Antibodies to human IL4RA and uses thereof

Abstract

The present invention relates to an anti-human interleukin-4 receptor A antibody, a pharmaceutical composition or kit containing said antibody, and uses thereof.

Description

[Technical Field]

[0001] The present invention relates to the fields of treatment of allergic diseases and molecular immunology, and in particular to an anti-human interleukin-4 receptor A antibody, a pharmaceutical composition or kit containing the same, and uses thereof. [Background technology]

[0002] The interleukin-4 receptor (IL4R) is a transmembrane receptor that exists in two distinct forms: type I IL4R, which binds interleukin-4 (IL-4) from a high-affinity IL4Rα subunit (referred to herein as IL4RA) and a moderate-affinity γc subunit and mediates IL-4-induced cell proliferation, activation, and other biological functions; and type II IL-4R, which consists of a high-affinity IL4Rα subunit (IL4RA) and an interleukin-13 receptor α subunit (IL-13Rα), a homologous functional receptor capable of binding interleukin-13 (IL-13) (Wang and Secombes, Cytokine, 2015, 75(1):8-13). IL-4R is expressed in T cells, B cells, hematopoietic stem cells and endothelial cells, epithelial cells, muscle, fibroblasts, hepatocytes, and brain tissue. IL4RA binds γc subunits. c After binding to its receptor, IL-4, together with the IL-13Rα subunit or IL-13Rα subunit, activates various non-receptor protein tyrosine kinases in the cytoplasm, initiating further downstream signaling pathways (Nelms et al., Annu. Rev. Immunol., 1999, 17:701-738; LaPorte et al., Cell, 2008, 132(2):259-272).

[0003] IL4RA can bind IL-4 and IL-13 with high affinity and is the major functional subunit of the aforementioned type I and type II IL4Rs. Inhibition of IL4RA can effectively block the relevant biological functions mediated by IL-4 and IL-13 (Gessner et al., Immunobiology, 2000, 201:285).

[0004] IL-4 inhibits CD4 + IL-13 is a pleiotropic cytokine secreted by immune cells, including T cell subsets, B cells, and mast cells; in humans, it is mainly produced by activated T cells (Th2 in mice) and exerts various biological effects on monocytes (macrophages), B lymphocytes, NK cells, vascular endothelial cells, etc. In addition, in vitro studies have shown that IL-4 and IL-13 can exert corresponding effector functions in various cells, such as T cells, B cells, eosinophils, mast cells, basophils, airway smooth muscle cells, airway epithelial cells, fibroblasts, and endothelial cells. These cells are the main effector cells involved in the development of allergic diseases, such as allergic rhinitis and food allergies, as well as asthma (May et al., Cytokine, 2015, 75(1):89-116). Furthermore, airway smooth muscle cells, airway epithelial cells, fibroblasts, and endothelial cells are also involved in the development, progression, and maintenance of chronic obstructive pulmonary disease (for reviews, see Steinke et al., RespRes, 2001, 2(66):66-70 and Willis-Karp et al., Immunol Rev, 2004, 202:175-190); dysfunction of T cells and B cells is a major mechanism of autoimmune disease, and IL-4 contributes to the development of autoimmune disease by activating downstream signaling pathways through binding to IL-4R on the surface of immune cells (May et al., Cytokine, 2015, 75(1):89-116).

[0005] The IL-4 / IL-13 pathway plays an important role in the pathology of asthma (Chatila et al., Trends in Molecular Med., 2004, 10(10):493-499) and other diseases reviewed elsewhere herein. Airway hyperresponsiveness, mucus hypersecretion, and airway remodeling are key pathological features of asthma. Studies have demonstrated that IL-4 and IL-13 are involved in the development and maintenance of the above pathological processes (May et al., Cytokine, 2015, 75(1):89-116). IL-13 is considered a key cytokine for inducing airway hyperresponsiveness (AHR), and IL-4 is primarily responsible for the polarization of Th2 immune cells and IgE production (Wynn et al., Annu. Rev. Immunol., 2003, 21:425-456).

[0006] Atopic dermatitis, particularly moderate and severe atopic dermatitis, is a severe chronic inflammatory skin disease characterized primarily by severe pruritus, pronounced eczematous changes, and dry skin. Atopic dermatitis typically develops during infancy and persists lifelong in some patients. Atopic dermatitis can significantly impact patients' quality of life due to chronic recurrent eczema, severe pruritus, sleep deprivation, dietary restrictions, and psychosocial factors. IL-4 / IL-13 are considered important drivers of persistent endogenous inflammation in atopic dermatitis (Malajian et al., Cytokine, 2015, 73(2):311-318). Clinical studies have demonstrated that dupilumab, an anti-human IL4RA monoclonal antibody, is effective in treating moderate and severe atopic dermatitis (Beck et al., N. Engl. J. Med., 2014, 371(2):130-139) and has been approved by the U.S. Food and Drug Administration (FDA) for the treatment of moderate and severe atopic dermatitis.

[0007] Basic medical and clinical research has also demonstrated that the IL-4, IL-13, and IL-4R pathways are involved in the development and progression of chronic obstructive pulmonary disease, rhinosinusitis, and tumors, and that inhibition of IL4RA has the potential to treat chronic obstructive pulmonary disease (Jin Lin et al., Journal of Practical Medicine, 2014, 30(22):3543-3544), rhinosinusitis, pulmonary fibrosis, and tumors (May et al., Cytokine, 2015, 75(1):89-116; Guo Changkuo et al., Chemistry of Life, 2017, 37(3):413-418). In adult patients with symptomatic chronic rhinosinusitis and nasal polyposis resistant to intranasal glucocorticoids, the anti-human IL4RA monoclonal antibody dupilumab in combination with glucocorticoids can significantly improve symptoms and reduce nasal polyps (Bachert et al., JAMA, 2016, 315(5):469-79).

[0008] The anti-human IL4RA antibody pharmaceuticals of the present invention have broad application prospects and can be used to treat allergic diseases such as allergic rhinitis, asthma, allergies, and atopic dermatitis, as well as rhinosinusitis, nasal polyps, chronic obstructive pulmonary disease, tissue fibrosis, tumors, and autoimmune diseases. Therefore, the development of antibody pharmaceuticals with high affinity for human IL4RA for the treatment of allergic diseases more effectively with less toxicity and side effects is of great significance. However, available anti-human IL4RA antibody pharmaceuticals exhibit insufficient affinity, and there remains a need for anti-human IL4RA antibodies with high affinity. Summary of the Invention

[0009] As a result of intensive research and creative efforts, the present inventors used a mammalian cell expression system to express recombinant IL4RA as an antigen, immunized mice, and obtained hybridoma cells by fusing mouse spleen cells with myeloma cells. The present inventors screened a large number of samples to obtain the following hybridoma cell lines:

[0010] The inventors have discovered that: The hybridoma cell line 13E5 can secrete and produce a specific antibody (designated 13E5) that specifically binds to human IL4RA, and this antibody can effectively block the binding of human IL4RA to IL-4. Furthermore, the present inventors creatively prepared humanized anti-human IL4RA antibodies (designated 13E5H1L1, 13E5H2L2, 13E5H3L3, 13E5H4L4, and 13E5H4L2, respectively).

[0011] The hybridoma cell line 18H7 can secrete and produce a specific antibody (designated 18H7) that specifically binds to human IL4RA, and this antibody can effectively block the binding of human IL4RA to IL-4. Furthermore, the present inventors creatively prepared humanized anti-human IL4RA antibodies (designated 18H7H1L1, 18H7H2L2, 18H7H2L3, and 18H H3L2, respectively).

[0012] The hybridoma cell line 20G10 can secrete and produce an antibody (designated 20G10) that specifically binds to human IL4RA, and this antibody can effectively block the binding of human IL4RA to IL-4. Furthermore, the present inventors creatively prepared a humanized anti-human IL4RA antibody (designated 20G10H3L3).

[0013] The antibody effectively binds to human IL4RA, blocks the binding of human IL4RA to its ligands IL-4 or IL-13, and inhibits the activation of downstream signaling pathways of human IL4RA. The antibody has the potential to be used in the preparation of medicines for the prevention and treatment of allergic rhinitis, asthma, allergies, atopic dermatitis, rhinosinusitis, nasal polyps, chronic obstructive pulmonary disease, tissue fibrosis, and autoimmune diseases.

[0014] The present invention is described in detail below. One aspect of the present invention relates to an antibody or an antigen-binding fragment thereof, The antibody HCDR1 comprising or consisting of the sequence set forth in SEQ ID NO: 9, a sequence having at least 90%, preferably at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity thereto, or an amino acid sequence having one or more (preferably 1, 2 or 3) conservative amino acid mutations (preferably substitutions, insertions or deletions) compared to said sequence, an HCDR2 comprising or consisting of the sequence set forth in SEQ ID NO: 10, a sequence having at least 90%, preferably at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity thereto, or an amino acid sequence having one or more (preferably 1, 2 or 3) conservative amino acid mutations (preferably substitutions, insertions or deletions) compared to said sequence, and an HCDR3 comprising or consisting of the sequence set forth in SEQ ID NO: 11, a sequence having at least 90%, preferably at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to said sequence, or an amino acid sequence which has one or more (preferably 1, 2 or 3) conservative amino acid mutations (preferably substitutions, insertions or deletions) compared to said sequence, and the antibody LCDR1 comprising or consisting of the sequence set forth in SEQ ID NO: 12, a sequence having at least 90%, preferably at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to said sequence, or an amino acid sequence having one or more (preferably 1, 2 or 3) conservative amino acid mutations (preferably substitutions, insertions or deletions) compared to said sequence, an LCDR2 comprising or consisting of the sequence set forth in SEQ ID NO: 13, a sequence having at least 90%, preferably at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity thereto, or an amino acid sequence having one or more (preferably 1, 2 or 3) conservative amino acid mutations (preferably substitutions, insertions or deletions) compared to said sequence, and an LCDR3 comprising or consisting of the sequence set forth in SEQ ID NO: 14, a sequence having at least 90%, preferably at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity thereto, or an amino acid sequence having one or more (preferably 1, 2 or 3) conservative amino acid mutations (preferably substitutions, insertions or deletions) compared to said sequence, or, The antibody HCDR1 comprising or consisting of the sequence set forth in SEQ ID NO: 15, a sequence having at least 90%, preferably at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to said sequence, or an amino acid sequence having one or more (preferably 1, 2 or 3) conservative amino acid mutations (preferably substitutions, insertions or deletions) compared to said sequence, an HCDR2 comprising or consisting of the sequence set forth in SEQ ID NO: 16, a sequence having at least 90%, preferably at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity thereto, or an amino acid sequence having one or more (preferably 1, 2 or 3) conservative amino acid mutations (preferably substitutions, insertions or deletions) compared to said sequence, and an HCDR3 comprising or consisting of the sequence set forth in SEQ ID NO: 17, a sequence having at least 90%, preferably at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity thereto, or an amino acid sequence which has one or more (preferably 1, 2 or 3) conservative amino acid mutations (preferably substitutions, insertions or deletions) compared to said sequence, And the antibody is LCDR1 comprising or consisting of the sequence set forth in SEQ ID NO: 18, a sequence having at least 90%, preferably at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to said sequence, or an amino acid sequence having one or more (preferably 1, 2 or 3) conservative amino acid mutations (preferably substitutions, insertions or deletions) compared to said sequence, LCDR2 comprising or consisting of the sequence set forth in SEQ ID NO: 19, a sequence having at least 90%, preferably at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity thereto, or an amino acid sequence having one or more (preferably 1, 2 or 3) conservative amino acid mutations (preferably substitutions, insertions or deletions) compared to said sequence, and an LCDR3 comprising or consisting of the sequence set forth in SEQ ID NO: 20, a sequence having at least 90%, preferably at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity thereto, or an amino acid sequence having one or more (preferably 1, 2 or 3) conservative amino acid mutations (preferably substitutions, insertions or deletions) compared to said sequence, or, The antibody HCDR1 comprising or consisting of the sequence set forth in SEQ ID NO: 130, a sequence having at least 90%, preferably at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to said sequence, or an amino acid sequence having one or more (preferably two or three) conservative amino acid mutations (preferably substitutions, insertions or deletions) compared to said sequence, an HCDR2 comprising or consisting of the sequence set forth in SEQ ID NO: 131, a sequence having at least 90%, preferably at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity thereto, or an amino acid sequence having one or more (preferably two or three) conservative amino acid mutations (preferably substitutions, insertions or deletions) compared to said sequence, and an HCDR3 comprising or consisting of the sequence set forth in SEQ ID NO: 132, a sequence having at least 90%, preferably at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to said sequence, or an amino acid sequence which has one or more (preferably two or three) conservative amino acid mutations (preferably substitutions, insertions or deletions) compared to said sequence, and the antibody LCDR1 comprising or consisting of the sequence set forth in SEQ ID NO: 133, a sequence having at least 90%, preferably at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to said sequence, or an amino acid sequence having one or more (preferably two or three) conservative amino acid mutations (preferably substitutions, insertions or deletions) compared to said sequence; LCDR2 comprising or consisting of the sequence set forth in SEQ ID NO: 134, a sequence having at least 90%, preferably at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity thereto, or an amino acid sequence having one or more (preferably two or three) conservative amino acid mutations (preferably substitutions, insertions or deletions) compared to said sequence, and The LCDR3 further comprises or consists of the sequence set forth in SEQ ID NO: 135, a sequence having at least 90%, preferably at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to said sequence, or an amino acid sequence having one or more (preferably two or three) conservative amino acid mutations (preferably substitutions, insertions or deletions) compared to said sequence.

[0015] In one embodiment of the invention, the antibody comprises: (1) the amino acid sequence set forth in SEQ ID NO: 2, a sequence having at least 80%, 85%, or 90%, preferably at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to the sequence set forth in SEQ ID NO: 2, or a heavy chain variable region comprising or consisting of an amino acid sequence having one or more (preferably 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) conservative amino acid mutations (preferably substitutions, insertions, or deletions) compared to the sequence set forth in SEQ ID NO:2; and the amino acid sequence set forth in SEQ ID NO: 4; a sequence having at least 80%, 85% or 90%, preferably at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to the sequence set forth in SEQ ID NO: 4, or a light chain variable region comprising or consisting of an amino acid sequence having one or more (preferably 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10) conservative amino acid mutations (preferably substitutions, insertions or deletions) compared to the sequence set forth in SEQ ID NO: 4; (2) the amino acid sequence set forth in SEQ ID NO: 6; a sequence having at least 80%, 85% or 90%, preferably at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to the sequence set forth in SEQ ID NO: 6, or a heavy chain variable region comprising or consisting of an amino acid sequence having one or more (preferably 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) conservative amino acid mutations (preferably substitutions, insertions, or deletions) compared to the sequence set forth in SEQ ID NO: 6; and the amino acid sequence set forth in SEQ ID NO: 8; a sequence having at least 80%, 85% or 90%, preferably at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to the sequence set forth in SEQ ID NO: 8, or a light chain variable region comprising or consisting of an amino acid sequence having one or more (preferably 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10) conservative amino acid mutations (preferably substitutions, insertions or deletions) compared to the sequence set forth in SEQ ID NO: 8; (3) the amino acid sequence set forth in SEQ ID NO: 22; a sequence having at least 80%, 85% or 90%, preferably at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to the sequence set forth in SEQ ID NO: 22, or a heavy chain variable region comprising or consisting of an amino acid sequence having one or more (preferably 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10) conservative amino acid mutations (preferably substitutions, insertions or deletions) compared to the sequence set forth in SEQ ID NO: 22; and the amino acid sequence set forth in SEQ ID NO: 24; a sequence having at least 80%, 85% or 90%, preferably at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to the sequence set forth in SEQ ID NO: 24, or a light chain variable region comprising or consisting of an amino acid sequence having one or more (preferably 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10) conservative amino acid mutations (preferably substitutions, insertions or deletions) compared to the sequence set forth in SEQ ID NO: 24; (4) the amino acid sequence set forth in SEQ ID NO: 26; a sequence having at least 80%, 85% or 90%, preferably at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to the sequence set forth in SEQ ID NO: 26, or a heavy chain variable region comprising or consisting of an amino acid sequence having one or more (preferably 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10) conservative amino acid mutations (preferably substitutions, insertions or deletions) compared to the sequence set forth in SEQ ID NO: 26; and the amino acid sequence set forth in SEQ ID NO: 28; a sequence having at least 80%, 85% or 90%, preferably at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to the sequence set forth in SEQ ID NO: 28, or a light chain variable region comprising or consisting of an amino acid sequence having one or more (preferably 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10) conservative amino acid mutations (preferably substitutions, insertions or deletions) compared to the sequence set forth in SEQ ID NO: 28; (5) the amino acid sequence set forth in SEQ ID NO: 30; a sequence having at least 80%, 85% or 90%, preferably at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to the sequence set forth in SEQ ID NO: 30, or a heavy chain variable region comprising or consisting of an amino acid sequence having one or more (preferably 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10) conservative amino acid mutations (preferably substitutions, insertions or deletions) compared to the sequence set forth in SEQ ID NO: 30; and the amino acid sequence set forth in SEQ ID NO: 32; a sequence having at least 80%, 85% or 90%, preferably at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to the sequence set forth in SEQ ID NO: 32, or a light chain variable region comprising or consisting of an amino acid sequence having one or more (preferably 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10) conservative amino acid mutations (preferably substitutions, insertions or deletions) compared to the sequence set forth in SEQ ID NO: 32; (6) the amino acid sequence set forth in SEQ ID NO: 34; a sequence having at least 80%, 85% or 90%, preferably at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to the sequence set forth in SEQ ID NO: 34, or a heavy chain variable region comprising or consisting of an amino acid sequence having one or more (preferably 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10) conservative amino acid mutations (preferably substitutions, insertions or deletions) compared to the sequence set forth in SEQ ID NO: 34; and the amino acid sequence set forth in SEQ ID NO: 36; a sequence having at least 80%, 85% or 90%, preferably at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to the sequence set forth in SEQ ID NO: 36, or a light chain variable region comprising or consisting of an amino acid sequence having one or more (preferably 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10) conservative amino acid mutations (preferably substitutions, insertions or deletions) compared to the sequence set forth in SEQ ID NO: 36; (7) The amino acid sequence set forth in SEQ ID NO: 38; a sequence having at least 80%, 85% or 90%, preferably at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to the sequence set forth in SEQ ID NO: 38, or a heavy chain variable region comprising or consisting of an amino acid sequence having one or more (preferably 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10) conservative amino acid mutations (preferably substitutions, insertions or deletions) compared to the sequence set forth in SEQ ID NO: 38; and the amino acid sequence set forth in SEQ ID NO: 40; a sequence having at least 80%, 85% or 90%, preferably at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to the sequence set forth in SEQ ID NO: 40, or a light chain variable region comprising or consisting of an amino acid sequence having one or more (preferably 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10) conservative amino acid mutations (preferably substitutions, insertions or deletions) compared to the sequence set forth in SEQ ID NO: 40; (8) The amino acid sequence set forth in SEQ ID NO: 42; a sequence having at least 80%, 85% or 90%, preferably at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to the sequence set forth in SEQ ID NO: 42, or a heavy chain variable region comprising or consisting of an amino acid sequence having one or more (preferably 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10) conservative amino acid mutations (preferably substitutions, insertions or deletions) compared to the sequence set forth in SEQ ID NO: 42; and the amino acid sequence set forth in SEQ ID NO: 44; a sequence having at least 80%, 85% or 90%, preferably at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to the sequence set forth in SEQ ID NO: 44, or a light chain variable region comprising or consisting of an amino acid sequence having one or more (preferably 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10) conservative amino acid mutations (preferably substitutions, insertions or deletions) compared to the sequence set forth in SEQ ID NO: 44; (9) The amino acid sequence set forth in SEQ ID NO: 46; a sequence having at least 80%, 85% or 90%, preferably at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to the sequence set forth in SEQ ID NO: 46, or a heavy chain variable region comprising or consisting of an amino acid sequence having one or more (preferably 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10) conservative amino acid mutations (preferably substitutions, insertions or deletions) compared to the sequence set forth in SEQ ID NO: 46; and the amino acid sequence set forth in SEQ ID NO: 48; a sequence having at least 80%, 85% or 90%, preferably at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to the sequence set forth in SEQ ID NO: 48, or a light chain variable region comprising or consisting of an amino acid sequence having one or more (preferably 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10) conservative amino acid mutations (preferably substitutions, insertions or deletions) compared to the sequence set forth in SEQ ID NO: 48; (10) The amino acid sequence set forth in SEQ ID NO: 42; a sequence having at least 80%, 85% or 90%, preferably at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to the sequence set forth in SEQ ID NO: 42, or a heavy chain variable region comprising or consisting of an amino acid sequence having one or more (preferably 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10) conservative amino acid mutations (preferably substitutions, insertions or deletions) compared to the sequence set forth in SEQ ID NO: 42; and the amino acid sequence set forth in SEQ ID NO: 48; a sequence having at least 80%, 85% or 90%, preferably at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to the sequence set forth in SEQ ID NO: 48, or a light chain variable region comprising or consisting of an amino acid sequence having one or more (preferably 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10) conservative amino acid mutations (preferably substitutions, insertions or deletions) compared to the sequence set forth in SEQ ID NO: 48; (11) The amino acid sequence set forth in SEQ ID NO: 46; a sequence having at least 80%, 85% or 90%, preferably at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to the sequence set forth in SEQ ID NO: 46, or a heavy chain variable region comprising or consisting of an amino acid sequence having one or more (preferably 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10) conservative amino acid mutations (preferably substitutions, insertions or deletions) compared to the sequence set forth in SEQ ID NO: 46; and a sequence having at least 80%, 85% or 90%, preferably at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to the sequence set forth in SEQ ID NO: 44, or a light chain variable region comprising or consisting of an amino acid sequence having one or more (preferably 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10) conservative amino acid mutations (preferably substitutions, insertions or deletions) compared to the sequence set forth in SEQ ID NO: 44; (12) The amino acid sequence set forth in SEQ ID NO: 34. a sequence having at least 80%, 85% or 90%, preferably at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to the sequence set forth in SEQ ID NO: 34, or a heavy chain variable region comprising or consisting of an amino acid sequence having one or more (preferably 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10) conservative amino acid mutations (preferably substitutions, insertions or deletions) compared to the sequence set forth in SEQ ID NO: 34; and the amino acid sequence set forth in SEQ ID NO: 28; a sequence having at least 80%, 85% or 90%, preferably at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to the sequence set forth in SEQ ID NO: 28, or a light chain variable region comprising or consisting of an amino acid sequence having one or more (preferably 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10) conservative amino acid mutations (preferably substitutions, insertions or deletions) compared to the sequence set forth in SEQ ID NO: 28; or (13) The amino acid sequence set forth in SEQ ID NO: 127; a sequence having at least 80%, 85% or 90%, preferably at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to the sequence set forth in SEQ ID NO: 127, or a heavy chain variable region comprising or consisting of an amino acid sequence having one or more (preferably 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10) conservative amino acid mutations (preferably substitutions, insertions or deletions) compared to the sequence set forth in SEQ ID NO: 127; and the amino acid sequence set forth in SEQ ID NO: 129; a sequence having at least 80%, 85% or 90%, preferably at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to the sequence set forth in SEQ ID NO: 129, or a light chain variable region comprising or consisting of an amino acid sequence having one or more (preferably 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10) conservative amino acid mutations (preferably substitutions, insertions or deletions) compared to the sequence set forth in SEQ ID NO: 129; Includes.

[0016] The amino acid sequences of the CDR regions of the antibodies in (1) to (13) above can be analyzed by technical means well known to those skilled in the art, for example, using the VBASE2 database.

