Antibody, isolated polynucleotide, host cell, method of preparing antibody, antibody conjugate, multispecific antibody, fusion protein, pharmaceutical composition, kit, uses of antibody and of a kit, hybridoma cell and monoclonal antibody

Description

[001] The present invention relates to the field of treatment of allergic diseases and molecular immunology and, in particular, to an anti-receptor A antibody of human interleukin-4, a pharmaceutical composition or a kit comprising the same, and use thereof. Background of the Invention

[002] The interleukin-4 receptor (IL-4R) is a transmembrane receptor that exists in two distinct forms: IL-4R type I, which consists of a high-affinity IL-4R α subunit (referred to here as IL-4RA) and a moderate-affinity Yc subunit, and binds to other biological functions of interleukin-4 (IL-4) and mediates IL-4-induced cell proliferation, activation, and other biological functions; and IL-4R type II, which consists of a high-affinity IL-4R α subunit (IL-4RA) and an α subunit of the interleukin-13 receptor (IL-13Ra), and is a functional homologous receptor for interleukin-13 (IL-13) capable of binding to 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, muscles, fibroblasts, hepatocytes, and brain tissue.IL-4RA, together with the Y subunit or IL-13R α subunit, activates several non-receptor tyrosine kinase proteins in the cytoplasm after IL-4 binds to its receptor, further initiating downstream signal transduction pathways (Nelms et al., Annu. Rev. Immunol., 1999, 17: 701-738; LaPorte et al., Cell, 2008, 132 (2): 259-272). Petition 870260061493, dated 06 / 23 / 2026, p. 15 / 182 2 / 130

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

[004] IL-4 is a pleiotropic cytokine secreted by immune cells, such as subsets of CD4+ T cells, B cells, mast cells, and the like; IL-13 is produced primarily by activated T cells (Th2 in mice) in humans and has various biological effects on monocytes (macrophages), B lymphocytes, NK cells, vascular endothelial cells, and the like. In vitro studies have demonstrated that IL-4 and IL-13 can exert corresponding effector functions on a variety of cells, such as T cells, B cells, eosinophils, mast cells, basophils, airway smooth muscle cells, respiratory tract epithelial cells, fibroblasts, and endothelial cells, which are the main effector cells responsible for the development of allergic diseases such as allergic rhinitis and food allergy, and asthma (May et al., Cytokine, 2015, 75 (1): 89-116); in addition, airway smooth muscle cells, respiratory tract epithelial cells, fibroblasts, and endothelial cells, etc. are also involved in the development, progression, and maintenance of chronic obstructive pulmonary disease (for reviews, see Steinke et al., Resp. Res., 2001, 2 (66): 66-70 and WillisKarp et al., Immunol. Rev., 2004, 202: 175-190); T and B cell dysfunctions are the main mechanisms of autoimmune diseases, and IL-4 is involved in the development of autoimmune diseases 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).

[005] The IL-4 / IL-13 pathways play an important role in the pathology of asthma (Chatila et al., Trends in Molecular Med., 2004, 10 (10): 493-499), as well as in other diseases described herein. Airway hyperreactivity, mucus hypersecretion, and airway remodeling, etc., are the Petition 870260061493, dated 06 / 23 / 2026, page 16 / 182 3 / 130 main pathological characteristics of asthma. Studies have shown 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 triggering airway hyperreactivity (AHR), and IL-4 is one of the main causes of Th2 immune cell polarization and IgE production (Wynn et al., Annu. Rev. Immunol., 2003, 21: 425-456).

[006] Atopic dermatitis, especially moderate and severe atopic dermatitis, is a chronic inflammatory skin disease characterized primarily by intense itching, pronounced eczematous changes, and dry skin. Atopic dermatitis usually begins in infancy and continues throughout life in some patients. It can seriously affect patients' quality of life due to chronic recurrent eczematous rash, intense itching, sleep deficit, dietary restrictions, and psychosocial reasons. IL-4 / IL-13 are considered one of the main drivers of the persistent intrinsic inflammation of atopic dermatitis (Malajian et al., Cytokine, 2015, 73 (2): 311-318). Clinical studies have demonstrated that dupilumab, a human anti-IL-4RA monoclonal antibody, is effective in treating moderate and severe atopic dermatitis (Beck et al., N. Engl. J. Med., 2014, 371 (2): 130- 139) and was approved by the U.S. Food and Drug Administration (FDA) for the treatment of moderate to severe atopic dermatitis.

[007] Furthermore, basic medical and clinical research has also proven 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 the inhibition of IL-4RA has the potential for the treatment of 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 refractory nasal polyposis Petition 870260061493, dated 06 / 23 / 2026, page 17 / 182 4 / 130 intranasal glucocorticoid, the human anti-IL-4RA monoclonal antibody dupilumab in combination with glucocorticoids can significantly improve symptoms and reduce nasal polyps (Bachert et al., JAMA, 2016, 315 (5): 469-79).

[008] Human anti-IL-4RA antibody drugs have broad application prospects and can be used to treat allergic diseases such as allergic rhinitis, asthma, allergy and atopic dermatitis, while also treating rhinosinusitis, nasal polyps, chronic obstructive pulmonary disease, tissue fibrosis, tumors, autoimmune diseases and the like. Therefore, the development of high-affinity human IL-4RA antibody drugs for the treatment of allergic diseases with improved efficacy and less severe toxic and side effects is of great significance. However, available human anti-IL-4RA antibody drugs have shown insufficient affinities, and there is still a need for a high-affinity human anti-IL-4RA antibody. Brief Description of the Invention

[009] After intensive studies and creative efforts, the inventors used mammalian cell expression systems to express recombinant IL-4RA as an antigen to immunize mice and obtained hybridoma cells by fusing mouse spleen cells and myeloma cells. The inventors obtained the following hybridoma cell lines by screening a large number of samples.

[010] The inventor discovered that: The 13E5 hybridoma cell line is capable of secreting and producing a specific antibody (called 13E5) that binds specifically to human IL-4RA, and the antibody can effectively block the binding of human IL-4RA to IL-4.

[011] In addition, the inventors have creatively prepared humanized anti-IL-4RA human antibodies (designated as 13E5 H1L1, Petition 870260061493, dated 06 / 23 / 2026, page 18 / 182 5 / 130 13E5 H2L2, 13E5 H3L3, 13E5 H4L4 and 13E5 H4L2, respectively).

[012] The 18H7 hybridoma cell line is capable of secreting and producing a specific antibody (called 18H7) that specifically binds to human IL-4RA, and the antibody can effectively block the binding of human IL-4RA to IL-4.

[013] In addition, the inventors creatively prepared humanized anti-IL-4RA human antibodies (named 18H7 H1L1, 18H7 H2L2, 18H7 H2L3 and 18H7 H3L2, respectively).

[014] The 20G10 hybridoma cell line is capable of secreting and producing a specific antibody (called 20G10) that specifically binds to human IL-4RA, and the antibody can effectively block the binding of human IL-4RA and IL-4.

[015] In addition, the inventors creatively prepared a humanized anti-human IL-4RA antibody (named 20G10 H3L3).

[016] Previous antibodies can effectively bind to human IL4RA, block the binding of human IL-4RA to its IL-4 or IL-13 ligand, and inhibit the activation of the downstream signaling pathway of human IL-4RA. Antibodies have potential in the preparation of a drug to prevent and treat allergic rhinitis, asthma, allergies, atopic dermatitis, rhinosinusitis, nasal polyps, chronic obstructive pulmonary disease, tissue fibrosis, and autoimmune diseases.

[017] The present invention is detailed below: One aspect of the present invention relates to an antibody or an antigen-binding fragment thereof, the antibody comprising: an HCDR1, comprising or consisting of the sequence established in SEQ ID NO: 9, a sequence with at least 90%, preferably at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity with the sequence, or an amino acid sequence possessing one or more (preferably 1, 2 or 3) amino acid mutations. Petition 870260061493, dated 06 / 23 / 2026, page 19 / 182 6 / 130 conservatives (preferably substitutions, insertions, or deletions) compared to the sequence, an HCDR2, comprising or consisting of the sequence established in SEQ ID NO: 10, a sequence with at least 90%, preferably at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity with the sequence, or an amino acid sequence possessing one or more (preferably 1, 2, or 3) conservative amino acid mutations (preferably substitutions, insertions, or deletions) compared to the sequence, and an HCDR3, comprising or consisting of the sequence established in SEQ ID NO: 11, a sequence with at least 90%, preferably at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity with the sequence, or an amino acid sequence possessing one or more (preferably 1, 2, or 3) conservative amino acid mutations (preferably substitutions, insertions, or deletions) compared to the sequence.and the antibody further comprising:, an LCDR1, comprising or consisting of the sequence established in SEQ ID NO: 12, a sequence with at least 90%, preferably at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity with the sequence, or an amino acid sequence possessing one or more (preferably 1, 2 or 3) conservative amino acid mutations (preferably substitutions, insertions or deletions) compared to the sequence; an LCDR2, comprising or consisting of the sequence established in SEQ ID NO: 13, a sequence with at least 90%, preferably at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity with the sequence, or an amino acid sequence possessing one or more (preferably 1, 2 or 3) amino acid mutations Petition 870260061493, dated 06 / 23 / 2026, page 20 / 182 7 / 130 conservatives (preferably substitutions, insertions or deletions) compared to the sequence, and an LCDR3, comprising or consisting of the sequence established in SEQ ID NO: 14, a sequence with at least 90%, preferably at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity with the sequence, or an amino acid sequence possessing one or more (preferably 1, 2 or 3) conservative amino acid mutations (preferably substitutions, insertions or deletions) compared to the sequence; or, the antibody comprising: an HCDR1, comprising or consisting of the sequence established in SEQ ID NO: 15, a sequence with at least 90%, preferably at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity with the sequence, or an amino acid sequence possessing one or more (preferably 1, 2 or 3) conservative amino acid mutations (preferably substitutions, insertions or deletions) compared to the sequence; an HCDR2, comprising or consisting of the sequence established in SEQ ID NO: 16, a sequence with at least 90%, preferably at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity with the sequence, or an amino acid sequence with one or more (preferably 1, 2 or 3) Conservative amino acid mutations (preferably substitutions, insertions, or deletions) compared to the sequence, and an HCDR3, comprising or consisting of the sequence established in SEQ ID NO: 17, a sequence with at least 90%,preferably at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% of, Petition 870260061493, dated 06 / 23 / 2026, page 21 / 182 8 / 130 sequence identity with the sequence, or an amino acid sequence possessing one or more (preferably 1, 2 or 3) conservative amino acid mutations (preferably substitutions, insertions or deletions) compared to the sequence, and the antibody further comprising: an LCDR1, comprising or consisting of the sequence established in SEQ ID NO: 18, a sequence with at least 90%, preferably at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity with the sequence, or an amino acid sequence possessing one or more (preferably 1, 2 or 3) conservative amino acid mutations (preferably substitutions, insertions or deletions) compared to the sequence; an LCDR2, comprising or consisting of the sequence established in SEQ ID NO: 19, a sequence with at least 90%, preferably at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity with the sequence, or an amino acid sequence possessing one or more (preferably 1, 2 or 3) Conservative amino acid mutations (preferably substitutions, insertions, or deletions) compared to the sequence, and an LCDR3, comprising or consisting of the sequence established in SEQ ID NO: 20, a sequence with at least 90%,preferably at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity with the sequence, or an amino acid sequence possessing one or more (preferably 1, 2 or 3) conservative amino acid mutations (preferably substitutions, insertions or deletions) compared to the sequence; or, the antibody comprising: Petition 870260061493, dated 06 / 23 / 2026, page 22 / 182 9 / 130 an HCDR1, comprising or consisting of the sequence established in SEQ ID NO: 130, a sequence with at least 90%, preferably at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity with the sequence, or an amino acid sequence with one or more (preferably 2 or 3) conservative amino acid mutations (preferably substitutions, insertions or deletions) compared to the sequence, an HCDR2, comprising or consisting of the sequence established in SEQ ID NO: 131, a sequence with at least 90%, preferably at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity with the sequence, or an amino acid sequence with one or more (preferably 2 or 3) Conservative amino acid mutations (preferably substitutions, insertions, or deletions) compared to the sequence, and an HCDR3, comprising or consisting of the sequence established in SEQ ID NO: 132, a sequence with at least 90%,preferably at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity with the sequence, or an amino acid sequence with one or more (preferably 2 or 3) conservative amino acid mutations (preferably substitutions, insertions or deletions) compared to the sequence, and the antibody further comprising: an LCDR1, comprising or consisting of the sequence established in SEQ ID NO: 133, a sequence with at least 90%, preferably at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity with the sequence, or an amino acid sequence with one or more (preferably 2 or 3) conservative amino acid mutations (preferably substitutions, insertions or deletions) compared to the Petition 870260061493, dated 06 / 23 / 2026, page 23 / 182 10 / 130 sequence, an LCDR2, comprising or consisting of the sequence established in SEQ ID NO: 134, a sequence with at least 90%, preferably at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity with the sequence, or an amino acid sequence having one or more (preferably 2 or 3) conservative amino acid mutations (preferably substitutions, insertions or deletions) compared to the sequence, and an LCDR3, comprising or consisting of the sequence established in SEQ ID NO: 135, a sequence with at least 90%, preferably at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity with the sequence, or an amino acid sequence having one or more (preferably 2 or 3) Conservative amino acid mutations (preferably substitutions, insertions, or deletions) compared to the sequence.

[018] In one embodiment of the present invention, the antibody comprises: (1) a variable heavy chain region comprising or consisting of: in the amino acid sequence established in SEQ ID NO: 2, a sequence with at least 80%, 85% or 90%, preferably at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity with the sequence presented in SEQ ID NO: 2, or an amino acid sequence with 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 presented in SEQ ID NO: 2, and a variable light chain region comprising or consisting of Petition 870260061493, dated 06 / 23 / 2026, page 24 / 182 11 / 130 in: in the amino acid sequence established in SEQ ID NO: 4, a sequence with at least 80%, 85% or 90%, preferably at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity with the sequence presented in SEQ ID NO: 4, or an amino acid sequence with 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 presented in SEQ ID NO: 4; (2) a variable heavy chain region comprising or consisting of: in the amino acid sequence established in SEQ ID NO: 6, a sequence with at least 80%, 85% or 90%, preferably at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity with the sequence presented in SEQ ID NO: 6, or an amino acid sequence with 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 presented in SEQ ID NO: 6, and a variable light chain region comprising or consisting of: In the amino acid sequence established in SEQ ID NO: 8, a sequence with at least 80%, 85%, or 90%, preferably at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity with the sequence presented in SEQ ID NO: 8, or an amino acid sequence with 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. Petition 870260061493, dated 06 / 23 / 2026, page 25 / 182 12 / 130 presented in SEQ ID NO: 8; (3) a variable heavy chain region comprising or consisting of: in the amino acid sequence established in SEQ ID NO: 22, a sequence with at least 80%, 85% or 90%, preferably at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity with the sequence presented in SEQ ID NO: 22, or an amino acid sequence with 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 presented in SEQ ID NO: 22, and a variable light chain region comprising or consisting of: in the amino acid sequence established in SEQ ID NO: 24, a sequence with at least 80%, 85% or 90%, preferably at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity with the sequence shown in SEQ ID NO: 24, or an amino acid sequence with 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 shown in SEQ ID NO: 24; (4) a variable heavy chain region comprising or consisting of: in the amino acid sequence established in SEQ ID NO: 26, a sequence with at least 80%, 85% or 90%, preferably at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity with the sequence shown in SEQ ID NO: 26, or an amino acid sequence with one or more (preferably 1, Petition 870260061493, dated 06 / 23 / 2026, p. 26 / 182 13 / 130 2, 3, 4, 5, 6, 7, 8, 9, or 10) conservative amino acid mutations (preferably substitutions, insertions, or deletions) compared to the sequence presented in SEQ ID NO: 26, and a variable light chain region comprising or consisting of: in the amino acid sequence established in SEQ ID NO: 28, a sequence with at least 80%, 85% or 90%, preferably at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity with the sequence presented in SEQ ID NO: 28, or an amino acid sequence with 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 presented in SEQ ID NO: 28; (5) a variable heavy chain region comprising or consisting of: in the amino acid sequence established in SEQ ID NO: 30, a sequence with at least 80%, 85% or 90%, preferably at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity with the sequence presented in SEQ ID NO: 30, or an amino acid sequence with 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 presented in SEQ ID NO: 30, and a variable light chain region comprising or consisting of: in the amino acid sequence established in SEQ ID NO: 32, a sequence with at least 80%, 85% or 90%, preferably at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity Petition 870260061493, dated 06 / 23 / 2026, page 27 / 182 14 / 130 of the sequence with the sequence presented in SEQ ID NO: 32, or an amino acid sequence with 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 presented in SEQ ID NO: 32; (6) a variable heavy chain region comprising or consisting of: in the amino acid sequence established in SEQ ID NO: 34, a sequence with at least 80%, 85% or 90%, preferably at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity with the sequence presented in SEQ ID NO: 34, or an amino acid sequence with 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 presented in SEQ ID NO: 34, and a variable light chain region comprising or consisting of: in the amino acid sequence established in SEQ ID NO: 36, a sequence with at least 80%, 85% or 90%, preferably at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity with the sequence presented in SEQ ID NO: 36, or an amino acid sequence with 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 presented in SEQ ID NO: 36; (7) a variable heavy chain region comprising or consisting of: in the amino acid sequence established in SEQ ID NO: 38, Petition 870260061493, dated 06 / 23 / 2026, page 28 / 182 15 / 130 a sequence with at least 80%, 85% or 90%, preferably at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity with the sequence presented in SEQ ID NO: 38, or an amino acid sequence with 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 presented in SEQ ID NO: 38, and a variable light chain region comprising or consisting of: in the amino acid sequence established in SEQ ID NO: 40, a sequence with at least 80%, 85% or 90%, preferably at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity with the sequence presented in SEQ ID NO: 40, or an amino acid sequence with 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 presented in SEQ ID NO: 40; (8) a variable heavy chain region comprising or consisting of: in the amino acid sequence established in SEQ ID NO: 42, a sequence with at least 80%, 85% or 90%, preferably at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity with the sequence presented in SEQ ID NO: 42, or an amino acid sequence with 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 presented in SEQ ID NO: 42, and a variable light chain region comprising or consisting of Petition 870260061493, dated 06 / 23 / 2026, page 29 / 182 16 / 130 in: in the amino acid sequence established in SEQ ID NO: 44, a sequence with at least 80%, 85% or 90%, preferably at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity with the sequence presented in SEQ ID NO: 44, or an amino acid sequence with 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 presented in SEQ ID NO: 44; (9) a variable heavy chain region comprising or consisting of: in the amino acid sequence established in SEQ ID NO: 46, a sequence with at least 80%, 85% or 90%, preferably at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity with the sequence presented in SEQ ID NO: 46, or an amino acid sequence with 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 presented in SEQ ID NO: 46, and a variable light chain region comprising or consisting of: In the amino acid sequence established in SEQ ID NO: 48, a sequence with at least 80%, 85%, or 90%, preferably at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity with the sequence presented in SEQ ID NO: 48, or an amino acid sequence with 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. Petition 870260061493, dated 06 / 23 / 2026, page 30 / 182 17 / 130 presented in SEQ ID NO: 48; (10) a variable heavy chain region comprising or consisting of: in the amino acid sequence established in SEQ ID NO: 42, a sequence with at least 80%, 85% or 90%, preferably at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity with the sequence presented in SEQ ID NO: 42, or an amino acid sequence with 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 presented in SEQ ID NO: 42, and a variable light chain region comprising or consisting of: in the amino acid sequence established in SEQ ID NO: 48, a sequence with at least 80%, 85% or 90%, preferably at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity with the sequence shown in SEQ ID NO: 48, or an amino acid sequence with 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 shown in SEQ ID NO: 48; (11) a variable heavy chain region comprising or consisting of: in the amino acid sequence established in SEQ ID NO: 46, a sequence with at least 80%, 85% or 90%, preferably at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity with the sequence shown in SEQ ID NO: 46, or an amino acid sequence with one or more (preferably 1, Petition 870260061493, dated 06 / 23 / 2026, p. 31 / 182 18 / 130 2, 3, 4, 5, 6, 7, 8, 9, or 10) conservative amino acid mutations (preferably substitutions, insertions, or deletions) compared to the sequence presented in SEQ ID NO: 46, and a variable light chain region comprising or consisting of: a sequence with at least 80%, 85% or 90%, preferably at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity with the sequence presented in SEQ ID NO: 44, or an amino acid sequence with 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 presented in SEQ ID NO: 44; (12) a variable heavy chain region comprising or consisting of: in the amino acid sequence established in SEQ ID NO: 34, a sequence with at least 80%, 85% or 90%, preferably at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity with the sequence presented in SEQ ID NO: 34, or an amino acid sequence with 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 presented in SEQ ID NO: 34, and a variable light chain region comprising or consisting of: in the amino acid sequence established in SEQ ID NO: 28, a sequence with at least 80%, 85% or 90%, preferably at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity with the sequence presented in SEQ ID NO: 28, or Petition 870260061493, dated 06 / 23 / 2026, page 32 / 182 19 / 130 an amino acid sequence with 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 presented in SEQ ID NO: 28; or (13) a variable heavy chain region comprising or consisting of: in the amino acid sequence established in SEQ ID NO: 127, a sequence with at least 80%, 85% or 90%, preferably at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity with the sequence presented in SEQ ID NO: 127, or an amino acid sequence with 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 presented in SEQ ID NO: 127, and a variable light chain region comprising or consisting of: in the amino acid sequence established in SEQ ID NO: 129, a sequence with at least 80%, 85% or 90%, preferably at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity with the sequence shown in SEQ ID NO: 129, or an amino acid sequence with 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 shown in SEQ ID NO: 129.

