodies selected accordingly to be further evaluated in functional assays such as blocking ELISA, basophil activation test (BAT), or mast cell activation test (MAT).

[0495] For the measurement of kinetic parameters, the antibody was first coupled to an HC30M sensor chip, which was then activated. The antibody was coupled to the activated surface at various concentrations, and the remaining reactive groups were subsequently inactivated. Native Ara h 2 or Ara h 6 (InBio) was injected serially at various concentrations onto the antibody-coupled chip using a Carterra LSA single flow cell, without regeneration between injections. Association and dissociation curves were fitted using a 1:1 Langmuir binding model to obtain kd, ka, and KD using Kinetics software (Carterra).

[0496] For epitope binning, the surface was functionalized with antibodies as described above. Each binding cycle consisted of natural Ara h 2 or Ara h 6 injected using a Carterra LSA single flow cell, followed by antibody and subsequent regeneration. Analysis of epitope binning was performed using Epitope software (Carterra). Antibody binding was normalized relative to the signal from only buffer injection after antigen injection. Antibody pairs were classified as blocking or sandwich based on whether they reached the binding signal threshold above the buffer injection background.

[0497] Using SPR, we determined that over 90% of the 64 Ara h 2-specific mAbs had high affinities in the subnanomolar range. Furthermore, 90% of these mAbs were found to belong to epitope bins 1, 2, or 3 ( Figure 2 This led to the selection and engineering of mAbs belonging to these three epitope bins for in vitro characterization. Figure 2 The distribution of 64 mAbs according to Ara h 2 epitope bins is shown, with three immunodominant epitope bins highlighted.

[0498] Example 3. ELISA in vitro characterization

[0499] In vitro ELISA was used to characterize the binding and inhibitory abilities of IgG mAbs. In vitro blocking ELISA was used to assess the ability of one or more IgG monoclonal antibodies to block the binding of allergic plasma IgE to recombinant Ara h 2. In this assay (a simplified version of which is shown in Figure 3A In this assay, human FcεRIα-IgG Fc fusion protein captures human IgE from peanut-allergic plasma. Following capture, a pre-incubation mixture of His-tagged recombinant Ara h 2 and a titrated series of antibodies is added. An anti-His HRP-conjugated detection antibody and TMB are used to measure recombinant Ara h 2 binding by plasma IgE. Inhibition is calculated relative to control wells without antibody.

[0500] It was found that molecules-2d, -2e and -2f independently inhibited the binding of allergic plasma IgE to recombinant Ara h 2 to varying degrees ( Figure 3B ), whereas the combination of Molecule-2d and Molecule-2e had higher and more consistent inhibition, achieving an average inhibition of 91% in 9 peanut-allergic plasmas. Molecule-2d, Molecule-2e, and Molecule-2f are high-affinity IgG4 antibodies with an S228P hinge-stabilizing mutation belonging to epitope bins 1, 2, and 3, respectively.

[0501] Table 5. Molecule-2 Nomenclature Reference

[0502]

[0503] Subsequently, a variety of human IgG4-scFv antibodies, designated with the prefix "Molecule-1," were engineered based on combinations of binding domains from Molecule-2d, Molecule-2e, and Molecule-2f, which were optionally further modified to remove chemistry, manufacturing, and control (CMC) responsibilities. These engineered antibodies are bispecific, but more specifically, possess bi-epitopic specificity. These bi-epitopic antibodies bind to one Ara h 2 epitope, either "bin 1," "bin 2," or "bin 3," via the Fab domain, and to a different epitope selected from the same set via the scFv domain. The bin 1 and bin 2 epitopes are conserved in the homologous peanut protein Ara h 6, but the bin 3 epitope is unique to Ara h 2.

[0504] Table 6. Molecule-1 Nomenclature Reference

[0505]

[0506] Four molecule-1 mAbs were evaluated for their ability to bind to recombinant Ara h 2. All were found to bind in a concentration-dependent manner similar to each other and to molecule-2d, molecule-2e, and combinations thereof ( Figure 3CNext, the ability of these molecules to inhibit the binding of recombinant Ara h 2 to polyclonal peanut allergic plasma IgE was assessed. All four molecule-1 mAbs showed inhibition greater than either molecule-2d or molecule-2e alone, and with an IC50 lower than the combination of molecule-2d and molecule-2e ( Figure 3D ).