[0017] The antibodies 13E5, 13E5H1L1, 13E5H2L2, 13E5H3L3, 13E5H4L4 and 13E5H4L2 disclosed herein share the same HCDR1-3 and LCDR1-3. According to the IMGT numbering system, the amino acid sequences of the three HCDR regions of the heavy chain variable region are as follows: HCDR1: GYTFTEYT SEQ ID NO: 9 HCDR2: INPNNGGT SEQ ID NO: 10 HCDR3: ARVRRGMDY SEQ ID NO: 11 The amino acid sequences of the three CDR regions of the light chain variable region are as follows: LCDR1:QDVTTA SEQ ID NO: 12 LCDR2: SAS SEQ ID NO: 13 LCDR3:QQHYSAPWT SEQ ID NO: 14

[0018] The antibodies 18H7, 18H7H1L1, 18H7H2L2, 18H7H2L3, and 18H7H3L2 disclosed herein share the same HCDR1-3 and LCDR1-3. According to the IMGT numbering system, the amino acid sequences of the three HCDR regions of the heavy chain variable region are as follows: HCDR1: GFTFSSSY SEQ ID NO: 15 HCDR2: INSNGGKT SEQ ID NO: 16 HCDR3: TRQRGNYVGAMDY SEQ ID NO: 17 The amino acid sequences of the three CDR regions of the early light chain variable region are as follows: LCDR1:QDVSTA SEQ ID NO: 18 LCDR2: SAS SEQ ID NO: 19 LCDR3:HQYYGSPPT SEQ ID NO:20

[0019] The antibody 20G10H3L3 disclosed in the present specification has the following HCDRs 1 to 3 and LCDRs 1 to 3. According to the IMGT numbering system, the amino acid sequences of the three HCDR regions of the heavy chain variable region are as follows: HCDR1: GFSLSTSGMG SEQ ID NO: 130 HCDR2: IWWADDK SEQ ID NO: 131 HCDR3: ARITRGNSAMDF SEQ ID NO: 132 The amino acid sequences of the three CDR regions of the light chain variable region are as follows: LCDR1:ENVYSY SEQ ID NO: 133 LCDR2:NAK SEQ ID NO: 134 LCDR3:QHHYGIPWT SEQ ID NO: 135

[0020] In one embodiment of the invention, the antibody further comprises framework regions (FRs) in the heavy chain variable region, preferably FRs comprising FR-H1, FR-H2, FR-H3 and FR-H4, wherein FR-H1 comprises or consists of the amino acid sequence set forth in SEQ ID NO: 49, a sequence having at least 80%, 85% or 90%, preferably at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to said sequence set forth in SEQ ID NO: 49, or an amino acid sequence having one or more (preferably 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10) conservative amino acid mutations (preferably substitutions, insertions or deletions) compared to said amino acid sequence set forth in SEQ ID NO: 49; and FR-H2 comprises or consists of the amino acid sequence set forth in SEQ ID NO: 50, a sequence having at least 80%, 85% or 90%, preferably at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to said sequence set forth in SEQ ID NO: 50. FR-H3 comprises or consists of the amino acid sequence set forth in SEQ ID NO: 51, a sequence having at least 80%, 85% or 90%, preferably at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to the sequence set forth in SEQ ID NO: 51, or an amino acid sequence having one or more (preferably 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10) conservative amino acid mutations (preferably substitutions, insertions or deletions) compared to the amino acid sequence set forth in SEQ ID NO: 51; FR-H4 comprises or consists of the amino acid sequence set forth in SEQ ID NO: 51, a sequence having at least 80%, 85% or 90%, preferably at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to the sequence set forth in SEQ ID NO: 51, or an amino acid sequence having one or more (preferably 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10) conservative amino acid mutations (preferably substitutions, insertions or deletions) compared to the amino acid sequence set forth in SEQ ID NO: 51;and FR-H4 comprises or consists of the amino acid sequence set forth in SEQ ID NO: 52, a sequence having at least 80%, 85% or 90%, preferably at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to said sequence set forth in SEQ ID NO: 52, or an amino acid sequence having one or more (preferably 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10) conservative amino acid mutations (preferably substitutions, insertions or deletions) compared to said amino acid sequence set forth in SEQ ID NO: 52;

[0021] In one embodiment of the invention, the antibody further comprises said light chain variable region, preferably FR comprising FR-L1, FR-L2, FR-L3 and FR-L4, wherein FR-L1 has the amino acid sequence set forth in SEQ ID NO: 53, a sequence having at least 80%, 85% or 90%, preferably at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to said sequence set forth in SEQ ID NO: 53, or one or more (preferably 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10) amino acids identical to said amino acid sequence set forth in SEQ ID NO: 53. FR-L2 comprises or consists of the amino acid sequence set forth in SEQ ID NO: 54, a sequence having at least 80%, 85% or 90%, preferably at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to said sequence set forth in SEQ ID NO: 54, or a sequence having one or more (preferably 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10) conservative amino acid mutations (preferably substitutions, insertions or deletions) compared to said amino acid sequence set forth in SEQ ID NO: 54; FR-L3 comprises or consists of the amino acid sequence set forth in SEQ ID NO: 55, a sequence having at least 80%, 85% or 90%, preferably at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to said sequence set forth in SEQ ID NO: 55, or an amino acid sequence having one or more (preferably 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10) conservative amino acid mutations (preferably substitutions, insertions or deletions) compared to the amino acid sequence set forth in SEQ ID NO: 55. and FR-L4 comprises or consists of the amino acid sequence set forth in SEQ ID NO: 56, a sequence having at least 80%, 85% or 90%, preferably at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to said sequence set forth in SEQ ID NO: 56, or an amino acid sequence having one or more (preferably 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10) conservative amino acid mutations (preferably substitutions, insertions or deletions) compared to said amino acid sequence set forth in SEQ ID NO: 56.

[0022] In one embodiment of the invention, the antibody further comprises the heavy chain variable region, preferably FR, comprising FR-H1, FR-H2, FR-H3 and FR-H4, wherein FR-H1 has the amino acid sequence set forth in SEQ ID NO: 57, a sequence having at least 80%, 85% or 90%, preferably at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to the sequence set forth in SEQ ID NO: 57, or one or more (preferably 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10) amino acids compared to the amino acid sequence set forth in SEQ ID NO: 57. FR-H2 comprises or consists of the amino acid sequence set forth in SEQ ID NO: 58, a sequence having at least 80%, 85% or 90%, preferably at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to said sequence set forth in SEQ ID NO: 58, or a sequence having one or more (preferably 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10) conservative amino acid mutations (preferably substitutions, insertions or deletions) compared to said amino acid sequence set forth in SEQ ID NO: 58. FR-H3 comprises or consists of the amino acid sequence set forth in SEQ ID NO: 59, a sequence having at least 80%, 85% or 90%, preferably at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to said sequence set forth in SEQ ID NO: 59, or an amino acid sequence having one or more (preferably 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10) conservative amino acid mutations (preferably substitutions, insertions or deletions) compared to said amino acid sequence set forth in SEQ ID NO: 59. and FR-H4 comprises or consists of the amino acid sequence set forth in SEQ ID NO: 60, a sequence having at least 80%, 85% or 90%, preferably at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to said sequence set forth in SEQ ID NO: 60, or an amino acid sequence having one or more (preferably 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10) conservative amino acid mutations (preferably substitutions, insertions or deletions) compared to said amino acid sequence set forth in SEQ ID NO: 60.

[0023] In one embodiment of the invention, the antibody further comprises the light chain variable region, preferably FR, comprising FR-L1, FR-L2, FR-L3 and FR-L4, wherein FR-L1 has the amino acid sequence set forth in SEQ ID NO: 61, a sequence having at least 80%, 85% or 90%, preferably at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to said sequence set forth in SEQ ID NO: 61, or one or more (preferably 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10) amino acids compared to said amino acid sequence set forth in SEQ ID NO: 61. FR-L2 comprises or consists of the amino acid sequence set forth in SEQ ID NO: 62, a sequence having at least 80%, 85% or 90%, preferably at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to said sequence set forth in SEQ ID NO: 62, or a sequence having one or more (preferably 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10) conservative amino acid mutations (preferably substitutions, insertions or deletions) compared to said amino acid sequence set forth in SEQ ID NO: 62; FR-L3 comprises or consists of the amino acid sequence set forth in SEQ ID NO: 63, a sequence having at least 80%, 85% or 90%, preferably at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to said sequence set forth in SEQ ID NO: 63, or an amino acid sequence having one or more (preferably 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10) conservative amino acid mutations (preferably substitutions, insertions or deletions) compared to said amino acid sequence set forth in SEQ ID NO: 63. and FR-L4 comprises or consists of the amino acid sequence set forth in SEQ ID NO: 64, a sequence having at least 80%, 85% or 90%, preferably at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to said sequence set forth in SEQ ID NO: 64, or an amino acid sequence having one or more (preferably 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10) conservative amino acid mutations (preferably substitutions, insertions or deletions) compared to said amino acid sequence set forth in SEQ ID NO: 64.

[0024] In one embodiment of the invention, the antibody further comprises the heavy chain variable region, preferably FR, comprising FR-H1, FR-H2, FR-H3 and FR-H4, wherein FR-H1 has the amino acid sequence set forth in SEQ ID NO: 65, a sequence having at least 80%, 85% or 90%, preferably at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to said sequence set forth in SEQ ID NO: 65, or one or more (preferably 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10) amino acids compared to said amino acid sequence set forth in SEQ ID NO: 65. FR-H2 comprises or consists of the amino acid sequence set forth in SEQ ID NO: 66, a sequence having at least 80%, 85% or 90%, preferably at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to said sequence set forth in SEQ ID NO: 66, or a sequence having one or more (preferably 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10) conservative amino acid mutations (preferably substitutions, insertions or deletions) compared to said amino acid sequence set forth in SEQ ID NO: 66; FR-H3 comprises or consists of the amino acid sequence set forth in SEQ ID NO: 67, a sequence having at least 80%, 85% or 90%, preferably at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to said sequence set forth in SEQ ID NO: 67, or an amino acid sequence having one or more (preferably 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10) conservative amino acid mutations (preferably substitutions, insertions or deletions) compared to said amino acid sequence set forth in SEQ ID NO: 67. and FR-H4 comprises or consists of the amino acid sequence set forth in SEQ ID NO: 68, a sequence having at least 80%, 85% or 90%, preferably at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to said sequence set forth in SEQ ID NO: 68, or an amino acid sequence having one or more (preferably 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10) conservative amino acid mutations (preferably substitutions, insertions or deletions) compared to said amino acid sequence set forth in SEQ ID NO: 68.

[0025] In one embodiment of the invention, the antibody further comprises the light chain variable region, preferably FR, comprising FR-L1, FR-L2, FR-L3 and FR-L4, wherein FR-L1 has the amino acid sequence set forth in SEQ ID NO: 69, a sequence having at least 80%, 85% or 90%, preferably at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to said sequence set forth in SEQ ID NO: 69, or one or more (preferably 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10) amino acids compared to said amino acid sequence set forth in SEQ ID NO: 69. FR-L2 comprises or consists of the amino acid sequence set forth in SEQ ID NO: 70, a sequence having at least 80%, 85% or 90%, preferably at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to said sequence set forth in SEQ ID NO: 70, or a sequence having one or more (preferably 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10) conservative amino acid mutations (preferably substitutions, insertions or deletions) compared to said amino acid sequence set forth in SEQ ID NO: 70. FR-L3 comprises or consists of the amino acid sequence set forth in SEQ ID NO: 71, a sequence having at least 80%, 85% or 90%, preferably at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to said sequence set forth in SEQ ID NO: 71, or an amino acid sequence having one or more (preferably 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10) conservative amino acid mutations (preferably substitutions, insertions or deletions) compared to said amino acid sequence set forth in SEQ ID NO: 71. and FR-L4 comprises or consists of the amino acid sequence set forth in SEQ ID NO: 72, a sequence having at least 80%, 85% or 90%, preferably at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to said sequence set forth in SEQ ID NO: 72, or an amino acid sequence having one or more (preferably 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10) conservative amino acid mutations (preferably substitutions, insertions or deletions) compared to said amino acid sequence set forth in SEQ ID NO: 72.

[0026] In one embodiment of the invention, the antibody further comprises the heavy chain variable region, preferably FRs comprising FR-H1, FR-H2, FR-H3 and FR-H4, wherein FR-H1 has the amino acid sequence set forth in SEQ ID NO: 73, a sequence having at least 80%, 85% or 90%, preferably at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to said sequence set forth in SEQ ID NO: 73, or one or more (preferably 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10) amino acids compared to said amino acid sequence set forth in SEQ ID NO: 73. FR-H2 comprises or consists of the amino acid sequence set forth in SEQ ID NO: 74, a sequence having at least 80%, 85% or 90%, preferably at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to said sequence set forth in SEQ ID NO: 74, or a sequence having one or more (preferably 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10) conservative amino acid mutations (preferably substitutions, insertions or deletions) compared to said amino acid sequence set forth in SEQ ID NO: 74; FR-H3 comprises or consists of the amino acid sequence set forth in SEQ ID NO: 75, a sequence having at least 80%, 85% or 90%, preferably at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to said sequence set forth in SEQ ID NO: 75, or an amino acid sequence having one or more (preferably 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10) conservative amino acid mutations (preferably substitutions, insertions or deletions) compared to said amino acid sequence set forth in SEQ ID NO: 75. and FR-H4 comprises or consists of the amino acid sequence set forth in SEQ ID NO: 76, a sequence having at least 80%, 85% or 90%, preferably at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to said sequence set forth in SEQ ID NO: 76, or an amino acid sequence having one or more (preferably 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10) conservative amino acid mutations (preferably substitutions, insertions or deletions) compared to said amino acid sequence set forth in SEQ ID NO: 76.

[0027] In one embodiment of the invention, the antibody further comprises the light chain variable region, preferably FR, comprising FR-L1, FR-L2, FR-L3 and FR-L4, wherein FR-L1 has the amino acid sequence set forth in SEQ ID NO: 77, a sequence having at least 80%, 85% or 90%, preferably at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to the sequence set forth in SEQ ID NO: 77, or one or more (preferably 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10) amino acids compared to the amino acid sequence set forth in SEQ ID NO: 77. FR-L2 comprises or consists of the amino acid sequence set forth in SEQ ID NO: 78, a sequence having at least 80%, 85% or 90%, preferably at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to said sequence set forth in SEQ ID NO: 78, or a sequence having one or more (preferably 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10) conservative amino acid mutations (preferably substitutions, insertions or deletions) compared to said amino acid sequence set forth in SEQ ID NO: 78. FR-L3 comprises or consists of the amino acid sequence set forth in SEQ ID NO: 79, a sequence having at least 80%, 85% or 90%, preferably at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to said sequence set forth in SEQ ID NO: 79, or an amino acid sequence having one or more (preferably 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10) conservative amino acid mutations (preferably substitutions, insertions or deletions) compared to said amino acid sequence set forth in SEQ ID NO: 79. and FR-L4 comprises or consists of the amino acid sequence set forth in SEQ ID NO: 80, a sequence having at least 80%, 85% or 90%, preferably at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%, sequence identity to said sequence set forth in SEQ ID NO: 80, or an amino acid sequence having one or more (preferably 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10) conservative amino acid mutations (preferably substitutions, insertions or deletions) compared to said amino acid sequence set forth in SEQ ID NO: 80.

[0028] In one embodiment of the invention, the antibody further comprises the heavy chain variable region, preferably FRs comprising FR-H1, FR-H2, FR-H3 and FR-H4, wherein FR-H1 has the amino acid sequence set forth in SEQ ID NO: 81, a sequence having at least 80%, 85% or 90%, preferably at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to said sequence set forth in SEQ ID NO: 81, or one or more (preferably 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10) amino acids compared to said amino acid sequence set forth in SEQ ID NO: 81. FR-H2 comprises or consists of the amino acid sequence set forth in SEQ ID NO: 82, a sequence having at least 80%, 85% or 90%, preferably at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to said sequence set forth in SEQ ID NO: 82, or a sequence having one or more (preferably 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10) conservative amino acid mutations (preferably substitutions, insertions or deletions) compared to said amino acid sequence set forth in SEQ ID NO: 82. FR-H3 comprises or consists of the amino acid sequence set forth in SEQ ID NO: 83, a sequence having at least 80%, 85% or 90%, preferably at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to said sequence set forth in SEQ ID NO: 83, or an amino acid sequence having one or more (preferably 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10) conservative amino acid mutations (preferably substitutions, insertions or deletions) compared to said amino acid sequence set forth in SEQ ID NO: 83. and FR-H4 comprises or consists of the amino acid sequence set forth in SEQ ID NO: 84, a sequence having at least 80%, 85% or 90%, preferably at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to said sequence set forth in SEQ ID NO: 84, or an amino acid sequence having one or more (preferably 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10) conservative amino acid mutations (preferably substitutions, insertions or deletions) compared to said amino acid sequence set forth in SEQ ID NO: 84.

[0029] In one embodiment of the invention, the antibody further comprises the light chain variable region, preferably FR, comprising FR-L1, FR-L2, FR-L3 and FR-L4, wherein FR-L1 has the amino acid sequence set forth in SEQ ID NO: 85, a sequence having at least 80%, 85% or 90%, preferably at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to the sequence set forth in SEQ ID NO: 85, or one or more (preferably 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10) amino acids compared to the amino acid sequence set forth in SEQ ID NO: 85. FR-L2 comprises or consists of an amino acid sequence having conservative amino acid mutations (preferably substitutions, insertions or deletions); FR-L2 comprises the amino acid sequence set forth in SEQ ID NO: 86, a sequence having at least 80%, 85% or 90%, preferably at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to said sequence set forth in SEQ ID NO: 86, or a sequence having one or more (preferably 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10) conservative amino acid mutations (preferably substitutions, insertions or deletions) compared to said amino acid sequence set forth in SEQ ID NO: 86. FR-L3 comprises or consists of the amino acid sequence set forth in SEQ ID NO: 87, a sequence having at least 80%, 85% or 90%, preferably at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to said sequence set forth in SEQ ID NO: 87, or an amino acid sequence having one or more (preferably 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10) conservative amino acid mutations (preferably substitutions, insertions or deletions) compared to said amino acid sequence set forth in SEQ ID NO: 87. and FR-L4 comprises or consists of the amino acid sequence set forth in SEQ ID NO: 88, a sequence having at least 80%, 85% or 90%, preferably at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to said sequence set forth in SEQ ID NO: 88, or an amino acid sequence having one or more (preferably 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10) conservative amino acid mutations (preferably substitutions, insertions or deletions) compared to said amino acid sequence set forth in SEQ ID NO: 88.

[0030] In one embodiment of the invention, the antibody further comprises the heavy chain variable region, preferably FR, comprising FR-H1, FR-H2, FR-H3 and FR-H4, wherein FR-H1 has the amino acid sequence set forth in SEQ ID NO: 89, a sequence having at least 80%, 85% or 90%, preferably at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to said sequence set forth in SEQ ID NO: 89, or one or more (preferably 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10) amino acids compared to said amino acid sequence set forth in SEQ ID NO: 89. FR-H2 comprises or consists of the amino acid sequence set forth in SEQ ID NO: 90, a sequence having at least 80%, 85% or 90%, preferably at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to said sequence set forth in SEQ ID NO: 90, or a sequence having one or more (preferably 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10) conservative amino acid mutations (preferably substitutions, insertions or deletions) compared to said amino acid sequence set forth in SEQ ID NO: 90. FR-H3 comprises or consists of the amino acid sequence set forth in SEQ ID NO: 91, a sequence having at least 80%, 85% or 90%, preferably at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to said sequence set forth in SEQ ID NO: 91, or an amino acid sequence having one or more (preferably 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10) conservative amino acid mutations (preferably substitutions, insertions or deletions) compared to said amino acid sequence set forth in SEQ ID NO: 91. and FR-H4 comprises or consists of the amino acid sequence set forth in SEQ ID NO: 92, a sequence having at least 80%, 85% or 90%, preferably at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to said sequence set forth in SEQ ID NO: 92, or an amino acid sequence having one or more (preferably 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10) conservative amino acid mutations (preferably substitutions, insertions or deletions) compared to said amino acid sequence set forth in SEQ ID NO: 92.

[0031] In one embodiment of the invention, the antibody further comprises the light chain variable region, preferably FR, comprising FR-L1, FR-L2, FR-L3 and FR-L4, wherein FR-L1 has the amino acid sequence set forth in SEQ ID NO: 93, a sequence having at least 80%, 85% or 90%, preferably at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to said sequence set forth in SEQ ID NO: 93, or one or more (preferably 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10) amino acids compared to said amino acid sequence set forth in SEQ ID NO: 93. FR-L2 comprises or consists of the amino acid sequence set forth in SEQ ID NO: 94, a sequence having at least 80%, 85% or 90%, preferably at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to said sequence set forth in SEQ ID NO: 94, or a sequence having one or more (preferably 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10) conservative amino acid mutations (preferably substitutions, insertions or deletions) compared to said amino acid sequence set forth in SEQ ID NO: 94. FR-L3 comprises or consists of the amino acid sequence set forth in SEQ ID NO: 95, a sequence having at least 80%, 85% or 90%, preferably at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to said sequence set forth in SEQ ID NO: 95, or an amino acid sequence having one or more (preferably 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10) conservative amino acid mutations (preferably substitutions, insertions or deletions) compared to said amino acid sequence set forth in SEQ ID NO: 95. and FR-L4 comprises or consists of the amino acid sequence set forth in SEQ ID NO: 96, a sequence having at least 80%, 85% or 90%, preferably at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to said sequence set forth in SEQ ID NO: 96, or an amino acid sequence having one or more (preferably 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10) conservative amino acid mutations (preferably substitutions, insertions or deletions) compared to said amino acid sequence set forth in SEQ ID NO: 96.

[0032] In one embodiment of the invention, the antibody further comprises the heavy chain variable region, preferably FR, comprising FR-H1, FR-H2, FR-H3 and FR-H4, wherein FR-H1 has the amino acid sequence set forth in SEQ ID NO: 97, a sequence having at least 80%, 85% or 90%, preferably at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to said sequence set forth in SEQ ID NO: 97, or one or more (preferably 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10) amino acids compared to said amino acid sequence set forth in SEQ ID NO: 97. FR-H2 comprises or consists of an amino acid sequence having conservative amino acid mutations (preferably substitutions, insertions or deletions); FR-H2 comprises or consists of the amino acid sequence set forth in SEQ ID NO: 98, a sequence having at least 80%, 85% or 90%, preferably at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to said sequence set forth in SEQ ID NO: 98, or a sequence having one or more (preferably 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10) conservative amino acid mutations (preferably substitutions, insertions or deletions) compared to said amino acid sequence set forth in SEQ ID NO: 98. FR-H3 comprises or consists of an amino acid sequence having one or more (preferably 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10) conservative amino acid mutations (preferably substitutions, insertions or deletions) compared to the amino acid sequence set forth in SEQ ID NO: 99; FR-H4 comprises or consists of an amino acid sequence set forth in SEQ ID NO: 99, a sequence having at least 80%, 85% or 90%, preferably at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to said sequence set forth in SEQ ID NO: 99, or an amino acid sequence having one or more (preferably 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10) conservative amino acid mutations (preferably substitutions, insertions or deletions) compared to said amino acid sequence set forth in SEQ ID NO: 99. and FR-H4 comprises or consists of the amino acid sequence set forth in SEQ ID NO: 100, a sequence having at least 80%, 85% or 90%, preferably at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to said sequence set forth in SEQ ID NO: 100, or an amino acid sequence having one or more (preferably 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10) conservative amino acid mutations (preferably substitutions, insertions or deletions) compared to said amino acid sequence set forth in SEQ ID NO: 100.

[0033] In one embodiment of the invention, the antibody further comprises the light chain variable region, preferably FR, comprising FR-L1, FR-L2, FR-L3 and FR-L4, wherein FR-L1 has the amino acid sequence set forth in SEQ ID NO: 101, a sequence having at least 80%, 85% or 90%, preferably at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to said sequence set forth in SEQ ID NO: 101, or one or more (preferably 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10) amino acids compared to said amino acid sequence set forth in SEQ ID NO: 101. FR-L2 comprises or consists of the amino acid sequence set forth in SEQ ID NO: 102, a sequence having at least 80%, 85% or 90%, preferably at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to said sequence set forth in SEQ ID NO: 102, or a sequence having one or more (preferably 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10) conservative amino acid mutations (preferably substitutions, insertions or deletions) compared to said amino acid sequence set forth in SEQ ID NO: 102. FR-L3 comprises or consists of the amino acid sequence set forth in SEQ ID NO: 103, a sequence having at least 80%, 85% or 90%, preferably at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to said sequence set forth in SEQ ID NO: 103, or an amino acid sequence having one or more (preferably 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10) conservative amino acid mutations (preferably substitutions, insertions or deletions) compared to said amino acid sequence set forth in SEQ ID NO: 103. and FR-L4 comprises or consists of the amino acid sequence set forth in SEQ ID NO: 104, a sequence having at least 80%, 85% or 90%, preferably at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to said sequence set forth in SEQ ID NO: 104, or an amino acid sequence having one or more (preferably 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10) conservative amino acid mutations (preferably substitutions, insertions or deletions) compared to said amino acid sequence set forth in SEQ ID NO: 104.