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

[020] Antibodies 13E5, 13E5 H1L1, 13E5 H2L2, 13E5 H3L3, Petition 870260061493, dated 06 / 23 / 2026, p. 33 / 182 20 / 130 The 13E5 H4L4 and 13E5 H4L2 compounds disclosed in this document share the same HCDR1-3 and LCDR1-3.

[021] According to the IMGT numbering system, the amino acid sequences of the 3 HCR regions of the variable region of the heavy chain are as follows: HCDR1: GYTFTEYT SEQ ID NO: 9; HCDR2: INPNNGGT SEQ ID NO: 10; and HCDR3: ARVRRGMDY SEQ ID NO: 11.

[022] The amino acid sequences of the 3 CDR regions of the variable region of the light chain are as follows: LCDR1: QDVTTA SEQ ID NO: 12; LCDR2: SAS SEQ ID NO: 13; and LCDR3: QQHYSAPWT SEQ ID NO: 14.

[023] The antibodies 18H7, 18H7 H1L1, 18H7 H2L2, 18H7 H2L3 and 18H7 H3L2 disclosed here share the same HCDR1-3 and LCDR1-3.

[024] According to the IMGT numbering system, the amino acid sequences of the 3 HCR regions of the variable region of the heavy chain are as follows: HCDR1: GFTFSSSY SEQ ID NO: 15; HCDR2: INSNGGKT SEQ ID NO: 16; and HCDR3: TRQRGNYVGAMDY SEQ ID NO: 17.

[025] The amino acid sequences of the 3 CDR regions of the variable region of the light chain are as follows: LCDR1: QDVSTA SEQ ID NO: 18; LCDR2: SAS SEQ ID NO: 19; and LCDR3: HQYYGSPPT SEQ ID NO: 20.

[026] The 20G10 H3L3 antibody disclosed here has the following HCDR1-3 and LCDR1-3. Petition 870260061493, dated 06 / 23 / 2026, p. 34 / 182 21 / 130

[027] According to the IMGT numbering system, the amino acid sequences of the 3 HCR regions of the variable region of the heavy chain are as follows: HCDR1: GFSLSTSGMG SEQ ID NO: 130; HCDR2: IWWADDK SEQ ID NO: 131; and HCDR3: ARITRGNSAMDF SEQ ID NO: 132.

[028] The amino acid sequences of the 3 CDR regions of the variable region of the light chain are as follows: LCDR1: ENVYSY SEQ ID NO: 133; LCDR2: NAK SEQ ID NO: 134; and LCDR3: QHHYGIPWT SEQ ID NO: 135.

[029] In one embodiment of the present invention, the antibody further comprises structural regions (FRs) in the variable region of the heavy chain, preferably FRs including FR-H1, FR-H2, FR-H3 and FR-H4, wherein FR-H1 comprises or consists of the amino acid sequence established in SEQ ID NO: 49, a sequence with at least 80%, 85% or 90%, preferably at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity with the sequence established 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 the amino acid sequence established in SEQ ID NO: 49;FR-H2 comprises or consists of the amino acid sequence established in SEQ ID NO: 50, a sequence with at least 80%, 85% or 90%, preferably at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity with the sequence established in SEQ ID NO: 50, 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) in; Petition 870260061493, dated 06 / 23 / 2026, p. 35 / 182 22 / 130 comparison with the amino acid sequence established in SEQ ID NO: 50; FR-H3 comprises or consists of the amino acid sequence established in SEQ ID NO: 51, a sequence with at least 80%, 85% or 90%, preferably at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity with the sequence established 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 with the amino acid sequence established in SEQ ID NO: 51;and FR-H4 comprises or consists of the amino acid sequence established in SEQ ID NO: 52, a sequence with at least 80%, 85% or 90%, preferably at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity with the sequence established 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 the amino acid sequence established in SEQ ID NO: 52.;

[030] In one embodiment of the present invention, the antibody further comprises FRs in the variable region of the light chain, preferably FRs including FR-L1, FR-L2, FR-L3 and FR-L4, wherein FR-L1 comprises or consists of 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 with the sequence set forth in SEQ ID NO: 53, 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: 53; FR-L2 comprises or consists of the amino acid sequence set forth in SEQ ID NO: 54, a sequence with at least 80%, 85%, or 90% of Petition 870260061493, dated 06 / 23 / 2026, p. 36 / 182 23 / 130 preference at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity with the sequence established in SEQ ID NO: 54, 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 established in SEQ ID NO: 54; FR-L3 comprises or consists of the amino acid sequence established in SEQ ID NO: 55, a sequence with at least 80%, 85% or 90%, preferably at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity with the sequence established 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 established in SEQ ID NO: 55;and FR-L4 comprises or consists of the amino acid sequence established in SEQ ID NO: 56, a sequence with at least 80%, 85% or 90%, preferably at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity with the sequence established 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 the amino acid sequence established in SEQ ID NO: 56.

[031] In one embodiment of the present invention, the antibody further comprises FRs in the variable region of the heavy chain, preferably FRs including 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: 57, a sequence with at least 80%, 85% or 90%, preferably at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity with the sequence set forth in SEQ ID NO: 57, or a sequence Petition 870260061493, dated 06 / 23 / 2026, p. 37 / 182 24 / 130 amino acids 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 established in SEQ ID NO: 57; FR-H2 comprises or consists of the amino acid sequence established in SEQ ID NO: 58, a sequence with at least 80%, 85% or 90%, preferably at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity with the sequence established in SEQ ID NO: 58, 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 established in SEQ ID NO: 58;FR-H3 comprises or consists of the amino acid sequence established in SEQ ID NO: 59, a sequence with at least 80%, 85% or 90%, preferably at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity with the sequence established 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 the amino acid sequence established in SEQ ID NO: 59;and FR-H4 comprises or consists of the amino acid sequence established in SEQ ID NO: 60, a sequence with at least 80%, 85% or 90%, preferably at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity with the sequence established 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 the amino acid sequence established in SEQ ID NO: 60.

[032] In one embodiment of the present invention, the antibody further comprises RFs in the variable region of the light chain, of Petition 870260061493, dated 06 / 23 / 2026, p. 38 / 182 25 / 130 preference FRs including FR-L1, FR-L2, FR-L3 and FR-L4, wherein FR-L1 comprises or consists of the amino acid sequence established 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 with the sequence established in SEQ ID NO: 61, 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 established in SEQ ID NO: 61;FR-L2 comprises or consists of the amino acid sequence established in SEQ ID NO: 62, a sequence with at least 80%, 85% or 90%, preferably at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity with the sequence established in SEQ ID NO: 62, 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 established in SEQ ID NO: 62;FR-L3 comprises or consists of the amino acid sequence established in SEQ ID NO: 63, a sequence with at least 80%, 85% or 90%, preferably at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity with the sequence established 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 the amino acid sequence established 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 with at least 80%, 85% or 90%, preferably at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity with the sequence set forth in SEQ ID NO: 64, or an amino acid sequence having a; Petition 870260061493, dated 06 / 23 / 2026, p. 39 / 182 26 / 130 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 established in SEQ ID NO: 64.

[033] In one embodiment of the present invention, the antibody further comprises RFs in the variable region of the heavy chain, preferably RFs including RF-H1, RF-H2, RF-H3 and RF-H4, wherein RF-H1 comprises or consists of 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 with the sequence set forth in SEQ ID NO: 65, 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: 65;FR-H2 comprises or consists of the amino acid sequence established in SEQ ID NO: 66, a sequence with at least 80%, 85% or 90%, preferably at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity with the sequence established in SEQ ID NO: 66, 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 established in SEQ ID NO: 66;FR-H3 comprises or consists of the amino acid sequence established in SEQ ID NO: 67, a sequence with at least 80%, 85% or 90%, preferably at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity with the sequence established 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 the sequence of; Petition 870260061493, dated 06 / 23 / 2026, p. 40 / 182 27 / 130 amino acids established in SEQ ID NO: 67; and FR-H4 comprises or consists of the amino acid sequence established in SEQ ID NO: 68, a sequence with at least 80%, 85% or 90%, preferably at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity with the sequence established 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 the amino acid sequence established in SEQ ID NO: 68.

[034] In one embodiment of the present invention, the antibody further comprises FRs in the variable region of the light chain, preferably FRs including FR-L1, FR-L2, FR-L3 and FR-L4, wherein FR-L1 comprises or consists of 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 with the sequence set forth in SEQ ID NO: 69, 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: 69;FR-L2 comprises or consists of the amino acid sequence established in SEQ ID NO: 70, a sequence with at least 80%, 85% or 90%, preferably at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity with the sequence established in SEQ ID NO: 70, 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 established in SEQ ID NO: 70; FR-L3 comprises or consists of the amino acid sequence established in; Petition 870260061493, dated 06 / 23 / 2026, p. 41 / 182 28 / 130 SEQ ID NO: 71, a sequence with at least 80%, 85% or 90%, preferably at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity with the sequence established 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 the amino acid sequence established in SEQ ID NO: 71;and FR-L4 comprises or consists of the amino acid sequence established in SEQ ID NO: 72, a sequence with at least 80%, 85% or 90%, preferably at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity with the sequence established 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 the amino acid sequence established in SEQ ID NO: 72.

[035] In one embodiment of the present invention, the antibody further comprises FRs in the variable region of the heavy chain, preferably FRs including 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: 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 with the sequence set forth in SEQ ID NO: 73, 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: 73; FR-H2 comprises or consists of the amino acid sequence set forth in SEQ ID NO: 74, a sequence with at least 80%, 85% or 90%, preferably at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity with the sequence Petition 870260061493, dated 06 / 23 / 2026, p. 42 / 182 29 / 130 established in SEQ ID NO: 74, 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 established in SEQ ID NO: 74; FR-H3 comprises or consists of the amino acid sequence established in SEQ ID NO: 75, a sequence with at least 80%, 85% or 90%, preferably at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity with the sequence established 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 the amino acid sequence established in SEQ ID NO: 75;and FR-H4 comprises or consists of the amino acid sequence established in SEQ ID NO: 76, a sequence with at least 80%, 85% or 90%, preferably at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity with the sequence established 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 the amino acid sequence established in SEQ ID NO: 76.;

[036] In one embodiment of the present invention, the antibody further comprises FRs in the variable region of the light chain, preferably FRs including FR-L1, FR-L2, FR-L3 and FR-L4, wherein FR-L1 comprises or consists of 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 with the sequence set forth in SEQ ID NO: 77, or an amino acid sequence having one or more (preferably 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10) Petition 870260061493, dated 06 / 23 / 2026, p. 43 / 182 30 / 130 conservative amino acid mutations (preferably substitutions, insertions, or deletions) compared to the amino acid sequence established in SEQ ID NO: 77; FR-L2 comprises or consists of the amino acid sequence established in SEQ ID NO: 78, a sequence with at least 80%, 85%, or 90%, preferably at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity with the sequence established in SEQ ID NO: 78, 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 established in SEQ ID NO: 78;FR-L3 comprises or consists of the amino acid sequence established in SEQ ID NO: 79, a sequence with at least 80%, 85% or 90%, preferably at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity with the sequence established 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 the amino acid sequence established in SEQ ID NO: 79;and FR-L4 comprises or consists of the amino acid sequence established in SEQ ID NO: 80, a sequence with at least 80%, 85% or 90%, preferably at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity with the sequence established 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 the amino acid sequence established in SEQ ID NO: 80.

[037] In one embodiment of the present invention, the antibody further comprises RFs in the variable region of the heavy chain, preferably RFs including RF-H1, RF-H2, RF-H3 and RF-H4, wherein RF-H1 Petition 870260061493, dated 06 / 23 / 2026, p. 44 / 182 31 / 130 comprises or consists of the amino acid sequence established in SEQ ID NO: 81, a sequence with at least 80%, 85% or 90%, preferably at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity with the sequence established in SEQ ID NO: 81, 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 established in SEQ ID NO: 81;FR-H2 comprises or consists of the amino acid sequence established in SEQ ID NO: 82, a sequence with at least 80%, 85% or 90%, preferably at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity with the sequence established in SEQ ID NO: 82, 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 established in SEQ ID NO: 82;FR-H3 comprises or consists of the amino acid sequence established in SEQ ID NO: 83, a sequence with at least 80%, 85% or 90%, preferably at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity with the sequence established 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 the amino acid sequence established in SEQ ID NO: 83; and FR-H4 comprises or consists of the amino acid sequence established in SEQ ID NO: 84, a sequence with at least 80%, 85% or 90%, preferably at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity with the sequence established 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) mutations of; Petition 870260061493, dated 06 / 23 / 2026, p. 45 / 182 32 / 130 conservative amino acids (preferably substitutions, insertions or deletions) compared to the amino acid sequence established in SEQ ID NO: 84.

[038] In one embodiment of the present invention, the antibody further comprises FRs in the variable region of the light chain, preferably FRs including FR-L1, FR-L2, FR-L3 and FR-L4, wherein FR-L1 comprises or consists of 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 with the sequence set forth in SEQ ID NO: 85, 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: 85;FR-L2 comprises or consists of the amino acid sequence established in SEQ ID NO: 86, a sequence with at least 80%, 85% or 90%, preferably at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity with the sequence established in SEQ ID NO: 86, 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 established in SEQ ID NO: 86;FR-L3 comprises or consists of the amino acid sequence established in SEQ ID NO: 87, a sequence with at least 80%, 85% or 90%, preferably at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity with the sequence established 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 the sequence of; Petition 870260061493, dated 06 / 23 / 2026, p. 46 / 182 33 / 130 amino acids established in SEQ ID NO: 87; and FR-L4 comprises or consists of the amino acid sequence established in SEQ ID NO: 88, a sequence with at least 80%, 85% or 90%, preferably at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity with the sequence established 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 the amino acid sequence established in SEQ ID NO: 88.