[0507] Figure 3A Schematic representation of a simplified ELISA for evaluating the ability of IgG mAbs to block the binding of allergic plasma IgE to labeled allergens. Figure 3B Figure 1 shows the inhibition of recombinant Ara h 2 binding to peanut allergic plasma IgE by one or more molecule-2 mAbs in a blocking ELISA. Isotype control = F080-F1, an IgG4 mAb specific for a non-peanut allergen. Data are shown for individual peanut allergic plasma (n=9), with bars representing mean ± SD. Figure 3C The binding of Molecule-1 and Molecule-2 mAbs to recombinant Ara h 2 is shown. Figure 3D Shown is the inhibition of peanut allergic plasma IgE binding to recombinant Ara h 2 by Molecule-1 mAb relative to Molecule-2 mAb alone or in combination in a sample of peanut allergic plasma. Isotype Control = F080-F1, an IgG4 mAb specific for a non-peanut allergen.

[0508] Example 4. Mast Cell Activation Test (MAT) In Vitro Characterization.

[0509] An overview diagram of the MAT experimental design is shown in Figure 4A Murine Hoxb8 mast cells expressing human FcεRIα were first sensitized with patient plasma, allowing them to capture polyclonal IgE via the high-affinity FcεRI. The cells were then washed, incubated with an IgG4 antibody for 30 minutes, and then, without washing, a predetermined optimal concentration of Ara h 2 or peanut protein was added. For each plasma aliquot, this optimal concentration, slightly above half-maximal activation, was predetermined. Activation was assessed by CD107a expression using flow cytometry, and percent inhibition was calculated relative to activation in control wells without antibody.

[0510] mAbs with both human IgG1 and human IgG4 S228P constant regions were evaluated in the MAT using seven peanut allergic plasmas. When comparing otherwise identical Molecule-2 mAbs (e.g., Molecule-2g and Molecule-2d, Molecule-2h and Molecule-2e, and Molecule-2i and Molecule-2f), the constant region had little effect ( Figure 4BCombinations of two or three enhanced the level of inhibition compared to either molecule-2 mAb alone, with the greatest inhibition of peanut-mediated mast cell activation achieved by the combination of molecule-2f (IgG4S228P) and the bi-epitope molecule-1g (IgG4S228P).

[0511] Figure 4A An overview of the Mast Cell Activation Test (MAT) is shown. Figure 4B Graphed are the percentage inhibition of peanut-mediated and Ara h 2-mediated mast cell activation by human IgG1 and human IgG4 S228P mAbs. All test articles were tested at a total antibody concentration of 10 μg / mL. Isotype control (IgG1 and IgG4 S228P) = G010-F5, a mAb specific for a non-peanut allergen. Mean ± SEM of n = 7 peanut-allergic plasma is shown.

[0512] Example 5. In vitro characterization of combination therapy.

[0513] Based on the experiments in the above examples, a combination therapy (combination-1) was developed. Combination-1 consists of Figure 5A The results are shown in Figure 1. The results are composed of a 1:1 mixture of molecules-1a and molecule-2c by mass. Molecule-1a is an IgG4 antibody with a stabilized hinge region (S228P) in which the scFv domain is fused to the c-terminus of each heavy chain. Binder-1 of molecule-1 binds to epitope bin 1 on Ara h 2 and Ara h 6. Binder-2 of molecule-1 binds to epitope bin 2 on Ara h 2 and Ara h 6. Binding is bivalent for both epitopes. Molecule-2 is an IgG4 S228P antibody lacking the c-terminal lysine of the heavy chain constant region. Binder-3 binds to epitope bin 3 present only on Ara h 2. Binding is bivalent for this epitope.

[0514] Monoclonal antibodies are produced by transient transfection of mammalian cells. After codon optimization, the heavy and light chain variable region genes from each mAb are synthesized and cloned into pcDNA3.4 vectors containing the appropriate constant region (IgG1 or IgG4 S228P, and either λ or κ, as appropriate), and transiently co-transfected into Chinese hamster ovary (CHO) cells. After approximately 7 days of culture, the antibodies are purified from the supernatant using a 1-step protein A purification. After washing and elution, the eluted fractions are combined and the buffer is replaced with a suitable formulation buffer. The antibodies are characterized by SDS-PAGE under reducing and non-reducing conditions.