[0034] In one embodiment of the invention, the antibody further comprises the heavy chain variable region, preferably FR, comprising FR-H1, FR-H2, FR-H3 and FR-H4, wherein FR-H1 has the amino acid sequence set forth in SEQ ID NO: 105, a sequence having at least 80%, 85% or 90%, preferably at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to said sequence set forth in SEQ ID NO: 105, or one or more (preferably 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10) amino acids compared to said amino acid sequence set forth in SEQ ID NO: 105. FR-H2 comprises or consists of the amino acid sequence set forth in SEQ ID NO: 106, a sequence having at least 80%, 85% or 90%, preferably at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to said sequence set forth in SEQ ID NO: 106, or one or more (preferably 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10) conservative amino acid mutations (preferably substitutions, insertions or deletions) compared to said amino acid sequence set forth in SEQ ID NO: 106; FR-H3 comprises or consists of the amino acid sequence set forth in SEQ ID NO: 107, a sequence having at least 80%, 85% or 90%, preferably at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to said sequence set forth in SEQ ID NO: 107, or an amino acid sequence having one or more (preferably 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10) conservative amino acid mutations (preferably substitutions, insertions or deletions) compared to said amino acid sequence set forth in SEQ ID NO: 107. and FR-H4 comprises or consists of the amino acid sequence set forth in SEQ ID NO: 108, a sequence having at least 80%, 85% or 90%, preferably at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to said sequence set forth in SEQ ID NO: 108, or an amino acid sequence having one or more (preferably 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10) conservative amino acid mutations (preferably substitutions, insertions or deletions) compared to said amino acid sequence set forth in SEQ ID NO: 108.

[0035] In one embodiment of the invention, the antibody further comprises said light chain variable region, preferably FR comprising FR-L1, FR-L2, FR-L3 and FR-L4, wherein FR-L1 has the amino acid sequence set forth in SEQ ID NO: 109, a sequence having at least 80%, 85% or 90%, preferably at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to said sequence set forth in SEQ ID NO: 109, or one or more (preferably 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10) amino acids identical to said amino acid sequence set forth in SEQ ID NO: 109. FR-L2 comprises or consists of the amino acid sequence set forth in SEQ ID NO: 110, a sequence having at least 80%, 85% or 90%, preferably at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to said sequence set forth in SEQ ID NO: 110, or a sequence having one or more (preferably 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10) conservative amino acid mutations (preferably substitutions, insertions or deletions) compared to said amino acid sequence set forth in SEQ ID NO: 110; FR-L3 comprises or consists of the amino acid sequence set forth in SEQ ID NO: 111, a sequence having at least 80%, 85% or 90%, preferably at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to said sequence set forth in SEQ ID NO: 111, or an amino acid sequence having one or more (preferably 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10) conservative amino acid mutations (preferably substitutions, insertions or deletions) compared to the amino acid sequence set forth in SEQ ID NO: 111. and FR-L4 comprises or consists of the amino acid sequence set forth in SEQ ID NO: 112, a sequence having at least 80%, 85% or 90%, preferably at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to said sequence set forth in SEQ ID NO: 112, or an amino acid sequence having one or more (preferably 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10) conservative amino acid mutations (preferably substitutions, insertions or deletions) compared to said amino acid sequence set forth in SEQ ID NO: 112.

[0036] In one embodiment of the invention, the antibody further comprises the heavy chain variable region, preferably FRs comprising FR-H1, FR-H2, FR-H3 and FR-H4, wherein FR-H1 has the amino acid sequence set forth in SEQ ID NO: 113, a sequence having at least 80%, 85% or 90%, preferably at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to said sequence set forth in SEQ ID NO: 113, or one or more (preferably 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10) amino acids compared to said amino acid sequence set forth in SEQ ID NO: 113. FR-H2 comprises or consists of the amino acid sequence set forth in SEQ ID NO: 114, a sequence having at least 80%, 85% or 90%, preferably at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to said sequence set forth in SEQ ID NO: 114, or a sequence having one or more (preferably 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10) conservative amino acid mutations (preferably substitutions, insertions or deletions) compared to said amino acid sequence set forth in SEQ ID NO: 114; FR-H3 comprises or consists of the amino acid sequence set forth in SEQ ID NO: 115, a sequence having at least 80%, 85% or 90%, preferably at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to said sequence set forth in SEQ ID NO: 115, or an amino acid sequence having one or more (preferably 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10) conservative amino acid mutations (preferably substitutions, insertions or deletions) compared to said amino acid sequence set forth in SEQ ID NO: 115. and FR-H4 comprises or consists of the amino acid sequence set forth in SEQ ID NO: 116, a sequence having at least 80%, 85% or 90%, preferably at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to said sequence set forth in SEQ ID NO: 116, or an amino acid sequence having one or more (preferably 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10) conservative amino acid mutations (preferably substitutions, insertions or deletions) compared to said amino acid sequence set forth in SEQ ID NO: 116.

[0037] In one embodiment of the invention, the antibody further comprises the light chain variable region, preferably FR, comprising FR-L1, FR-L2, FR-L3 and FR-L4, wherein FR-L1 has the amino acid sequence set forth in SEQ ID NO: 117, a sequence having at least 80%, 85% or 90%, preferably at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to said sequence set forth in SEQ ID NO: 117, or one or more (preferably 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10) amino acids compared to said amino acid sequence set forth in SEQ ID NO: 117. FR-L2 comprises or consists of the amino acid sequence set forth in SEQ ID NO: 118, a sequence having at least 80%, 85% or 90%, preferably at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to said sequence set forth in SEQ ID NO: 118, or one or more (preferably 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10) conservative amino acid mutations (preferably substitutions, insertions or deletions) compared to said amino acid sequence set forth in SEQ ID NO: 118. FR-L3 comprises or consists of the amino acid sequence set forth in SEQ ID NO: 119, a sequence having at least 80%, 85% or 90%, preferably at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to said sequence set forth in SEQ ID NO: 119, or an amino acid sequence having one or more (preferably 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10) conservative amino acid mutations (preferably substitutions, insertions or deletions) compared to said amino acid sequence set forth in SEQ ID NO: 119. and FR-L4 comprises or consists of the amino acid sequence set forth in SEQ ID NO: 120, a sequence having at least 80%, 85% or 90%, preferably at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to said sequence set forth in SEQ ID NO: 120, or an amino acid sequence having one or more (preferably 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10) conservative amino acid mutations (preferably substitutions, insertions or deletions) compared to said amino acid sequence set forth in SEQ ID NO: 120.

[0038] In one embodiment of the invention, the antibody further comprises the heavy chain variable region, preferably FR, comprising FR-H1, FR-H2, FR-H3 and FR-H4, wherein FR-H1 has the amino acid sequence set forth in SEQ ID NO: 136, a sequence having at least 80%, 85% or 90%, preferably at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to said sequence set forth in SEQ ID NO: 136, or one or more (preferably 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10) amino acids compared to said amino acid sequence set forth in SEQ ID NO: 136. FR-H2 comprises or consists of the amino acid sequence set forth in SEQ ID NO: 137, a sequence having at least 80%, 85% or 90%, preferably at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to said sequence set forth in SEQ ID NO: 137, or one or more (preferably 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10) conservative amino acid mutations (preferably substitutions, insertions or deletions) compared to said amino acid sequence set forth in SEQ ID NO: 137; FR-H3 comprises or consists of the amino acid sequence set forth in SEQ ID NO: 138, a sequence having at least 80%, 85% or 90%, preferably at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to said sequence set forth in SEQ ID NO: 138, or an amino acid sequence having one or more (preferably 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10) conservative amino acid mutations (preferably substitutions, insertions or deletions) compared to said amino acid sequence set forth in SEQ ID NO: 138. and FR-H4 comprises or consists of the amino acid sequence set forth in SEQ ID NO: 139, a sequence having at least 80%, 85% or 90%, preferably at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to said sequence set forth in SEQ ID NO: 139, or an amino acid sequence having one or more (preferably 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10) conservative amino acid mutations (preferably substitutions, insertions or deletions) compared to said amino acid sequence set forth in SEQ ID NO: 139.

[0039] In one embodiment of the invention, the antibody further comprises the light chain variable region, preferably FR, comprising FR-L1, FR-L2, FR-L3 and FR-L4, wherein FR-L1 has the amino acid sequence set forth in SEQ ID NO: 140, a sequence having at least 80%, 85% or 90%, preferably at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to said sequence set forth in SEQ ID NO: 140, or one or more (preferably 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10) amino acids compared to said amino acid sequence set forth in SEQ ID NO: 140. FR-L2 comprises or consists of the amino acid sequence set forth in SEQ ID NO: 141, a sequence having at least 80%, 85% or 90%, preferably at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to said sequence set forth in SEQ ID NO: 141, or a sequence having one or more (preferably 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10) conservative amino acid mutations (preferably substitutions, insertions or deletions) compared to said amino acid sequence set forth in SEQ ID NO: 141. FR-L3 comprises or consists of the amino acid sequence set forth in SEQ ID NO: 142, a sequence having at least 80%, 85% or 90%, preferably at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to said sequence set forth in SEQ ID NO: 142, or an amino acid sequence having one or more (preferably 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10) conservative amino acid mutations (preferably substitutions, insertions or deletions) compared to said amino acid sequence set forth in SEQ ID NO: 142. and FR-L4 comprises or consists of the amino acid sequence set forth in SEQ ID NO: 143, a sequence having at least 80%, 85% or 90%, preferably at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to said sequence set forth in SEQ ID NO: 143, or an amino acid sequence having one or more (preferably 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10) conservative amino acid mutations (preferably substitutions, insertions or deletions) compared to said amino acid sequence set forth in SEQ ID NO: 143.

[0040] One aspect of the present invention relates to an isolated polypeptide comprising the sequence set forth in SEQ ID NOs: 9, 10 and 11, wherein the polypeptide specifically binds to human IL4RA as part of an anti-human IL4RA antibody, and the antibody further comprises the sequence set forth in SEQ ID NOs: 12, 13 and 14.

[0041] One aspect of the present invention relates to an isolated polypeptide comprising the sequence set forth in SEQ ID NOs: 15, 16 and 17, wherein the polypeptide specifically binds to human IL4RA as part of an anti-human IL4RA antibody, and the antibody further comprises the sequence set forth in SEQ ID NOs: 18, 19 and 20.

[0042] One aspect of the present invention relates to an isolated polypeptide comprising the sequence set forth in SEQ ID NOs: 12, 13 and 14, wherein the polypeptide specifically binds to human IL4RA as part of an anti-human IL4RA antibody, and the antibody further comprises the sequence set forth in SEQ ID NOs: 9, 10 and 11.

[0043] One aspect of the present invention relates to an isolated polypeptide comprising the sequence set forth in SEQ ID NOs: 18, 19 and 20, wherein the polypeptide specifically binds to human IL4RA as part of an anti-human IL4RA antibody, and the antibody further comprises the sequence set forth in SEQ ID NOs: 15, 16 and 17.

[0044] One aspect of the present invention relates to an isolated polypeptide comprising the sequence set forth in SEQ ID NOs: 130, 131 and 132, wherein the polypeptide specifically binds to human IL4RA as part of an anti-human IL4RA antibody, and the antibody further comprises the sequence set forth in SEQ ID NOs: 133, 134 and 135.

[0045] One aspect of the present invention relates to an isolated polypeptide comprising the sequence set forth in SEQ ID NOs: 133, 134 and 135, wherein The polypeptide specifically binds to human IL4RA as part of an anti-human IL4RA antibody, the antibody further comprising the sequences set forth in SEQ ID NOs: 130, 131 and 132.

[0046] One aspect of the present invention is 2. An isolated polypeptide comprising a sequence selected from the sequences set forth in SEQ ID NOs: 2, 6, 22, 26, 30, 34 and 38, a sequence having at least 80%, 85% or 90%, preferably at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to said sequence, or an amino acid sequence having one or more (preferably 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10) conservative amino acid mutations (preferably substitutions, insertions or deletions) compared to said sequence, wherein said polypeptide is used in combination with human IL4RA as part of an anti-human IL4RA antibody. an isolated polypeptide that specifically binds to human IL4RA, wherein the antibody further comprises an amino acid sequence selected from the sequences set forth in SEQ ID NOs: 4, 8, 24, 28, 32, 36 and 40, or a sequence having at least 80%, 85% or 90%, preferably at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%, sequence identity to said sequence, or an amino acid sequence having one or more (preferably 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10) conservative amino acid mutations (preferably substitutions, insertions or deletions) compared to said sequence; 1. An isolated polypeptide comprising a sequence selected from the sequence set forth in SEQ ID NO: 42, a sequence having at least 80%, 85% or 90%, preferably at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to said sequence, or an amino acid sequence having one or more (preferably 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10) conservative amino acid mutations (preferably substitutions, insertions or deletions) compared to said sequence, wherein said polypeptide is a portion of an anti-human IL4RA antibody. an isolated polypeptide which specifically binds to human IL4RA as SEQ ID NO: 44, wherein the antibody further comprises an amino acid sequence selected from the sequence set forth in SEQ ID NO: 44, a sequence having at least 80%, 85% or 90%, preferably at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%, sequence identity to said sequence, or an amino acid sequence having one or more (preferably 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10) conservative amino acid mutations (preferably substitutions, insertions or deletions) compared to said sequence; 1. An isolated polypeptide comprising a sequence selected from the sequence set forth in SEQ ID NO: 42, a sequence having at least 80%, 85% or 90%, preferably at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to said sequence, or an amino acid sequence having one or more (preferably 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10) conservative amino acid mutations (preferably substitutions, insertions or deletions) compared to said sequence, wherein said polypeptide is a portion of an anti-human IL4RA antibody. an isolated polypeptide which specifically binds to human IL4RA as SEQ ID NO: 48, wherein the antibody further comprises an amino acid sequence selected from the sequence set forth in SEQ ID NO: 48, a sequence having at least 80%, 85% or 90%, preferably at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%, sequence identity to said sequence, or an amino acid sequence having one or more (preferably 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10) conservative amino acid mutations (preferably substitutions, insertions or deletions) compared to said sequence; 1. An isolated polypeptide comprising a sequence selected from the sequence set forth in SEQ ID NO: 46, a sequence having at least 80%, 85% or 90%, preferably at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to said sequence, or an amino acid sequence having one or more (preferably 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10) conservative amino acid mutations (preferably substitutions, insertions or deletions) compared to said sequence, wherein said polypeptide is used as part of an anti-human IL4RA antibody. or an isolated polypeptide which specifically binds to human IL4RA, wherein the antibody further comprises a sequence selected from the sequence set forth in SEQ ID NO: 48, a sequence having at least 80%, 85% or 90%, preferably at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to said sequence, or an amino acid sequence having one or more (preferably 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10) conservative amino acid mutations (preferably substitutions, insertions or deletions) compared to said sequence; or 1. An isolated polypeptide comprising a sequence selected from the sequence set forth in SEQ ID NO: 34, a sequence having at least 80%, 85% or 90%, preferably at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to said sequence, or an amino acid sequence having one or more (preferably 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10) conservative amino acid mutations (preferably substitutions, insertions or deletions) compared to said sequence, wherein said polypeptide is a portion of an anti-human IL4RA antibody. 28. An isolated polypeptide that specifically binds to human IL4RA as Regarding.

[0047] One aspect of the present invention is 1. An isolated polypeptide comprising a sequence selected from the sequences set forth in SEQ ID NOs: 4, 8, 24, 28, 32, 36 and 40, a sequence having at least 80%, 85% or 90%, preferably at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to said sequence, or an amino acid sequence having one or more (preferably 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10) conservative amino acid mutations (preferably substitutions, insertions or deletions) compared to said sequence, wherein said polypeptide is used as part of an anti-human IL4RA antibody. an isolated polypeptide which specifically binds to human IL4RA, wherein the antibody further comprises a sequence selected from the sequences set forth in SEQ ID NOs: 2, 6, 22, 26, 30, 34 and 38, respectively, a sequence having at least 80%, 85% or 90%, preferably at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to said antibody, or an amino acid sequence having one or more (preferably 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10) conservative amino acid mutations (preferably substitutions, insertions or deletions) compared to said sequence; 1. An isolated polypeptide comprising a sequence selected from the sequence set forth in SEQ ID NO: 44, a sequence having at least 80%, 85% or 90%, preferably at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to said sequence, or an amino acid sequence having one or more (preferably 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10) conservative amino acid mutations (preferably substitutions, insertions or deletions) compared to said sequence, wherein said polypeptide is a portion of an anti-human IL4RA antibody. an isolated polypeptide which specifically binds to human IL4RA and which antibody further comprises a sequence selected from the sequence set forth in SEQ ID NO: 42, a sequence having at least 80%, 85% or 90%, preferably at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to said sequence, or an amino acid sequence having one or more (preferably 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10) conservative amino acid mutations (preferably substitutions, insertions or deletions) compared to said sequence; 1. An isolated polypeptide comprising a sequence selected from the sequence set forth in SEQ ID NO: 48, a sequence having at least 80%, 85% or 90%, preferably at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to said sequence, or an amino acid sequence having one or more (preferably 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10) conservative amino acid mutations (preferably substitutions, insertions or deletions) compared to said sequence, wherein said polypeptide is a portion of an anti-human IL4RA antibody. an isolated polypeptide which specifically binds to human IL4RA and which antibody further comprises a sequence selected from the sequence set forth in SEQ ID NO: 42, a sequence having at least 80%, 85% or 90%, preferably at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to said sequence, or an amino acid sequence having one or more (preferably 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10) conservative amino acid mutations (preferably substitutions, insertions or deletions) compared to said sequence; 1. An isolated polypeptide comprising a sequence selected from the sequence set forth in SEQ ID NO: 48, a sequence having at least 80%, 85% or 90%, preferably at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to said sequence, or an amino acid sequence having one or more (preferably 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10) conservative amino acid mutations (preferably substitutions, insertions or deletions) compared to said sequence, wherein said polypeptide is a portion of an anti-human IL4RA antibody. an isolated polypeptide which specifically binds to human IL4RA and which antibody further comprises a sequence selected from the sequence set forth in SEQ ID NO: 46, a sequence having at least 80%, 85% or 90%, preferably at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to said sequence, or an amino acid sequence having one or more (preferably 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10) conservative amino acid mutations (preferably substitutions, insertions or deletions) compared to said sequence; 2. An isolated polypeptide comprising a sequence selected from the sequence set forth in SEQ ID NO: 28, a sequence having at least 80%, 85% or 90%, preferably at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to said sequence, or an amino acid sequence having one or more (preferably 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10) conservative amino acid mutations (preferably substitutions, insertions or deletions) compared to said sequence, wherein said polypeptide is a portion of an anti-human IL4RA antibody. an isolated polypeptide which specifically binds to human IL4RA and which antibody further comprises a sequence selected from the sequence set forth in SEQ ID NO: 34, a sequence having at least 80%, 85% or 90%, preferably at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to said sequence, or an amino acid sequence having one or more (preferably 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10) conservative amino acid mutations (preferably substitutions, insertions or deletions) compared to said sequence; 1. An isolated polypeptide comprising a sequence selected from the sequence set forth in SEQ ID NO: 127, a sequence having at least 80%, 85% or 90%, preferably at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to said sequence, or an amino acid sequence having one or more (preferably 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10) conservative amino acid mutations (preferably substitutions, insertions or deletions) compared to said sequence, wherein said polypeptide is used as part of an anti-human IL4RA antibody. or an isolated polypeptide which specifically binds to human IL4RA, wherein the antibody further comprises a sequence selected from the sequence set forth in SEQ ID NO: 129, a sequence having at least 80%, 85% or 90%, preferably at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to said sequence, or an amino acid sequence having one or more (preferably 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10) conservative amino acid mutations (preferably substitutions, insertions or deletions) compared to said sequence; or 1. An isolated polypeptide comprising a sequence selected from the sequence set forth in SEQ ID NO: 129, a sequence having at least 80%, 85% or 90%, preferably at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to said sequence, or an amino acid sequence having one or more (preferably 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10) conservative amino acid mutations (preferably substitutions, insertions or deletions) compared to said sequence, wherein said polypeptide is used as part of an anti-human IL4RA antibody. and specifically binds to human IL4RA, wherein said antibody further comprises an amino acid sequence selected from the sequence set forth in SEQ ID NO: 127, or a sequence having at least 80%, 85% or 90%, preferably at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%, sequence identity to said sequence, or an amino acid sequence having one or more (preferably 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10) conservative amino acid mutations (preferably substitutions, insertions or deletions) compared to said sequence.

[0048] In one embodiment of the invention, the antigen-binding fragment is selected from Fab, Fab', F(ab')2, Fd, Fv, dAb, Fab / c, a complementarity determining region (CDR) fragment, a single chain antibody (e.g., scFv), a bivalent antibody, and a domain antibody.

[0049] In one embodiment of the invention, the antibody is a humanized antibody, a chimeric antibody or a multispecific antibody (e.g., a bispecific antibody).

[0050] In one embodiment of the invention, the antibody is about 10 -5 Less than, for example, about 10 -6 M, 10 -7 M, 10 -8 M, 10 -9 M or 10 -10 K below M D Preferably, the K D is measured by a Fortebio molecular interaction instrument.

[0051] In one embodiment of the invention, the antibody has an EC of less than about 100 nM, for example about 10 nM, 1 nM, 0.9 nM, 0.8 nM, 0.7 nM, 0.6 nM, 0.5 nM, 0.4 nM, 0.3 nM, 0.2 nM, 0.1 nM or less. 50 It binds to the human IL4RA protein. 50 is measured by indirect ELISA.

[0052] In one embodiment of the invention, the antibody comprises a constant region, and the constant region is derived from a species other than mouse, such as a human antibody, preferably human IgG, more preferably IgG4.

[0053] In one embodiment of the invention, the constant region of the antibody is humanized, e.g., the heavy chain constant region is the Igγ-4 chain C region of GenBank Accession No. P01861.1, preferably the Igγ-4 chain C region; and the light chain constant region is the Igκ chain C region, preferably the Igκ chain C region of GenBank Accession No. P01834.

[0054] Another aspect of the present invention relates to an isolated polynucleotide encoding a polypeptide comprising the sequences set forth in SEQ ID NOs: 9, 10 and 11, wherein said polypeptide specifically binds to human IL4RA as part of an anti-human IL4RA antibody, said antibody further comprising the sequences set forth in SEQ ID NOs: 12, 13 and 14.

[0055] One aspect of the present invention relates to an isolated polynucleotide encoding a polypeptide comprising the sequences set forth in SEQ ID NOs: 15, 16 and 17, wherein said polypeptide specifically binds to human IL4RA as part of an anti-human IL4RA antibody, said antibody further comprising the sequences set forth in SEQ ID NOs: 18, 19 and 20.

[0056] One aspect of the present invention relates to an isolated polynucleotide encoding a polypeptide comprising the sequences set forth in SEQ ID NOs: 12, 13 and 14, wherein said polypeptide specifically binds to human IL4RA as part of an anti-human IL4RA antibody, and said antibody further comprises the sequences set forth in SEQ ID NOs: 9, 10 and 11.

[0057] One aspect of the present invention relates to an isolated polynucleotide encoding a polypeptide comprising the sequences set forth in SEQ ID NOs: 18, 19 and 20, wherein said polypeptide specifically binds to human IL4RA as part of an anti-human IL4RA antibody, and said antibody further comprises the sequences set forth in SEQ ID NOs: 15, 16 and 17.