[039] In one embodiment of the present invention, the antibody further comprises RFs in the variable region of the heavy chain, preferably RFs including RF-H1, RF-H2, RF-H3 and RF-H4, wherein RF-H1 comprises or consists of 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 with the sequence set forth in SEQ ID NO: 89, 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: 89;FR-H2 comprises or consists of the amino acid sequence established in SEQ ID NO: 90, a sequence with at least 80%, 85% or 90%, preferably at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity with the sequence established in SEQ ID NO: 90, 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 established in SEQ ID NO: 90; FR-H3 comprises or consists of the amino acid sequence established in SEQ ID NO: 91, a sequence with at least 80%, 85% or 90% of; Petition 870260061493, dated 06 / 23 / 2026, p. 47 / 182 34 / 130 preference at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity with the sequence established 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 the amino acid sequence established in SEQ ID NO: 91; and FR-H4 comprises or consists of the amino acid sequence established in SEQ ID NO: 92, a sequence with at least 80%, 85% or 90%, preferably at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity with the sequence established 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 the amino acid sequence established in SEQ ID NO: 92.

[040] In one embodiment of the present invention, the antibody further comprises FRs in the variable region of the light chain, preferably FRs including FR-L1, FR-L2, FR-L3 and FR-L4, wherein FR-L1 comprises or consists of 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 with the sequence set forth in SEQ ID NO: 93, 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: 93; FR-L2 comprises or consists of the amino acid sequence set forth in SEQ ID NO: 94, a sequence with at least 80%, 85% or 90%, preferably at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity with the sequence Petition 870260061493, dated 06 / 23 / 2026, p. 48 / 182 35 / 130 established in SEQ ID NO: 94, 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 established in SEQ ID NO: 94; FR-L3 comprises or consists of the amino acid sequence established in SEQ ID NO: 95, a sequence with at least 80%, 85% or 90%, preferably at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity with the sequence established 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 the amino acid sequence established in SEQ ID NO: 95;and FR-L4 comprises or consists of the amino acid sequence established in SEQ ID NO: 96, a sequence with at least 80%, 85% or 90%, preferably at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity with the sequence established 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 the amino acid sequence established in SEQ ID NO: 96.

[041] In one embodiment of the present invention, the antibody further comprises RFs in the variable region of the heavy chain, preferably RFs including RF-H1, RF-H2, RF-H3 and RF-H4, wherein RF-H1 comprises or consists of 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 with the sequence set forth in SEQ ID NO: 97, 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, Petition 870260061493, dated 06 / 23 / 2026, p. 49 / 182 36 / 130 insertions or deletions) compared to the amino acid sequence established in SEQ ID NO: 97; FR-H2 comprises or consists of the amino acid sequence established in SEQ ID NO: 98, a sequence with at least 80%, 85% or 90%, preferably at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity with the sequence established in SEQ ID NO: 98, 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 established in SEQ ID NO: 98;FR-H3 comprises or consists of the amino acid sequence established in SEQ ID NO: 99, a sequence with at least 80%, 85% or 90%, preferably at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity with the sequence established 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 the amino acid sequence established in SEQ ID NO: 99;and FR-H4 comprises or consists of the amino acid sequence established in SEQ ID NO: 100, a sequence with at least 80%, 85% or 90%, preferably at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity with the sequence established 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 the amino acid sequence established in SEQ ID NO: 100.

[042] In one embodiment of the present invention, the antibody further comprises FRs in the variable region of the light chain, preferably FRs including FR-L1, FR-L2, FR-L3 and FR-L4, wherein FR-L1 Petition 870260061493, dated 06 / 23 / 2026, p. 50 / 182 37 / 130 comprises or consists of the amino acid sequence established in SEQ ID NO: 101, a sequence with at least 80%, 85% or 90%, preferably at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity with the sequence established in SEQ ID NO: 101, 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 established in SEQ ID NO: 101;FR-L2 comprises or consists of the amino acid sequence established in SEQ ID NO: 102, a sequence with at least 80%, 85% or 90%, preferably at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity with the sequence established in SEQ ID NO: 102, 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 established in SEQ ID NO: 102;FR-L3 comprises or consists of the amino acid sequence established in SEQ ID NO: 103, a sequence with at least 80%, 85% or 90%, preferably at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity with the sequence established 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 the amino acid sequence established 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 with at least 80%, 85% or 90%, preferably at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity with the 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); Petition 870260061493, dated 06 / 23 / 2026, p. 51 / 182 38 / 130 conservative amino acid mutations (preferably substitutions, insertions, or deletions) compared to the amino acid sequence established in SEQ ID NO: 104.

[043] In one embodiment of the present invention, the antibody further comprises FRs in the variable region of the heavy chain, preferably FRs including 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: 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 with the sequence set forth in SEQ ID NO: 105, 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: 105. SEQ ID NO: 105;FR-H2 comprises or consists of the amino acid sequence established in SEQ ID NO: 106, a sequence with at least 80%, 85% or 90%, preferably at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity with the sequence established in SEQ ID NO: 106, 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 established in SEQ ID NO: 106;FR-H3 comprises or consists of the amino acid sequence established in SEQ ID NO: 107, a sequence with at least 80%, 85% or 90%, preferably at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity with the sequence established 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 the sequence of; Petition 870260061493, dated 06 / 23 / 2026, p. 52 / 182 39 / 130 amino acids established in SEQ ID NO: 107; and FR-H4 comprises or consists of the amino acid sequence established in SEQ ID NO: 108, a sequence with at least 80%, 85% or 90%, preferably at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity with the sequence established 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 the amino acid sequence established in SEQ ID NO: 108.

[044] In one embodiment of the present invention, the antibody further comprises FRs in the variable region of the light chain, preferably FRs including FR-L1, FR-L2, FR-L3 and FR-L4, wherein FR-L1 comprises or consists of 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 with the sequence set forth in SEQ ID NO: 109, 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: 109. SEQ ID NO: 109;FR-L2 comprises or consists of the amino acid sequence established in SEQ ID NO: 110, a sequence with at least 80%, 85% or 90%, preferably at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity with the sequence established in SEQ ID NO: 110, 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 established in SEQ ID NO: 110; FR-L3 comprises or consists of the amino acid sequence established in; Petition 870260061493, dated 06 / 23 / 2026, p. 53 / 182 40 / 130 SEQ ID NO: 111, a sequence with at least 80%, 85% or 90%, preferably at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity with the sequence established 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 established in SEQ ID NO: 111;and FR-L4 comprises or consists of the amino acid sequence established in SEQ ID NO: 112, a sequence with at least 80%, 85% or 90%, preferably at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity with the sequence established 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 the amino acid sequence established in SEQ ID NO: 112.

[045] In one embodiment of the present invention, the antibody further comprises RFs in the variable region of the heavy chain, preferably RFs including RF-H1, RF-H2, RF-H3 and RF-H4, wherein RF-H1 comprises or consists of 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 with the sequence set forth in SEQ ID NO: 113, 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: 113; FR-H2 comprises or consists of the amino acid sequence set forth in SEQ ID NO: 114, a sequence with at least 80%, 85% or 90%, preferably at least 91%, 92%, 93%, Petition 870260061493, dated 06 / 23 / 2026, p. 54 / 182 41 / 130 94%, 95%, 96%, 97%, 98% or 99% sequence identity with the sequence established in SEQ ID NO: 114, 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 established in SEQ ID NO: 114; FR-H3 comprises or consists of the amino acid sequence established in SEQ ID NO: 115, a sequence with at least 80%, 85% or 90%, preferably at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity with the sequence established 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 the amino acid sequence established in SEQ ID NO: 115;and FR-H4 comprises or consists of the amino acid sequence established in SEQ ID NO: 116, a sequence with at least 80%, 85% or 90%, preferably at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity with the sequence established 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 the amino acid sequence established in SEQ ID NO: 116.

[046] In one embodiment of the present invention, the antibody further comprises FRs in the variable region of the light chain, preferably FRs including FR-L1, FR-L2, FR-L3 and FR-L4, wherein FR-L1 comprises or consists of the amino acid sequence set forth in SEQ ID NO: 117, a sequence with at least 80%, 85% or 90%, preferably at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity with the sequence set forth in SEQ ID NO: 117, or a Petition 870260061493, dated 06 / 23 / 2026, p. 55 / 182 42 / 130 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 established in SEQ ID NO: 117; FR-L2 comprises or consists of the amino acid sequence established in SEQ ID NO: 118, a sequence with at least 80%, 85% or 90%, preferably at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity with the sequence established in SEQ ID NO: 118, 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 established in SEQ ID NO: 118;FR-L3 comprises or consists of the amino acid sequence established in SEQ ID NO: 119, a sequence with at least 80%, 85% or 90%, preferably at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity with the sequence established 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 the amino acid sequence established in SEQ ID NO: 119;and FR-L4 comprises or consists of the amino acid sequence established in SEQ ID NO: 120, a sequence with at least 80%, 85% or 90%, preferably at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity with the sequence established 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 the amino acid sequence established in SEQ ID NO: 120.

[047] In one embodiment of the present invention, the Petition 870260061493, dated 06 / 23 / 2026, p. 56 / 182 43 / 130 antibody further comprises RFs in the variable region of the heavy chain, preferably RFs including RF-H1, RF-H2, RF-H3 and RF-H4, wherein RF-H1 comprises or consists of the amino acid sequence established in SEQ ID NO: 136, a sequence with at least 80%, 85% or 90%, preferably at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity with the sequence established in SEQ ID NO: 136, 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 established in SEQ ID NO: 136;FR-H2 comprises or consists of the amino acid sequence established in SEQ ID NO: 137, a sequence with at least 80%, 85% or 90%, preferably at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity with the sequence established in SEQ ID NO: 137, 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 established in SEQ ID NO: 137;FR-H3 comprises or consists of the amino acid sequence established in SEQ ID NO: 138, a sequence with at least 80%, 85% or 90%, preferably at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity with the sequence established 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 the amino acid sequence established 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 with at least 80%, 85% or 90%, preferably at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity with; Petition 870260061493, dated 06 / 23 / 2026, p. 57 / 182 44 / 130 the sequence established 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 the amino acid sequence established in SEQ ID NO: 139.

[048] In one embodiment of the present invention, the antibody further comprises FRs in the variable region of the light chain, preferably FRs including FR-L1, FR-L2, FR-L3 and FR-L4, wherein FR-L1 comprises or consists of 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 with the sequence set forth in SEQ ID NO: 140, 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: 140;FR-L2 comprises or consists of the amino acid sequence established in SEQ ID NO: 141, a sequence with at least 80%, 85% or 90%, preferably at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity with the sequence established in SEQ ID NO: 141, 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 established in SEQ ID NO: 141; FR-L3 comprises or consists of the amino acid sequence established in SEQ ID NO: 142, a sequence with at least 80%, 85% or 90%, preferably at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity with the sequence established in SEQ ID NO: 142, or an amino acid sequence having one or more (preferably 1, 2, 3, 4, 5,; Petition 870260061493, dated 06 / 23 / 2026, p. 58 / 182 45 / 130, 7, 8, 9 or 10) conservative amino acid mutations (preferably substitutions, insertions or deletions) compared to the amino acid sequence established in SEQ ID NO: 142; and FR-L4 comprises or consists of the amino acid sequence established in SEQ ID NO: 143, a sequence with at least 80%, 85% or 90%, preferably at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity with the sequence established 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 the amino acid sequence established in SEQ ID NO: 143.

[049] One aspect of the present invention relates to an isolated polypeptide comprising the sequences set forth in SEQ ID NOS: 9, 10 and 11, wherein the polypeptide binds specifically to human IL-4RA as part of an anti-human IL-4RA antibody, the antibody further comprising the sequences set forth in SEQ ID NOS: 12, 13 and 14.

[050] One aspect of the present invention relates to an isolated polypeptide comprising the sequences set forth in SEQ ID NOS: 15, 16 and 17, wherein the polypeptide binds specifically to human IL-4RA as part of an anti-human IL-4RA antibody, the antibody further comprising the sequences set forth in SEQ ID NOS: 18, 19 and 20.

[051] One aspect of the present invention relates to an isolated polypeptide comprising the sequences set forth in SEQ ID NOS: 12, 13 and 14, wherein the polypeptide binds specifically to human IL-4RA as part of an anti-human IL-4RA antibody, the antibody further comprising the sequences set forth in SEQ ID NOS: 9, 10 and 11.

[052] One aspect of the present invention relates to a Petition 870260061493, dated 06 / 23 / 2026, p. 59 / 182 46 / 130 isolated polypeptide comprising the sequences set forth in SEQ ID NOs: 18, 19 and 20, wherein the polypeptide binds specifically to human IL-4RA as part of an anti-human IL-4RA antibody, the antibody further comprising the sequences set forth in SEQ ID NOs: 15, 16 and 17.

[053] One aspect of the present invention relates to an isolated polypeptide comprising the sequences set forth in SEQ ID NOS: 130, 131 and 132, wherein the polypeptide binds specifically to human IL-4RA as part of an anti-human IL-4RA antibody, the antibody further comprising the sequences set forth in SEQ ID NOS: 133, 134 and 135.

[054] One aspect of the present invention relates to an isolated polypeptide comprising the sequences set forth in SEQ ID NOs: 133, 134 and 135, wherein the polypeptide binds specifically to human IL-4RA as part of an anti-human IL-4RA antibody, the antibody further comprising the sequences set forth in SEQ ID NOs: 130, 131 and 132.

[055] One aspect of the present invention relates to an isolated polypeptide comprising a sequence selected from the sequences established in SEQ ID NOs: 2, 6, 22, 26, 30, 34 and 38, a sequence with at least 80%, 85% or 90%, preferably at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity with sequences, or an amino acid sequence with 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 sequences, wherein the polypeptide specifically binds to human IL-4RA as part of an anti-human IL-4RA antibody, the antibody further comprising a sequence selected from the sequences established in Petition 870260061493, dated 06 / 23 / 2026, p. 60 / 182 47 / 130 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 with the sequences, or an amino acid sequence with 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 sequences; an isolated polypeptide comprising a sequence selected from the sequence established in SEQ ID NO: 42, a sequence with at least 80%, 85% or 90%, preferably at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity with the 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 the sequence, wherein the polypeptide specifically binds to human IL-4RA as part of an anti-human IL-4RA antibody, the antibody further comprising a sequence selected from the sequence established in SEQ ID NO: 44, a sequence with at least 80%, 85% or 90%, preferably at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity with the 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 the sequence; an isolated polypeptide comprising a sequence selected from the sequence established in SEQ ID NO: 42, a sequence with at least 80%, 85% or 90%, preferably at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity with the 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. Petition 870260061493, dated 06 / 23 / 2026, page 61 / 182 48 / 130 (preferably substitutions, insertions or deletions) compared to the sequence, wherein the polypeptide specifically binds to human IL-4RA as part of an anti-human IL-4RA antibody, the antibody further comprising a sequence selected from the sequence established in SEQ ID NO: 48, a sequence with at least 80%, 85% or 90%, preferably at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity with the 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 the sequence; an isolated polypeptide comprising a sequence selected from the sequence established in SEQ ID NO: 46, a sequence with at least 80%, 85% or 90%, preferably at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity with the 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 the sequence, wherein the polypeptide specifically binds to human IL-4RA as part of an anti-human IL-4RA antibody, the antibody further comprising a sequence selected from the sequence established in SEQ ID NO: 48, a sequence with at least 80%, 85% or 90%, preferably at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity with the 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 the sequence; or an isolated polypeptide comprising a sequence selected from the sequence established in SEQ ID NO: 34, a, Petition 870260061493, dated 06 / 23 / 2026, page 62 / 182 49 / 130 sequence with at least 80%, 85% or 90%, preferably at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity with the 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 the sequence, wherein the polypeptide specifically binds to human IL-4RA as part of an anti-human IL-4RA antibody, the antibody further comprising a sequence selected from the sequence established in SEQ ID NO: 28, a sequence with at least 80%, 85% or 90%, preferably at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity with the 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 the sequence.