[0515] For larger-scale monoclonal antibody production, a suitable retroviral system is used to generate stable cell lines. Characterized CHO cell lines are transfected with cDNA corresponding to the heavy and light chains, and subsequently single-cell subcloning and clonal characterization in shake flasks and small-scale bioreactors are performed to select stable cell lines. To produce each mAb, CHO cells are grown in bioreactors and the mAb secreted into the culture medium is recovered by conventional IgG purification techniques.

[0516] To evaluate the efficacy and activity of Combination-1, several experiments were performed. Using the blocking ELISA format described in Example 3, Combination-1 completely inhibited the binding of recombinant Ara h 2 to IgE in five peanut allergic plasmas, whereas no inhibition was observed with the isotype control ( Figure 5B Next, Combination-1 was evaluated relative to its constituent components, Molecule-1a and Molecule-2c, using the MAT described in Example 4. Combination-1 significantly inhibited peanut-mediated mast cell activation in 19 peanut-allergic plasma samples compared to isotype controls ( Figure 5C Compared to the 5.8% average inhibition of the isotype control (IgG4 trastuzumab), Combination-1 had an average inhibition of 82.6%, with a maximum inhibition of 97.5%. The average inhibition of molecule-1a alone was 61.4%, and the average inhibition of molecule-2c alone was 48.7%, both significantly lower than Combination-1. The coefficients of variation for molecules-1a and 2c alone were also greater than those for Combination-1.

[0517] Figure 5A Combination-1 comprising two molecules is shown. Figure 5B Graph depicting the blocking of rAra h 2 binding to peanut allergic plasma IgE by Combination-1. Isotype control = F080-F1, an IgG4 mAb specific for a non-peanut allergen. Mean ± SEM of n = 5 plasma are shown. Figure 5C Figure 1 shows the inhibition of peanut-mediated mast cell activation by Combination-1 and its components in peanut-allergic plasma from n=19 subjects. The total antibody concentration for all test articles was 10 μg / mL. Isotype control = IgG4 trastuzumab. Mean ± SEM is shown. ****P < 0.001 by one-way ANOVA followed by Bonferroni's multiple comparison test.

[0518] Example 6. In vivo characterization of combination therapy in a peanut allergy mouse model.

[0519] The efficacy of Combination-1 was evaluated in a peanut allergy mouse model based on a protocol modified from Landers et al. Targeted allergen-specific immunotherapy within the skin improves allergen delivery to induce desensitization to peanut. Immunotherapy. 2022 May;14(7):539-552.doi:10.2217 / imt-2021-0206.Epub 2022 Feb 24. Briefly, naive C3H / HeJ female mice were sensitized with 2 mg peanut protein + 10 μg cholera toxin (CTx) delivered via oral gavage from week 0 to week 5. The peanut challenge protocol was initiated on day 49. The challenge protocol consisted of 7 challenges by oral gavage of 25 mg peanut protein every other day for 2 weeks. On day 61 (48 hours before the 7th peanut protein challenge), mice were treated with test article or excipient buffer (vehicle) by subcutaneous injection ( Figure 6A Responses to the seventh peanut protein challenge, performed 48 hours after test article administration, were recorded. The core body temperature of the mice was monitored, and the observers were blinded to the treatments. Sixty minutes after the final peanut protein challenge, the mice were euthanized and blood was collected by cardiac puncture. Serum was collected and analyzed for levels of human IgG and mast cell protease 1 (MCPT-1), an indicator of mast cell degranulation.

[0520] Unless otherwise stated, all data were analyzed using one-way ANOVA followed by Dunnett's multiple comparison test to compare each treatment group to the vehicle buffer treated group. Statistical significance is indicated as *P<0.05; **P<0.01 and ***P<0.001, and values are reported as mean ± SEM.

[0521] In this study, animals were dosed with test article (combination-1, molecule-1a, molecule-2c at doses of 0.625, 1.25, 2.5, or 5.0 mg / kg), isotype control (5.0 mg / kg IgG4 trastuzumab), or vehicle buffer forty-eight hours prior to the seventh challenge. The seventh peanut protein challenge induced a severe allergic reaction ( ) as measured by a decrease in rectal temperature of 3.9 ± 0.5°C in animals treated with vehicle buffer. Figure 6A). This hypothermic response to peanut challenge was dose-dependently reversed in animals treated with Combination-1, and the reduced response in the 2.5 and 5.0 mg / kg Combination-1 treated groups was statistically significant compared to that measured in the vehicle buffer treated group. In animals pretreated with Molecule-1a alone, there was a dose-dependent reduction in the hypothermic response to peanut challenge; however, the responses at all dose levels were not statistically different from those seen in the vehicle buffer treated group. A direct comparison (unpaired Student's t-test) between the highest dose of Combination-1 and Molecule-1a showed a significant difference between the two treatments. Molecule-2c alone did not significantly reduce the hypothermic response to peanut protein challenge at any dose tested. An isotype control antibody (IgG4 trastuzumab) had no effect on the hypothermic response.