[0058] One aspect of the present invention relates to an isolated polynucleotide encoding a polypeptide comprising the sequences set forth in SEQ ID NOs: 130, 131 and 132, wherein said polypeptide specifically binds to human IL4RA as part of an anti-human IL4RA antibody, and said antibody further comprises the sequences set forth in SEQ ID NOs: 133, 134 and 135.

[0059] One aspect of the present invention relates to an isolated polynucleotide encoding a polypeptide comprising the sequences set forth in SEQ ID NOs: 133, 134 and 135, wherein said polypeptide specifically binds to human IL4RA as part of an anti-human IL4RA antibody, and said antibody further comprises the sequences set forth in SEQ ID NOs: 130, 131 and 132.

[0060] One aspect of the present invention is 1. An isolated polynucleotide encoding a polypeptide comprising a sequence selected from the sequences set forth in SEQ ID NOs: 2, 6, 22, 26, 30, 34 and 38, a sequence having at least 80%, 85% or 90%, preferably at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to said sequence, or an amino acid sequence having one or more (preferably 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10) conservative amino acid mutations (preferably substitutions, insertions or deletions) compared to said sequence, wherein said polypeptide is an anti-human IL4RA antibody. an isolated polynucleotide that specifically binds to human IL4RA as part of a polypeptide chain, said antibody further comprising a sequence selected from the sequences set forth in SEQ ID NOs: 4, 8, 24, 28, 32, 36 and 40, respectively, a sequence having at least 80%, or 90%, preferably at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to said sequence, or an amino acid sequence having one or more (preferably 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10) conservative amino acid mutations (preferably substitutions, insertions or deletions) compared to said sequence; 1. An isolated polynucleotide encoding a polypeptide comprising a sequence selected from the sequence set forth in SEQ ID NO: 42, a sequence having at least 80%, 85% or 90%, preferably at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to said sequence, or an amino acid sequence having one or more (preferably 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10) conservative amino acid mutations (preferably substitutions, insertions or deletions) compared to said sequence, wherein said polypeptide is an anti-human IL4RA antibody. an isolated polynucleotide which specifically binds to human IL4RA as part of an antibody, said antibody further comprising a sequence selected from the sequence set forth in SEQ ID NO: 44, a sequence having at least 80%, 85% or 90%, preferably at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to said sequence, or an amino acid sequence having one or more (preferably 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10) conservative amino acid mutations (preferably substitutions, insertions or deletions) compared to said sequence; 1. An isolated polynucleotide encoding a polypeptide comprising a sequence selected from the sequence set forth in SEQ ID NO: 42, a sequence having at least 80%, 85% or 90%, preferably at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to said sequence, or an amino acid sequence having one or more (preferably 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10) conservative amino acid mutations (preferably substitutions, insertions or deletions) compared to said sequence, wherein said polypeptide is an anti-human IL4RA antibody. an isolated polynucleotide which specifically binds to human IL4RA as part of an antibody, said antibody further comprising a sequence selected from the sequence set forth in SEQ ID NO: 48, a sequence having at least 80%, 85% or 90%, preferably at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to said sequence, or an amino acid sequence having one or more (preferably 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10) conservative amino acid mutations (preferably substitutions, insertions or deletions) compared to said sequence; 1. An isolated polynucleotide encoding a polypeptide comprising a sequence selected from the sequence set forth in SEQ ID NO: 46, a sequence having at least 80%, 85% or 90%, preferably at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to said sequence, or an amino acid sequence having one or more (preferably 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10) conservative amino acid mutations (preferably substitutions, insertions or deletions) compared to said sequence, wherein said polypeptide is an anti-human IL4RA antibody. or an isolated polynucleotide which specifically binds to human IL-4RA as part of 1. An isolated polynucleotide encoding a polypeptide comprising a sequence selected from the sequence set forth in SEQ ID NO: 34, a sequence having at least 80%, 85% or 90%, preferably at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to said sequence, or an amino acid sequence having one or more (preferably 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10) conservative amino acid mutations (preferably substitutions, insertions or deletions) compared to said sequence, wherein said polypeptide is an anti-human IL4RA antibody. The present invention relates to an isolated polynucleotide that specifically binds to human IL4RA as part of a polypeptide chain, wherein the antibody further comprises an amino acid sequence selected from the sequence set forth in SEQ ID NO: 28, a sequence having at least 80%, 85% or 90%, preferably at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%, sequence identity to said sequence, or an amino acid sequence having one or more (preferably 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10) conservative amino acid mutations (preferably substitutions, insertions or deletions) compared to said sequence.

[0061] One aspect of the present invention is 1. An isolated polynucleotide encoding a polypeptide comprising a sequence selected from the sequences set forth in SEQ ID NOs: 4, 8, 24, 28, 32, 36 and 40, a sequence having at least 80%, 85% or 90%, preferably at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to said sequence, or an amino acid sequence having one or more (preferably 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10) conservative amino acid mutations (preferably substitutions, insertions or deletions) compared to said sequence, wherein said polypeptide is an anti-human IL4RA antibody. an isolated polynucleotide which specifically binds to human IL4RA as part of an antibody, said antibody further comprising a sequence selected from the sequences set forth in SEQ ID NOs: 2, 6, 22, 26, 30, 34 and 38, respectively, a sequence having at least 80%, or 90%, preferably at least 91%, 92%, 93%, 94%, 85%, 96%, 97%, 98% or 99% sequence identity to said sequence, or an amino acid sequence having one or more (preferably 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10) conservative amino acid mutations (preferably substitutions, insertions or deletions) compared to said sequence; 1. An isolated polynucleotide encoding a polypeptide comprising a sequence selected from the sequence set forth in SEQ ID NO: 44, a sequence having at least 80%, 85% or 90%, preferably at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to said sequence, or an amino acid sequence having one or more (preferably 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10) conservative amino acid mutations (preferably substitutions, insertions or deletions) compared to said sequence, wherein said polypeptide is an anti-human IL4RA antibody. an isolated polynucleotide which specifically binds to human IL4RA as part of an antibody, said antibody further comprising a sequence selected from the sequence set forth in SEQ ID NO: 42, a sequence having at least 80%, 85% or 90%, preferably at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to said sequence, or an amino acid sequence having one or more (preferably 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10) conservative amino acid mutations (preferably substitutions, insertions or deletions) compared to said sequence; 1. An isolated polynucleotide encoding a polypeptide comprising a sequence selected from the sequence set forth in SEQ ID NO: 48, a sequence having at least 80%, 85% or 90%, preferably at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to said sequence, or an amino acid sequence having one or more (preferably 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10) conservative amino acid mutations (preferably substitutions, insertions or deletions) compared to said sequence, wherein said polypeptide is an anti-human IL4RA antibody. an isolated polynucleotide which specifically binds to human IL4RA as part of an antibody, said antibody further comprising a sequence selected from the sequence set forth in SEQ ID NO: 42, a sequence having at least 80%, 85% or 90%, preferably at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to said sequence, or an amino acid sequence having one or more (preferably 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10) conservative amino acid mutations (preferably substitutions, insertions or deletions) compared to said sequence; 1. An isolated polynucleotide encoding a polypeptide comprising a sequence selected from the sequence set forth in SEQ ID NO: 48, a sequence having at least 80%, 85% or 90%, preferably at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to said sequence, or an amino acid sequence having one or more (preferably 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10) conservative amino acid mutations (preferably substitutions, insertions or deletions) compared to said sequence, wherein said polypeptide is an anti-human IL4RA antibody. an isolated polynucleotide which specifically binds to human IL4RA as part of an antibody, said antibody further comprising a sequence selected from the sequence set forth in SEQ ID NO: 46, a sequence having at least 80%, 85% or 90%, preferably at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to said sequence, or an amino acid sequence having one or more (preferably 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10) conservative amino acid mutations (preferably substitutions, insertions or deletions) compared to said sequence; 1. An isolated polynucleotide encoding a polypeptide comprising a sequence selected from the sequence set forth in SEQ ID NO: 28, a sequence having at least 80%, 85% or 90%, preferably at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to said sequence, or an amino acid sequence having one or more (preferably 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10) conservative amino acid mutations (preferably substitutions, insertions or deletions) compared to said sequence, wherein said polypeptide is an anti-human IL4RA antibody. an isolated polynucleotide which specifically binds to human IL4RA as part of an antibody, said antibody further comprising a sequence selected from the sequence set forth in SEQ ID NO: 34, a sequence having at least 80%, 85% or 90%, preferably at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to said sequence, or an amino acid sequence having one or more (preferably 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10) conservative amino acid mutations (preferably substitutions, insertions or deletions) compared to said sequence; 1. An isolated polynucleotide encoding a polypeptide comprising a sequence selected from the sequence set forth in SEQ ID NO: 127, a sequence having at least 80%, 85% or 90%, preferably at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to said sequence, or an amino acid sequence having one or more (preferably 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10) conservative amino acid mutations (preferably substitutions, insertions or deletions) compared to said sequence, wherein said polypeptide is an anti-human IL4RA antibody. or an isolated polynucleotide which specifically binds to human IL4RA as part of 1. An isolated polynucleotide encoding a polypeptide comprising a sequence selected from the sequence set forth in SEQ ID NO: 129, a sequence having at least 80%, 85% or 90%, preferably at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to said sequence, or an amino acid sequence having one or more (preferably 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10) conservative amino acid mutations (preferably substitutions, insertions or deletions) compared to said sequence, wherein said polypeptide is an anti-human IL4RA antibody. The present invention relates to an isolated polynucleotide that specifically binds to human IL4RA as part of a polypeptide chain, wherein the antibody further comprises an amino acid sequence selected from the sequence set forth in SEQ ID NO: 127, or a sequence having at least 80%, 85% or 90%, preferably at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%, sequence identity to said sequence, or an amino acid sequence having one or more (preferably 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10) conservative amino acid mutations (preferably substitutions, insertions or deletions) compared to said sequence.

[0062] In particular, the polynucleotide molecule comprises or consists of the sequence set forth in SEQ ID NO:1, SEQ ID NO:5, SEQ ID NO:21, SEQ ID NO:25, SEQ ID NO:29, SEQ ID NO:33, SEQ ID NO:37, SEQ ID NO:41, SEQ ID NO:45 or SEQ ID NO:126, or a sequence having at least 80%, 85% or 90%, preferably at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity thereto.

[0063] In particular, the polynucleotide molecule comprises or consists of the sequence set forth in SEQ ID NO:3, SEQ ID NO:7, SEQ ID NO:23, SEQ ID NO:27, SEQ ID NO:31, SEQ ID NO:35, SEQ ID NO:39, SEQ ID NO:43, SEQ ID NO:47 or SEQ ID NO:128, or a sequence having at least 80%, 85% or 90%, preferably at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity thereto.

[0064] Yet another aspect of the present invention pertains to a vector comprising any one of the polynucleotide molecules disclosed herein.

[0065] Yet another aspect of the present invention relates to a host cell comprising any one of the polynucleotide molecules disclosed herein or the vector disclosed herein.

[0066] Yet another aspect of the present invention relates to a method for preparing any one of the antibodies or antigen-binding fragments thereof disclosed herein, comprising culturing under suitable conditions a host cell disclosed herein and isolating the antibody or antigen-binding fragment thereof from the cell culture.

[0067] One aspect of the present invention further provides an antibody conjugate comprising the anti-human IL4RA antibody or antigen-binding fragment thereof and a conjugate moiety attached thereto, wherein the conjugate moiety is a purification tag (e.g., a His tag), a cytotoxic agent, or a detectable label. Preferably, the conjugate moiety is a radioisotope, a luminescent substance, a colored substance, an enzyme, or polyethylene glycol.

[0068] One aspect of the present invention further provides a multispecific antibody, preferably a bispecific antibody, comprising the anti-human IL4RA antibody or antigen-binding fragment thereof, and an antibody or antigen-binding fragment against another antigen and / or another antigen epitope.

[0069] One aspect of the present invention further provides a fusion protein comprising any one of the anti-human IL4RA antibodies or antigen-binding fragments thereof disclosed herein.

[0070] One aspect of the present invention further provides a kit comprising any one of the antibodies or antigen-binding fragments thereof disclosed herein, or the antibody conjugate or the multispecific antibody disclosed herein. Preferably, the kit further comprises a second antibody that specifically recognizes the antibody or its antigen-binding fragment; optionally, the second antibody further comprises a detectable label such as a radioisotope, a luminescent substance, a colored substance, an enzyme, or polyethylene glycol.

[0071] Yet another aspect of the present invention relates to the use of any one of the antibodies or antigen-binding fragments thereof disclosed herein, or the antibody conjugates or the multispecific antibodies disclosed herein, in the preparation of a kit for detecting the presence or level of human IL4RA in a sample, or for the prevention and / or treatment and / or adjunctive treatment and / or diagnosis of allergic diseases, tumors, autoimmune diseases, skin infections, tissue fibrosis, rhinosinusitis, nasal polyps and chronic obstructive pulmonary disease, preferably wherein the allergic disease is selected from atopic dermatitis, allergic rhinitis, asthma and allergy, more preferably wherein the atopic dermatitis is moderate and severe atopic dermatitis.

[0072] Yet another aspect of the present invention relates to a pharmaceutical composition comprising any one of the antibodies or antigen-binding fragments thereof disclosed herein, or the antibody conjugates, multispecific antibodies, or fusion proteins disclosed herein, and optionally a pharmaceutically acceptable carrier and / or excipient. Preferably, the pharmaceutical composition is used alone or in combination with one or more drugs. If the pharmaceutical composition cannot be directly mixed with the drugs to be combined, the drugs to be combined with the pharmaceutical composition are present separately in a kit.

[0073] Yet another aspect of the present invention is a method for producing a semiconductor device comprising: an agent for blocking the binding of human IL4RA to IL-4 or IL-13; Agents for blocking the activity of or downregulating the levels of human IL4RA, and Agents for blocking cell biological responses mediated by binding of human IL-4 or human IL-13 to IL4RA The present invention relates to use of any one of the antibodies or antigen-binding fragments thereof, or the antibody conjugates, multispecific antibodies, or fusion proteins disclosed herein, in the preparation of a therapeutic agent for treating a disease in which the ligand of human IL4RA is human IL-4 or human IL-13, more preferably human IL-4.

[0074] One aspect of the present invention relates to the use of any one of the antibodies or antigen-binding fragments thereof disclosed herein, or the antibody conjugates, multispecific antibodies, or fusion proteins disclosed herein, in the preparation of a medicament for treating a disease selected from atopic dermatitis, including moderate and severe atopic dermatitis; nasal polyps; asthma; skin infections; autoimmune diseases, etc.

[0075] Yet another aspect of the present invention relates to an in vivo or in vitro method comprising administering a cell comprising the antibody or antigen-binding fragment thereof, the antibody conjugate disclosed herein, the multispecific antibody or the fusion protein disclosed herein; or administering an effective amount of any one of the antibody or antigen-binding fragment thereof, or the antibody conjugate disclosed herein, the multispecific antibody or the fusion protein disclosed herein to a subject in need thereof, the method comprising: A method for blocking the binding of IL4RA to IL-4 or IL-13; A method for downregulating the activity or levels of IL4RA, or A method for blocking a cell biological response mediated by the binding of human IL-4 or human IL-13 to IL4RA, wherein preferably the ligand of IL4RA is IL-4 or IL-13, more preferably IL-4.

[0076] In one embodiment of the invention, the in vitro method is non-therapeutic and / or non-diagnostic.

[0077] Yet another aspect of the present invention relates to the use of any one of the antibodies or antigen-binding fragments thereof, the antibody conjugates, or the multispecific antibodies disclosed herein in the preparation of a medicament for the prevention and / or treatment and / or adjunctive treatment and / or diagnosis of allergic diseases, tumors, skin infections, autoimmune diseases, tissue fibrosis, rhinosinusitis, nasal polyps, and chronic obstructive pulmonary disease, particularly wherein the allergic disease is selected from atopic dermatitis, allergic rhinitis, asthma, and allergies.

[0078] In one embodiment of the invention, the medicament is in a dosage form suitable for oral administration to the gastrointestinal (GI) tract, preferably selected from tablets, capsules, pills, powders, granules, emulsions, microemulsions, solutions, suspensions, syrups and elixirs.

[0079] In one embodiment of the invention, the medicament is in a form suitable for administration by subcutaneous, intradermal, intravenous, intramuscular or intralesional injection.

[0080] Yet another aspect of the present invention relates to a method for the prevention and / or treatment and / or adjunctive treatment and / or diagnosis of allergic diseases, tumors, autoimmune diseases, tissue fibrosis, skin infections, rhinosinusitis, nasal polyps, chronic obstructive pulmonary disease, comprising administering to a subject in need thereof any of the antibodies or antigen-binding fragments thereof, antibody conjugates, or multispecific antibodies disclosed herein, in particular, wherein the allergic diseases are selected from atopic dermatitis, allergic rhinitis, asthma, and allergies.

[0081] In the present invention, unless otherwise defined, scientific and technical terms used herein have the meanings commonly understood by those skilled in the art. Furthermore, the experimental procedures of cell culture, molecular genetics, nucleic acid chemistry, and immunology used in the present invention are routine procedures widely used in the corresponding fields. Meanwhile, in order to better understand the present invention, the definitions and explanations of relevant terms are provided below.

[0082] As used herein, the term "antigen-binding fragment" refers to a protein or a portion of a protein that specifically binds to a given antigen. For example, a portion of an antibody that contains amino acid residues that interact with an antigen and confer specificity and affinity to the antibody for the antigen is called an "antigen-binding fragment." The antigen-binding fragment generally contains one or more complementarity-determining regions (CDRs). Certain antigen-binding fragments further contain one or more framework regions (FRs). CDRs are amino acid sequences that contribute to antigen-binding specificity and affinity.

[0083] As used herein, the term "antibody" refers to an intact immunoglobulin of any isotype or antigen-binding fragment thereof that can compete with an intact antibody for specific binding to a target antigen, including, for example, chimeric, humanized, fully human, and bispecific antibodies or antigen-binding fragments thereof. Such "antibodies" are antigen-binding proteins. Intact antibodies generally comprise at least two full-length heavy chains and two full-length light chains, although in some cases, camelidic antibodies may comprise only heavy chains. The antibody or antigen-binding fragment thereof may contain fewer chains, such as antibodies naturally occurring in a species of the same family. An antibody or antigen-binding fragment thereof may be derived from only a single source, or may be "chimeric," i.e., different portions of the antibody may be derived from two different sources, as described further below. Antibodies or antigen-binding fragments thereof may be produced in hybridomas, by recombinant DNA techniques, or by enzymatic or chemical cleavage of intact antibodies. Unless otherwise specified, the term "antibody" includes antibodies containing two full-length heavy chains and two full-length light chains, as well as derivatives, variants, and fragments thereof.

[0084] As used herein, the term "antigen-binding fragment" (or simply "fragment") of an "antibody" or "immunoglobulin chain" (heavy or light chain) includes a portion of an antibody (whether obtained or synthetic) that lacks at least some of the amino acid residues present in the full-length antibody, but is capable of specifically binding to an antigen. Such fragments are biologically active for specifically binding to a target antigen and can compete with other antibodies or antigen-binding fragments thereof for specific binding to a given epitope. In one aspect, such a fragment retains at least one CDR present in a full-length light or heavy chain of the antibody, and in some embodiments, comprises a single heavy and / or light chain or portion thereof. Such biologically active fragments can be produced by recombinant DNA techniques or by, for example, enzymatic or chemical cleavage of intact antibodies. Immunologically functional immunoglobulin fragments include, but are not limited to, Fab, Fab', F(ab')2, Fv, domain antibodies, and single-chain antibodies, and can be derived from any mammalian source, including, but not limited to, human, mouse, rat, camelid species, and rabbit. It is further contemplated that functional portions of the antibodies disclosed herein, such as one or more CDRs, can be covalently linked to a second protein or small molecule to generate therapeutic agents that target specific targets within the body, thereby possessing bifunctional therapeutic properties, such as fusion proteins, or having extended serum half-lives.

[0085] As used herein, the terms "full antibody chain," "full length antibody," "intact antibody," and "whole antibody" are used interchangeably herein and refer to antibodies having a structure substantially similar to a native antibody structure or having a heavy chain that includes an Fc region, as defined herein.

[0086] The term "light chain" includes full-length light chains and fragments thereof that contain sufficient variable region sequence to confer binding specificity. A full-length light chain contains a variable region domain, VL, and a constant region domain, CL. The variable region domain of a light chain is at the amino terminus of the polypeptide. Light chains include kappa (κ) chains and lambda (λ) chains.

[0087] The term "heavy chain" includes full-length heavy chains and fragments thereof containing sufficient variable region sequence to confer binding specificity. A full-length heavy chain contains a variable region domain, VH, and three constant region domains, CH1, CH2, and CH3. The VH domain is at the amino-terminus of the polypeptide, and the CH domain is at the carboxyl-terminus, with CH3 being closest to the carboxyl terminus of the polypeptide. The heavy chain may be of any isotype, including IgG (including IgG1, IgG2, IgG3, and IgG4 subtypes), IgA (including IgA1 and IgA2 subtypes), IgM, and IgE.

[0088] As used herein, the term "Fab" fragment consists of one light chain, CH1, and the variable region of one heavy chain. The heavy chain of a Fab molecule cannot form disulfide bonds with other heavy chain molecules.

[0089] As used herein, the term "Fc" region comprises two heavy chain fragments comprising the CH1 and CH2 domains of an antibody, held together by two or more disulfide bonds and hydrophobic interactions of the CH3 domain.

[0090] As used herein, the term "Fab" fragment comprises one light chain and a portion of one heavy chain comprising the VH domain and the region between the CH1 and CH2 domains, such that interchain disulfide bonds can form between the two heavy chains of two Fab' fragments to give an F(ab')2 molecule.

[0091] As used herein, the term "F(ab')2" fragment comprises two light chains and two heavy chains, including portions of the constant regions between the CH1 and CH2 domains, such that an interchain disulfide bond is formed between the two heavy chains. Thus, an F(ab')2 fragment consists of two Fab' fragments held together by disulfide bonds between the two heavy chains.

[0092] As used herein, the term "Fv" region comprises the variable regions from the heavy and light chains, but lacks the constant regions.

[0093] As used herein, the term "Fd" fragment refers to an antibody fragment consisting of the VH and CH1 domains (Ward et al., Nature, 341:544-546 (1989)).

[0094] As used herein, the term "DAC" fragment consists of a VH domain (Ward et al., Nature 341:544-546 (1989)).

[0095] As used herein, the term "Fab'-SH" is the designation herein for Fab' in which one or more cysteine ​​residues of the constant domains bear a free thiol group.

[0096] As used herein, the term "Fab / c" fragment refers to an intermediate formed by pepsin digestion of immunoglobulins, which combines the advantages of the Fab and Fc regions, i.e., high diffusibility in vivo and low metabolic clearance, while retaining high affinity (Liu Jianjun, Chinese Journal of Cellular and Molecular Immunology, 1989(4):29-29).

[0097] As used herein, the term "single-chain antibody" refers to an Fv molecule in which the heavy and light chain variable regions are linked by a flexible linker to form a single polypeptide chain (which is the antibody binding region) (see, e.g., Bird et al., Science, 242:423-426 (1988), and Huston et al., Proc. Natl. Acad. Sci., USA, 90:5879-5883 (1988)). Single-chain antibodies are described in detail in International Patent Publication No. 88 / 01649 and U.S. Pat. Nos. 4,946,778 and 5,260,203, the disclosures of which are incorporated herein by reference.

[0098] As used herein, the term "domain antibody" refers to an immunologically functional immunoglobulin fragment containing only the variable region of a heavy or light chain. In some cases, two or more VH regions are covalently linked by a peptide linker to generate multivalent domain antibodies (particularly bivalent domain antibodies). The two VH regions of a bivalent domain antibody may target the same or different antigens.

[0099] As used herein, the term "bivalent antigen-binding protein" or "bivalent antibody" refers to an antibody that contains two antigen-binding sites. In some cases, the two binding sites have specificity for the same antigen. A bivalent antibody may be bispecific.