[056] One aspect of the present invention relates to an isolated polypeptide comprising a sequence selected from the sequences established in SEQ ID Nos: 4, 8, 24, 28, 32, 36 and 40, a sequence with at least 80%, 85% or 90%, preferably at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity with sequences, or an amino acid sequence with 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 sequences, wherein the polypeptide specifically binds to human IL-4RA as part of an anti-human IL-4RA antibody, the antibody further comprising a sequence, respectively, selected from the sequences established 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 with the sequences, Petition 870260061493, dated 06 / 23 / 2026, p. 63 / 182 50 / 130 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 sequences; an isolated polypeptide comprising a sequence selected from the sequence established in SEQ ID NO: 44, a sequence with at least 80%, 85% or 90%, preferably at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity with the 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 the sequence, wherein the polypeptide specifically binds to human IL-4RA as part of an anti-human IL-4RA antibody, the antibody further comprising a sequence selected from the sequence established in SEQ ID NO: 42, a sequence with at least 80%, 85% or 90%, preferably at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity with the 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 the sequence; an isolated polypeptide comprising a sequence selected from the sequence established in SEQ ID NO: 48, a sequence with at least 80%, 85% or 90%, preferably at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity with the 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 the sequence, wherein the polypeptide specifically binds to human IL-4RA as part of an anti-human IL-4RA antibody, the antibody comprising Petition 870260061493, dated 06 / 23 / 2026, page 64 / 182 51 / 130 still a sequence selected from the sequence established in SEQ ID NO: 42, a sequence with at least 80%, 85% or 90%, preferably at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity with the 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 the sequence; an isolated polypeptide comprising a sequence selected from the sequence established in SEQ ID NO: 48, a sequence with at least 80%, 85% or 90%, preferably at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity with the 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 the sequence, wherein the polypeptide specifically binds to human IL-4RA as part of an anti-human IL-4RA antibody, the antibody further comprising a sequence selected from the sequence established in SEQ ID NO: 46, a sequence with at least 80%, 85% or 90%, preferably at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity with the 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 the sequence; an isolated polypeptide comprising a sequence selected from the sequence established in SEQ ID NO: 28, a sequence with at least 80%, 85% or 90%, preferably at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity with the sequence, or an amino acid sequence having one or more (of Petition 870260061493, dated 06 / 23 / 2026, page 65 / 182 52 / 130 preference 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10) conservative amino acid mutations (preferably substitutions, insertions or deletions) compared to the sequence, wherein the polypeptide specifically binds to human IL-4RA as part of an anti-human IL-4RA antibody, the antibody further comprising a sequence selected from the sequence established in SEQ ID NO: 34, a sequence with at least 80%, 85% or 90%, preferably at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity with the 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 the sequence; an isolated polypeptide comprising a sequence selected from the sequence established 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 with the 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 the sequence, wherein the polypeptide specifically binds to human IL-4RA as part of an anti-human IL-4RA antibody, the antibody further comprising a sequence selected from the sequence established 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 with the 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 the sequence; or an isolated polypeptide comprising a sequence, Petition 870260061493, dated 06 / 23 / 2026, page 66 / 182 53 / 130 selected from the sequence established in SEQ ID NO: 129, a sequence with at least 80%, 85% or 90%, preferably at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity with the 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 the sequence, wherein the polypeptide specifically binds to human IL-4RA as part of an anti-human IL-4RA antibody, the antibody further comprising a sequence selected from the sequence established in SEQ ID NO: 127, a sequence with at least 80%, 85% or 90%, preferably at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity with the 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 the sequence.

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

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

[059] In one embodiment of the present invention, the antibody binds to the human IL-4RA protein with a Kd less than about 10-5M, for example, less than about 10-6M, 10-7M, 10-8M, 10-9M or 10-10M or less. Preferably, the Kd is measured by a Fortebio molecular interaction instrument. Petition 870260061493, dated 06 / 23 / 2026, p. 67 / 182 54 / 130

[060] In one embodiment of the present invention, the antibody binds to the human IL-4RA protein with an EC50 lower than about 100 nM, for example, lower than 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. Specifically, the EC50 is measured by indirect ELISA.

[061] In one embodiment of the present invention, the antibody comprises a constant region, and the constant region is derived from a different murine species, for example, from a human antibody, preferably from a human IgG, more preferably from IgG4.

[062] In one embodiment of the present invention, the antibody constant region is humanized, for example, the constant regions of the heavy chain are C regions of the Ig gamma-4 chain, preferably the C region of the Ig gamma-4 chain from GenBank Accession No.: P01861.1; constant regions of the light chain are C regions of the Ig kappa chain, preferably the C region of the Ig kappa chain from GenBank Accession No.: P01834.

[063] Another aspect of the present invention relates to an isolated polynucleotide encoding a polypeptide comprising the sequences set forth in SEQ IDs 9, 10 and 11, wherein the polypeptide binds specifically to human IL-4RA as part of an anti-human IL-4RA antibody, the antibody further comprising the sequences set forth in SEQ IDs 12, 13 and 14.

[064] One aspect of the present invention relates to an isolated polynucleotide encoding a polypeptide comprising the sequences set forth in SEQ IDs 15, 16 and 17, wherein the polypeptide binds specifically to human IL-4RA as part of an anti-human IL-4RA antibody, the antibody further comprising the sequences set forth in SEQ IDs 18, 19 and 20.

[065] One aspect of the present invention relates to a Petition 870260061493, dated 06 / 23 / 2026, p. 68 / 182 55 / 130 isolated polynucleotide encoding a polypeptide comprising the sequences set forth in SEQ IDs 12, 13 and 14, wherein the polypeptide binds specifically to human IL-4RA as part of an anti-human IL-4RA antibody, the antibody further comprising the sequences set forth in SEQ IDs 9, 10 and 11.

[066] One aspect of the present invention relates to an isolated polynucleotide encoding a polypeptide comprising the sequences set forth in SEQ IDs 18, 19 and 20, wherein the polypeptide binds specifically to human IL-4RA as part of an anti-human IL-4RA antibody, the antibody further comprising the sequences set forth in SEQ IDs 15, 16 and 17.

[067] One aspect of the present invention relates to an isolated polynucleotide encoding a polypeptide comprising the sequences set forth in SEQ IDs 130, 131 and 132, wherein the polypeptide binds specifically to human IL-4RA as part of an anti-human IL-4RA antibody, the antibody further comprising the sequences set forth in SEQ IDs 133, 134 and 135.

[068] One aspect of the present invention relates to an isolated polynucleotide encoding a polypeptide comprising the sequences set forth in SEQ IDs 133, 134 and 135, wherein the polypeptide binds specifically to human IL-4RA as part of an anti-human IL-4RA antibody, the antibody further comprising the sequences set forth in SEQ IDs 130, 131 and 132.

[069] One aspect of the present invention relates to an isolated polynucleotide encoding a polypeptide comprising a sequence selected from the sequences established in SEQ ID Nos: 2, 6, 22, 26, 30, 34 and 38, a sequence with at least 80%, 85% or 90%, preferably at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% of Petition 870260061493, dated 06 / 23 / 2026, p. 69 / 182 56 / 130 sequence identity with the sequences, 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 sequences, wherein the polypeptide specifically binds to human IL-4RA as part of an anti-human IL-4RA antibody, the antibody further comprising a sequence, respectively, selected from the sequences established in SEQ ID Nos: 4, 8, 24, 28, 32, 36 and 40, a sequence with at least 80%, 85% or 90%, preferably at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity with the sequences, 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 sequences; an isolated polynucleotide encoding a polypeptide comprising a sequence selected from the sequence established in SEQ ID NO: 42, a sequence with at least 80%, 85% or 90%, preferably at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity with the 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 the sequence, wherein the polypeptide specifically binds to human IL-4RA as part of an anti-human IL-4RA antibody, the antibody further comprising a sequence selected from the sequence established in SEQ ID NO: 44, a sequence with at least 80%, 85% or 90%, of preferably at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity with the 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, Petition 870260061493, dated 06 / 23 / 2026, p. 70 / 182 57 / 130 replacements, insertions or deletions) compared to the sequence; an isolated polynucleotide encoding a polypeptide comprising a sequence selected from the sequence established in SEQ ID NO: 42, a sequence with at least 80%, 85% or 90%, preferably at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity with the 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 the sequence, wherein the polypeptide specifically binds to human IL-4RA as part of an anti-human IL-4RA antibody, the antibody further comprising a sequence selected from the sequence established in SEQ ID NO: 48, a sequence with at least 80%, 85% or 90%, of preferably at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity with the 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 the sequence; an isolated polynucleotide encoding a polypeptide comprising a sequence selected from the sequence established in SEQ ID NO: 46, a sequence with at least 80%, 85% or 90%, preferably at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity with the 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 the sequence, wherein the polypeptide specifically binds to human IL-4RA as part of an anti-human IL-4RA antibody, the antibody further comprising a sequence selected from the sequence established in SEQ ID NO: 48, a sequence with at least Petition 870260061493, dated 06 / 23 / 2026, page 71 / 182 58 / 130 80%, 85% or 90%, preferably at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity with the 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 the sequence; or an isolated polynucleotide encoding a polypeptide comprising a sequence selected from the sequence established in SEQ ID NO: 34, a sequence with at least 80%, 85% or 90%, preferably at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity with the 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 the sequence, wherein the polypeptide specifically binds to human IL-4RA as part of an anti-human IL-4RA antibody,the antibody further comprising a sequence selected from the sequence established in SEQ ID NO: 28, a sequence with at least 80%, 85% or 90%, preferably at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity with the 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 the sequence.

[070] One aspect of the present invention relates to an isolated polynucleotide encoding a polypeptide comprising a sequence selected from the sequences established in SEQ ID Nos: 4, 8, 24, 28, 32, 36 and 40, a sequence with at least 80%, 85% or 90%, preferably at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity with sequences, or an amino acid sequence having one or more (preferably 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10) mutations of Petition 870260061493, dated 06 / 23 / 2026, p. 72 / 182 59 / 130 conservative amino acid mutations (preferably substitutions, insertions, or deletions) compared to sequences in which the polypeptide specifically binds to human IL-4RA as part of an anti-human IL-4RA antibody, the antibody further comprising a sequence, respectively, selected from the sequences established in SEQ ID NOs: 2, 6, 22, 26, 30, 34, and 38, a sequence with at least 80%, 85%, or 90%, preferably at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity with the sequences, 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) in comparison with sequences; an isolated polynucleotide encoding a polypeptide comprising a sequence selected from the sequence established in SEQ ID NO: 44, a sequence with at least 80%, 85% or 90%, preferably at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity with the 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 the sequence, wherein the polypeptide specifically binds to human IL-4RA as part of an anti-human IL-4RA antibody, the antibody further comprising a sequence selected from the sequence established in SEQ ID NO: 42, a sequence with at least 80%, 85% or 90%, of preferably at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity with the 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 the sequence; an isolated polynucleotide that codes for a polypeptide Petition 870260061493, dated 06 / 23 / 2026, page 73 / 182 60 / 130 comprising a sequence selected from the sequence established in SEQ ID NO: 48, a sequence with at least 80%, 85% or 90%, preferably at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity with the 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 the sequence, wherein the polypeptide specifically binds to human IL-4RA as part of an anti-human IL-4RA antibody, the antibody further comprising a sequence selected from the sequence established in SEQ ID NO: 42, a sequence with at least 80%, 85% or 90%, preferably at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity with the 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 the sequence; an isolated polynucleotide encoding a polypeptide comprising a sequence selected from the sequence established in SEQ ID NO: 48, a sequence with at least 80%, 85% or 90%, preferably at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity with the 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 the sequence, wherein the polypeptide specifically binds to human IL-4RA as part of an anti-human IL-4RA antibody, the antibody further comprising a sequence selected from the sequence established in SEQ ID NO: 46, a sequence with at least 80%, 85% or 90%, of preference for at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity with the sequence, or a Petition 870260061493, dated 06 / 23 / 2026, page 74 / 182 61 / 130 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; an isolated polynucleotide encoding a polypeptide comprising a sequence selected from the sequence established in SEQ ID NO: 28, a sequence with at least 80%, 85% or 90%, preferably at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity with the 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 the sequence, wherein the polypeptide specifically binds to human IL-4RA as part of an anti-human IL-4RA antibody, the antibody further comprising a sequence selected from the sequence established in SEQ ID NO: 34, a sequence with at least 80%, 85% or 90%, of preferably at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity with the 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 the sequence; an isolated polynucleotide encoding a polypeptide comprising a sequence selected from the sequence established in SEQ ID NO: 127, a sequence with at least 80%, 85% or 90%, preferably at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity with the 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 the sequence, wherein the polypeptide specifically binds to human IL-4RA as part of an anti-IL-4RA antibody. Petition 870260061493, dated 06 / 23 / 2026, page 75 / 182 62 / 130 human, the antibody further comprising a sequence selected from the sequence established in SEQ ID NO: 129, a sequence with at least 80%, 85% or 90%, preferably at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity with the 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 the sequence; or an isolated polynucleotide encoding a polypeptide comprising a sequence selected from the sequence established in SEQ ID NO: 129, a sequence with at least 80%, 85% or 90%, preferably at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity with the 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 the sequence, wherein the polypeptide specifically binds to human IL-4RA as part of an anti-human IL-4RA antibody, the antibody further comprising a sequence selected from the sequence established in SEQ ID NO: 127, a sequence with at least 80%, 85% or 90%, preferably at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity with the 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 the sequence.

[071] In particular, the polynucleotide molecule comprises or consists of the sequences set out 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 with at least 80%, 85% or 90%, preferably at least 91%, 92%, 93%, 94%, Petition 870260061493, dated 06 / 23 / 2026, p. 76 / 182 63 / 130 95%, 96%, 97%, 98%, or 99% sequence identity with the sequences.

[072] In particular, the polynucleotide molecule comprises or consists of the sequences set out 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 with at least 80%, 85% or 90%, preferably at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity with the sequences.

[073] Yet another aspect of the present invention relates to a vector comprising any of the polynucleotide molecules disclosed herein.

[074] Yet another aspect of the present invention relates to a host cell comprising any of the polynucleotide molecules disclosed in this document, or the vector disclosed in this document.

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

[076] One aspect of the present invention further provides an antibody conjugate comprising the human anti-IL-4RA antibody or the antigen-binding fragment thereof, and a conjugate portion coupled thereto, wherein the conjugate portion is a purification label (e.g., a His label), a cytotoxic agent or a detectable marker. Preferably, the conjugate portion is a radioisotope, a luminescent substance, a colored substance, an enzyme or polyethylene glycol.

[077] One aspect of the present invention further provides a Petition 870260061493, dated 06 / 23 / 2026, p. 77 / 182 64 / 130 multispecific antibody, preferably a bispecific antibody, comprising the anti-human IL-4RA antibody or antigen-binding fragment thereof, and an antibody or antigen-binding fragment against another antigen and / or another antigenic epitope.

[078] One aspect of the present invention further provides a fusion protein comprising either of the anti-human IL-4RA antibodies or antigen-binding fragments thereof disclosed herein.

[079] One aspect of the present invention further provides a kit comprising any of the antibodies or antigen-binding fragments thereof disclosed herein, or the antibody conjugate or multispecific antibody disclosed herein.

[080] Preferably, the kit also includes a second antibody that specifically recognizes the antibody or antigen-binding fragment thereof; optionally, the second antibody also includes a detectable marker, such as a radioisotope, a luminescent substance, a colored substance, an enzyme, or polyethylene glycol.

[081] Yet another aspect of the present invention relates to the use of any of the antibodies or antigen-binding fragments thereof disclosed herein, or the antibody conjugate or multispecific antibody disclosed herein, in the preparation of a kit for detecting the presence or level of human IL-4RA in a sample or for the prevention and / or treatment and / or adjuvant treatment and / or diagnosis of an allergic disease, a tumor, an autoimmune disease, a skin infection, tissue fibrosis, rhinosinusitis, nasal polyps and chronic obstructive pulmonary disease, wherein preferably the allergic disease is selected from atopic dermatitis, allergic rhinitis, asthma and allergy and, more preferably, atopic dermatitis includes moderate and severe atopic dermatitis.

[082] Yet another aspect of the present invention relates to a Petition 870260061493, dated 06 / 23 / 2026, p. 78 / 182 65 / 130 pharmaceutical composition comprising any of the antibodies or antigen-binding fragments thereof disclosed in this document or the antibody conjugate, multispecific antibody or fusion protein disclosed in this document and, optionally, a pharmaceutically acceptable carrier and / or excipient. Preferably, the pharmaceutical composition is used alone or in combination with one or more medicinal products. When the pharmaceutical composition cannot be directly mixed with the combined medicinal product, the pharmaceutical composition and the combined medicinal product are separately present in the kit.

[083] Yet another aspect of the present invention relates to the use of any of the antibodies or antigen-binding fragments thereof disclosed herein, or the antibody conjugate, multispecific antibody, or fusion protein disclosed herein, in the preparation of: a drug to block the binding of human IL-4RA to IL-4 or IL-13, a drug to block the activity of human IL-4RA or negatively regulate the level of human IL-4RA, and a drug to block a cellular biological response mediated by the binding of human IL-4 or human IL-13 to IL-4RA; whereby the ligand for human IL-4RA is preferably human IL-4 or human IL-13, more preferably human IL-4.

[084] One aspect of the present invention relates to the use of any of the antibodies or antigen-binding fragments thereof disclosed herein or the antibody conjugate, multispecific antibody or fusion protein disclosed herein in the preparation of a medicament for the treatment of a disease selected from: atopic dermatitis including moderate and severe atopic dermatitis; Petition 870260061493, dated 06 / 23 / 2026, p. 79 / 182 66 / 130 nasal polyps; asthma; a skin infection; an autoimmune disease and similar conditions.

[085] 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 disclosed herein, the antibody conjugate, the multispecific antibody or the fusion protein disclosed herein, or administering to a subject in need of an effective amount of any of the antibodies or antigen-binding fragments thereof or the antibody conjugate, the multispecific antibody or the fusion protein disclosed herein. The method is selected from: a method for blocking the binding of IL-4RA to IL-4 or IL-13, a method for negatively regulating the activity or level of IL-4RA, or a method for blocking a cellular biological response mediated by the binding of human IL-4 or human IL-13 to IL-4RA; whereby the IL-4RA ligand is preferably IL-4 or IL-13, more preferably IL-4.

[086] In one embodiment of the present invention, the in vitro method is not therapeutic and / or not diagnostic.

[087] Yet another aspect of the present invention relates to the use of any of the antibodies or antigen-binding fragments thereof or the antibody conjugate or multispecific antibody disclosed herein in the preparation of a medicament for the prevention and / or treatment and / or adjuvant treatment and / or diagnosis of an allergic disease, a tumor, a skin infection, an autoimmune disease, tissue fibrosis, rhinosinusitis, nasal polyps and chronic obstructive pulmonary disease. In particular, the allergic disease is selected from atopic dermatitis, rhinitis Petition 870260061493, dated 06 / 23 / 2026, p. 80 / 182 67 / 130 allergic, asthma and allergy.