[0522] At the end of the 60-minute post-challenge observation period, animals were euthanized and a terminal blood sample was collected. A portion of this sample was assayed for MCPT-1, a direct measure of mast cell degranulation. Combination-1 reduced MCPT-1 in a dose-dependent manner relative to animals treated with vehicle buffer, reaching levels comparable to those seen in unsensitized animals at 5 mg / kg. Molecule-1a alone produced a significant reduction in MCPT-1 serum levels, but this was significantly less than the reduction associated with combination-1 at a comparable dose (5.0 mg / kg). Neither the isotype control antibody (IgG4 trastuzumab) nor molecule-2c significantly reduced MCPT-1 levels.

[0523] Figure 6A The scheme of the mouse model of peanut allergy oral sensitization / oral peanut challenge is shown. On day 61 (48 hours before the seventh peanut protein challenge), mice were treated with test article or excipient buffer (vehicle) by subcutaneous (sc) injection. Sixty minutes after the final peanut protein challenge on day 63, mice were euthanized and blood was collected by cardiac puncture. Serum was collected and analyzed for human IgG and MCPT-1 levels. Figure 6B Figure 1 shows the dose-dependent effects of Combination-1 and its components on hypothermia in peanut-allergic animals when challenged with 25 mg peanut protein delivered via oral gavage. Isotype control = IgG4 trastuzumab. All data were compared to the effects of the buffer vehicle. The effects of Combination-1 and Molecule-1a (5.0 mg / kg) were compared using an unpaired Student's t-test (#P<0.05). Figure 6CThe graph shows the dose-dependent effects of Combination-1, Molecule-1a, and Molecule-2c on serum MCPT-1, a direct measure of mast cell degranulation, in peanut-allergic animals when challenged with 25 mg of peanut protein delivered via oral gavage. Isotype control = IgG4 trastuzumab. All data were compared to the effect of the buffer vehicle. The effects of Combination-1 and Molecule-1a (5.0 mg / kg) were compared using an unpaired Student's t-test (###). Note that serum levels of MCPT-1 in animals treated with 5 mg / kg of Combination-1 were comparable to those in unsensitized animals.

Claims

1. A composition comprising a first binding domain that binds to Ara h 2 and Ara h 6, wherein the first binding domain comprises a heavy chain variable domain (VH) comprising complementarity determining regions (CDRs): HC-CDR1, HC-CDR2, HC-CDR3, wherein the HC-CDR1, HC-CDR2, HC-CDR3 comprise the amino acid sequence according to HC-CDR1: SEQ ID NO: 1, HC-CDR2: SEQ ID NO: 2 or SEQ ID NO: 3, HC-CDR-3: SEQ ID NO: 4 or SEQ ID NO: 5, and the first binding domain comprises a light chain variable (VL) domain comprising CDRs: LC-CDR1, LC-CDR2, LC-CDR3, wherein the LC-CDR1, LC-CDR2, LC-CDR3 comprise the amino acid sequence according to LC-CDR1: SEQ ID NO: 6, LC-CDR2: SEQ ID NO: 7, LC-CDR-3: SEQ ID NO: 8, wherein the composition comprises a heavy chain variable domain (VH) comprising complementarity determining regions (CDRs): HC-CDR1, HC-CDR2, HC-CDR3, wherein the HC-CDR1, HC-CDR2, HC-CDR3 comprise the amino acid sequence according to LC-CDR1: SEQ ID NO: 6, LC-CDR2: SEQ ID NO: 7, LC-CDR-3: SEQ ID NO: 8, wherein the composition comprises a heavy chain variable domain (VL) comprising CDRs: LC-CDR1, LC-CDR2, LC-CDR3 2 and Ara h 6, wherein the second binding domain comprises a VH comprising CDRs: HC-CDR1, HC-CDR2, HC-CDR3, wherein the HC-CDR1, HC-CDR2, HC-CDR3 comprise the amino acid sequence according to HC-CDR1: SEQ ID NO: 18, HC-CDR2: SEQ ID NO: 19, HC-CDR-3: SEQ ID NO: 20 or SEQ ID NO: 21, and the second binding domain comprises a light chain variable (VL) domain comprising CDRs: LC-CDR1, LC-CDR2, LC-CDR3, wherein the LC-CDR1, LC-CDR2, LC-CDR3 comprise the amino acid sequence according to LC-CDR1: SEQ ID NO: 22, LC-CDR2: SEQ ID NO: 23, LC-CDR-3: SEQ ID NO: 24, and wherein the composition comprises a VH comprising CDRs: HC-CDR1, HC-CDR2, HC-CDR3, wherein the VH comprising CDRs: LC-CDR1, LC-CDR2, LC-CDR3 2, wherein the third binding domain comprises a VH comprising CDRs: HC-CDR1, HC-CDR2, HC-CDR3, wherein the HC-CDR1, HC-CDR2, HC-CDR3 comprise the amino acid sequence according to HC-CDR1: SEQ ID NO: 35, HC-CDR2: SEQ ID NO: 36 or SEQ ID NO: 37, HC-CDR3: SEQ ID NO: 38, and the third binding domain comprises a light chain variable (VL) domain comprising CDRs: LC-CDR1, LC-CDR2, LC-CDR3,wherein the LC-CDR1, LC-CDR2, and LC-CDR3 comprise the amino acid sequences of LC-CDR1: SEQ ID NO: 39, LC-CDR2: SEQ ID NO: 40, and LC-CDR-3: SEQ ID NO:

41.

2. The composition of claim 1, wherein the VH of the first binding domain comprises an amino acid sequence having at least 80%, 85%, 90%, 95%, 98%, 99% or 100% sequence identity to SEQ ID NO: 9 or SEQ ID NO:

10.

3. The composition of claim 1, wherein the VL of the first binding domain comprises an amino acid sequence having at least 80%, 85%, 90%, 95%, 98%, 99% or 100% sequence identity to SEQ ID NO:

11.

4. The composition of claim 1 , wherein the VH of the first binding domain comprises an amino acid sequence having at least 80%, 85%, 90%, 95%, 98%, 99% or 100% sequence identity to SEQ ID NO: 9 or SEQ ID NO: 10, and wherein the VL of the first binding domain comprises an amino acid sequence having at least 80%, 85%, 90%, 95%, 98%, 99% or 100% sequence identity to SEQ ID NO:

11.

5. The composition of claim 1, wherein the first binding domain comprises Fab, Fab', F(ab')2, or a single-chain variable fragment (scFv).

6. The composition of claim 1, wherein the first binding domain is Fab, Fab', F(ab')2, or a single-chain variable fragment (scFv).

7. The composition of claim 5, wherein the first binding domain comprises the scFv.

8. The composition of claim 1, wherein the VH of the first binding domain and the VL of the first binding domain are connected by a scFv linker sequence.

9. The composition of claim 8, wherein the scFv linker sequence of the first binding domain comprises the amino acid sequence according to SEQ ID No:

12.

10. The composition of claim 7, wherein the scFv of the first binding domain comprises an amino acid sequence having at least 80%, 85%, 90%, 95%, 98%, 99% or 100% sequence identity to SEQ ID NO: 13 or SEQ ID NO:

14.

11. The composition of claim 1, wherein the first binding domain comprises a constant domain.

12. The composition of claim 11, wherein the constant domain of the first binding domain comprises a human IgG4 sequence.

13. The composition of claim 12, wherein the human IgG4 sequence of the first binding domain comprises an S228P point mutation, wherein amino acid numbering follows the EU index as in Kabat et al.

14. The composition of claim 12, wherein the human IgG4 sequence of the first binding domain does not have a C-terminal lysine residue.

15. The composition of claim 11, wherein the constant domain of the first binding domain comprises a human IgG1 sequence.

16. The composition of claim 11, wherein the constant domain of the first binding domain comprises C H 1. C H 2. C H 3 or C L Amino acid sequence.

17. The composition of claim 11, wherein the first binding domain comprises C H 1. C H 2. C H 3 and C L Amino acid sequence.

18. The composition of claim 1, wherein the first binding domain comprises an amino acid sequence that has at least 80%, 85%, 90%, 95%, 98%, 99% or 100% sequence identity to SEQ ID NO: 15, SEQ ID NO: 16, SEQ ID NO: 72 or SEQ ID NO: 73, and the first binding domain comprises an amino acid sequence that has at least 80%, 85%, 90%, 95%, 98%, 99% or 100% sequence identity to SEQ ID NO:

17.