[0100] As used herein, the term "multispecific antigen-binding protein" or "multispecific antibody" is an antigen-binding protein or antibody that targets more than one antigen or epitope.

[0101] As used herein, the terms "bispecific," "dual-specificity," or "bifunctional" antigen-binding protein or antibody refer to a hybrid antigen-binding protein or antibody, each having two different antigen-binding sites. Bispecific antibodies are multispecific antigen-binding proteins or antibodies and can be produced by a variety of methods, including, but not limited to, fusion of hybridomas or linking of Fab' fragments. See, e.g., Songsivilai and Lachmann, 1990, Clin. Exp. Immunol., 79:315-321; Kostelny et al., 1992, J. Immunol., 148:1547-1553. The two binding sites of a bispecific antigen-binding protein or antibody bind to two different epitopes present in the same or different protein targets.

[0102] As used herein, the terms "mAb" and "monoclonal antibody" refer to antibodies or antibody fragments derived from a group of highly homologous antibodies, i.e., a group of identical antibody molecules, excluding naturally occurring mutations that may occur naturally. Such monoclonal antibodies have high specificity for a single epitope on an antigen. Compared to monoclonal antibodies, polyclonal antibodies generally contain at least two or more different antibodies that recognize different epitopes on an antigen. Monoclonal antibodies can generally be obtained using hybridoma technology, first described by Kohler et al. (Nature, 256:495, 1975), but can also be obtained using recombinant DNA technology (see, e.g., U.S. Pat. No. 4,816,567).

[0103] As used herein, the term "humanized antibody" refers to an antibody or antibody fragment obtained when all or part of the CDR regions of a human immunoglobulin (receptor antibody) are replaced by the CDR regions of a non-human antibody (donor antibody), where the donor antibody may be a non-human (e.g., mouse, rat, or rabbit) antibody with the expected specificity, affinity, or reactivity. Furthermore, some amino acid residues in the framework regions (FRs) of the receptor antibody can be replaced with corresponding amino acid residues of the non-human antibody or other antibodies, thereby further improving or optimizing the performance of the antibody. For further details on humanized antibodies, see, e.g., Jones et al., Nature, 321:522-525 (1986); Reichmann et al., Nature, 332:323-329 (1988); Presta, Curr. Op. Struct. Biol., 2:593-596 (1992); and Clark, Immunol. Today, 21:397-402 (2000).

[0104] As used herein, the term "epitope" refers to a site on an antigen to which an immunoglobulin or antibody specifically binds. "Epitope" is also referred to in the art as "antigenic determinant." Epitopes or antigenic determinants generally consist of chemically active surface groupings of molecules such as amino acids, carbohydrates, or sugar side chains, and usually have specific three-dimensional structural and charge characteristics. For example, an epitope generally includes at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 consecutive or non-contiguous amino acids in a unique spatial conformation, which can be "linear" or "conformational." See, e.g., Epitope Mapping Protocols in Methods in Molecular Biology, Vol. 66, G.E. Morris, Ed. (1996). In a linear epitope, all interaction sites between a protein and an interacting molecule (e.g., an antibody) are contiguous along the primary amino acid sequence of the protein. In a conformational epitope, the interaction site is located across a segment of amino acid residues.

[0105] The terms "polypeptide" and "protein" are used interchangeably herein to refer to a polymer of amino acid residues. The terms are also used to refer to amino acid polymers in which one or more amino acid residues are analogs or mimetics of naturally occurring amino acids, as well as to naturally occurring amino acid polymers. The terms also include amino acid polymers that have been modified, for example, by the addition of sugar residues to form glycoproteins, or that are phosphorylated. Polypeptides and proteins can be produced by naturally occurring cells and non-recombinant cells; or they can be produced by genetically engineered or recombinant cells, and include molecules with the amino acid sequence of a native protein or molecules with deletions, insertions, and / or substitutions of one or more amino acids of the native sequence.

[0106] In particular, the terms "polypeptide" and "protein" include antibodies, such as anti-human IL4RA antibodies (also called IL4RA antibodies), IL4RA binding proteins, and antibodies or sequences having deletions, insertions and / or substitutions in one or more amino acids of antigen-binding proteins.

[0107] The term "polypeptide fragment" refers to a polypeptide having an amino-terminal deletion, a carboxyl-terminal deletion, and / or an internal deletion compared to the full-length protein. Such fragments may also contain modified amino acids compared to the full-length protein. In certain embodiments, such fragments are about 5 to 500 amino acids in length. For example, fragments can be at least 5, 6, 8, 10, 14, 20, 50, 70, 100, 110, 150, 200, 250, 300, 350, 400, or 450 amino acids in length. Useful polypeptide fragments include immunologically functional fragments of antibodies containing the binding domain. In the case of human IL4RA antibodies, useful fragments include, but are not limited to, CDR regions, heavy or light chain variable domains, portions of antibody chains, and variable domains containing only two CDRs.

[0108] The terms "human IL4RA," "hIL4RA," "human IL4 receptor A," and "human IL4 receptor α subunit" are used interchangeably to refer to the human interleukin-4 receptor α subunit. Human IL4RA refers to its mature peptide (GenBank accession number NP1244336.1). IL-4 and IL-13 are the major endogenous agonists of IL4RA. Unless otherwise indicated or clear from the context in which the term is used, "IL4RA" refers to human IL4RA.

[0109] A "derivative" of a polypeptide is a polypeptide (e.g., an antigen-binding protein or antibody) that is chemically modified in a way other than by insertion, deletion, or substitution, e.g., by conjugation with another chemical moiety, (e.g., a polypeptide conjugated to PEG).

[0110] As used herein, the term "isolated" refers to "obtained by artificial means from a natural state." When a particular "isolated" substance or component exists in nature, it may be altered in its natural environment, or isolated from its natural environment, or both. For example, a non-isolated polynucleotide or polypeptide naturally exists in a living animal, and the same polynucleotide or polypeptide, isolated in high purity from such a natural state, is referred to as an isolated polynucleotide or polypeptide. The term "isolated" does not exclude the presence of other artificial or synthetic impurities that do not affect the substance or activity of the substance.

[0111] As used herein, the term "vector" refers to a nucleic acid vehicle into which a polynucleotide can be inserted. If the vector allows for the expression of a protein encoded by the inserted polynucleotide, the vector is called an expression vector. A vector can be introduced into a host cell by transformation, transduction, or transfection, thereby allowing the expression of the genetic material carried by the vector in the host cell. Examples of vectors include, but are not limited to, plasmids; phagemids; cosmids; artificial chromosomes, such as yeast artificial chromosomes (YACs), bacterial artificial chromosomes (BACs), or P1-derived artificial chromosomes (PACs); phages, such as lambda phage and M13 phage; and animal viruses, all of which are well known to those skilled in the art. Animal viruses that can be used as vectors include, but are not limited to, retroviruses (including lentiviruses), adenoviruses, adeno-associated viruses, herpesviruses (such as herpes simplex viruses), poxviruses, baculoviruses, papillomaviruses, and papovaviruses (such as SV40). The vector can contain various elements that control expression, including, but not limited to, promoter sequences, transcription initiation sequences, enhancer sequences, selection elements, and reporter genes. In addition, the vector may further contain a replication origin.

[0112] As used herein, the term "host cell" refers to a cell that can be introduced with a vector, including, but not limited to, a prokaryotic cell such as E. coli or Bacillus subtilis; a fungal cell such as a yeast cell or Aspergillus; an insect cell such as S2 Drosophila cell or Sf9; or an animal cell such as a fibroblast, CHO cell, COS cell, NSO cell, HeLa cell, BHK cell, HEK293 cell, or human cell.

[0113] As used herein, the term "specifically binds" refers to a non-random binding reaction between two molecules, such as the reaction between an antibody and its target antigen. In some embodiments, an antibody that specifically binds to an antigen (or is specific for an antigen) has a binding affinity of about 10 -5 M or less, for example, about 10 -6 M, 10 -7 M, 10 -8 M, 10 -9 M or 10 -10 Refers to an antibody that binds to an antigen with an affinity (KD) of M or less.

[0114] As used herein, the term "K D " refers to the dissociation equilibrium constant for a specific antibody-antigen interaction, which is used to describe the binding affinity between an antibody and an antigen. Among several parameters measured by molecular binding kinetics, K D The value is the dissociation equilibrium constant. In antibody drug research, it is a parameter that characterizes the strength of the affinity effect between the antibody of interest and the target antigen molecule, and is expressed by the formula: K D =k dis / k on A smaller equilibrium dissociation constant indicates stronger antibody-antigen binding and higher affinity between the antibody and the antigen. K on (association rate constant) is the rate of formation of the antigen-antibody complex, and is the smaller of k on indicates a faster binding rate of the antibody to the antigen. dis (dissociation rate constant) is the rate at which an antibody dissociates from an antigen-antibody complex, and is the smaller of kdis indicates that the antibody dissociates from the antigen more slowly and that the binding between the antibody and the antigen is stronger. Generally, antibodies have a dissociation equilibrium constant (K), as measured, for example, with a BIACORE surface plasmon resonance (SPR) instrument or a ForteBio molecular interaction instrument. D ) is about 10 -6 M, 10 -7 M, 10 -8 M, 10 -9 M or 10 -10 M, about 10 -5 It binds to antigens (e.g., L1 protein) at less than M.

[0115] As used herein, the terms "monoclonal antibody" and "McAb" have the same meaning and can be used interchangeably; the terms "polyclonal antibody" and "PcAb" have the same meaning and can be used interchangeably; and the terms "polypeptide" and "protein" have the same meaning and can be used interchangeably. Furthermore, amino acids are generally referred to herein by their one-letter and three-letter abbreviations known in the art. For example, alanine can be represented by A or Ala.

[0116] As used herein, the terms "hybridoma" and "hybridoma cell" can be used interchangeably, and when the terms "hybridoma" and "hybridoma cell" are referenced, subclones and progeny of the hybridoma are also included.

[0117] As used herein, the terms "percent sequence identity" and "percent sequence homology" are used interchangeably.

[0118] As used herein, the terms "similarity," "sequence similarity," and "identity" refer to the relationship between the sequences of two or more protein or polypeptide molecules, as determined by aligning and comparing the sequences. "Percent identity" refers to the percentage of identical amino acid residues in the compared molecules and can be calculated based on the size of the smallest molecule for comparison. For such calculations, gaps in the alignment, if any, must be addressed by a particular mathematical model or computer program (i.e., "algorithm"). When used in reference to polypeptides, the term "substantial identity" means that two peptide sequences have at least 70%, 75%, or 80% sequence identity, at least 90% or 95% sequence identity, or at least 97%, 98%, or 99% sequence identity when optimally aligned using, for example, the programs GAP or BESTFIT, using the default gap weights provided by the programs. In some cases, residue positions that are not identical differ by conservative amino acid substitutions. A "conservative amino acid substitution" is one in which an amino acid residue is substituted with another amino acid residue having a side chain R group possessing similar chemical properties (e.g., charge or hydrophilicity). Generally, conservative amino acid substitutions substantially preserve the function and properties of a protein. When two or more amino acid sequences differ from each other by conservative substitutions, the percent sequence identity may be increased to correct for the conservative nature of the substitution. Methods for making this adjustment are well known to those of skill in the art. See, e.g., Pearson Methods Mol. Biol., 243:307-31 (1994). Examples of groups of amino acids having side chains with similar chemical properties include: 1) aliphatic hydroxy side chains: glycine, alanine, valine, leucine, and isoleucine, 2) aliphatic hydroxy side chains: serine and threonine, 3) amide-containing side chains: asparagine and glutamine, 4) aromatic side chains: phenylalanine, tyrosine, and tryptophan, 5) basic side chains: lysine, arginine, and histidine, 6) acidic side chains: aspartic acid and glutamic acid, and 7) sulfur-containing side chains: cysteine ​​and methionine. Conservative amino acid substitution groups are valine-leucine-isoleucine, phenylalanine-tyrosine, lysine-arginine, alanine-valine, glutamic acid-aspartic acid, and asparagine-glutamine.

[0119] Optionally, a conservative substitution is any change that has a positive value in the PAM250 log-likelihood matrix disclosed in Gonnet et al., Science, 256:1443-45 (1992), which is incorporated herein by reference. A "moderately conservative" substitution is any change that has a non-negative value in the PAM250 log-likelihood matrix.

[0120] Polypeptide sequence identity is typically measured using sequence analysis software. Protein analysis software matches sequences using measures of similarity assigned to different substitutions, deletions, and other modifications (including conservative amino acid substitutions). For example, GCG, including programs such as "Gap" and "Bestfit" (using default parameters specified by the program), can be used to determine sequence homology or sequence identity between closely related polypeptides (e.g., homologous polypeptides from different species) or between a wild-type protein and its mutant protein. See, for example, GCG version 6.1 (University of Wisconsin, WI). Polypeptide sequences can also be compared using FASTA with default or recommended parameters. See GCG version 6.10 FASTA (e.g., FASTA2 and FASTA3), which provides alignments for the regions of optimal overlap between the challenge and query sequences (Pearson Methods Enzymol. 183:63-98 (1990); Pearson Methods Mol. Biol., 132:185-219 (2000)). Another preferred algorithm for comparing sequences to databases containing large sequences from different organisms is the computer program BLAST, particularly blastp or tblastn (using the default parameters provided by the program). See, e.g., Altschul et al., Mol. Biol., 215:403-410 (1990); Altschul et al., Nucleic Acids Res., 25:3389-402 (1997).

[0121] Compared with the prior art, the present invention has the following advantages:

[0122] The anti-human IL4RA antibodies disclosed herein can bind to human IL4RA with high affinity and, by blocking the binding of human IL-4 and human IL-13 to human IL4RA, can inhibit associated cell biological actions mediated by IL-4 and human IL-13, such as cell proliferation and IL-4- and IL-13-induced upregulation of CD23 expression levels. The antibodies have advantages such as high activity and elimination of species differences, and can be used to prepare drugs that block the binding of human IL-4 and IL-13 to human IL4RA, and to prepare drugs for the treatment or prevention of allergic diseases such as allergic rhinitis, asthma, allergy and atopic dermatitis (including moderate and severe atopic dermatitis), sinusitis, nasal polyps, chronic obstructive pulmonary disease, tissue fibrosis, and autoimmune diseases, and therefore have promising applications and commercial prospects. [Brief explanation of the drawings]

[0123] [Figure 1] Binding activity of 13E5 and dupilumab to the antigen IL4RA-mFc [Figure 2] Binding activity of 13E5H1L1, 13E5H2L2, 13E5H3L3, and dupilumab to the antigen IL4RA-mFc [Figure 3] Binding activity of 13E5H4L2, 13E5H4L4, and dupilumab to the antigen IL4RA-mFc [Figure 4] The ability of 13E5 and dupilumab to compete with human IL4N-His for binding to human IL4RA-mFc [Figure 5] Activity of 13E5H1L1, 13E5H2L2, 13E5H3L3, and dupilumab to compete with human IL4N-His for binding to human IL4RA-mFc [Figure 6] Activity of 13E5H4L2, 13E5H4L4, and dupilumab to compete with human IL4N-His for binding to human IL4RA-mFc [Figure 7] Binding activity of 18H7 and dupilumab to the antigen IL4RA-mFc [Figure 8]Binding activity of 18H7H1L1, 18H7H2L2, 18H7H L3, 18H7H3L2, 18H7H3L3, and dupilumab to the antigen IL4RA-mFc [Figure 9] Activity assay of 18H7 and dupilumab competing with human IL4NHis for binding to human IL4RA-mFc [Figure 10] Activity assay of 18H7H1L1, 18H7H2L2, 18H7H2L3, 18H7H3L2 and dupilumab competing with human IL4NHis for binding to human IL4RA-mFc. [Figure 11] Activity assay of 20G10H3L3, 13E5H4L4 and dupilumab competing with human IL4NHis for binding to human IL4RA-mFc. [Figure 12] The antibody concentrations for the curve pair of 13E5H4L4 against human IL4RA, from top to bottom, were 25 nM, 6.25 nM, 3.13 nM, 1.56 nM, 0.78 nM, and 0.39 nM, respectively. [Figure 13] Affinity constant assay of 18H7H1L1 for human IL4RA. Antibody concentrations for the curve pair, from top to bottom, were 25 nM, 6.25 nM, 3.13 nM, 1.56 nM, 0.78 nM, and 0.39 nM, respectively. [Figure 14] Affinity constant assay of dupilumab for human IL4RA. Antibody concentrations for the curve pair, from top to bottom, were 12.5 nM, 6.25 nM, 3.13 nM, 1.56 nM, 0.78 nM, and 0.39 nM, respectively. [Figure 15] Affinity constant assay of 13E5H1L1 for human IL4RA. Antibody concentrations for the curve pair, from top to bottom, were 25 nM, 12.5 nM, 6.25 nM, 3.13 nM, 1.56 nM, 0.7 nM, and 0.39 nM, respectively. [Figure 16] Affinity constant assay of 13E5H2L2 for human IL4RA. Antibody concentrations for the curve pair, from top to bottom, were 25 nM, 12.5 nM, 6.25 nM, 3.13 nM, 1.56 nM, 0.78 nM, and 0.39 nM, respectively. [Figure 17] Affinity constant assay of 13E5H3L3 for human IL4RA. Antibody concentrations for the curve pair, from top to bottom, were 25 nM, 12.5 nM, 6.25 nM, 3.13 nM, 1.56 nM, and 0.39 nM, respectively. [Figure 18] Affinity constant assay of 13E5H4L2 for human IL4RA. Antibody concentrations for the curve pair, from top to bottom, were 12.5 nM, 6.25 nM, 3.13 nM, 1.56 nM, 0.78 nM, and 0.39 nM, respectively. [Figure 19] Affinity constant assay of 18H7H2L2 for human IL4RA. Antibody concentrations for the curve pair, from top to bottom, were 6.25 nM, 3.13 nM, 1.56 nM, 0.78 nM, and 0.39 nM, respectively. [Figure 20] Affinity constant assay of 18H7H3L2 for human IL4RA. Antibody concentrations for the curve pair, from top to bottom, were 25 nM, 12.5 nM, 6.25 nM, 3.13 nM, 1.56 nM, 0.78 nM, and 0.39 nM, respectively. [Figure 21] Affinity constant assay of dupilumab for human IL4RA. Antibody concentrations for the curve pair, from top to bottom, were 6.25 nM, 3.13 nM, 1.56 nM, 0.78 nM, and 0.39 nM, respectively. [Figure 22] 13E5H1L1, 13E5H2L2 and dupilumab inhibit IL-4-induced TF-1 cell proliferation. [Figure 23] 13E5H1L1, 13E5H2L2 and dupilumab inhibit IL-13-induced TF-1 cell proliferation. [Figure 24] 13E5H4L2, 13E5H4L4 and dupilumab inhibit IL-4-induced TF-1 cell proliferation. [Figure 25] 13E5H4L2, 13E5H4L4 and dupilumab inhibit IL-13-induced TF-1 cell proliferation. [Figure 26] 18H7H1L1, 18H7H2L2 and dupilumab inhibit IL-4-induced TF-1 cell proliferation. [Figure 27]18H7H1L1, 18H7H2L2, and dupilumab inhibit IL-13-induced TF-1 cell proliferation [Figure 28] 18H7H1L1, 13E5H4L4 and dupilumab inhibit IL-4-induced upregulation of CD23 expression in monocytes. [Figure 29] 18H7H1L1, 13E5H4L4 and dupilumab inhibit IL-13-induced CD23 expression upregulation in monocytes. [Figure 30] 13E5H4L4 inhibits the increase in epidermal thickness in a B-hIL4Ra mouse skin inflammation model. [Figure 31] Pathological sections (HE staining, 400x) showing epidermal thickness in mice from all experimental groups. a. Control (normal saline); b. Dupilumab (80 mg / kg); c. Dupilumab (20 mg / kg); d. hIgG4 (80 mg / kg); e. 13E5H4L4 (80 mg / kg); f. 13E5H4L4 (20 mg / kg).

[0124] Detailed Description Hereinafter, the embodiments of the present invention will be described in detail with reference to examples. Those skilled in the art will understand that the following examples are used only to illustrate the present invention and should not be considered to limit the scope of the present invention. If techniques or conditions are not specified, they are carried out according to the techniques or conditions described in the literature of the art (see, for example, Molecular Cloning: A Laboratory Manual, authored by J. Sambrook et al., and translated by Huang Peitang et al., Third Edition, Science Press J.) or product manuals. If the manufacturer of the reagents or equipment used is not specified, they are conventional products that are commercially available.

[0125] In the following examples of the present invention, BALB / C mice were purchased from Guangdong Medical Experimental Animal Center.

[0126] In the following examples of the present invention, the control antibody dupilumab VAB16F3-1 (hereinafter referred to as dupilumab), whose sequence is set forth in patent application no. PCT / US2007 / 021210 assigned to Regeneron Pharmaceuticals, Inc., was produced by Akeso, Inc. The heavy chain variable region of antibody VAB16F3-1 is set forth in SEQ ID NO: 124, the constant region is the Ig gamma-1 chain C region, accession number P01857, and the coding sequence of the light chain variable region of antibody VAB16F3-1 is set forth in SEQ ID NO: 125, the constant region is the Ig kappa chain C region, accession number P01834. Example 1

[0127] Preparation of anti-human IL4RA antibodies 20G10, 13E5, and 18H7 1. Preparation of Hybridoma Cell Lines 20G10, 13E5, and 18H7 The anti-IL4RA antibody production antigen, IL4RA-mFc, is a fusion protein of human IL-4RA mature peptide (Genbank accession number NP001244336.1) and mFc tag (SEQ ID NO: 121) synthesized by Akeso, Inc., and was used to immunize BALB / C mice (purchased from the Guangdong Medical Laboratory Animal Center). Spleen cells from immunized BALB / C mice (purchased from the Guangdong Medical Laboratory Animal Center) were fused with mouse myeloma cells to form hybridoma cells using existing cell fusion techniques (e.g., Stewart, SJ, "Monoclonal Antibody Production," in Basic Methods in Antibody Production and Characterization, Eds. G.C. Howard and D.R. Bethell, Boca Raton: CRC Press, 2000). For indirect ELISA, plates were coated with IL4RA-hFc protein (IL-4RA is described above, and hFc is the human IgG Fc purification tag, specifically, the Igγ-1 chain C region, GenBank accession number P01857, positions 114-330). Hybridoma cell lines secreting antibodies specifically binding to IL4RA-hFc were obtained by screening. Hybridoma cell lines obtained by indirect ELISA screening were subjected to competitive ELISA to select hybridoma cell lines secreting monoclonal antibodies that compete with the ligand IL4N-his (IL4NCBI gene ID: AAH70123.1) for binding to IL4RA-hFc. Two hybridoma cell lines stably secreting anti-human IL-4RA antibodies were obtained by limiting dilution. The hybridoma cell lines were designated LT018, LT008, and LT009, and the secreting monoclonal antibodies were designated 20G10, 13E5, and 18H7. The hybridoma cell line LT018 (IL4RA-20G10) was deposited with the China Culture Collection Center (CCTCC), Wuhan University, Wuhan, China, postal code: 430072, on December 25, 2019, with the accession number CCTCCNO: C202010. The hybridoma cell line LT008 (IL4RA-13E5) was deposited with the China Culture Collection Center (CCTCC), Wuhan University, Wuhan, China, postal code: 430072, on January 21, 2018, with the accession number CCTCCNO: C201831. The hybridoma cell line LT009 (IL4RA-18H7) was deposited with the China Culture Collection Center (CCTCC), Wuhan University, Wuhan, China, postal code: 430072, on January 21, 2018, with the accession number CCTCCNO: C201832.