[088] In one embodiment of the present invention, the medicament 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.

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

[090] Yet another aspect of the present invention relates to a method for the prevention and / or treatment and / or adjuvant treatment and / or diagnosis of an allergic disease, a tumor, an autoimmune disease, tissue fibrosis, a skin infection, rhinosinusitis, nasal polyps, chronic obstructive pulmonary disease, comprising administering any of the antibody or antigen-binding fragment thereof, the antibody conjugate or the multispecific antibody disclosed herein to a subject in need. In particular, the allergic disease is selected from atopic dermatitis, allergic rhinitis, asthma and allergy.

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

[092] As used here, the term “link fragment to Petition 870260061493, dated 06 / 23 / 2026, page 81 / 182 68 / 130 “antigen” means a protein or portion of a protein that binds specifically to a particular antigen. For example, a portion of an antibody comprising amino acid residues that interact with an antigen and confer specificity and affinity for the antigen to the antibody is referred to as an “antigen-binding fragment”. The antigen-binding fragment generally comprises one or more complementarity-determining regions (CDRs). Certain antigen-binding fragments further comprise one or more structural regions (FRs). CDRs are amino acid sequences that contribute to antigen-binding specificity and affinity.

[093] As used herein, the term “antibody” refers to an intact immunoglobulin of any isotype or an antigen-binding fragment thereof that can compete with an intact antibody to bind specifically to a target antigen and includes, for example, chimeric, humanized, fully human, and bispecific antibodies or antigen-binding fragments thereof. These “antibodies” are antigen-binding proteins. An intact antibody generally comprises at least two full-length heavy chains and two full-length light chains, but in some cases, it may comprise fewer chains, such as an antibody that occurs naturally in Camelidae species which may comprise only one heavy chain. An antibody or antigen-binding fragment thereof may be derived from a single source only or may be “chimeric,” that is, different portions of an antibody may be derived from two different sources, as described 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 indicated, the term “antibody” includes antibodies comprising two full-length heavy chains and two chains. Petition 870260061493, dated 06 / 23 / 2026, p. 82 / 182 69 / 130 light overall length, also includes derivatives, variants and fragments thereof.

[094] 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 (obtained or synthesized) that lacks at least some of the amino acid residues present in the full length of the antibody, but is capable of specifically binding to the antigen. Such fragments are biologically active because they specifically bind to a target antigen and can compete with other antibodies or antigen-binding fragments of the same for specific binding to a given epitope. In one aspect, such fragments will retain at least one CDR present in the full-length light or heavy chain of the antibody and, in some embodiments, will comprise a single heavy and / or light chain or a portion thereof.These biologically active fragments can be produced by recombinant DNA techniques or, for example, by 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, humans, mice, rats, Camelidae species, and rabbits. It is further contemplated that a functional portion of an antibody disclosed in this document, such as one or more CDRs, can be covalently linked to a second protein or small molecule to generate a therapeutic agent that targets a specific target in the body, thus having bifunctional therapeutic properties or having an extended serum half-life, such as a fusion protein.

[095] As used herein, the terms “full-length antibody chain”, “full-length antibody”, “intact antibody” and Petition 870260061493, dated 06 / 23 / 2026, page 83 / 182 70 / 130 “whole antibody” are used interchangeably herein to refer to such an antibody having a structure substantially similar to a natural antibody structure or having a heavy chain comprising an Fc region as defined in this document.

[096] The term “light chain” includes full-length light chains and their fragments having a variable region sequence sufficient to confer binding specificity. The full-length light chain comprises a variable region domain (VL) and a constant region domain (CL). The variable region domain of the light chain is at the amino terminus of the polypeptide. Light chains include kappa (κ) and lambda (λ) chains.

[097] The term “heavy chain” includes full-length heavy chains and their fragments with a variable region sequence sufficient to confer binding specificity. The full-length heavy chain comprises a variable region domain VH and 3 constant region domains CH1, CH2, and CH3. The VH domain is at the amino terminus of the polypeptide and the CH domains are at the carboxyl terminus, where CH3 is closest to the carboxyl terminus of the polypeptide. The heavy chain can be of any isotype, including IgG (including subtypes IgG1, IgG2, IgG3, and IgG4), IgA (including subtypes IgA1 and IgA2), IgM, and IgE.

[098] As used herein, the term “Fab” fragment consists of a light chain, CH1, and the variable region of a heavy chain. The heavy chain of a Fab molecule cannot form disulfide bonds with another heavy chain molecule.

[099] As used herein, the term “Fc” region comprises two heavy chain fragments comprising the CH1 and CH2 domains of an antibody. The two heavy chain fragments are held together by two or more disulfide bonds and the hydrophobic interaction of the CH3 domains.

[100] As used here, the term fragment “Fab’” Petition 870260061493, dated 06 / 23 / 2026, page 84 / 182 71 / 130 comprises portions of a light chain and a heavy chain, including the VH domain and the CH1 domain and the region between the CH1 and CH2 domains), so that interchain disulfide bonds can be formed between the two heavy chains of two Fab' fragments to give an F(ab')2 molecule.

[101] As used herein, the term fragment “F(ab')2” comprises two light chains and two heavy chains containing portions of the constant region between the CH1 and CH2 domains, such that interchain disulfide bonds are formed between the two heavy chains. Thus, the F(ab')2 fragment consists of two Fab' fragments held together by disulfide bonds between the two heavy chains.

[102] As used here, the term “Fv” region includes the variable regions of the heavy and light chains, but lacks the constant regions.

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

[104] As used here, the term fragment “dAb” consists of a VH domain (Ward et al., Nature 341: 544-546 (1989)).

[105] As used herein, the term “Fab’-SH” is the designation herein for Fab’, in which one or more cysteine ​​residues of the constant domain carry a free thiol group.

[106] As used here, the term “Fab / c” fragment is an intermediate formed by pepsin digestion of an immunoglobulin, which combines the advantages of the Fab and Fc regions, i.e., strong diffusibility and low metabolic clearance in vivo, while maintaining high affinity (Liu Jianjun, Chinese Journal of Cellular and Molecular Immunology, 1989 (4): 29-29).

[107] As used herein, the term “single-chain antibody” is an Fv molecule in which the variable regions of the heavy and light chains are Petition 870260061493, dated 06 / 23 / 2026, p. 85 / 182 72 / 130 connected by a flexible linker to form a single polypeptide chain (which forms an antigen-binding region) (see, for example, 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. WO 88 / 01649 and U.S. Patents Nos. 4,946,778 and 5,260,203, disclosures of which are incorporated herein by reference.

[108] As used herein, the term “domain antibody” is an immunofunctional immunoglobulin fragment comprising only the variable region of the heavy chain or light chain. In some cases, two or more VH regions are covalently linked by a peptide linker to generate a multivalent domain antibody (particularly a bivalent domain antibody). The two VH regions of the bivalent domain antibody may target the same antigens or different antigens.

[109] As used herein, the term “bivalent antigen-binding protein” or “bivalent antibody” comprises two antigen-binding sites. In some cases, the two binding sites have specificity against the same antigen. The bivalent antibody may be bispecific.

[110] 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.

[111] As used herein, the term “bispecific,” “dual-specificity,” or “bifunctional” antigen-binding protein or antibody refers to a hybrid antigen-binding protein or antibody possessing two different antigen-binding sites, respectively. A bispecific antibody is a multispecific antigen-binding protein or multispecific antibody and can be produced by a variety of methods, including but not limited to hybridoma fusion or Fab fragment ligation. See, for example. Petition 870260061493, dated 06 / 23 / 2026, p. 86 / 182 73 / 130 example, 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 will bind to two different epitopes that are present on the same or different protein targets.

[112] As used in the present invention, the terms “mAb” and “monoclonal antibody” refer to an antibody or fragment of an antibody that is derived from a group of highly homologous antibodies, that is, from a group of antibody molecules identical except for natural mutations that may occur spontaneously. The monoclonal antibody has a high specificity for a single epitope on an antigen. The polyclonal antibody, in relation to the monoclonal antibody, generally comprises at least two or more different antibodies that generally recognize different epitopes on an antigen. Monoclonal antibodies can generally be obtained using the hybridoma technique first reported by Kohler et al. (Nature, 256: 495, 1975), but can also be obtained using recombinant DNA technique (see, for example, US Patent No. 4,816,567).

[113] As used in the present invention, the term “humanized antibody” refers to an antibody or antibody fragment obtained when all or part of the CDR regions of a human immunoglobulin (recipient antibody) are replaced by the CDR regions of a non-human antibody (donor antibody), wherein the donor antibody may be a non-human antibody (e.g., mouse, rat, or rabbit) with expected specificity, affinity, or reactivity. Furthermore, some amino acid residues in the structural regions (FRs) of the recipient antibody may also be replaced by amino acid residues from corresponding non-human antibodies or by amino acid residues from other antibodies to further improve or optimize antibody performance. For more details Petition 870260061493, dated 06 / 23 / 2026, p. 87 / 182 74 / 130 on humanized antibodies, see, for example, 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).

[114] As used herein, the term “epitope” refers to a site on an antigen to which an immunoglobulin or antibody binds specifically. “Epitope” is also referred to in the field as an “antigenic determinant.” The epitope or antigenic determinant generally consists of groups of chemically active surface molecules, such as amino acids, carbohydrates, or sugar side chains, and usually has specific three-dimensional structural features and specific charge characteristics. For example, the epitope usually includes at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 consecutive or non-consecutive amino acids in a unique spatial conformation, which may be “linear” or “conformational.” See, for example, Epitope Mapping Protocols in Methods in Molecular Biology, Vol. 66, GE Morris, Ed. (1996).In a linear epitope, all interaction sites between a protein and an interacting molecule (e.g., an antibody) are located adjacently along the protein's primary amino acid sequence. In a conformational epitope, the interaction sites are located within sections of the amino acid residue.

[115] The terms “polypeptide” or “protein” are used interchangeably herein to refer to a polymer of amino acid residues. The term is also used to refer to an amino acid polymer in which one or more amino acid residues are analogs or mimetics of naturally occurring amino acids and to polymers of naturally occurring amino acids. The term may also include, for example, amino acid polymers that have been modified by the addition of saccharide residues to form glycoproteins, or have been phosphorylated. Polypeptides and proteins can be produced by naturally occurring cells and non-existent cells. Petition 870260061493, dated 06 / 23 / 2026, p. 88 / 182 75 / 130 recombinants; or they can be produced by genetically modified or recombinant cells and comprise a molecule with the amino acid sequence of a native protein or a molecule with deletions, insertions and / or substitutions in one or more amino acids of the native sequence.

[116] In particular, the terms “polypeptide” and “protein” include antibodies, such as human anti-IL-4RA antibodies (also referred to as IL-4RA antibodies), IL-4RA-binding proteins, antibodies or sequences with deletions, insertions, and / or substitutions in one or more amino acids of an antigen-binding protein.

[117] The term “polypeptide fragment” refers to a polypeptide possessing amino-terminal deletions, carboxyl-terminal deletions, and / or internal deletions compared to a full-length protein. These 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 long. For example, a fragment may be at least 5, 6, 8, 10, 14, 20, 50, 70, 100, 110, 150, 200, 250, 300, 350, 400, or 450 amino acids long. Useful polypeptide fragments include immunologically functional antibody fragments, including binding domains. In the case of human IL-4RA antibodies, useful fragments include, but are not limited to, CDR regions, variable domains of heavy or light chains, portions of antibody chains, variable domains comprising only 2 CDRs, or similar.

[118] The terms “human IL-4RA”, “hIL-4RA”, “human IL-4 receptor A”, “human IL-4 receptor alpha subunit” are used interchangeably to refer to the alpha subunit of the human interleukin-4 receptor. Human IL-4RA refers to its mature peptide (Genbank ID: NP_001244336.1). IL-4 and IL-13 are the main endogenous agonists of IL-4. Petition 870260061493, dated 06 / 23 / 2026, p. 89 / 182 76 / 130 4RA. Unless otherwise indicated or clear from the context in which the term is used, “IL-4RA” refers to human IL-4RA.

[119] A “derivative” of a polypeptide is a polypeptide (for example, an antigen-binding protein or antibody) that is chemically modified in ways other than insertion, deletion or substitution, for example, by conjugation with another chemical moiety, for example, a PEG-conjugated polypeptide.

[120] As used herein, the term “isolate” refers to “obtained by artificial means from a natural state.” If a particular “isolated” substance or component appears in nature, it may be that the change occurs in its natural environment, or that it is isolated from the natural environment, or both. For example, a certain non-isolated polynucleotide or polypeptide exists naturally in a particular living animal, and the same polynucleotide or polypeptide with a high purity isolated from such a natural state is termed an isolated polynucleotide or polypeptide. The term “isolate” does not exclude the existence of artificial or synthetic substances or other impurities that do not affect the activity of the substance.

[121] As used herein, the term “vector” refers to a nucleic acid carrier into which a polynucleotide can be inserted. When a vector allows the expression of the protein encoded by the inserted polynucleotide, the vector is termed an expression vector. A vector can be introduced into a host cell by transformation, transduction, or transfection so that the elements of the genetic substance carried by the vector can be expressed in the host cell. Vectors are well known to those skilled in the art, including, but not limited to: plasmids; phagomids; cosmids; artificial chromosomes, such as yeast artificial chromosome (YAC), bacterial artificial chromosome (BAC), or P1-derived artificial chromosome (PAC); phages, such as lambda phages or M13 phages; and animal viruses. Petition 870260061493, dated 06 / 23 / 2026, page 90 / 182 77 / 130 animal viruses that can be used as vectors include, but are not limited to, retroviruses (including lentiviruses), adenoviruses, adeno-associated viruses, herpes viruses (such as herpes simplex virus), poxviruses, baculoviruses, papillomaviruses, and papovaviruses (such as SV40). A vector may contain a variety of 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 also contain a replication initiation site.

[122] As used herein, the term “host cell” refers to cells that can be introduced with vectors, including, but not limited to, prokaryotic cells, such as E. coli or Bacillus subtilis, fungal cells, such as yeast or Aspergillus cells, insect cells, such as Drosophila S2 or Sf9 cells, or animal cells, such as fibroblasts, CHO cells, COS cells, NSO cells, HeLa cells, BHK cells, HEK 293 cells, or human cells.

[123] As used herein, the term “specifically binding” refers to a non-random binding reaction between two molecules, such as a reaction between an antibody and an antigen that it targets. In some embodiments, an antibody that specifically binds to an antigen (or an antibody that is specific for an antigen) refers to the antibody binding to the antigen with an affinity (Kd) of less than about 10-5M, such as less than about 10-6M, 10-7M, 10-8M, 10-9M or 10-10M or less.

[124] As used herein, the term “Kd” refers to a dissociation equilibrium constant for a specific antibody-antigen interaction, which is used to describe the binding affinity between the antibody and the antigen. Among the various parameters measured by molecular binding kinetics, the Kd value is the dissociation equilibrium constant. In a Petition 870260061493, dated 06 / 23 / 2026, pp. 91 / 182 78 / 130 antibody drug research, is the parameter that characterizes the intensity of the affinity effect of an antibody of interest and the target antigen molecule, and is calculated by the formula: Kd = kdis / kon. A smaller equilibrium dissociation constant indicates a stronger antibody-antigen binding and a higher affinity between the antibody and the antigen. kon (association rate constant) is the rate of formation of the antigen-antibody complex, and a smaller kon suggests a faster binding of an antibody to an antigen. kdis (dissociation rate constant) is the rate at which an antibody dissociates from an antigen-antibody complex, and a smaller kdis suggests a slower rate of antibody dissociation from the antigen and a stronger binding between the antibody and the antigen.Generally, an antibody binds to an antigen (e.g., L1 protein) with a dissociation equilibrium constant (Kd) of less than about 10⁻⁵ M, such as less than about 10⁻⁶ M, 10⁻⁷ M, 10⁻⁸ M, 10⁻⁹ M, or 10⁻¹⁰ M or less, for example, as determined on a BIACORE surface plasmon resonance (SPR) instrument or a ForteBio molecular interaction instrument.

[125] As used herein, the terms “monoclonal antibody” and “McAb” have the same meaning and may be used interchangeably; the terms “polyclonal antibody” and “PcAb” have the same meaning and may be used interchangeably; the terms “polypeptide” and “protein” have the same meaning and may be used interchangeably. In addition, herein, amino acids are generally represented by single-letter and three-letter abbreviations known in the art. For example, alanine may be represented by A or Ala.

[126] As used herein, the terms “hybridome” and “hybridome cells” may be used interchangeably, and when referring to the terms “hybridome” and “hybridome cells”, subclones and descendant cells of the hybridoma are also included. Petition 870260061493, dated 06 / 23 / 2026, p. 92 / 182 79 / 130

[127] As used herein, the terms “sequence identity percentage” and “sequence homology percentage” are used interchangeably.