19. The composition of claim 1, wherein the VH of the second binding domain comprises an amino acid sequence having at least 80%, 85%, 90%, 95%, 98%, 99% or 100% sequence identity to SEQ ID NO: 25 or SEQ ID NO:

26.

20. The composition of claim 1, wherein the VL of the second binding domain comprises an amino acid sequence having at least 80%, 85%, 90%, 95%, 98%, 99% or 100% sequence identity to SEQ ID NO: 27 or SEQ ID NO:

28.

21. The composition of claim 1, wherein the VH of the second binding domain comprises an amino acid sequence having at least 80%, 85%, 90%, 95%, 98%, 99% or 100% sequence identity to SEQ ID NO: 25 or SEQ ID NO: 26, and wherein the VL of the second binding domain comprises an amino acid sequence having at least 80%, 85%, 90%, 95%, 98%, 99% or 100% sequence identity to SEQ ID NO: 27 or SEQ ID NO:

28.

22. The composition of claim 1, wherein the second binding domain comprises a Fab, a Fab', a F(ab')2, or a single-chain variable fragment (scFv).

23. The composition of claim 1, wherein the second binding domain is a Fab, Fab', F(ab')2, or a single-chain variable fragment (scFv).

24. The composition of claim 22, wherein the second binding domain comprises the scFv.

25. The composition of claim 24, wherein the VH of the second binding domain and the VL of the second binding domain are connected by a scFv linker sequence.

26. The composition of claim 25, wherein the scFv linker sequence of the second binding domain comprises the amino acid sequence according to SEQ ID NO:

29.

27. The composition of claim 22, wherein the scFv of the second binding domain comprises an amino acid sequence having at least 80%, 85%, 90%, 95%, 98%, 99% or 100% sequence identity to SEQ ID NO: 30 or SEQ ID NO:

31.

28. The composition of claim 1, wherein the second binding domain comprises a constant domain.

29. The composition of claim 28, wherein the constant domain of the second binding domain comprises a human IgG4 sequence.

30. The composition of claim 29, wherein the human IgG4 sequence of the second binding domain comprises an S228P point mutation, wherein amino acid numbering follows the EU index as in Kabat et al.

31. The composition of claim 29, wherein the human IgG4 sequence of the second binding domain does not have a C-terminal lysine residue.

32. The composition of claim 28, wherein the constant domain of the second binding domain comprises a human IgG1 sequence.

33. The composition of claim 28, wherein the constant domain of the second binding domain comprises C H 1. C H 2. C H 3 or C L Amino acid sequence.

34. The composition of claim 28, wherein the second binding domain comprises C H 1. C H 2. C H 3 and C L Amino acid sequence.

35. The composition of claim 1, wherein the second binding domain comprises an amino acid sequence that is at least 80%, 85%, 90%, 95%, 98%, 99% or 100% identical to SEQ ID NO:32, SEQ ID NO:33, SEQ ID NO:74 or SEQ ID NO:75, and the isolated antibody comprises an amino acid sequence that is at least 80%, 85%, 90%, 95%, 98%, 99% or 100% identical to SEQ ID NO:34 or SEQ ID NO:

76.

36. The composition of claim 1, wherein the VH of the third binding domain comprises an amino acid sequence having at least 80%, 85%, 90%, 95%, 98%, 99% or 100% sequence identity to SEQ ID NO:42 or SEQ ID NO:

43.

37. The composition of claim 1, wherein the VL of the third binding domain comprises an amino acid sequence having at least 80%, 85%, 90%, 95%, 98%, 99% or 100% sequence identity to SEQ ID NO:

44.

38. The composition of claim 1, wherein the VH of the third binding domain comprises an amino acid sequence having at least 80%, 85%, 90%, 95%, 98%, 99% or 100% sequence identity to SEQ ID NO:42 or SEQ ID NO:43, and wherein the VL of the third binding domain comprises an amino acid sequence having at least 80%, 85%, 90%, 95%, 98%, 99% or 100% sequence identity to SEQ ID NO:

44.

39. The composition of claim 1, wherein the third binding domain comprises a Fab, a Fab', a F(ab')2, or a single-chain variable fragment (scFv).

40. The composition of claim 1, wherein the third binding domain is a Fab, Fab', F(ab')2, or a single-chain variable fragment (scFv).