[0128] 2. Preparation of anti-human IL4RA antibodies 20G10, 13E5, and 18H7 The cell lines LT018, LT008, and LT009 prepared as described above were separately cultured in a chemically defined medium (CD medium; containing 1% streptomycin) in a 5% CO2, 37°C incubator. After 7 days, the supernatants were collected and purified by high-speed centrifugation, microfiltration, and vacuum filtration through a HiTrap Protein AHP column to obtain the antibodies 20G10, 13E5, and 18H7. Example 2

[0129] Sequence analysis of anti-human IL4RA antibody 13E5 mRNA was extracted from the cell line LT008 cultured in Example 1 according to the method described in the manual for the RNAprep pure Cell / Bacteria Kit (Tiangen, Cat. No. DP430). cDNA was synthesized according to the Invitrogen SuperScript(R) III First-Strand Synthesis System for RT-PCR manual and amplified by PCR. The PCR-amplified product was directly subjected to TA cloning according to the manual for the pEASY-T1 Cloning Kit (Transgen CT101). The TA cloned product was directly sequenced, and the sequencing results are as follows: The nucleic acid sequence of the heavy chain variable region is set forth in SEQ ID NO: 1, having a length of 48 bp. The encoded amino acid sequence is set forth in SEQ ID NO: 2, having a length of 116 amino acids, and the sequences of the heavy chain CDR1, CDR2, and CDR3 are set forth in SEQ ID NOs: 9, 10, and 11, respectively. The nucleic acid sequence of the light chain variable region is set forth in SEQ ID NO: 3, having a length of 321 bp. The encoded amino acid sequence is set forth in SEQ ID NO: 4, having a length of 107 amino acids, and the sequences of the light chain CDR1, CDR2, and CDR3 are set forth in SEQ ID NOs: 12, 13, and 14, respectively. Example 3

[0130] Design and preparation of humanized anti-human IL4RA antibodies 13E5H1L1, 13E5H2L2, 13E5H3L3, 13E5H4L2, and 13E5H4L4 1. Design of the light and heavy chain sequences of humanized anti-human IL4RA antibodies 13E5H1L1, 13E5H2L2, 13E5H3L3, 13E5H4L2, and 13E5H4L4 Based on the three-dimensional crystal structure of the human IL4RA protein obtained in Example 2 (Hage T, Reinemer P, Sebald W., Crystals of a 1:1 Complex Between Human Interleukin-4 and the Extracellular Domain of Its Receptor Alpha Chain, Eur. J. Biochem., 1998; 258(2):831-6.) and the sequence of antibody 13E5, computer modeling and mutation design (antibody constant region sequences from the NCBI database: the heavy chain constant region is the Ig γ-4 chain C region, accession number P01861.1; the light chain constant region is the Ig κ chain C region, accession number P01834) gave the variable region sequences of antibodies 13E5H1L1, 13E5H2L2, 13E5H3L3, 13E5H4L2, and 13E5H4L4.

[0131] The designed variable region sequences are as follows: (1) Heavy and light chain sequences of humanized monoclonal antibody 13E5H1L1 The nucleic acid sequence of the heavy chain variable region is set forth in SEQ ID NO: 21, having a length of 348 bp. The encoded amino acid sequence is set forth in SEQ ID NO: 22, having a length of 116 amino acids, and the sequences of the heavy chain CDR1, CDR2, and CDR3 are set forth in SEQ ID NOs: 9, 10, and 11, respectively. The nucleic acid sequence of the light chain variable region is set forth in SEQ ID NO: 23, having a length of 321 bp. The encoded amino acid sequence is set forth in SEQ ID NO: 24, having a length of 107 amino acids, and the sequences of the light chain CDR1, CDR2, and CDR3 are set forth in SEQ ID NOs: 12, 13, and 14, respectively. (2) Heavy and light chain sequences of humanized monoclonal antibody 13E5H2L2 The nucleic acid sequence of the heavy chain variable region is set forth in SEQ ID NO: 25, having a length of 348 bp. The encoded amino acid sequence is set forth in SEQ ID NO: 26, having a length of 116 amino acids, and the sequences of the heavy chain CDR1, CDR2, and CDR3 are set forth in SEQ ID NOs: 9, 10, and 11, respectively. The nucleic acid sequence of the light chain variable region is set forth in SEQ ID NO: 27, having a length of 321 bp. The encoded amino acid sequence is set forth in SEQ ID NO: 28, having a length of 107 amino acids, and the sequences of the light chain CDR1, CDR2, and CDR3 are set forth in SEQ ID NOs: 12, 13, and 14, respectively. (3) Heavy and light chain sequences of humanized monoclonal antibody 13E5H3L3 The nucleic acid sequence of the heavy chain variable region is set forth in SEQ ID NO: 29, having a length of 348 bp. The encoded amino acid sequence is set forth in SEQ ID NO: 30, having a length of 116 amino acids, and the sequences of the heavy chain CDR1, CDR2, and CDR3 are set forth in SEQ ID NOs: 9, 10, and 11, respectively. The nucleic acid sequence of the light chain variable region is set forth in SEQ ID NO: 31, having a length of 321 bp. The encoded amino acid sequence is set forth in SEQ ID NO: 32, having a length of 107 amino acids, and the sequences of the light chain CDR1, CDR2, and CDR3 are set forth in SEQ ID NOs: 12, 13, and 14, respectively. (4) Heavy and light chain sequences of humanized monoclonal antibody 13E5H4L4 The nucleic acid sequence of the heavy chain variable region is set forth in SEQ ID NO: 33, having a length of 348 bp. The encoded amino acid sequence is set forth in SEQ ID NO: 34, having a length of 116 amino acids, and the sequences of the heavy chain CDR1, CDR2, and CDR3 are set forth in SEQ ID NOs: 9, 10, and 11, respectively. The nucleic acid sequence of the light chain variable region is set forth in SEQ ID NO: 35, which has a length of 321 bp. The encoded amino acid sequence is set forth in SEQ ID NO: 36, which has a length of 107 amino acids, and the sequences of the light chain CDR1, CDR2, and CDR3 are set forth in SEQ ID NOs: 12, 13, and 14, respectively. (5) Heavy and light chain sequences of humanized monoclonal antibody 13E5H4L2 the nucleic acid sequence of the heavy chain variable region is set forth in SEQ ID NO: 33, and The encoded amino acid sequence is set forth in SEQ ID NO:34. the nucleic acid sequence of the light chain variable region is set forth in SEQ ID NO: 27, and The encoded amino acid sequence is set forth in SEQ ID NO:28. 2. Preparation of humanized antibodies 13E5H1L1, 13E5H2L2, 13E5H3L3, 13E5H4L2, and 13E5H4L4 The heavy chain constant region is the Ig gamma-4 chain C region, accession number P01861.1, and the light chain constant region is the Ig kappa chain C region, accession number P01834. The heavy and light chain variable region cDNAs of 13E5H1L1, 13E5H2L2, 13E5H3L3, 13E5H4L2, and 13E5H4L4 were separately cloned into pUC57 simple vectors (provided by Genscript Biotech Corporation) to give pUC57-13E5H1, pUC57 simple-13E5L1, pUC57 simple-13E5H2, pUC57 simple-13E5L2, pUC57 simple-13E5H3, pUC57 simple-13E5L3, pUC57 simple-13E5H4, and pUC57 simple-13E5L4. Variable region fragments were obtained by digestion and subcloned into pcDNA3.1 vectors containing the corresponding heavy or light chain constant region fragments (for pcDNA3.1 vectors containing heavy and light chain constant regions, the restriction enzymes were HindIII and EcoRI) according to standard techniques described in Molecular Cloning: A Laboratory Manual (Second Edition), to give pcDNA3.1-13E5H1, pcDNA3.1-13E5L1, pcDNA3.1-13E5H2, pcDNA3.1-13E5L2, pcDNA3.1-13E5H3, pcDNA3.1-13E5L3, pcDNA3.1-13E5H4 and pcDNA3.1-13E5L4. Recombinant plasmid pairs containing the corresponding light and heavy chains (pcDNA3.1-13E5H1 and pcDNA3.1-13E5L1, pcDNA3.1-13E5H2 and pcDNA3.1-13E5L2, pcDNA3.1-13E5H3 and pcDNA3.1-13E5L3, pcDNA3.1-13E5H4 and pcDNA3.1-13E5L4, pcDNA3.1-13E5H4 and pcDNA3.1-13E5L2) were cotransfected into 293F cells. The culture medium was harvested and purified. After sequence confirmation, endotoxin-free expression plasmids were prepared and transiently transfected into HEK293 cells for antibody expression.Cultures were harvested after 7 days and purified on a protein A column to give humanized antibodies 13E5H1L1, 13E5H2L2, 13E5H3L3, 13E5H4L2 and 13E5H4L4. Example 4

[0132] Sequence analysis of anti-human IL-4RA antibody 18H7 mRNA was extracted from the cell line LT009 cultured in Example 1 according to the method described in the manual for the RNAprep pure Cell / Bacteria Kit (Tiangen, Cat. No. DP430). cDNA was synthesized according to the Invitrogen SuperScript® III First-Strand Synthesis System for RT-PCR® manual and amplified by PCR. The PCR-amplified product was directly subjected to TA cloning according to the manual for the pEASY-T1 Cloning Kit (Transgen CT101). The TA cloned product was directly sequenced, and the sequencing results are as follows: The nucleic acid sequence of the heavy chain variable region is set forth in SEQ ID NO: 5, which has a length of 360 bp. The encoded amino acid sequence is set forth in SEQ ID NO: 6, which has a length of 120 amino acids, and the sequences of the heavy chain CDR1, CDR2, and CDR3 are set forth in SEQ ID NOs: 15, 16, and 17, respectively. The nucleic acid sequence of the light chain variable region is set forth in SEQ ID NO: 7, having a length of 333 bp. The encoded amino acid sequence is set forth in SEQ ID NO: 8, having a length of 111 amino acids, and the sequences of the light chain CDR1, CDR2, and CDR3 are set forth in SEQ ID NOs: 18, 19, and 20, respectively. Example 5

[0133] Design and preparation of humanized anti-human IL4RA antibodies 18H7H1L1, 18H7H2L2, 18H7H2L3, 18H7H3L2, and 18H7H3L3 1. Design of the Light and Heavy Chain Sequences of Humanized Anti-IL4RA Antibodies 18H7H1L1, 18H7H2L2, 18H7H2L3, 18H7H3L2, and 18H7H3L3 Based on the three-dimensional crystal structure of the human IL4RA protein obtained in Example 4 (Nat. Hage T, Reinemer P, Sebald W., Crystals of a 1:1 Complex Between Human Interleukin-4 and the Extracellular Domain of Its Receptor Alpha Chain, Eur. J. Biochem., 1998; 258(2):831-6.) and the sequence of antibody 18H7, the variable region sequences of antibodies 18H7H1L1, 18H7H2L2, 18H7H2L3, 18H7H3L2, and 18H7H3L3 were obtained by computer modeling and mutation design (antibody constant region sequences from the NCBI database: the heavy chain constant region is the Ig γ-4 chain C region, accession number P01861.1; the light chain constant region is the Ig κ chain C region, accession number P01834).

[0134] The designed variable region sequences are as follows: (1) Heavy and light chain sequences of humanized monoclonal antibody 18H7H1L1 The nucleic acid sequence of the heavy chain variable region is set forth in SEQ ID NO: 37, having a length of 360 bp. The encoded amino acid sequence is set forth in SEQ ID NO: 38, having a length of 120 amino acids, and the sequences of the heavy chain CDR1, CDR2, and CDR3 are set forth in SEQ ID NOs: 15, 16, and 17, respectively. The nucleic acid sequence of the light chain variable region is set forth in SEQ ID NO: 39, having a length of 333 bp. The encoded amino acid sequence is set forth in SEQ ID NO: 40, having a length of 111 amino acids, and the amino acid sequences of the light chain CDR1, CDR2, and CDR3 are set forth in SEQ ID NOs: 18, 19, and 20, respectively. (2) Heavy and light chain sequences of humanized monoclonal antibody 18H7H2L2 The nucleic acid sequence of the heavy chain variable region is set forth in SEQ ID NO: 41, having a length of 360 bp. The encoded amino acid sequence is set forth in SEQ ID NO: 42, having a length of 120 amino acids, and the sequences of the heavy chain CDR1, CDR2, and CDR3 are set forth in SEQ ID NOs: 15, 16, and 17, respectively. The nucleic acid sequence of the light chain variable region is set forth in SEQ ID NO: 43, having a length of 333 bp. The encoded amino acid sequence is set forth in SEQ ID NO: 44, having a length of 111 amino acids, and the sequences of the light chain CDR1, CDR2, and CDR3 are set forth in SEQ ID NOs: 18, 19, and 20, respectively. (3) Heavy and light chain sequences of humanized monoclonal antibody 18H7H3L3 The nucleic acid sequence of the heavy chain variable region is set forth in SEQ ID NO: 45, which has a length of 360 bp. The encoded amino acid sequence is set forth in SEQ ID NO: 46, which has a length of 120 amino acids, and the sequences of the heavy chain CDR1, CDR2, and CDR3 are set forth in SEQ ID NOs: 15, 16, and 17, respectively. The nucleic acid sequence of the light chain variable region is set forth in SEQ ID NO: 47, having a length of 333 bp. The encoded amino acid sequence is set forth in SEQ ID NO: 48, having a length of 111 amino acids, and the sequences of the light chain CDR1, CDR2, and CDR3 are set forth in SEQ ID NOs: 18, 19, and 20, respectively. (4) Heavy and light chain sequences of humanized monoclonal antibody 18H7H2L3 the nucleic acid sequence of the heavy chain variable region is set forth in SEQ ID NO: 41, and The encoded amino acid sequence is set forth in SEQ ID NO:42. the nucleic acid sequence of the light chain variable region is set forth in SEQ ID NO: 47, and The encoded amino acid sequence is set forth in SEQ ID NO:48. (5) Heavy and light chain sequences of humanized monoclonal antibody 18H7H3L2 the nucleic acid sequence of the heavy chain variable region is set forth in SEQ ID NO: 45, and The encoded amino acid sequence is set forth in SEQ ID NO:46. the nucleic acid sequence of the light chain variable region is set forth in SEQ ID NO: 43, and The encoded amino acid sequence is set forth in SEQ ID NO:44.

[0135] 2. Preparation of humanized antibodies 18H7H1L1, 18H7H2L2, 18H7H2L3, 18H7H3L3, and 18H7H3L2 The heavy chain constant region is the Ig gamma-4 chain C region, accession number P01861.1; the light chain constant region is the Ig kappa chain C region, accession number P01834. The heavy and light chain variable region cDNAs of 18H7H1L1, 18H7H2L2, 18H7H3L3, 18H7H3L3, and 18H7H3L2 were separately cloned into pUC57 simple vectors (provided by Genscript Biotech Corporation) to give pUC57 simple-18H7H1, pUC57 simple-18H7L1, pUC57 simple-18H7H2, pUC57 simple-18H7L2, pUC57 simple-18H7H3, and pUC57 simple-18H7L3. Variable region fragments were obtained by digestion according to standard techniques described in Molecular Cloning: A Laboratory Manual (Second Edition) and subcloned into pcDNA3.1 vectors containing the corresponding heavy or light chain constant region fragments to give pcDNA3.1-18H7H1, pcDNA3.1-18H7L1, pcDNA3.1-18H7H2, pcDNA3.1-18H7L2, pcDNA3.1-18H7H3, and pcDNA3.1-18H7L3. Recombinant plasmid pairs containing the corresponding light and heavy chains (pcDNA3.1-18H7H1 and pcDNA3.1-18H7L1, pcDNA3.1-18H7H2 and pcDNA3.1-18H7L2, pcDNA3.1-18H7H3 and pcDNA3.1-18H7L3, pcDNA3.1-18H7H2 and pcDNA3.1-18H7L3, and pcDNA3.1-18H7H3 and pcDNA3.1-18H7L2) were cotransfected into 293F cells. The culture medium was harvested and purified. After sequence confirmation, endotoxin-free expression plasmids were prepared and transiently transfected into HEK293 cells for antibody expression. Cultures were harvested after 7 days and purified on a protein A column (GE) to give humanized antibodies 18H7H1L1, 18H7H2L2, 18H7H2L3, 18H7H3L2 and 18H7H3L3. Example 6

[0136] Design and preparation of humanized anti-human IL4RA antibody 20G10H3L3 1. Design of the light and heavy chain sequences of the humanized anti-IL4RA antibody 20G10H3L3 Based on the three-dimensional crystal structure of the human IL4RA protein (Nat. Hage T, Reinemer P, Sebald W., Crystals of a 1:1 Complex Between Human Interleukin-4 and the Extracellular Domain of Its Receptor Alpha Chain, Eur. J. Biochem., 1998; 258(2):831-6.), the variable region sequence of antibody 20G10H3L3 was determined by computer modeling and mutation design (antibody constant region sequences from the NCBI database: the heavy chain constant region is the Ig γ-4 chain C region, accession number P01861.1; the light chain constant region is the Ig κ chain C region, accession number P01834).

[0137] The designed variable region sequences are as follows: (1) Heavy and light chain sequences of humanized monoclonal antibody 20G10H3L3 The nucleic acid sequence of the heavy chain variable region is set forth in SEQ ID NO: 126, having a length of 360 bp. The encoded amino acid sequence is set forth in SEQ ID NO: 127, having a length of 120 amino acids, and the sequences of the heavy chain CDR1, CDR2, and CDR3 are set forth in SEQ ID NOs: 130, 131, and 132, respectively. The nucleic acid sequence of the light chain variable region is set forth in SEQ ID NO: 128, having a length of 321 bp. The encoded amino acid sequence is set forth in SEQ ID NO: 129, having a length of 107 amino acids, and the amino acid sequences of the light chain CDR1, CDR2, and CDR3 are set forth in SEQ ID NOs: 133, 134, and 135, respectively.

[0138] 2. Preparation of Humanized Antibody 20G10H3L3 The heavy chain constant region is the Ig gamma-4 chain C region, accession number P01861.1, and the light chain constant region is the Ig kappa chain C region, accession number P01834. The heavy and light chain variable region cDNAs of 20G10H3L3 were cloned into pUC57Simple vectors (provided by Genscript Biotech Corporation) to give pUC57Simple-20G10H3 and pUC57Simple-20G10L3. Variable region fragments were obtained by digestion and subcloned into pcDNA3.1 vectors containing the corresponding heavy or light chain constant region fragments, according to standard techniques described in Molecular Cloning: A Laboratory Manual (Second Edition), to give pcDNA3.1-20G10H3 and pcDNA3.1-20G10L3. Recombinant plasmid pairs containing the corresponding light and heavy chains (pcDNA3.1-20G10H3 and pcDNA3.1-20G10L3) were cotransfected into 293F cells. The culture medium was harvested and purified. After sequence confirmation, endotoxin-free expression plasmids were prepared and transiently transfected into HEK293 cells for antibody expression. The culture was harvested after 7 days and purified on a protein A column (GE) to give the humanized antibody 20G10H3L3. Example 7

[0139] Antibody binding activity to antigen by ELISA 1. Binding activity of mouse antibody 13E5 and humanized antibodies 13E5H1L1, 13E5H2L2, 13E5H3L3, 13E5H4L2, and 13E5H4L4 to the antigen human IL4RA-hFc or human IL4RA-mFc 1.1 The binding activity of antibodies 13E5, 13E5H1L1, 13E5H2L2, 13E5H3L3, 13E5H4L2, and 13E5H4L4 to the antigen human IL4RA-hFc or human IL4RA-mFc was measured by indirect ELISA. Procedure: ELISA plates were coated with human IL4RA-hFc or human IL4RA-mFc, incubated, and blocked before adding target antibodies. Goat anti-mouse IgG (H+L) and HRP (purchased from Jackson ImmunoResearch Inc., Cat. No. 109-035-062) or goat anti-human IgG and HRP (purchased from Jackson ImmunoResearch Inc., Cat. No. 109-035-088) were added. The plates were incubated and washed before adding TMB (Neogen, 308177) for color development. At the end of the reaction, absorbance at 450 nM was measured using a plate reader. Data were analyzed using SoftMax Pro 6.2.1. The reading at 450 nM indicates that antibodies 13E5, 13E5H1L1, 13E5H2L2, 13E5H3L3, 13E5H4L2, and 13E5H4L4 can all effectively bind to the antigen human IL4RA-hFc or human IL4RA-mFc in a dose-dependent manner. Four-parameter logistic regression of absorbance versus antibody concentration, as shown in Tables 1, 2, and 3, indicates that 13E5, 13E5H1L1, 13E5H2L2, 13E5H3L3, 13E5H4L2, and 13E5H4L4 can all effectively bind to the antigen human IL4RA-hFc or human IL4RA-mFc, exhibiting binding activity comparable to that of the control antibody dupilumab against the same targets (Figures 1, 2, and 3). [Table 1] [Table 2] [Table 3] 1.2 The binding activity of antibodies 13E5, 13E5H1L1, 13E5H2L2, 13E5H3L3, 13E5H4L2 and 13E5H4L4 to block the binding between IL4N-his and the antigen IL4RAhFc was measured by competitive ELISA. To investigate the activity of 13E5, 13E5H1L1, 13E5H2L2, 13E5H3L3, 13E5H4L2, and 13E5H4L4 to block ligand binding to the target antigen human IL4RA-hFc, the EC values ​​of 13E5, 13E5H1L1, 13E5H2L2, 13E5H3L3, 13E5H4L2, and 13E5H4L4 to compete with the ligand human IL4N-His for binding to the antigen human IL4RA-hFc were calculated. 50 (Median effective concentrations) were assayed by ELISA. Before adding the antibodies, the ELISA plate was coated with human IL4RA-hFc and blocked. An equal volume of human IL4N-His (synthesized by Akeso, Inc.) was added, and the mixture was mixed well and incubated. After washing the plate, mouse anti-His, HRP (purchased from CoWin Biosciences, Cat. No. CW0285A) was added for incubation. The plate was washed again. The color reaction was initiated by adding TMB (Neogen, 308177) and then terminated. At the end of the reaction, the OD value at a wavelength of 450 nM was measured using a plate reader and analyzed and processed using SoftMax Pro 6.2.1. The results are shown in Tables 4, 5, and 6. Blocking EC values ​​of antibodies were calculated using a four-parameter logistic regression of absorbance versus antibody concentration. 50 was calculated. As shown in Figures 4, 5, and 6, 13E5, 13E5H1L1, 13E5H2L2, 13E5H4L2, and 13E5H4L4 can all effectively block the binding of the ligand human IL4N-His to the antigen human IL4RA-hFc in a dose-dependent manner. Antibodies 13E5H1L1, 13E5H2L2, 13E5H4L2, and 13E5H4L4 show superior activity in competing with human IL4N-His for binding to human IL4RA-hFc compared to the control antibody dupilumab against the same antigen. [Table 4] [Table 5] [Table 6]