[128] As used herein, the terms “similarity”, “sequence similarity” and “identity” refer to the correlation of the sequences of two or more proteins or polypeptide molecules, as determined by sequence alignment and comparison. “Percentage of 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 alignment (if any) must be handled by a specific mathematical model or computer program (i.e., an “algorithm”).The term “substantial identity,” when used for polypeptides, refers to two peptide sequences that, when ideally aligned, for example, using the GAP or BESTFIT programs, using standard gap weights provided by the programs, 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. In some cases, the positions of residues that are not identical differ due to conservative amino acid substitutions. “Conservative amino acid substitution” is one in which the amino acid residue is replaced by another amino acid residue possessing a side-chain R group that has similar chemical properties (e.g., charge or hydrophilicity). Generally, conservative amino acid substitutions will substantially retain the functions and properties of the protein.In cases where two or more amino acid sequences differ from one another by conservative substitutions, the percentage sequence identity may be high to correct for the conservative nature of the substitution. The methods for making this adjustment are well known to those skilled in the art. See, for example. Petition 870260061493, dated 06 / 23 / 2026, p. 93 / 182 80 / 130 example, Pearson, Methods Mol. Biol., 243: 307-31 (1994). Examples of amino acid groups with side chains with similar chemical properties include: 1) aliphatic hydroxyl side chain: glycine, alanine, valine, leucine, and isoleucine, 2) aliphatic hydroxyl side chain: serine and threonine, 3) amide-containing side chain: asparagine and glutamine, 4) aromatic side chain: phenylalanine, tyrosine, and tryptophan, 5) basic side chain: lysine, arginine, and histidine, 6) acidic side chain: aspartic acid and glutamic acid, and 7) sulfur-containing side chain: cysteine ​​and methionine. The conservative amino acid substitution groups are valine-leucine-isoleucine, phenylalanine-tyrosine, lysine-arginine, alanine-valine, glutamic acid-aspartic acid, and asparagine-glutamine.

[129] Optionally, a conservative replacement is any change with a positive value in the PAM250 logarithmic likelihood matrix disclosed in Gonnet et al., Science, 256: 1443-45 (1992), which is incorporated here by reference. A “moderately conservative” replacement is any change with a non-negative value in the PAM250 logarithmic likelihood matrix.

[130] Polypeptide sequence identity is generally measured by sequence analysis software. Protein analysis software matches sequences using a similarity measure assigned to different substitutions, deletions, and other modifications (including conservative amino acid substitutions). For example, GCG, including programs such as “Gap” and “Bestfit,” which (using standard 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 biological species) or between a wild-type protein and its mutant protein. See, for example, GCG Version 6.1 (University of Wisconsin, WI). Polypeptide sequences also Petition 870260061493, dated 06 / 23 / 2026, page 94 / 182 81 / 130 can be compared using FASTA with standard or recommended parameters. See GCG Version 6.10 FASTA (e.g., FASTA2 and FASTA3) which provides alignments for optimal overlap regions between challenge and query sequences and the percentage of sequence identities (Pearson, Methods Enzymol. 183: 63-98 (1990); Pearson, Methods Mol. Biol., 132: 185-219 (2000)). Another preferred algorithm when comparing sequences with a database containing massive sequences from different organisms is the BLAST computer program, in particular, blastp or tblastn (using standard parameters provided by the program). See, for example, Altschul et al., Mol. Biol., 215: 403-410 (1990); Altschul et al., Nucleic Acids Res., 25: 3389-402 (1997).

[131] Compared with the prior art, the present invention has the following advantages: The anti-human IL-4RA antibody disclosed in this document can bind to human IL-4RA with high affinity and inhibit relevant cellular biological effects mediated by human IL-4 and human IL-13, such as cell proliferation, IL-4 and IL-13 induced upregulation of CD23 expression levels, and similar effects, blocking the binding of human IL-4 and human IL-13 to human IL-4RA. The antibody has advantages of high activity, exclusion of species differences, and similar effects, and can be used in the preparation of drugs to block the binding of human IL-4 and IL-13 to human IL-4RA and in the preparation of 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, thus having potential for application and commercialization. Brief Description of the Drawings

[132] Figure 1: Binding activity of 13E5 and dupilumab to Petition 870260061493, dated 06 / 23 / 2026, page 95 / 182 82 / 130 IL4RA-mFc antigen.

[133] Figure 2: Binding activity of 13E5 H1L1, 13E5 H2L2, 13E5 H3L3 and dupilumab to IL4RA-mFc antigen.

[134] Figure 3: Binding activity of 13E5 H4L2, 13E5 H4L4 and dupilumab to IL4RA-mFc antigen.

[135] Figure 4: Activity of 13E5 and dupilumab in competition with human IL4-N-His for binding to human IL4RA-mFc.

[136] Figure 5: Activity of 13E5 H1L1, 13E5 H2L2, 13E5 H3L3 and dupilumab in competition with human IL4-N-His for binding to human IL4RA-mFc.

[137] Figure 6: Activity of 13E5 H4L2, 13E5 H4L4 and dupilumab in competition with human IL4-N-His for binding to human IL4RA-mFc.

[138] Figure 7: Binding activity of 18H7 and dupilumab to the IL4RA-mFc antigen.

[139] Figure 8: Binding activity of 18H7 H1L1, 18H7 H2L2, 18H7 H2L3, 18H7 H3L2, 18H7 H3L3 and dupilumab to the IL4RA-mFc antigen.

[140] Figure 9: Activity assay of 18H7 and dupilumab in competition with human IL4-N-His for binding to human IL4RA-mFc.

[141] Figure 10: Activity assay of 18H7 H1L1, 18H7 H2L2, 18H7 H2L3, 18H7 H3L2 and dupilumab in competition with human IL4-N-His for binding to human IL4RA-mFc.

[142] Figure 11: Activity assay of 20G10 H3L3, 13E5 H4L4 and dupilumab in competition with human IL4-N-His for binding to human IL4RA-mFc.

[143] Figure 12: Assay of the affinity constant of 13E5 H4L4 to human IL4RA. Antibody concentrations for pairs of curves from top to bottom were 25 nM, 6.25 nM, 3.13 nM, 1.56 nM, 0.78 nM and 0.39 nM, respectively. Petition 870260061493, dated 06 / 23 / 2026, p. 96 / 182 83 / 130

[144] Figure 13: 18H7 H1L1 affinity constant assay for human IL4RA. Antibody concentrations for top-down curve pairs were 25 nM, 6.25 nM, 3.13 nM, 1.56 nM, 0.78 nM, and 0.39 nM, respectively.

[145] Figure 14: Dupilumab affinity constant assay for human IL4RA. Antibody concentrations for the top-down curve pairs were 12.5 nM, 6.25 nM, 3.13 nM, 1.56 nM, 0.78 nM, and 0.39 nM, respectively.

[146] Figure 15: Affinity constant assay of 13E5 H1L1 for human IL4RA. Antibody concentrations for top-down curve pairs were 25 nM, 12.5 nM, 6.25 nM, 3.13 nM, 1.56 nM, 0.78 nM and 0.39 nM, respectively.

[147] Figure 16: Affinity constant assay of 13E5 H2L2 for human IL4RA. Antibody concentrations for top-down curve pairs were 25 nM, 12.5 nM, 6.25 nM, 3.13 nM, 1.56 nM, 0.78 nM and 0.39 nM, respectively.

[148] Figure 17: Affinity constant assay of 13E5 H3L3 for human IL4RA. Antibody concentrations for top-down curve pairs were 25 nM, 12.5 nM, 6.25 nM, 3.13 nM, 1.56 nM and 0.39 nM, respectively.

[149] Figure 18: Affinity constant assay of 13E5 H4L2 for human IL4RA. Antibody concentrations for the top-down curve pairs were 12.5 nM, 6.25 nM, 3.13 nM, 1.56 nM, 0.78 nM and 0.39 nM, respectively.

[150] Figure 19: 18H7 H2L2 affinity constant assay for human IL4RA. Antibody concentrations for top-down curve pairs were 6.25 nM, 3.13 nM, 1.56 nM, 0.78 nM, and 0.39 nM, respectively. Petition 870260061493, dated 06 / 23 / 2026, p. 97 / 182 84 / 130

[151] Figure 20: Assay of the 18H7 H3L2 affinity constant for human IL4RA. Antibody concentrations for the top-down curve pairs were 25 nM, 12.5 nM, 6.25 nM, 3.13 nM, 1.56 nM, 0.78 nM, and 0.39 nM, respectively.

[152] Figure 21: Assay of the affinity constant of dupilumab for human IL4RA. Antibody concentrations for the top-down curve pairs were 6.25 nM, 3.13 nM, 1.56 nM, 0.78 nM and 0.39 nM, respectively.

[153] Figure 22: 13E5 H1L1, 13E5 H2L2 and dupilumab inhibiting IL-4-induced TF-1 cell proliferation.

[154] Figure 23: 13E5 H1L1, 13E5 H2L2 and dupilumab inhibiting IL-13-induced TF-1 cell proliferation.

[155] Figure 24: 13E5 H4L2, 13E5 H4L4 and dupilumab inhibiting IL-4-induced TF-1 cell proliferation.

[156] Figure 25: 13E5 H4L2, 13E5 H4L4 and dupilumab inhibiting IL-13-induced TF-1 cell proliferation.

[157] Figure 26: 18H7 H1L1, 18H7 H2L2 and dupilumab inhibiting IL-4-induced TF-1 cell proliferation.

[158] Figure 27: 18H7 H1L1, 18H7 H2L2 and dupilumab inhibiting IL-13-induced TF-1 cell proliferation.

[159] Figure 28: 18H7 H1L1, 13E5 H4L4 and dupilumab inhibiting the upregulation of IL-4-induced CD23 expression in monocytes.

[160] Figure 29: 18H7 H1L1, 13E5 H4L4 and dupilumab inhibiting the upregulation of IL-13-induced CD23 expression in monocytes.

[161] Figure 30: 13E5 H4L4 inhibiting epidermal thickness increase in the B-hIL4Ra mouse skin inflammation model.

[162] Figure 31: Pathological sections showing epidermal thickness in mice from all experimental groups (HE staining, Petition 870260061493, dated 06 / 23 / 2026, page 98 / 182 85 / 130 400*). a. control (normal saline solution); b. dupilumab (80 mg / kg); c. dupilumab (20 mg / kg); d. hIgG4 (80 mg / kg); e. 13E5 H4L4 (80 mg / kg); f. 13E5 H4L4 (20 mg / kg). Detailed Description of the Invention

[163] The embodiments of the present invention will be described in detail below 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 as limiting the scope of the present invention. In cases where techniques or conditions are not specified, the examples have been carried out in accordance with techniques or conditions described in the literature of the art (for example, see Molecular Cloning: A Laboratory Manual, by J. Sambrook et al., and translated by Huang Peitang et al., third edition, Science Press) or in accordance with the product manual. Reagents or instruments used are conventional products available on the market, unless their manufacturers are specified.

[164] In the following examples of this invention, BALB / C mice were acquired from the Guangdong Medical Laboratory Animal Center.

[165] In the following examples of the present invention, the reference antibody dupilumab VAB 16F3-1 (hereinafter referred to as dupilumab) was produced by Akeso, Inc., whose sequence can be found in Patent Application No. PCT / US2007 / 021210 granted to Regeneron Pharmaceuticals, Inc. The variable region of the heavy chain of the VAB 16F3-1 antibody is presented in SEQ ID NO: 124, with the constant region being a C region of the Ig gamma-1 chain, Accession No. P01857, while the coding sequence of the variable region of the light chain of the VAB 16F3-1 antibody is presented in SEQ ID NO: 125, with the constant region being a C region of the Ig kappa chain, Accession No. P01834). Petition 870260061493, dated 06 / 23 / 2026, page 99 / 182 86 / 130 Example 1. Preparation of anti-human IL-4RA antibodies 20G10, 13E5 and 18H7 1. Preparation of 20G10, 13E5 and hybridoma cell lines 18H7

[166] The IL-4RA-mFc antigen for anti-IL-4RA antibody production was a mature human IL-4RA peptide fusion protein (Genbank ID: NP_001244336.1) and mFc marker (SEQ ID NO: 121) synthesized by Akeso, Inc., and was used to immunize BALB / C mice (acquired from the Guangdong Medical Laboratory Animal Center). Spleen cells from immunized BALB / C mice (acquired from the Guangdong Medical Laboratory Animal Center) and mouse myeloma cells were fused to form hybridoma cells with reference to existing cell fusion techniques (e.g., Stewart, SJ, “Monoclonal Antibody Production”, in Basic Methods in Antibody Production and Characterization, Eds. GC Howard and DR Bethell, Boca Raton: CRC Press, 2000).The plate was coated with IL-4RA-hFc protein (IL-4RA is described above, and hFc is a purification marker for human IgG Fc, specifically the C region of the Ig gamma-1 chain, Genbank ID: P01857, positions 114-330) for indirect ELISA. Hybridoma cell lines secreting antibodies that specifically bind to IL-4RA-hFc were obtained by screening. The 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 IL4-N-his ligand (IL4 NCBI Gene ID: AAH70123.1) for binding to IL-4RA-hFc. Two stably secreting anti-human IL-4RA antibody hybridoma cell lines were obtained by limiting dilution. The hybridoma cell lines were named LT018, LT008, and LT009, and the secreted monoclonal antibodies were named 20G10, 13E5, and 18H7. Petition 870260061493, dated 06 / 23 / 2026, pp. 100 / 182 87 / 130

[167] The LT018 hybridoma cell line (IL4RA-20G10) was deposited at the China Center for Type Culture Collection (CCTCC) on December 25, 2019 with an accession number CCTCC NO: C202010 and a preservation address of Wuhan University, Wuhan, China, postal code: 430072.

[168] The LT008 (IL4RA-13E5) hybridoma cell line was deposited at the China Center for Type Culture Collection (CCTCC) on June 21, 2018 with a CCTCC accession number NO: C2018131 and a preservation address of Wuhan University, Wuhan, China, postal code: 430072.

[169] The LT009 (IL4RA-18H7) hybridoma cell line was deposited at the China Center for Type Culture Collection (CCTCC) on June 21, 2018 with a CCTCC accession number NO: C2018132 and a preservation address of Wuhan University, Wuhan, China, postal code: 430072. 2. Preparation of anti-human IL-4RA antibodies 20G10, 13E5 and 18H7

[170] The LT018, LT008 and LT009 cell lines, prepared as described above, were cultured separately with a defined chemical medium (CD medium; containing 1% streptomycin) in 5% CO2, incubated at 37 °C. After 7 days, the supernatants were collected and purified by high-speed centrifugation, vacuum filtration through a microfiltration membrane and an HP HiTrap protein A column to give the antibodies 20G10, 13E5 and 18H7. Example 2. Sequence analysis of human anti-IL-4RA 13E5 antibody.

[171] mRNA was extracted from the LT008 cell line cultured in Example 1 according to the method described in the manual for the pure RNAprep Cell / Bacteria Kit (Tiangen, Cat. No. DP430).

[172] cDNA was synthesized according to the Invitrogen SuperScript® III First-Strand Synthesis System manual for RT-PCR and amplified by PCR. Petition 870260061493, dated 06 / 23 / 2026, pp. 101 / 182 88 / 130

[173] The PCR-amplified products were directly subjected to TA cloning according to the pEASY-T1 Cloning kit manual (Transgen CT101).

[174] The cloned products with TA were sequenced directly and the sequencing results are as follows.

[175] The nucleic acid sequence of the variable region of the heavy chain is shown in SEQ ID NO: 1 with a length of 348 bp. The encoded amino acid sequence is shown in SEQ ID NO: 2 with a length of 116 amino acids, while the CDR1, CDR2 and CDR3 heavy chain sequences are shown in SEQ ID NOs: 9, 10 and 11, respectively.

[176] The nucleic acid sequence of the variable region of the light chain is presented in SEQ ID NO: 3 with a length of 321 bp. The encoded amino acid sequence is presented in SEQ ID NO: 4 with a length of 107 amino acids, while the CDR1, CDR2 and CDR3 light chain sequences are presented in SEQ ID NOs: 12, 13 and 14, respectively. Example 3. Design and preparation of humanized anti-human IL-4RA antibodies 13E5 H1L1, 13E5 H2L2, 13E5 H3L3, 13E5 H4L2 and 13E5 H4L4 1. Design of light and heavy chain sequences of humanized anti-IL4RA antibodies 13E5 H1L1, 13E5 H2L2, 13E5 H3L3, 13E5 H4L2 and 13E5 H4L4

[177] Based on the three-dimensional crystal structure of the human IL-4RA protein (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 13E5 antibody sequence obtained in Example 2, the variable region sequences of the antibodies 13E5 H1L1, 13E5 H2L2, 13E5 H3L3, 13E5 H4L2 and 13E5 H4L4 were given by Petition 870260061493, dated 06 / 23 / 2026, pp. 102 / 182 89 / 130 Computer modeling and mutation design (antibody constant region sequences from the NCBI database: the heavy chain constant region is the C region of the Ig gamma-4 chain, Accession No. P01861.1; the light chain constant region is the C region of the Ig kappa chain, Accession No. P01834).

[178] The projected variable region sequences are as follows. (1) Heavy and light chain sequences of humanized monoclonal antibody 13E5 H1L1

[179] The nucleic acid sequence of the variable region of the heavy chain is shown in SEQ ID NO: 21 with a length of 348 bp. The encoded amino acid sequence is shown in SEQ ID NO: 22 with a length of 116 amino acids, while the CDR1, CDR2 and CDR3 heavy chain sequences are shown in SEQ ID NOs: 9, 10 and 11, respectively.