41. The composition of claim 39, wherein the third binding domain comprises the scFv.

42. The composition of claim 39, wherein the VH of the third binding domain and the VL of the third binding domain are connected by a scFv linker sequence.

43. The composition of claim 42, wherein the scFv linker sequence of the third binding domain comprises an amino acid sequence according to SEQ ID NO:

45.

44. The composition of claim 39, wherein the scFv of the third binding domain comprises an amino acid sequence having at least 80%, 85%, 90%, 95%, 98%, 99% or 100% sequence identity to SEQ ID NO:46 or SEQ ID NO:

47.

45. The composition of claim 1, wherein the third binding domain comprises a constant domain.

46. The composition of claim 45, wherein the constant domain of the third binding domain comprises a human IgG4 sequence.

47. The composition of claim 46, wherein the human IgG4 sequence of the third binding domain comprises an S228P point mutation, wherein amino acid numbering follows the EU index as in Kabat et al.

48. The composition of claim 46, wherein the human IgG4 sequence of the third binding domain does not have a C-terminal lysine residue.

49. The composition of claim 45, wherein the constant domain of the third binding domain comprises a human IgG1 sequence.

50. The composition of claim 45, wherein the constant domain of the third binding domain comprises C H 1. C H 2. C H 3 or C L Amino acid sequence.

51. The composition of claim 45, wherein the third binding domain comprises C H 1. C H 2. C H 3 and C L Amino acid sequence.

52. The composition of claim 1, wherein the third binding domain comprises an amino acid sequence that is at least 80%, 85%, 90%, 95%, 98%, 99% or 100% identical to SEQ ID NO:48, SEQ ID NO:49, SEQ ID NO:77 or SEQ ID NO:78, and the isolated antibody comprises an amino acid sequence that is at least 80%, 85%, 90%, 95%, 98%, 99% or 100% identical to SEQ ID NO:

50.

53. The composition of claim 1, wherein the first binding domain, the second binding domain, and the third binding domain are linked within the same molecule.

54. The composition of claim 1, wherein the first binding domain, the second binding domain, and the third binding domain are separate molecules.

55. The composition of claim 1, wherein the first and second binding domains are within the same molecule and the third binding domain belongs to a separate molecule from the molecules having the first and second binding domains.

56. The composition of claim 1, wherein the first binding domain and the third binding domain are within the same molecule and the second binding domain belongs to a separate molecule from the molecules having the first binding domain and the third binding domain.

57. The composition of claim 1, wherein the second binding domain and the third binding domain are within the same molecule and the first binding domain belongs to a separate molecule from the molecule having the second binding domain and the third binding domain.

58. The composition of claim 1, wherein the first binding domain comprises an scFv and the second binding domain comprises a C H 1. C H 2. C H 3 and C L Amino acid sequence.

59. The composition of claim 1, wherein the second binding domain comprises an scFv and the first binding domain comprises a C H 1. C H 2. C H 3 and C L Amino acid sequence.

60. The composition of claim 1, wherein the first binding domain and the second binding domain are connected by a linking moiety.

61. The composition of claim 1, wherein the linking moiety is an amino acid sequence.

62. The composition of claim 1, wherein the linking moiety is at least 4 amino acids long.

63. The composition of claim 1, wherein the linking portion is between 4-20 amino acids in length.

64. The composition of claim 1, wherein the linking moiety connects the C H 3 amino acid sequence connected to the scFv of the first binding domain.

65. The composition of claim 1, wherein the linking moiety comprises the amino acid sequence of SEQ ID NO:

51.

66. The composition of claim 1, wherein the first and second binding domains comprise an amino acid sequence having at least 80%, 85%, 90%, 95%, 98%, 99% or 100% sequence identity to SEQ ID NO:53 and an amino acid sequence having at least 80%, 85%, 90%, 95%, 98%, 99% or 100% sequence identity to SEQ ID NO:52, and wherein the third binding domain comprises an amino acid sequence having at least 80%, 85%, 90%, 95%, 98%, 99% or 100% sequence identity to SEQ ID NO:48, SEQ ID NO:49, SEQ ID NO:77 or SEQ ID NO:78, and the third binding domain comprises an amino acid sequence having at least 80%, 85%, 90%, 95%, 98%, 99% or 100% sequence identity to SEQ ID NO:

50.