[0140] 2. Binding activity of mouse antibody 18H7 and humanized antibodies 18H7H1L1, 18H7H2L2, 18H7H2L3, 18H7H3L2, and 18H7H3L3 to the antigen IL4RA-hFc 2.1 The binding activity of antibodies 18H7, 18H7H1L1, 18H7H2L2, 18H7H2L3, 18H7H3L2 and 18H7H3L3 to the antigen human IL4RA-hFc or human IL4RA-mFc was measured by indirect ELISA. Procedure: ELISA plates were coated with human IL4RA-hFc or human IL4RA-mFc, incubated, and blocked before adding the target antibody. Goat anti-mouse IgG (H+L) and HRP (purchased from Jackson ImmunoResearch Inc., Cat. No. 109-035-062) or goat anti-human IgG and HRP (purchased from Jackson ImmunoResearch Inc., Cat. No. 109-035-088) were added. After incubation and washing, TMB (Neogen, 308177) was added for color development. At the end of the reaction, the absorbance at 450 nM was measured using a plate reader. Data were analyzed using SoftMax Pro 6.2.1S. The reading at 450 nM indicates that antibodies 18H7, 18H7H1L1, 18H7H2L2, 18H7H2L3, 18H7H3L2, and 18H7H3L3 can all effectively bind to the antigen human IL4RA-hFc or human IL4RA-mFc in a dose-dependent manner. Four-parameter logistic regression of absorbance versus antibody concentration, as shown in Tables 7 and 8, indicates that 18H7, 18H7H1L1, 18H7H2L2, 18H7H2L3, 18H7H3L2, and 18H7H3L3 can all effectively bind to the antigen human IL4RA-hFc or human IL4RA-mFc, and antibodies 18H7H1L1, 18H7H2L2, and 18H7H2L3 exhibit binding activity comparable to that of the control antibody dupilumab against the same targets (Figures 7 and 8). [Table 7] [Table 8] 2.2 Activity of Antibodies 18H7, 18H7H1L1, 18H7H2L2, 18H7H2L3, and 18H7H3L2 to Block Binding of IL4N-his to Antigen IL4RA-hFc by Competitive ELISA To examine the activity of 18H7, 18H7H1L1, 18H7H2L2, 18H7H3L2, and 18H7H3L2 to block ligand binding to the target antigen, human IL4RA-hFc, the EC values ​​of 18H7, 18H7H1L1, 18H7H2L2, 18H7H3L2, and 18H7H3L2 to compete with the ligand, human IL4N-His, for ligand binding to the antigen, human IL4RA-hFc were calculated. 50 (median effective concentrations) were assayed by ELISA. After coating and blocking the ELISA plate with human IL4RA-hFc, the antibody was added. An equal volume of human IL4-N-His (IL4 synthesized by Akeso, Inc., with a six-His tag attached to the N-terminus) was added, and the mixture was mixed well and incubated. After washing the plate, mouse anti-His, HRP (purchased from CoWin Biosciences, Cat. No. CW0285M) was added for incubation. The plate was washed again. The color reaction was initiated by adding TMB (Neogen, 308177) and then terminated. At the end of the reaction, the OD value at a wavelength of 450 nM was measured using a plate reader and analyzed and processed using SoftMax Pro 6.2.1. The results are shown in Tables 9 and 10. Blocking EC values ​​of antibodies were calculated using a four-parameter logistic regression of absorbance versus antibody concentration. 50was calculated. As shown in Figures 9 and 10, 18H7, 18H7H1L1, 18H7H2L2, and 18H7H3L2 can all effectively block the binding of the ligand human IL4N-His to the antigen human IL4RA-hFc in a dose-dependent manner. Antibodies 18H7H1L1, 18H7H2L2, and 18H7H3L2 show superior activity in competing with human IL4N-His for binding to human IL4RA-hFc compared to the control antibody dupilumab against the same antigen. [Table 9] [Table 10]

[0141] 3. Binding activity of humanized antibodies 20G10H3L3 and 13E5H4L4 to the antigen IL4RA-hFc 3.1 The activity of antibodies 20G10H3L3 and 13E5H4L4 to block the binding of IL4N-His to the antigen IL4RA-hFc was measured by competitive ELISA. To examine the activity of 20G10H3L3 and 13E5H4L4 to block ligand binding to the target antigen human IL4RA-hFc, the EC values ​​of 20G10H3L3 and 13E5H4L4 to compete with the ligand human IL4N-His for ligand binding to the antigen human IL4RA-hFc were calculated. 50 (Median effective concentrations) were assayed by ELISA. An ELISA plate was coated with human IL4RA-hFc and blocked before adding the antibody. An equal volume of human IL4-N-His (synthesized by Akeso, Inc.) was added, and the mixture was mixed well and incubated. After washing the plate, mouse anti-His, HRP (purchased from CoWin Biosciences, Cat. No. CW0285A) was added for incubation. The plate was washed again. The color reaction was initiated by adding TMB (Neogen, 308177) and then terminated. At the end of the reaction, the OD value at a wavelength of 450 nM was measured using a plate reader and analyzed and processed using SoftMax Pro 6.2.1. The results are shown in Table 11. Blocking EC values ​​of antibodies were calculated using a four-parameter logistic regression of absorbance versus antibody concentration. 50 was calculated. As shown in Figure 11, 20G10H3L3 and 13E5H4L4 can all effectively block the binding of the ligand human IL4N-His to the antigen human IL4RA-hFc in a dose-dependent manner. The antibodies 20G10H3L3 and 13E5H4L4 show superior activity in competing with human IL4N-His for binding to human IL4RA-hFc compared to the control antibody dupilumab against the same antigen. [Table 11] Example 8

[0142] Affinity constant assay of humanized antibodies 13E5H1L1, 13E5H2L2, 13E5H3L3, 13E5H4L2, 13E5H4L4, 18H7H1L1, 18H7H2L2, and 18H7H3L2 against human IL4RA The affinity constants for binding to human IL4RA of humanized antibodies 13E5H1L1, 13E5H2L2, 13E5H3L3, 13E5H4L2, 13E5H4L4, 18H7H1L1, 18H7H2L2, 18H7H3L2, and dupilumab were measured using a Fortebio molecular interaction instrument. 5 μg / mL of antigen was immobilized on the AMC sensor by incubation for 60 seconds. The sensor was then equilibrated in PBST for 300 seconds and incubated for 120 seconds with antibody at 0.39 to 25 nM (two-fold serial dilutions) to bind the antibody to the antigen immobilized on the sensor. The remaining antibody was dissociated from the antigen by incubation in PBST for 600 seconds. The sensor was refreshed with 10 mM glycine, pH 1.7. The data were analyzed using a 1:1 model fitting to obtain affinity constants. The affinity constants of the humanized antibodies 13E5H4L4, 18H7H1L1, and dupilumab (reference) for human IL4RA are shown in Table 12 and Figures 12 to 14. [Table 12] The results showed that the humanized antibodies 13E5H4L4, 18H7H1L1, and human IL4RA had high binding affinity to the target antigen, comparable to that of the control antibody dupilumab. The affinity constants of the humanized antibodies 13E5H1L1, 13E5H2L2, 13E5H3L3, 13E5H4L2, 18H7H2L2, 18H7H3L2, and dupilumab (control) for human IL4RA are shown in Table 13 and Figures 15 to 21. [Table 13]

[0143] The results showed that the affinity of humanized antibody 13E5H1L1 for the antigen was superior to that of the control antibody dupilumab; the dissociation rate constants k of 13E5H1L1, 13E5H2L2, 18H7H2L2, and 18H7H3L2 for human IL4RA were significantly higher than those of the control antibody dupilumab. dis is the dissociation rate constant k of the control antibody dupilumab disThe binding rate constants of 13E5H1L1 and 13E5H4L2 to the antigen human IL4RA were smaller than that of the control antibody dupilumab, suggesting that the binding of 13E5H1L1 and 13E5H4L2 to the antigen human IL4RA is faster than that of dupilumab. Example 9

[0144] Cellular bioactivity assays The cellular biological activities of 13E5H1L1, 13E5H2L2, 13E5H4L2, 13E5H4L4, 18H7H1L1, and 18H7H2L2 to inhibit human IL-4 / IL-13-induced TF-1 cell proliferation were analyzed. The procedure was as follows: TF-1 cells (purchased from American Type Culture Collection, Cat. No. CRL-2003) were cultured in complete medium: RPMI 1640 + 10% FBS + 2.5 g / L glucose + 2 ng / mL GM-CSF. On the day of the assay, TF-1 cells were separated by centrifugation, resuspended in medium without GM-CSF, and counted. Cells were seeded at 20,000 cells / well in 96-well plates. Final antibody concentrations were 0.05, 0.5, and 5 nM; IL-4 was administered at three concentrations: 0.041, 0.41, and 4.1 nM; IL-4 was administered at 0.41 nM for the antibody group; IL-13 was administered at concentrations of 1.58, 15.8, and 79 nM; and IL-13 was administered at 15.8 nM for the antibody panel. After administration, the 96-well plates were incubated at 37°C in a 5% carbon dioxide incubator for 72 hours. After 72 hours, CCK8 reagent was added according to the instructions of the CCK8 kit (purchased from Dojindo Laboratories, Japan, Cat No. CK04). The mixture was mixed well and incubated for 3-4 hours at 37°C in a 5% carbon dioxide incubator. The OD value at 450 nM was read. OD vs. cell number curves were plotted by seeding serially diluted TF-1 cells into a 96-well plate, adding CCK8 reagent, incubating the plate for 3-4 hours at 37°C in a 5% carbon dioxide incubator, and reading the OD value at 450 nM. The cell number of each group was calculated according to the OD value, and GraphPad Prism 5 was used for plotting. The isotype control antibody was human anti-hen egg lysozyme IgG (anti-HEL), derived from the variable region of the FabF10.6.6 sequence through affinity maturation to increase the stability and plasticity of the Fv domain of the anti-protein antibody (Acierno et al., J Mol Biol., 2007, 374(1):130-46). This isotype was synthesized by Akeso, Inc. Codon optimization and gene synthesis for the heavy and light chain (full sequence or variable region) genes of human IgG antibodies were commissioned to Nanjing Genscript Biology. Referring to Molecular Cloning: A Laboratory Manual (Second Edition), the heavy and light chain genes were subcloned into heavy and light chain expression vectors (both pcDNA3.1 vectors) for mammalian expression systems using standard molecular cloning techniques, such as PCR, enzyme digestion, DNA gel electrophoresis, ligation and transformation, colony PCR, or digestion and identification. The heavy and light chain genes of the recombinant expression vectors were further sequenced and analyzed (the heavy and light chain sequences are set forth in SEQ ID NOs: 122 and 123). After confirming the sequence accuracy, endotoxin-free expression plasmids were prepared on a large scale, and the heavy and light chain plasmids were transiently co-transfected into HEK293 cells to express the recombinant antibodies. After 7 days of culture, the cell culture medium was collected and affinity purified using a Protein A column (GE), and the quality of the resulting antibody sample was determined using SDS-PAGE and SEC-HPLC standard analytical techniques. The results are shown in Figures 22 to 27. As can be seen in Figures 22 to 27, both human IL-4 and human IL-13 can effectively promote the proliferation of TF-1 cells in a dose-dependent manner; compared with the isotype control antibody (human IgG), dupilumab, 13E5H1L1, 13E5H2L2, 13E5H4L2, 13E5H4L4, 18H7H1L1, and 18H7H2L2 can specifically inhibit the proliferation of TF-1 cells induced by IL-4 and IL-13 in a dose-dependent manner. The results show that 13E5H1L1, 13E5H2L2, 13E5H4L2, 13E5H4L4, 18H7H1L1 and 18H7H2L2 can specifically inhibit the proliferation of TF-1 cells induced by human IL-4 and human IL-13; antibodies 13E5H1L1, 13E5H4L4 and 18H7H1L1 show activity comparable to that of the control antibody dupilumab. Example 10

[0145] 13E5H4L4 and 18H7H1L1 inhibit the upregulation of CD23 expression in PBMCs This example was designed to examine the biological activity of 13E5H4L4 and 18H7H1L1 to neutralize the upregulation of CD23 expression on the surface of human PBMCs induced by human IL-4 and human IL-13 via flow cytometry. The procedure was as follows. Normal human peripheral blood (heparinized) was separated by Ficoll density gradient centrifugation to obtain fresh human PBMCs. After three rounds of centrifugation and washing, the cells were counted and the density was adjusted to 2.5 × 10 6 The cells were seeded into a low-attachment 96-well plate at 200 μL of PBMC per well (i.e., 500,000 cells / well); the antibodies dupilumab, 13E5H4L4, or 18H7H1L1 (final concentrations of 30, 3, and 0.3 nM, respectively) were added to each well, and a blank control and an isotype control human IgG (final concentration of 30 nM) were included. The cells were incubated at room temperature for 30 minutes. After 30 minutes, 25 μL of human IL-4 (final concentration of 100 pM) or 25 μL of human IL-13 (final concentration of 300 ng / mL) were added, and the system was incubated for 2.5 days. After 2.5 days, PBMCs were isolated and transferred to 1.5 mL EP tubes. 500 μL of 1% PBSA was added and centrifuged at 1000 × g for 5 minutes. The supernatant was discarded, and 50 μL of CD23-PE antibody (50x diluted in 1% PBSA) was added to the residue and incubated on ice for 40 minutes. After the 40-minute incubation, 1 mL of 1% PBSA was added to the system, and the system was centrifuged at 1000 × g for 5 minutes. The supernatant was discarded. The cells were resuspended in 200 μL of 1% PBSA and transferred to flow cytometry tubes for assay. The results are shown in Figures 28 and 29. The results show that human IL-4 and human IL-13 can upregulate the expression level of CD23 on the surface of human PBMCs, and that 13E5H4L4 and 18H7H1L1 can specifically bind to human IL4RA, thereby effectively blocking the upregulation of CD23 expression level by IL-4 and IL-13. Example 11

[0146] Effect of 13E5H4L4 on B-hIL4Ra mouse model of HDM-induced skin inflammation The procedure is as follows: A skin inflammation model was established in B-hIL4Ra mice (C57BL / 6 background) by inducing HDM (mite allergen, Greer Laboratories, Lot No. 348717). Mice were divided into six groups with seven mice each, including an isotype control group (anti-HEL), a high-dose group (80 mg / kg; dupilumab commercially available from Sanofi and Regeneron Pharmaceuticals) and a low-dose group (20 mg / kg; dupilumab commercially available from Sanofi and Regeneron Pharmaceuticals), and a high-dose group (80 mg / kg) and a low-dose group (20 mg / kg) of 13E5H4L4. Treatments were administered by subcutaneous injection on Days 1, 2, 5, and 8. In the normal group, the animal model was established by daily intradermal injection of saline. In the isotype control group, the animal model was established by intradermal administration of HDM (37.5 μg × 2 / 25 μL / day) daily for 7 days and HDM (25 μg × 2 / 25 μL / day) daily for 3 days. In the antibody-treated group, the animal model was established by intradermal administration of HDM (37.5 μg × 2 / 25 μL / day) daily for 7 days and HDM (25 μg × 2 / 25 μL / day) daily for 3 days. The epidermal thickness of the mice was measured to determine the effect of 13E5H4L4 in inhibiting epidermal thickness in the B-hIL4Ra mouse skin inflammation model. [Table 14] Pathological sections are shown in Figure 31. In a B-hIL4Ra mouse skin inflammation model established by intradermal injection of 37.5 μg + 25 μg HDM, the epidermal thickness of the model group was significantly thicker than that of the normal group. The epidermal thickening of the mice was significantly inhibited by subcutaneous injection of dupilumab 80 mg / kg and 13E5H4L4 80 mg / kg with a favorable dose-response relationship. 13E5H4L4 80 mg / kg was slightly superior to dupilumab 80 mg / kg. Although the preferred embodiments of the present invention have been described in detail above, the present invention is not limited to these embodiments. Those skilled in the art can make various equivalent modifications or substitutions without departing from the spirit of the present invention. These equivalent modifications or substitutions are included in the scope defined by the claims of this application.

[0147] Array List [ka] TIFF0007759255000016.tif252161 TIFF0007759255000017.tif244161 TIFF0007759255000018.tif252161 TIFF0007759255000019.tif248161 TIFF0007759255000020.tif247161 TIFF0007759255000021.tif242161 TIFF0007759255000022.tif242161 TIFF0007759255000023.tif240161 TIFF0007759255000024.tif248161 TIFF0007759255000025.tif176161

Claims

1. an antibody or antigen-binding fragment thereof that binds to IL4RA, preferably human IL4RA, wherein the antigen-binding fragment is selected from Fab, Fab', F(ab') 2 , Fv, Fab / c, scFv, and a bivalent antibody; (1) The antibody HCDR1 consisting of the sequence set forth in SEQ ID NO: 9, HCDR2 consisting of the sequence set forth in SEQ ID NO: 10, and HCDR3 consisting of the sequence set forth in SEQ ID NO: 11; and further comprising: LCDR1 consisting of the sequence set forth in SEQ ID NO: 12, LCDR2 consisting of the sequence set forth in SEQ ID NO: 13, and comprises an LCDR3 consisting of the sequence set forth in SEQ ID NO: 14; or (2) The antibody is HCDR1 consisting of the sequence set forth in SEQ ID NO: 15, HCDR2 consisting of the sequence set forth in SEQ ID NO: 16, and HCDR3 consisting of the sequence set forth in SEQ ID NO: 17; and further comprising: LCDR1 consisting of the sequence set forth in SEQ ID NO: 18, LCDR2 consisting of the sequence set forth in SEQ ID NO: 19, and or comprises an LCDR3 consisting of the sequence set forth in SEQ ID NO: 20; or The antibody or antigen-binding fragment thereof, wherein the antibody is secreted by a hybridoma cell having an accession number of CCTCC NO: C2018131 or CCTCC NO: C2018132.

2. below, (1) (i) the amino acid sequence set forth in SEQ ID NO: 2, or a sequence having at least 80%, 85% or 90%, preferably at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to the sequence set forth in SEQ ID NO: 2; a heavy chain variable region comprising or consisting of: (ii) the amino acid sequence set forth in SEQ ID NO: 4, or a sequence having at least 80%, 85% or 90%, preferably at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to the sequence set forth in SEQ ID NO: 4; a light chain variable region comprising or consisting of: (2) (i) the amino acid sequence set forth in SEQ ID NO: 6, or a sequence having at least 80%, 85% or 90%, preferably at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to the sequence set forth in SEQ ID NO: 6; a heavy chain variable region comprising or consisting of: (ii) the amino acid sequence set forth in SEQ ID NO: 8, or a sequence having at least 80%, 85% or 90%, preferably at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to the sequence set forth in SEQ ID NO: 8; a light chain variable region comprising or consisting of: (3) (i) the amino acid sequence set forth in SEQ ID NO: 22, or a sequence having at least 80%, 85% or 90%, preferably at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to the sequence set forth in SEQ ID NO: 22; a heavy chain variable region comprising or consisting of: (ii) the amino acid sequence set forth in SEQ ID NO: 24, or a sequence having at least 80%, 85% or 90%, preferably at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to the sequence set forth in SEQ ID NO: 24; a light chain variable region comprising or consisting of: (4) (i) the amino acid sequence set forth in SEQ ID NO: 26, or a sequence having at least 80%, 85% or 90%, preferably at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to the sequence set forth in SEQ ID NO: 26; a heavy chain variable region comprising or consisting of: (ii) the amino acid sequence set forth in SEQ ID NO: 28, or a sequence having at least 80%, 85% or 90%, preferably at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to the sequence set forth in SEQ ID NO: 28; a light chain variable region comprising or consisting of: (5) (i) the amino acid sequence set forth in SEQ ID NO: 30, or a sequence having at least 80%, 85% or 90%, preferably at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to the sequence set forth in SEQ ID NO: 30; a heavy chain variable region comprising or consisting of: (ii) the amino acid sequence set forth in SEQ ID NO: 32, or a sequence having at least 80%, 85% or 90%, preferably at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to the sequence set forth in SEQ ID NO: 32; a light chain variable region comprising or consisting of: (6) (i) the amino acid sequence set forth in SEQ ID NO: 34, or a sequence having at least 80%, 85% or 90%, preferably at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to the sequence set forth in SEQ ID NO: 34; a heavy chain variable region comprising or consisting of: (ii) the amino acid sequence set forth in SEQ ID NO: 36, or a sequence having at least 80%, 85% or 90%, preferably at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to the sequence set forth in SEQ ID NO: 36; a light chain variable region comprising or consisting of: (7) (i) the amino acid sequence set forth in SEQ ID NO: 38, or a sequence having at least 80%, 85% or 90%, preferably at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to the sequence set forth in SEQ ID NO: 38; a heavy chain variable region comprising or consisting of: (ii) the amino acid sequence set forth in SEQ ID NO: 40, or a sequence having at least 80%, 85% or 90%, preferably at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to the sequence set forth in SEQ ID NO: 40; a light chain variable region comprising or consisting of: (8) (i) the amino acid sequence set forth in SEQ ID NO: 42, or a sequence having at least 80%, 85% or 90%, preferably at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to the sequence set forth in SEQ ID NO: 42; a heavy chain variable region comprising or consisting of: (ii) the amino acid sequence set forth in SEQ ID NO: 44, or a sequence having at least 80%, 85% or 90%, preferably at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to the sequence set forth in SEQ ID NO: 44; a light chain variable region comprising or consisting of: (9) (i) the amino acid sequence set forth in SEQ ID NO: 46, or a sequence having at least 80%, 85% or 90%, preferably at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to the sequence set forth in SEQ ID NO: 46; a heavy chain variable region comprising or consisting of: (ii) the amino acid sequence set forth in SEQ ID NO: 48, or a sequence having at least 80%, 85% or 90%, preferably at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to the sequence set forth in SEQ ID NO: 48; a light chain variable region comprising or consisting of: (10) (i) the amino acid sequence set forth in SEQ ID NO: 42, or a sequence having at least 80%, 85% or 90%, preferably at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to the sequence set forth in SEQ ID NO: 42; a heavy chain variable region comprising or consisting of: (ii) the amino acid sequence set forth in SEQ ID NO: 48, or a sequence having at least 80%, 85% or 90%, preferably at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to the sequence set forth in SEQ ID NO: 48; a light chain variable region comprising or consisting of: (11) (i) the amino acid sequence set forth in SEQ ID NO: 46, or a sequence having at least 80%, 85% or 90%, preferably at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to the sequence set forth in SEQ ID NO: 46; a heavy chain variable region comprising or consisting of: (ii) the amino acid sequence set forth in SEQ ID NO: 44, or a sequence having at least 80%, 85% or 90%, preferably at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to the sequence set forth in SEQ ID NO: 44; a light chain variable region comprising or consisting of: (12) (i) the amino acid sequence set forth in SEQ ID NO: 34, or a sequence having at least 80%, 85% or 90%, preferably at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to the sequence set forth in SEQ ID NO: 34; a heavy chain variable region comprising or consisting of: (ii) the amino acid sequence set forth in SEQ ID NO: 28, or a sequence having at least 80%, 85% or 90%, preferably at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to the sequence set forth in SEQ ID NO: 28; a light chain variable region comprising or consisting of: The antibody of claim 1 , comprising:

3. The antibody or antigen-binding fragment thereof according to any one of claims 1 to 2, wherein the antibody further comprises framework regions FR-H1, FR-H2, FR-H3, and FR-H4 in the heavy chain variable region, and framework regions FR-L1, FR-L2, FR-L3, and FR-L4 in the light chain variable region, (1) the FR-H1 comprises or consists of the amino acid sequence set forth in SEQ ID NO: 49 or a sequence having at least 80%, 85%, or 90%, preferably at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to the sequence set forth in SEQ ID NO: 49; said FR-H2 comprises or consists of the amino acid sequence set forth in SEQ ID NO: 50 or a sequence having at least 80%, 85% or 90%, preferably at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to said sequence set forth in SEQ ID NO: 50; the FR-H3 comprises or consists of the amino acid sequence set forth in SEQ ID NO: 51 or a sequence having at least 80%, 85% or 90%, preferably at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to the sequence set forth in SEQ ID NO: 51; said FR-H4 comprises or consists of the amino acid sequence set forth in SEQ ID NO: 52 or a sequence having at least 80%, 85% or 90%, preferably at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to said sequence set forth in SEQ ID NO: 52; said FR-L1 comprises or consists of the amino acid sequence set forth in SEQ ID NO: 53 or a sequence having at least 80%, 85% or 90%, preferably at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to said sequence set forth in SEQ ID NO: 53; said FR-L2 comprises or consists of the amino acid sequence set forth in SEQ ID NO: 54 or a sequence having at least 80%, 85% or 90%, preferably at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to said sequence set forth in SEQ ID NO: 54; said FR-L3 comprises or consists of the amino acid sequence set forth in SEQ ID NO: 55 or a sequence having at least 80%, 85% or 90%, preferably at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to said sequence set forth in SEQ ID NO: 55; and said FR-L4 comprises or consists of the amino acid sequence set forth in SEQ ID NO: 56 or a sequence having at least 80%, 85% or 90%, preferably at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to said sequence set forth in SEQ ID NO: 56; (2) The FR-H1 comprises or consists of the amino acid sequence set forth in SEQ ID NO: 57 or a sequence having at least 80%, 85%, or 90%, preferably at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to the sequence set forth in SEQ ID NO: 57; said FR-H2 comprises or consists of the amino acid sequence set forth in SEQ ID NO: 58 or a sequence having at least 80%, 85% or 90%, preferably at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to said sequence set forth in SEQ ID NO: 58; the FR-H3 comprises or consists of the amino acid sequence set forth in SEQ ID NO: 59 or a sequence having at least 80%, 85% or 90%, preferably at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to the sequence set forth in SEQ ID NO: 59; said FR-H4 comprises or consists of the amino acid sequence set forth in SEQ ID NO: 60 or a sequence having at least 80%, 85% or 90%, preferably at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to said sequence set forth in SEQ ID NO: 60; said FR-L1 comprises or consists of the amino acid sequence set forth in SEQ ID NO: 61 or a sequence having at least 80%, 85% or 90%, preferably at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to said sequence set forth in SEQ ID NO: 61; said FR-L2 comprises or consists of the amino acid sequence set forth in SEQ ID NO: 62 or a sequence having at least 80%, 85% or 90%, preferably at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to said sequence set forth in SEQ ID NO: 62; said FR-L3 comprises or consists of the amino acid sequence set forth in SEQ ID NO: 63 or a sequence having at least 80%, 85% or 90%, preferably at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to said sequence set forth in SEQ ID NO: 63; and said FR-L4 comprises or consists of the amino acid sequence set forth in SEQ ID NO: 64 or a sequence having at least 80%, 85% or 90%, preferably at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to said sequence set forth in SEQ ID NO: 64; (3) The FR-H1 comprises or consists of the amino acid sequence set forth in SEQ ID NO: 65 or a sequence having at least 80%, 85%, or 90%, preferably at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to the sequence set forth in SEQ ID NO: 65; said FR-H2 comprises or consists of the amino acid sequence set forth in SEQ ID NO: 66 or a sequence having at least 80%, 85% or 90%, preferably at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to said sequence set forth in SEQ ID NO: 66; the FR-H3 comprises or consists of the amino acid sequence set forth in SEQ ID NO: 67 or a sequence having at least 80%, 85% or 90%, preferably at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to the sequence set forth in SEQ ID NO: 67; said FR-H4 comprises or consists of the amino acid sequence set forth in SEQ ID NO: 68 or a sequence having at least 80%, 85% or 90%, preferably at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to said sequence set forth in SEQ ID NO: 68; said FR-L1 comprises or consists of the amino acid sequence set forth in SEQ ID NO: 69 or a sequence having at least 80%, 85% or 90%, preferably at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to said sequence set forth in SEQ ID NO: 69; said FR-L2 comprises or consists of the amino acid sequence set forth in SEQ ID NO: 70 or a sequence having at least 80%, 85% or 90%, preferably at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to said sequence set forth in SEQ ID NO: 70; said FR-L3 comprises or consists of the amino acid sequence set forth in SEQ ID NO: 71 or a sequence having at least 80%, 85% or 90%, preferably at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to said sequence set forth in SEQ ID NO: 71; and said FR-L4 comprises or consists of the amino acid sequence set forth in SEQ ID NO: 72 or a sequence having at least 80%, 85% or 90%, preferably at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to said sequence set forth in SEQ ID NO: 72; (4) The FR-H1 comprises or consists of the amino acid sequence set forth in SEQ ID NO: 73 or a sequence having at least 80%, 85%, or 90%, preferably at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to the sequence set forth in SEQ ID NO: 73; said FR-H2 comprises or consists of the amino acid sequence set forth in SEQ ID NO: 74 or a sequence having at least 80%, 85% or 90%, preferably at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to said sequence set forth in SEQ ID NO: 74; the FR-H3 comprises or consists of the amino acid sequence set forth in SEQ ID NO: 75 or a sequence having at least 80%, 85% or 90%, preferably at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to the sequence set forth in SEQ ID NO: 75; said FR-H4 comprises or consists of the amino acid sequence set forth in SEQ ID NO: 76 or a sequence having at least 80%, 85% or 90%, preferably at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to said sequence set forth in SEQ ID NO: 76; said FR-L1 comprises or consists of the amino acid sequence set forth in SEQ ID NO: 77 or a sequence having at least 80%, 85% or 90%, preferably at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to said sequence set forth in SEQ ID NO: 77; said FR-L2 comprises or consists of the amino acid sequence set forth in SEQ ID NO: 78 or a sequence having at least 80%, 85% or 90%, preferably at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to said sequence set forth in SEQ ID NO: 78; said FR-L3 comprises or consists of the amino acid sequence set forth in SEQ ID NO: 79 or a sequence having at least 80%, 85% or 90%, preferably at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to said sequence set forth in SEQ ID NO: 79; and said FR-L4 comprises or consists of the amino acid sequence set forth in SEQ ID NO: 80 or a sequence having at least 80%, 85% or 90%, preferably at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to said sequence set forth in SEQ ID NO: 80; (5) The FR-H1 comprises or consists of the amino acid sequence set forth in SEQ ID NO: 81 or a sequence having at least 80%, 85% or 90%, preferably at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to the sequence set forth in SEQ ID NO: 81; said FR-H2 comprises or consists of the amino acid sequence set forth in SEQ ID NO: 82 or a sequence having at least 80%, 85% or 90%, preferably at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to said sequence set forth in SEQ ID NO: 82; the FR-H3 comprises or consists of the amino acid sequence set forth in SEQ ID NO: 83 or a sequence having at least 80%, 85% or 90%, preferably at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to the sequence set forth in SEQ ID NO: 83; said FR-H4 comprises or consists of the amino acid sequence set forth in SEQ ID NO: 84 or a sequence having at least 80%, 85% or 90%, preferably at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to said sequence set forth in SEQ ID NO: 84; said FR-L1 comprises or consists of the amino acid sequence set forth in SEQ ID NO: 85 or a sequence having at least 80%, 85% or 90%, preferably at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to said sequence set forth in SEQ ID NO: 85; the FR-L2 comprises or consists of the amino acid sequence set forth in SEQ ID NO: 86 or a sequence having at least 80%, 85% or 90%, preferably at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to the sequence set forth in SEQ ID NO: 86; said FR-L3 comprises or consists of the amino acid sequence set forth in SEQ ID NO: 87 or a sequence having at least 80%, 85% or 90%, preferably at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to said sequence set forth in SEQ ID NO: 87; and said FR-L4 comprises or consists of the amino acid sequence set forth in SEQ ID NO: 88 or a sequence having at least 80%, 85% or 90%, preferably at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to said sequence set forth in SEQ ID NO: 88; (6) The FR-H1 comprises or consists of the amino acid sequence set forth in SEQ ID NO: 89 or a sequence having at least 80%, 85%, or 90%, preferably at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to the sequence set forth in SEQ ID NO: 89; said FR-H2 comprises or consists of the amino acid sequence set forth in SEQ ID NO: 90 or a sequence having at least 80%, 85% or 90%, preferably at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to said sequence set forth in SEQ ID NO: 90; the FR-H3 comprises or consists of the amino acid sequence set forth in SEQ ID NO: 91 or a sequence having at least 80%, 85% or 90%, preferably at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to the sequence set forth in SEQ ID NO: 91; said FR-H4 comprises or consists of the amino acid sequence set forth in SEQ ID NO: 92 or a sequence having at least 80%, 85% or 90%, preferably at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to said sequence set forth in SEQ ID NO: 92; said FR-L1 comprises or consists of the amino acid sequence set forth in SEQ ID NO: 93 or a sequence having at least 80%, 85% or 90%, preferably at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to said sequence set forth in SEQ ID NO: 93; said FR-L2 comprises or consists of the amino acid sequence set forth in SEQ ID NO: 94 or a sequence having at least 80%, 85% or 90%, preferably at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to said sequence set forth in SEQ ID NO: 94; said FR-L3 comprises or consists of the amino acid sequence set forth in SEQ ID NO: 95 or a sequence having at least 80%, 85% or 90%, preferably at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to said sequence set forth in SEQ ID NO: 95; and said FR-L4 comprises or consists of the amino acid sequence set forth in SEQ ID NO: 96 or a sequence having at least 80%, 85% or 90%, preferably at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to said sequence set forth in SEQ ID NO: 96; (7) The FR-H1 comprises or consists of the amino acid sequence set forth in SEQ ID NO: 97 or a sequence having at least 80%, 85% or 90%, preferably at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to the sequence set forth in SEQ ID NO: 97; said FR-H2 comprises or consists of the amino acid sequence set forth in SEQ ID NO: 98 or a sequence having at least 80%, 85% or 90%, preferably at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to said sequence set forth in SEQ ID NO: 98; the FR-H3 comprises or consists of the amino acid sequence set forth in SEQ ID NO: 99 or a sequence having at least 80%, 85% or 90%, preferably at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to the sequence set forth in SEQ ID NO: 99; said FR-H4 comprises or consists of the amino acid sequence set forth in SEQ ID NO: 100 or a sequence having at least 80%, 85% or 90%, preferably at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to said sequence set forth in SEQ ID NO: 100; said FR-L1 comprises or consists of the amino acid sequence set forth in SEQ ID NO: 101 or a sequence having at least 80%, 85% or 90%, preferably at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to said sequence set forth in SEQ ID NO: 101; said FR-L2 comprises or consists of the amino acid sequence set forth in SEQ ID NO: 102 or a sequence having at least 80%, 85% or 90%, preferably at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to said sequence set forth in SEQ ID NO: 102; said FR-L3 comprises or consists of the amino acid sequence set forth in SEQ ID NO: 103 or a sequence having at least 80%, 85% or 90%, preferably at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to said sequence set forth in SEQ ID NO: 103; and said FR-L4 comprises or consists of the amino acid sequence set forth in SEQ ID NO: 104 or a sequence having at least 80%, 85% or 90%, preferably at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to said sequence set forth in SEQ ID NO: 104; (8) The FR-H1 comprises or consists of the amino acid sequence set forth in SEQ ID NO: 105, or a sequence having at least 80%, 85%, or 90%, preferably at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to the sequence set forth in SEQ ID NO: 105; said FR-H2 comprises or consists of the amino acid sequence set forth in SEQ ID NO: 106 or a sequence having at least 80%, 85% or 90%, preferably at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to said sequence set forth in SEQ ID NO: 106; the FR-H3 comprises or consists of the amino acid sequence set forth in SEQ ID NO: 107 or a sequence having at least 80%, 85% or 90%, preferably at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to the sequence set forth in SEQ ID NO: 107; said FR-H4 comprises or consists of the amino acid sequence set forth in SEQ ID NO: 108 or a sequence having at least 80%, 85% or 90%, preferably at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to said sequence set forth in SEQ ID NO: 108; said FR-L1 comprises or consists of the amino acid sequence set forth in SEQ ID NO: 109 or a sequence having at least 80%, 85% or 90%, preferably at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to said sequence set forth in SEQ ID NO: 109; said FR-L2 comprises or consists of the amino acid sequence set forth in SEQ ID NO: 110 or a sequence having at least 80%, 85% or 90%, preferably at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to said sequence set forth in SEQ ID NO: 110; said FR-L3 comprises or consists of the amino acid sequence set forth in SEQ ID NO: 111 or a sequence having at least 80%, 85% or 90%, preferably at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to said sequence set forth in SEQ ID NO: 111; and said FR-L4 comprises or consists of the amino acid sequence set forth in SEQ ID NO: 112 or a sequence having at least 80%, 85% or 90%, preferably at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to said sequence set forth in SEQ ID NO: 112; (9) The FR-H1 comprises or consists of the amino acid sequence set forth in SEQ ID NO: 113, or a sequence having at least 80%, 85% or 90%, preferably at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to the sequence set forth in SEQ ID NO: 113; said FR-H2 comprises or consists of the amino acid sequence set forth in SEQ ID NO: 114 or a sequence having at least 80%, 85% or 90%, preferably at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to said sequence set forth in SEQ ID NO: 114; the FR-H3 comprises or consists of the amino acid sequence set forth in SEQ ID NO: 115 or a sequence having at least 80%, 85% or 90%, preferably at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to the sequence set forth in SEQ ID NO: 115; said FR-H4 comprises or consists of the amino acid sequence set forth in SEQ ID NO: 116 or a sequence having at least 80%, 85% or 90%, preferably at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to said sequence set forth in SEQ ID NO: 116; said FR-L1 comprises or consists of the amino acid sequence set forth in SEQ ID NO: 117 or a sequence having at least 80%, 85% or 90%, preferably at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to said sequence set forth in SEQ ID NO: 117; said FR-L2 comprises or consists of the amino acid sequence set forth in SEQ ID NO: 118 or a sequence having at least 80%, 85% or 90%, preferably at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to said sequence set forth in SEQ ID NO: 118; said FR-L3 comprises or consists of the amino acid sequence set forth in SEQ ID NO: 119 or a sequence having at least 80%, 85% or 90%, preferably at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to said sequence set forth in SEQ ID NO: 119; and said FR-L4 comprises or consists of the amino acid sequence set forth in SEQ ID NO: 120 or a sequence having at least 80%, 85% or 90%, preferably at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to said sequence set forth in SEQ ID NO: 120; (10) The FR-H1 comprises or consists of the amino acid sequence set forth in SEQ ID NO: 89 or a sequence having at least 80%, 85% or 90%, preferably at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to the sequence set forth in SEQ ID NO: 89; said FR-H2 comprises or consists of the amino acid sequence set forth in SEQ ID NO: 90 or a sequence having at least 80%, 85% or 90%, preferably at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to said sequence set forth in SEQ ID NO: 90; the FR-H3 comprises or consists of the amino acid sequence set forth in SEQ ID NO: 91 or a sequence having at least 80%, 85% or 90%, preferably at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to the sequence set forth in SEQ ID NO: 91; said FR-H4 comprises or consists of the amino acid sequence set forth in SEQ ID NO: 92 or a sequence having at least 80%, 85% or 90%, preferably at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to said sequence set forth in SEQ ID NO: 92; said FR-L1 comprises or consists of the amino acid sequence set forth in SEQ ID NO: 77 or a sequence having at least 80%, 85% or 90%, preferably at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to said sequence set forth in SEQ ID NO: 77; said FR-L2 comprises or consists of the amino acid sequence set forth in SEQ ID NO: 78 or a sequence having at least 80%, 85% or 90%, preferably at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to said sequence set forth in SEQ ID NO: 78; said FR-L3 comprises or consists of the amino acid sequence set forth in SEQ ID NO: 79 or a sequence having at least 80%, 85% or 90%, preferably at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to said sequence set forth in SEQ ID NO: 79; and said FR-L4 comprises or consists of the amino acid sequence set forth in SEQ ID NO: 80 or a sequence having at least 80%, 85% or 90%, preferably at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to said sequence set forth in SEQ ID NO: 80; (11) The FR-H1 comprises or consists of the amino acid sequence set forth in SEQ ID NO: 105, or a sequence having at least 80%, 85%, or 90%, preferably at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to the sequence set forth in SEQ ID NO: 105; said FR-H2 comprises or consists of the amino acid sequence set forth in SEQ ID NO: 106 or a sequence having at least 80%, 85% or 90%, preferably at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to said sequence set forth in SEQ ID NO: 106; the FR-H3 comprises or consists of the amino acid sequence set forth in SEQ ID NO: 107 or a sequence having at least 80%, 85% or 90%, preferably at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to the sequence set forth in SEQ ID NO: 107; said FR-H4 comprises or consists of the amino acid sequence set forth in SEQ ID NO: 108 or a sequence having at least 80%, 85% or 90%, preferably at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to said sequence set forth in SEQ ID NO: 108; said FR-L1 comprises or consists of the amino acid sequence set forth in SEQ ID NO: 117 or a sequence having at least 80%, 85% or 90%, preferably at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to said sequence set forth in SEQ ID NO: 117; said FR-L2 comprises or consists of the amino acid sequence set forth in SEQ ID NO: 118 or a sequence having at least 80%, 85% or 90%, preferably at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to said sequence set forth in SEQ ID NO: 118; said FR-L3 comprises or consists of the amino acid sequence set forth in SEQ ID NO: 119 or a sequence having at least 80%, 85% or 90%, preferably at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to said sequence set forth in SEQ ID NO: 119; and said FR-L4 comprises or consists of the amino acid sequence set forth in SEQ ID NO: 120 or a sequence having at least 80%, 85% or 90%, preferably at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to said sequence set forth in SEQ ID NO: 120; or (12) The FR-H1 comprises or consists of the amino acid sequence set forth in SEQ ID NO: 113, or a sequence having at least 80%, 85%, or 90%, preferably at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to the sequence set forth in SEQ ID NO: 113; said FR-H2 comprises or consists of the amino acid sequence set forth in SEQ ID NO: 114 or a sequence having at least 80%, 85% or 90%, preferably at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to said sequence set forth in SEQ ID NO: 114; the FR-H3 comprises or consists of the amino acid sequence set forth in SEQ ID NO: 115 or a sequence having at least 80%, 85% or 90%, preferably at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to the sequence set forth in SEQ ID NO: 115; said FR-H4 comprises or consists of the amino acid sequence set forth in SEQ ID NO: 116 or a sequence having at least 80%, 85% or 90%, preferably at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to said sequence set forth in SEQ ID NO: 116; said FR-L1 comprises or consists of the amino acid sequence set forth in SEQ ID NO: 109 or a sequence having at least 80%, 85% or 90%, preferably at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to said sequence set forth in SEQ ID NO: 109; said FR-L2 comprises or consists of the amino acid sequence set forth in SEQ ID NO: 110 or a sequence having at least 80%, 85% or 90%, preferably at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to said sequence set forth in SEQ ID NO: 110; said FR-L3 comprises or consists of the amino acid sequence set forth in SEQ ID NO: 111 or a sequence having at least 80%, 85% or 90%, preferably at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to said sequence set forth in SEQ ID NO: 111; and The FR-L4 comprises or consists of the amino acid sequence set forth in SEQ ID NO: 112 or a sequence having at least 80%, 85% or 90%, preferably at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to the sequence set forth in SEQ ID NO: 112; The antibody or antigen-binding fragment thereof.

4. The antibody or antigen-binding fragment thereof according to any one of claims 1 to 3, wherein the antibody is a humanized antibody, a chimeric antibody, or a multispecific antibody (e.g., a bispecific antibody), and preferably the constant region of the antibody is humanized, preferably derived from human IgG, more preferably derived from IgG4.

5. The antibody or antigen-binding fragment thereof according to claim 1, wherein the heavy chain constant region of the antibody is an Igγ-4 chain C region, more preferably the Igγ-4 chain C region of GenBank Accession No. P01861.1, and the light chain constant region is an Igκ chain C region, more preferably the Igκ chain C region of GenBank Accession No. P01834.

6. below, (1) An isolated polypeptide comprising the sequences set forth in SEQ ID NOs: 9, 10, and 11 for HCDR1, HCDR2, and HCDR3, respectively, and the sequences set forth in SEQ ID NOs: 12, 13, and 14 for LCDR1, LCDR2, and LCDR3, respectively, wherein the polypeptide specifically binds to human IL4RA as an anti-human IL4RA antibody; (2) An isolated polypeptide comprising the sequences set forth in SEQ ID NOs: 15, 16, and 17 for HCDR1, HCDR2, and HCDR3, respectively, and SEQ ID NOs: 18, 19, and 20 for LCDR1, LCDR2, and LCDR3, respectively, wherein the polypeptide specifically binds to human IL4RA as an anti-human IL4RA antibody; (3) The following group: i) SEQ ID NOs: 2 and 4, ii) SEQ ID NOs: 6 and 8, iii) SEQ ID NOs: 22 and 24, iv) SEQ ID NOs: 26 and 28, v) SEQ ID NOs: 30 and 32, vi) SEQ ID NOs: 34 and 36, vii) SEQ ID NOs: 38 and 40, or viii) a combination of two corresponding sequences set forth in one of the above groups, wherein the corresponding sequences have at least 80%, 85% or 90%, preferably at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to the respective sequences, and the polypeptides specifically bind to human IL4RA as anti-human IL4RA antibodies. An isolated polypeptide according to (1) or (2) above, comprising the sequence set forth in each of (1) and (2); (4) The following group: i) SEQ ID NOs: 42 and 44, ii) SEQ ID NOs: 42 and 48, iii) SEQ ID NOs: 46 and 48, iv) SEQ ID NOs: 34 and 28, v) SEQ ID NOs: 44 and 46, or vi) a combination of two corresponding sequences set forth in one of the above groups, wherein the corresponding sequences have at least 80%, 85% or 90%, preferably at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to the respective sequences, and the polypeptides specifically bind to human IL4RA as anti-human IL4RA antibodies. An isolated polypeptide according to (1) or (2) above, comprising the sequence set forth in each of (1) and (2); An isolated polypeptide selected from the group consisting of:

7. An isolated polynucleotide encoding the isolated polypeptide of claim 6.

8. A vector comprising the isolated polynucleotide of claim 7.

9. A host cell comprising the isolated polynucleotide of claim 7 or the vector of claim 8.

10. A method for preparing the antibody or antigen-binding fragment thereof according to any one of claims 1 to 5, comprising culturing the host cell according to claim 9.

11. An antibody conjugate comprising the antibody or antigen-binding fragment thereof according to any one of claims 1 to 5 and a conjugate moiety bound thereto, wherein preferably the conjugate moiety is selected from a purification tag (e.g., a His tag), a cytotoxic drug, a detectable label, a radioisotope, a luminescent substance, a colored substance, an enzyme, or polyethylene glycol.

12. A multispecific antibody, preferably a bispecific antibody, comprising the antibody or antigen-binding fragment thereof according to any one of claims 1 to 5, and an antibody or antigen-binding fragment thereof against another antigen and / or another antigenic epitope.

13. A fusion protein comprising the antibody or antigen-binding fragment thereof according to any one of claims 1 to 5.

14. 14. A pharmaceutical composition comprising the antibody or antigen-binding fragment thereof according to any one of claims 1 to 5, the antibody conjugate according to claim 11, the multispecific antibody according to claim 12 or the fusion protein according to claim 13, and optionally a pharmaceutically acceptable carrier and / or excipient.

15. 15. The pharmaceutical composition of claim 14, wherein the pharmaceutical composition is used alone or in combination with one or more other drugs.

16. 15. The pharmaceutical composition of claim 14, wherein the pharmaceutical composition is in a dosage form suitable for oral administration to the gastrointestinal (GI) tract, preferably the dosage form is selected from tablets, capsules, pills, powders, granules, emulsions, microemulsions, solutions, suspensions, syrups and elixirs; or the pharmaceutical composition is in a dosage form suitable for subcutaneous, intradermal, intravenous, intramuscular or intralesional injection.

17. 14. A kit comprising the antibody or antigen-binding fragment thereof according to any one of claims 1 to 5, the antibody conjugate according to claim 11, the multispecific antibody according to claim 12, or the fusion protein according to claim 13, preferably further comprising a second antibody that specifically recognizes the antibody or antigen-binding fragment thereof according to any one of claims 1 to 5, the antibody conjugate according to claim 11, the multispecific antibody according to claim 12, or the fusion protein according to claim 13; optionally, the second antibody further comprises a detectable label such as a radioisotope, a luminescent substance, a colored substance, or an enzyme.

18. below: i) detecting the presence or level of human IL4RA in a sample or for the prevention and / or treatment and / or adjunctive treatment and / or diagnosis of allergic diseases, tumors, autoimmune diseases, skin infections, tissue fibrosis, rhinosinusitis, nasal polyps and chronic obstructive pulmonary disease. ii) inhibiting the activity of or down-regulating the levels of human IL4RA, or Blocking cell biological responses mediated by the binding of human IL-4 or human IL-13 to IL4RA; Preferably, the ligand for human IR-4RA is human IL-4 or human IL-13, more preferably human IL-4. iii) Prevention and / or treatment and / or adjunctive treatment and / or diagnosis of atopic dermatitis, allergic rhinitis, asthma and allergies For any of the uses of The antibody or antigen-binding fragment thereof according to any one of claims 1 to 5, the antibody conjugate according to claim 11, the multispecific antibody according to claim 12 or the fusion protein according to claim 13.

19. The antibody or antigen-binding fragment thereof according to any one of claims 1 to 5, the antibody conjugate according to claim 11, the multispecific antibody according to claim 12 or the fusion protein according to claim 13 for the prevention and / or treatment and / or adjunctive treatment and / or diagnosis of atopic dermatitis (wherein atopic dermatitis includes moderate and severe atopic dermatitis).

20. Hybridoma cells having accession numbers CCTCC NO: C2018131 or CCTCC NO: C2018132.

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