[180] The nucleic acid sequence of the variable region of the light chain is shown in SEQ ID NO: 23 with a length of 321 bp. The encoded amino acid sequence is shown in SEQ ID NO: 24 with a length of 107 amino acids, while the CDR1, CDR2 and CDR3 light chain sequences are shown in SEQ ID NOs: 12, 13 and 14, respectively. (2) Heavy and light chain sequences of humanized monoclonal antibody 13E5 H2L2

[181] The nucleic acid sequence of the variable region of the heavy chain is shown in SEQ ID NO: 25 with a length of 348 bp. The encoded amino acid sequence is shown in SEQ ID NO: 26 with a length of 116 amino acids, while the CDR1, CDR2 and CDR3 sequences of the heavy chain are shown in SEQ ID NOs: 9, 10 and 11, respectively. Petition 870260061493, dated 06 / 23 / 2026, pp. 103 / 182 90 / 130

[182] The nucleic acid sequence of the variable region of the light chain is shown in SEQ ID NO: 27 with a length of 321 bp. The encoded amino acid sequence is shown in SEQ ID NO: 28 with a length of 107 amino acids, while the CDR1, CDR2 and CDR3 light chain sequences are shown in SEQ ID NOs: 12, 13 and 14, respectively. (3) Humanized monoclonal antibody heavy and light chain sequences 13E5 H3L3

[183] ​​The nucleic acid sequence of the variable region of the heavy chain is shown in SEQ ID NO: 29 with a length of 348 bp. The encoded amino acid sequence is shown in SEQ ID NO: 30 with a length of 116 amino acids, while the CDR1, CDR2 and CDR3 heavy chain sequences are shown in SEQ ID NOs: 9, 10 and 11, respectively.

[184] The nucleic acid sequence of the variable region of the light chain is shown in SEQ ID NO: 31 with a length of 321 bp. The encoded amino acid sequence is shown in SEQ ID NO: 32 with a length of 107 amino acids, while the CDR1, CDR2 and CDR3 light chain sequences are shown in SEQ ID NOs: 12, 13 and 14, respectively. (4) Monoclonal antibody heavy and light chain sequences HUMANIZED 13E5 H4L4

[185] The nucleic acid sequence of the variable region of the heavy chain is shown in SEQ ID NO: 33 with a length of 348 bp. The encoded amino acid sequence is shown in SEQ ID NO: 34 with a length of 116 amino acids, while the CDR1, CDR2 and CDR3 sequences of the heavy chain are shown in SEQ ID NOs: 9, 10 and 11, respectively. Petition 870260061493, dated 06 / 23 / 2026, pp. 104 / 182 91 / 130

[186] The nucleic acid sequence of the variable region of the light chain is shown in SEQ ID NO: 35 with a length of 321 bp. The encoded amino acid sequence is shown in SEQ ID NO: 36 with a length of 107 amino acids, while the CDR1, CDR2 and CDR3 light chain sequences are shown in SEQ ID NOs: 12, 13 and 14, respectively. (5) Heavy and light chain sequences of humanized monoclonal antibody 13E5 H4L2

[187] The nucleic acid sequence of the variable region of the heavy chain is presented in SEQ ID NO: 33, and the encoded amino acid sequence is presented in SEQ ID NO: 34.

[188] The nucleic acid sequence of the variable region of the light chain is presented in SEQ ID NO: 27, and the encoded amino acid sequence is presented in SEQ ID NO: 28. 2. Preparation of humanized antibodies 13E5 H1L1, 13E5 H2L2, 13E5 H3L3, 13E5 H4L2 and 13E5 H4L4

[189] The constant regions of the heavy chain are the C region of the Ig gamma-4 chain, Accession No. P01861.1; the constant regions of the light chain are the C region of the Ig kappa chain, Accession No. P01834.

[190] The cDNA of the 13E5 H1L1 heavy and light chain variable region, the cDNA of the 13E5 H2L2 heavy and light chain variable region, the cDNA of the 13E5 H3L3 heavy and light chain variable region, the cDNA of the 13E5 H4L2 heavy and light chain variable region, and the cDNA of the 13E5 H4L4 heavy and light chain variable region were separately cloned into a pUC57 single vector (provided by Genscript Biotech Corporation) to give pUC57single-13E5H1, pUC57single-13E5L1, pUC57single-13E5H2, Petition 870260061493, dated 06 / 23 / 2026, pp. 105 / 182 92 / 130 pUC57simples-13E5L2, pUC57simples-13E5H3, pUC57simples-13E5L3, pUC57simples-13E5H4 and pUC57simples-13E5L4. The variable region fragments were acquired by digestion according to the 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 fragment (for pcDNA3.1 vectors containing both heavy and light chain constant regions, the restriction enzymes used were HindIII and EcoRI) 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. The recombinant plasmid pair 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 and pcDNA3.1-13E5H4 and pcDNA3.1-13E5L2) were co-transfected into 293F cells.Cultures were collected and purified. After sequence verification, endotoxin-free expression plasmids were prepared and transiently transfected into HEK293 cells for antibody expression. Cultures were collected after 7 days and purified on a Protein A column to yield the humanized antibodies 13E5 H1L1, 13E5 H2L2, 13E5 H3L3, 13E5 H4L2, and 13E5 H4L4. Example 4. Sequence analysis of human anti-IL-4RA 18H7 antibody.

[191] mRNA was extracted from the LT009 cell line cultured in Example 1 according to the method described in the RNAprep pure Cell / Bacteria Kit manual (Tiangen, Cat. No. DP430).

[192] cDNA was synthesized according to the Invitrogen SuperScript®III First-Strand Synthesis System manual for RT-PCR and amplified by PCR.

[193] The PCR-amplified products were submitted Petition 870260061493, dated 06 / 23 / 2026, pp. 106 / 182 93 / 130 directly to TA cloning according to the pEASY-T1 Cloning kit manual (Transgen CT101).

[194] The cloned products with TA were sequenced directly and the sequencing results are as follows.

[195] The nucleic acid sequence of the variable region of the heavy chain is shown in SEQ ID NO: 5 with a length of 360 bp. The encoded amino acid sequence is shown in SEQ ID NO: 6 with a length of 120 amino acids, while the CDR1, CDR2 and CDR3 heavy chain sequences are shown in SEQ ID NOs: 15, 16 and 17, respectively.

[196] The nucleic acid sequence of the variable region of the light chain is shown in SEQ ID NO: 7 with a length of 333 bp. The encoded amino acid sequence is shown in SEQ ID NO: 8 with a length of 111 amino acids, while the CDR1, CDR2 and CDR3 light chain sequences are shown in SEQ ID NOs: 18, 19 and 20, respectively. Example 5. Design and preparation of humanized anti-IL4RA antibodies 18H7 H1L1, 18H7 H2L2, 18H7 H2L3, 18H7 H3L2 and 18H7 H3L3 1. Design of light and heavy chain sequences of humanized anti-IL-4RA antibodies 18H7 H1L1, 18H7 H2L2, 18H7 H2L3, 18H7 H3L2 and 18H7 H3L3

[197] Based on the three-dimensional crystal structure of the human IL-4RA 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.) and the 18H7 antibody sequence obtained in Example 4, the variable region sequences of the antibodies 18H7 H1L1, 18H7 H2L2, 18H7 H2L3, 18H7 H3L2 and 18H7 H3L3 were given by computer modeling and mutation design. Petition 870260061493, dated 06 / 23 / 2026, pp. 107 / 182 94 / 130 (NCBI database antibody constant region sequences: heavy chain constant region is Ig gamma-4 chain C region, Accession No. P01861.1; light chain constant region is Ig kappa chain C region, Accession No. P01834).

[198] The projected variable region sequences are as follows. (1) Monoclonal antibody heavy and light chain sequences HUMANIZED 18H7 H1L1

[199] The nucleic acid sequence of the variable region of the heavy chain is presented in SEQ ID NO: 37 with a length of 360 bp. The encoded amino acid sequence is presented in SEQ ID NO: 38 with a length of 120 amino acids, while the CDR1, CDR2 and CDR3 heavy chain sequences are presented in SEQ ID NOs: 15, 16 and 17, respectively.

[200] The nucleic acid sequence of the variable region of the light chain is shown in SEQ ID NO: 39 with a length of 333 bp. The encoded amino acid sequence is shown in SEQ ID NO: 40 with a length of 111 amino acids, while the amino acid sequences of the CDR1, CDR2 and CDR3 light chain are shown in SEQ ID NOs: 18, 19 and 20, respectively. (2) Heavy and light chain sequences of humanized monoclonal antibody 18H7 H2L2

[201] The nucleic acid sequence of the variable region of the heavy chain is shown in SEQ ID NO: 41 with a length of 360 bp. The encoded amino acid sequence is shown in SEQ ID NO: 42 with a length of 120 amino acids, while the CDR1, CDR2 and CDR3 heavy chain sequences are shown in SEQ ID NOs: 15, 16 and 17, respectively.

[202] The nucleic acid sequence of the variable region of the light chain is shown in SEQ ID NO: 43 with a length of 333 Petition 870260061493, dated 06 / 23 / 2026, pp. 108 / 182 95 / 130 bp. The encoded amino acid sequence is shown in SEQ ID NO: 44 with a length of 111 amino acids, while the CDR1, CDR2, and CDR3 light chain sequences are shown in SEQ ID NOs: 18, 19, and 20, respectively. (3) Heavy and light chain sequences of humanized monoclonal antibody 18H7 H3L3

[203] The nucleic acid sequence of the variable region of the heavy chain is shown in SEQ ID NO: 45 with a length of 360 bp. The encoded amino acid sequence is shown in SEQ ID NO: 46 with a length of 120 amino acids, while the CDR1, CDR2 and CDR3 heavy chain sequences are shown in SEQ ID NOs: 15, 16 and 17, respectively.

[204] The nucleic acid sequence of the variable region of the light chain is shown in SEQ ID NO: 47 with a length of 333 bp. The encoded amino acid sequence is shown in SEQ ID NO: 48 with a length of 111 amino acids, while the CDR1, CDR2 and CDR3 light chain sequences are shown in SEQ ID NOs: 18, 19 and 20, respectively. (4) Heavy and light chain sequences of humanized monoclonal antibody 18H7 H2L3

[205] The nucleic acid sequence of the variable region of the heavy chain is shown in SEQ ID NO: 41, and the encoded amino acid sequence is shown in SEQ ID NO: 42.

[206] The nucleic acid sequence of the variable region of the light chain is shown in SEQ ID NO: 47, and the encoded amino acid sequence is shown in SEQ ID NO: 48. Petition 870260061493, dated 06 / 23 / 2026, pp. 109 / 182 96 / 130 (5) Humanized monoclonal antibody heavy and light chain sequences 18H7 H3L2

[207] The nucleic acid sequence of the variable region of the heavy chain is presented in SEQ ID NO: 45, and the encoded amino acid sequence is presented in SEQ ID NO: 46.

[208] The nucleic acid sequence of the variable region of the light chain is presented in SEQ ID NO: 43, and the encoded amino acid sequence is presented in SEQ ID NO: 44. 2. Preparation of humanized antibodies 18H7 H1L1, 18H7 H2L2, 18H7 H2L3, 18H7 H3L3 and 18H7 H3L2

[209] The constant regions of the heavy chain are the C region of the Ig gamma-4 chain, Accession No. P01861.1; the constant regions of the light chain are the C region of the Ig kappa chain, Accession No. P01834.

[210] The 18H7 H1L1 heavy and light chain variable region cDNA, the 18H7 H2L2 heavy and light chain variable region cDNA, the 18H7 H2L3 heavy and light chain variable region cDNA, the 18H7 H3L3 heavy and light chain variable region cDNA, and the 18H7 H3L2 heavy and light chain variable region cDNA were cloned separately into the pUC57 single vector (provided by Genscript Biotech Corporation) to give pUC57single-18H7H1, pUC57single-18H7L1, pUC57single-18H7H2, pUC57single-18H7H7L2, pUC57single-18H7L3, and pUC57single-18H7L3. The variable region fragments were acquired by digestion according to the standard techniques described in Molecular Cloning: A Laboratory Manual (Second Edition), and subcloned into pcDNA3.1 vectors containing the corresponding constant region fragment of the heavy or light chain to give pcDNA3.1-18H7H1, pcDNA3.1-18H7L1, Petition 870260061493, dated 06 / 23 / 2026, pp. 110 / 182 97 / 130 pcDNA3.1-18H7H2, pcDNA3.1-18H7L2, pcDNA3.1-18H7H3, and pcDNA3.118H7L3. The recombinant plasmid pair 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 pcDNA3.118H7L3, pcDNA3, pcDNA3.1-18H7H2 and pcDNA3.1-18H7L3, and pcDNA3.118H7H3 and pcDNA3.1-18H7L2) were co-transfected into 293F cells. Cultures were collected and purified. After the sequences were verified, endotoxin-free expression plasmids were prepared and transiently transfected into HEK293 cells for antibody expression. Cultures were collected after 7 days and purified on a Protein A (GE) column to yield the humanized antibodies 18H7 H1L1, 18H7 H2L2, 18H7 H2L3, 18H7 H3L2, and 18H7 H3L3. Example 6. Design and preparation of a humanized anti-IL-4RA antibody 20G10 H3L3 1. Humanized anti-IL-4RA antibody light and heavy chain sequence design 20G10 H3L3

[211] Based on the three-dimensional crystal structure of the human IL-4RA 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 sequences of the variable region of the 20G10 H3L3 antibody were given by computer modeling and mutation design (antibody constant region sequences from the NCBI database: the constant region of the heavy chain is the C region of the Ig gamma-4 chain, Accession No. P01861.1; the constant region of the light chain is the C region of the Ig kappa chain, Accession No. P01834).

[212] The projected variable region sequences are as follows. Petition 870260061493, dated 06 / 23 / 2026, pp. 111 / 182 98 / 130 (1) Humanized monoclonal antibody heavy and light chain sequences 20G10 H3L3

[213] The nucleic acid sequence of the variable region of the heavy chain is shown in SEQ ID NO: 126 with a length of 360 bp. The encoded amino acid sequence is shown in SEQ ID NO: 127 with a length of 120 amino acids, while the CDR1, CDR2 and CDR3 sequences of the heavy chain are shown in SEQ ID NO: 130, 131 and 132, respectively.

[214] The nucleic acid sequence of the variable region of the light chain is shown in SEQ ID NO: 128 with a length of 321 bp. The encoded amino acid sequence is shown in SEQ ID NO: 129 with a length of 107 amino acids, while the amino acid sequences of CDR1, CDR2 and CDR3 light chains are shown in SEQ ID NOs: 133, 134 and 135, respectively. 2. Preparation of humanized antibody 20G10 H3L3

[215] The constant regions of the heavy chain are the C region of the Ig gamma-4 chain, Accession No. P01861.1; the constant regions of the light chain are the C region of the Ig kappa chain, Accession No. P01834.

[216] The cDNA of the variable region of the heavy and light chain of 20G10H3L3 was cloned into the simple pUC57 vector (provided by Genscript Biotech Corporation) to give simple pUC57-20G10H3 and simple pUC57-20G10L3. Fragments of the variable region were acquired by digestion according to the standard techniques described in Molecular Cloning: A Laboratory Manual (Second Edition), and subcloned into pcDNA3.1 vectors containing the corresponding constant region fragment of the heavy or light chain to give pcDNA3.1-20G10H3 and pcDNA3.1-20G10L3. The recombinant plasmid pair containing the corresponding light and heavy chains (pcDNA3.1-20G10H3 and pcDNA3.1-20G10L3) was cotransfected into 293F cells. Cultures were collected and purified. After the sequences were verified, the endotoxin-free expression plasmids Petition 870260061493, dated 06 / 23 / 2026, pp. 112 / 182 99 / 130 were prepared and transiently transfected into HEK293 cells for antibody expression. Cultures were collected after 7 days and purified on a Protein A (GE) column to give the humanized antibody 20G10 H3L3. Example 7. Antibody-antigen binding activity by ELISA. Binding activity of murine antibody 13E5 and humanized antibodies 1. 13E5 H1L1, 13E5 H2L2, 13E5 H3L3, 13E5 H4L2 and 13E5 H4L4 for human IL4RA-hFc or human IL4RA-mFc antigens. 1.1 The binding activity of antibodies 13E5, 13E5 H1L1, 13E5 H2L2, 13E5 H3L3, 13E5 H4L2 and 13E5 H4L4 to human IL4RA-hFc or human IL4RA-mFc antigens was measured by indirect ELISA.

[217] Procedures: ELISA plates were coated with human IL4RA-hFc or human IL4RA-mFc and incubated, and target antibodies were added after blocking. Anti-mouse goat (H+L) and HRP IgG (acquired from Jackson ImmunoResearch Inc., Cat No. 109-035-062), or anti-human goat and HRP IgG (acquired from Jackson ImmunoResearch Inc., Cat No. 109035-088) were added. Plates were incubated and washed before the addition of TMB (Neogen, 308177) for the chromogenic reaction. At the end of the reaction, absorbance at 450 nm was measured by a plate reader. Data were analyzed using SoftMax Pro 6.2.1.