67. The composition of claim 1, wherein the first and second binding domains comprise an amino acid sequence having at least 80%, 85%, 90%, 95%, 98%, 99% or 100% sequence identity to SEQ ID NO:55 and an amino acid sequence having at least 80%, 85%, 90%, 95%, 98%, 99% or 100% sequence identity to SEQ ID NO:54, and wherein the third binding domain comprises an amino acid sequence having at least 80%, 85%, 90%, 95%, 98%, 99% or 100% sequence identity to SEQ ID NO:48, SEQ ID NO:49, SEQ ID NO:77 or SEQ ID NO:78, and the third binding domain comprises an amino acid sequence having at least 80%, 85%, 90%, 95%, 98%, 99% or 100% sequence identity to SEQ ID NO:

50.

68. The composition of claim 1, wherein the first and second binding domains comprise an amino acid sequence having at least 80%, 85%, 90%, 95%, 98%, 99% or 100% sequence identity to SEQ ID NO:65 and an amino acid sequence having at least 80%, 85%, 90%, 95%, 98%, 99% or 100% sequence identity to SEQ ID NO:64, and wherein the third binding domain comprises an amino acid sequence having at least 80%, 85%, 90%, 95%, 98%, 99% or 100% sequence identity to SEQ ID NO:48, SEQ ID NO:49, SEQ ID NO:77 or SEQ ID NO:78, and the third binding domain comprises an amino acid sequence having at least 80%, 85%, 90%, 95%, 98%, 99% or 100% sequence identity to SEQ ID NO:

50.

69. The composition of claim 1, wherein the first and second binding domains comprise an amino acid sequence having at least 80%, 85%, 90%, 95%, 98%, 99% or 100% sequence identity to SEQ ID NO:67 and an amino acid sequence having at least 80%, 85%, 90%, 95%, 98%, 99% or 100% sequence identity to SEQ ID NO:66, and wherein the third binding domain comprises an amino acid sequence having at least 80%, 85%, 90%, 95%, 98%, 99% or 100% sequence identity to SEQ ID NO:48, SEQ ID NO:49, SEQ ID NO:77 or SEQ ID NO:78, and the third binding domain comprises an amino acid sequence having at least 80%, 85%, 90%, 95%, 98%, 99% or 100% sequence identity to SEQ ID NO:

50.

70. The composition of claim 1, wherein the first and second binding domains comprise an amino acid sequence having at least 80%, 85%, 90%, 95%, 98%, 99% or 100% sequence identity to SEQ ID NO:69 and an amino acid sequence having at least 80%, 85%, 90%, 95%, 98%, 99% or 100% sequence identity to SEQ ID NO:68, and wherein the third binding domain comprises an amino acid sequence having at least 80%, 85%, 90%, 95%, 98%, 99% or 100% sequence identity to SEQ ID NO:48, SEQ ID NO:49, SEQ ID NO:77 or SEQ ID NO:78, and the third binding domain comprises an amino acid sequence having at least 80%, 85%, 90%, 95%, 98%, 99% or 100% sequence identity to SEQ ID NO:

50.

71. The composition of claim 1, wherein the first and second binding domains comprise an amino acid sequence having at least 80%, 85%, 90%, 95%, 98%, 99% or 100% sequence identity to SEQ ID NO:71 and an amino acid sequence having at least 80%, 85%, 90%, 95%, 98%, 99% or 100% sequence identity to SEQ ID NO:70, and wherein the third binding domain comprises an amino acid sequence having at least 80%, 85%, 90%, 95%, 98%, 99% or 100% sequence identity to SEQ ID NO:48, SEQ ID NO:49, SEQ ID NO:77 or SEQ ID NO:78, and the third binding domain comprises an amino acid sequence having at least 80%, 85%, 90%, 95%, 98%, 99% or 100% sequence identity to SEQ ID NO:

50.

72. The composition of claim 1, wherein the composition comprises a pharmaceutically acceptable excipient.

73. An isolated recombinant nucleic acid sequence encoding the amino acid sequence of the composition of any one of claims 1-72.

74. A vector comprising the isolated recombinant nucleic acid sequence of claim 73.

75. A kit comprising at least one of the following: a. A composition according to any one of claims 1-72; b. a vector according to claim 74; or c. The nucleic acid molecule of claim 73.

76. A method of treating food allergy in a subject in need thereof, comprising administering to the subject the composition of any one of claims 1-72.

77. The method of claim 76, wherein the food allergy comprises peanut allergy.

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