[218] Readings at 450 nm show that antibodies 13E5, 13E5 H1L1, 13E5 H2L2, 13E5 H3L3, 13E5 H4L2, and 13E5 H4L4 are all capable of effectively binding to human IL4RA-hFc or human IL4RA-mFc antigens in a dose-dependent manner. By 4-parameter absorbance vs. logistic regression At antibody concentrations, as shown in Tables 1, 2, and 3, 13E5, 13E5 H1L1, 13E5 H2L2, 13E5 H3L3, 13E5 H4L2, and 13E5 H4L4 are all capable of binding to human IL4RA-hFc or human IL4RA-mFc antigens effectively, and demonstrate binding activities comparable to those of the reference antibody dupilumab against the same target (Figures 1, 2, and 3). Petition 870260061493, dated 06 / 23 / 2026, pp. 113 / 182 100 / 130 Table 1. Binding activity of 13E5 and dupilumab to human IL4RAhFc or human IL4RA-mFc antigens. Antibody dilution (μg / ml) Antigen (1 μg / ml) IL4RA-hFc IL4RA-mFc 13E5 Dupilumab 0.333 2.300 2.313 2.758 2.858 1:3 2.318 2.215 2.748 2.801 1:9 1.923 1.878 2.388 2.500 1:27 1.251 1.207 1.469 1.679 1:81 0.558 0.563 0.599 0.673 1:243 0.244 0.237 0.250 0.281 1:729 0.112 0.113 0.126 0.137 0 0.047 0.053 0.076 0.069 Second antibody: Anti-mouse goat (H+L) IgG, HRP (1:5000) Anti-human goat (H+L) IgG, HRP (1:5000) EC50 (nM) 0.084 0.077 Table 2. Binding activity of 13E5 H1L1, 13E5 H2L2, 13E5 H3L3 and dupilumab to IL4RA-mFc antigen. Antibody dilution (μg / ml) Antigen: IL4RA-mFc 13E5 H1L1 13E5 H2L2 13E5 H3L3 Dupilumab 1 2.716 2.797 2.768 2.754 2.642 2.656 2.901 2.921 1:3 2.834 2.825 2.686 2.770 2.679 2.688 2.928 2.923 1:9 2.802 2.798 2.692 2.735 2.658 2.717 2.909 2.921 1:27 2.684 2.613 2.551 2.578 2.492 2,498 2,799 2,801 1:81 2,116 2,122 1,972 2,043 1,918 1,891 2,358 2,358 1:243 1,214 1,297 1,104 1,153 1,069 1,080 1,551 1,544 1:729 0,571 0,566 0,499 0,528 0,469 0,464 0,717 0,705 0 0,056 0,059 0,055 0,056 0,056 0,056 0,056 0,093 Second goat anti-human IgG antibody (H+L), HRP (1:5000) EC50 (nM) 0.035 0.040 0.042 0.028 Table 3. Binding activity of 13E5 H4L2, 13E5 H4L4 and dupilumab to IL4RA-mFc antigen. Antibody dilution (μg / ml) Antigen: IL4RA-mFc 13E5 H4L2 13E5 H4L4 Dupilumab 0.333 2.733 2.772 2.798 2.879 2.850 2.893 1:3 2.730 2.775 2.766 2.730 2.676 2.673 Petition 870260061493, dated 06 / 23 / 2026, pp. 114 / 182 101 / 130 Antibody dilution (μg / ml) Antigen: IL4RA-mFc 13E5 H4L2 13E5 H4L4 Dupilumab 1:9 2.359 2.406 2.370 2.392 2.482 2.408 1:27 1.492 1.523 1.474 1.608 1.637 1.722 1:81 0.673 0.707 0.709 0.778 0.861 0.816 1:243 0.305 0.293 0.317 0.313 0.335 0.336 1:729 0.145 0.134 0.146 0.147 0.147 0.147 0 0.063 0.063 0.064 0.064 0.067 0.064 Second goat anti-human IgG antibody (H+L), HRP (1:5000) EC50 (nM) 0.079 0.079 0.066 1.2 The binding activity of antibodies 13E5, 13E5 H1L1, 13E5 H2L2, 13E5 H3L3, 13E5 H4L2, and 13E5 H4L4 to block the binding between IL4-NHIS and the IL4RA-HFC antigen was measured by competitive ELISA.

[219] The EC50 (average effect concentration) of 13E5, 13E5 H1L1, 13E5 H2L2, 13E5 H3L3, 13E5 H4L2 and 13E5 H4L4 to compete with the human IL4N-His ligand for binding to the human IL4RA-hFc antigen was tested by ELISA, then to investigate the activity of 13E5, 13E5 H1L1, 13E5 H2L2, 13E5 H3L3, 13E5 H4L2 and 13E5 H4L4 to block the binding of the ligand to the target human IL4RA-hFc antigen.

[220] ELISA plates were coated with human IL4RA-hFc and blocked before antibodies were added. An equal volume of human IL4-NHis (synthesized by Akeso, Inc.) was added, and the mixture was thoroughly mixed and incubated. After the plates were washed, mouse anti-His, HRP (acquired from CoWin Biosciences, Cat No. CW0285A), was added for incubation. The plates were subjected to another wash. The chromogenic reaction was initiated by the addition of TMB (Neogen, 308177) and then terminated. At the end of the reaction, the OD value at a wavelength of 450 nm was measured by a plate reader and analyzed and processed by SoftMax Pro 6.2.1. The results are shown in Tables 4, 5, and 6.

[221] By logistic regression of 4 absorbance parameters vs Petition 870260061493, dated 06 / 23 / 2026, pages 115 / 182 At a 102 / 130 antibody concentration, the EC50 of antibody blockade was calculated. As shown in Figures 4, 5, and 6, 13E5, 13E5 H1L1, 13E5 H2L2, 13E5 H4L2, and 13E5 H4L4 are all capable of effectively blocking the binding of human IL4N-His ligand to human IL4RA-hFc antigen in a dose-dependent manner. The antibodies 13E5 H1L1, 13E5 H2L2, 13E5 H4L2, and 13E5 H4L4 demonstrate superior activities in competing with human IL4N-His for binding to human IL4RA-hFc compared to the reference antibody dupilumab for the same antigen. Table 4. Assay of 13E5 and dupilumab activity to compete with human IL4N-HIS for binding to human IL4RA-HFC. Antibody dilution (pg / ml) Antigen: IL4RA-hFc 13E5 Dupilumab 3 0.053 0.053 0.054 0.052 1:3 0.093 0.100 0.074 0.076 1:9 0.790 0.832 0.837 0.877 1:27 1.080 1.095 1.056 1.123 1:81 1.108 1.164 1.100 1.149 1:243 1.120 1.199 1.126 1.126 1:729 1.125 1.129 1.076 1.158 0 1.136 1.156 1,123 1,093 IL4-N-his Second mouse anti-His antibody, HRP (1:4000) EC50 (nM) 3,000 3,033 Table 5. Assay of the activity of 13E5 H1L1, 13E5 H2L2, 13E5 H3L3 and dupilumab to compete with human IL4-N-HIS for binding to IL4RA-HFC. HUMAN Antibody dilution (pg / ml) Antigen: IL4RA-hFc 13E5 H1L1 13E5 H2L2 13E5 H3L3 Dupilumab 3 0.070 0.078 0.230 0.216 0.645 0.620 0.050 0.049 1:3 0.095 0.103 0.282 0.306 0.727 0.708 0.059 0.057 1:9 0.179 0.225 0.443 0.455 1.047 0.955 0.186 0.159 1:27 0.921 1.415 1.048 1.096 1.450 0.845 1.230 1.053 Petition 870260061493, dated 06 / 23 / 2026, pages 116 / 182 103 / 130 Antibody dilution (pg / ml) Antigen: IL4RA-hFc 13E5 H1L1 13E5 H2L2 13E5 H3L3 Dupilumab 1:81 1.468 2.037 1.562 1.543 1.705 1.686 1.680 1.546 1:243 1.705 2.157 1.776 1.888 1.932 1.846 1.774 1.743 1:729 1.746 2.182 1.792 1.845 2.060 1.933 1.889 1.841 0 1.793 2.243 1.741 1.776 2.056 1,912 1,828 1,806 IL4-N-his Second mouse anti-His antibody, HRP (1:4000) EC50 (nM) 0.875 0.819 0.636 0.943 Table 6. Assay of activity of 13E5 H4L2, 13E5 H4L4 and dupilumab for COMPETING WITH HUMAN IL4-N-HIS FOR BINDING TO HUMAN IL4RA-HFC Antibody dilution (pg / ml) Antigen: IL4RA-hFc 13E5 H4L2 13E5 H4L4 Dupilumab 3 0.056 0.059 0.054 0.051 0.054 0.057 1:3 0.068 0.065 0.053 0.052 0.052 0.053 1:9 0.202 0.197 0.228 0.274 0.292 0.308 1:27 0.697 0.780 0.752 0.786 0.771 0.871 1:81 0.996 0.991 0.903 1.030 0.971 0.966 1:243 1.082 1.047 1.030 1.135 1.050 1.073 1:729 0.964 0.988 0.950 0.978 0.918 0.964 0 0.935 0.960 0.932 0.898 0.896 0.956 IL4-N-his Second mouse anti-His antibody, HRP (1:4000) EC50 (nM) 1.150 1.328 1.546 2. Binding activity of murine antibody 18H7 and humanized antibodies 18H7 H1L1, 18H7 H2L2, 18H7 H2L3, 18H7 H3L2 and 18H7 H3L3 to IL-4RA-hFc antigens. 2.1 The binding activity of antibodies 18H7, 18H7 H1L1, 18H7 H2L2, 18H7 H2L3, 18H7 H3L2 and 18H7 H3L3 to human IL4RA-HFC or human IL4RA-mFc antigens was measured by indirect ELISA.

[222] Procedures: ELISA plates were coated with human IL4RA-hFc or human IL4RA-mFc and incubated, and the target antibodies Petition 870260061493, dated 06 / 23 / 2026, pp. 117 / 182 104 / 130 were added after blocking. Anti-mouse goat IgG (H+L) and HRP (acquired from Jackson ImmunoResearch Inc., Cat No. 109-035-062), or anti-human goat IgG and HRP (acquired from Jackson ImmunoResearch Inc., Cat No. 109035-088) were added. Plates were incubated and washed before the addition of TMB (Neogen, 308177) for the chromogenic reaction. 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.

[223] Readings at 450 nm show that antibodies 18H7, 18H7 H1L1, 18H7 H2L2, 18H7 H2L3, 18H7 H3L2 and 18H7 H3L3 are all capable of effectively binding to human IL4RA-hFc or human IL4RA-mFc antigens in a dose-dependent manner. By 4-parameter absorbance vs. logistic regression Based on antibody concentration, as shown in Tables 7 and 8, 18H7, 18H7 H1L1, 18H7 H2L2, 18H7 H2L3, 18H7 H3L2, and 18H7 H3L3 are all capable of effectively binding to human IL4RA-hFc or human IL4RA-mFc antigens, and antibodies 18H7 H1L1, 18H7 H2L2, and 18H7 H2L3 demonstrate binding activities comparable to those of the reference antibody dupilumab against the same target (Figures 7 and 8). Table 7. Binding activity of 18H7 and dupilumab to human IL4RAhFc or human IL-4 RA-mFc antigens. Antibody dilution (μg / ml) Antigen (1 μg / ml) IL-4RA-hFc IL-4RA-mFc 18H7 Dupilumab 0.333 2.239 2.219 2.758 2.858 1:3 2.065 2.128 2.748 2.801 1:9 1.913 1.867 2.388 2.500 1:27 1.278 1.333 1.469 1.679 1:81 0.640 0.650 0.599 0.673 1:243 0.276 0.302 0.250 0.281 1:729 0.132 0.137 0.126 0.137 0 0.051 0.053 0.076 0.069 According to goat anti-mouse IgG (H+) goat anti-human IgG (H+L), Petition 870260061493, dated 06 / 23 / 2026, pages 118 / 182 105 / 130 Antibody dilution (μg / ml) Antibody Antigen (1 μg / ml) IL-4RA-hFc IL-4RA-mFc 18H7 Dupilumab L), HRP (1:5000) HRP (1:5000) EC50(nM) 0.068 0.077 Table 8: Binding activity of 18H7 H1L1, 18H7 H2L2, 18H7 H2L3, 18H7 H3L2, 18H7 H3L3 and dupilumab to IL4RA-mFc antigen Antibody dilution o ^g / ml) Antigen:IL-4RA-mFc 18H7 H1L1 18H7 H2L2 18H7 H2L3 18H7 H3L2 18H7 H3L3 Dupilumab 0.333 2.68 3 2.66 6 2.70 2.75 0 2.84 8 2.86 2 2.94 3 1.72 9 1.70 4 2.97 2 3.04 2 1:3 2.63 0 2.61 6 2.61 1 2.59 5 2.72 6 2.67 5 2.69 2.63 3.63 1.27 9 2.98 9 3.05 7 1:9 2.22 6 2.10 1 2.15 3 2.17 4 2.15 0 2.18 5 2.19 7 2.23 5 0.71 9 0.74 4 2.65 2.74 2.74 1.44 1 1.37 3 1.40 1 1.38 2 1.43 9 1.43 7 1.42 9 1.41 0 0.29 1 0.30 8 1.74 3 1.81 5 1:81 0.68 2 0.57 50.62 3.62 0.67 7 0.67 9 0.68 5 0.70 8 0.13 9 0.13 4 0.84 7 0.89 6 1:243 0.28 2 0.22 3 0.25 7 0.25 3 0.28 0.29 0.29 0.39 5 0.08 5 0.08 6 0.32 9 0.35 8 1:729 0.13 3 0.11 5 0.12 7 0.12 4 0.13 8 0.14 3 0.14 6 0.15 0 0.07 0.07 0.06 8 0.06 7 0.16 5 0 0.05 9 0.06 2 0.06 0 0.06 2 0.05 9 0.06 3 0.06 2 0.05 9 0.06 5 0.06 3 0.06 8 0.06 3 Second goat anti-human IgG antibody (HRPH), (1:5000) EC50 (nM) 0.087 0.087 0.094 0.100 0.446 0.067 2.2 Activity of antibodies 18H7, 18H7 H1L1, 18H7 H2L2, 18H7 H2L3 and 18H7 H3L2 to block the binding between IL4-N-his and the IL4RA-hFc antigen by competitive ELISA.

[224] The EC50 (median effect concentration) of 18H7, 18H7 H1L1, 18H7 H2L2, 18H7 H2L3 and 18H7 H3L2 to compete with the human IL4-N-His ligand for binding to the human IL4RA-hFc antigen was tested by ELISA in order to investigate the activity of 18H7, 18H7 H1L1, 18H7 H2L2, 18H7 H2L3 and 18H7 H3L2 to Petition 870260061493, dated 06 / 23 / 2026, pp. 119 / 182 106 / 130 block ligand binding to target antigen human IL4RA-hFc.

[225] ELISA plates were coated with human IL4RA-hFc and blocked before antibodies were added. An equal volume of human IL4-N-His (synthesized by Akeso, Inc., an IL4 connected with 6 His markers at the N-terminus) was added, and the mixture was thoroughly mixed and incubated. After the plates were washed, mouse anti-His, HRP (acquired from CoWin Biosciences, Cat No. CW0285M) was added for incubation. The plates were subjected to another wash. The chromogenic reaction was initiated by the addition of TMB (Neogen, 308177) and then terminated. At the end of the reaction, the OD value at a wavelength of 450 nm was measured by a plate reader and analyzed and processed by SoftMax Pro 6.2.1. The results are shown in Tables 9 and 10.

[226] By logistic regression of 4 absorbance parameters vs antibody concentration, the blocking EC50 of the antibodies was calculated. As shown in Figures 9 and 10, 18H7, 18H7 H1L1, 18H7 H2L2 and 18H7 H3L2 are all capable of effectively blocking the binding of human IL4-NHis ligand to human IL4RA-hFc antigen in a dose-dependent manner. The antibodies 18H7 H1L1, 18H7 H2L2 and 18H7 H3L2 demonstrate superior activities to compete with human IL4-NHis for binding to human IL4RA-hFc compared to that of the reference antibody dupilumab for the same antigen. Table 9. Assay of 18H7 and dupilumab activity in competition with human IL4N-HIS for binding to human IL4RA-HFC. Antibody dilution (μg / ml) Antigen: IL4RA-hFc (2 μg / ml) 18H7 Dupilumab 3 0.046 0.045 0.054 0.052 1:3 0.051 0.053 0.074 0.076 1:9 0.704 0.722 0.837 0.877 1:27 1.047 1.055 1.056 1.123 Petition 870260061493, dated 06 / 23 / 2026, pages 120 / 182 107 / 130 Antibody dilution (pg / ml) Antigen: IL4RA-hFc (2 pg / ml) 18H7 Dupilumab 1:81 1.117 1.144 1.100 1.149 1:243 1.113 1.162 1.126 1.126 1:729 1.097 1.115 1.076 1.158 0 1.157 1.127 1.123 1.093 IL-4-N-his: 0.15 pg / ml Second antibody Mouse anti-His, HRP (1:4000) EC50 (nM) 2.714 3.033 Table 10. Activity assay of 18H7 H1L1, 18H7 H2L2, 18H7 H2L3, 18H7 H3L2 and dupilumab compete with human IL4-N-His for binding to IL4RA-HFC HUMAN Antibody dilution (pg / ml) Antigen: IL4RA-hFc (2 pg / ml) 18H7 H1L1 18H7 H2L2 18H7 H2L3 18H7 H3L2 Dupilumab 3 0.053 0.051 0.057 0.061 0.781 0.806 0.183 0.184 0.086 0.079 1:3 0.051 0.054 0.074 0.083 0.956 1.011 0.280 0.279 0.127 0.126 1:9 0.564 0.735 0.985 1.072 1.439 1.388 1.036 1,100 1,326 1,341 1:27 1,599 1,671 1,835 1,785 1,840 1,775 1,761 1,673 1,887 1,947 1:81 1,839 1,884 1,939 2,009 1,971 1,926 1,947 1,964 2,029 2,059 1:243 1,938 1,993 2,037 2,055 2,086 2,057 1,960 1,946 2,079 2,049 1:729 1,979 1,995 2,101 2,043 2.048 2.002 1.975 1.948 2.039 2.029 0 1.919 1.991 2.063 2.024 2.096 1.973 1.928 1.938 2.034 1.975 IL-4-N-his: 0.15 pg / ml Second mouse anti-His antibody, HRP (1:4000) EC50 (nM) 1.655 2.297 2.513 2.329 2.800 3. Binding activity of humanized antibodies 20G10 H3L3 and 13E5 H4L4 to the IL-4RA-hFc antigen 3.1 The activity of antibodies 20G10 H3L3 and 13E5 H4L4 in blocking the binding of IL4-N-His to the IL4RA-hFc antigen was measured by competitive ELISA.

[227] The EC50 (median effect concentration) of 20G10 H3L3 and Petition 870260061493, dated 06 / 23 / 2026, pp. 121 / 182 108 / 130 The ability of 13E5 H4L4 to compete with the human IL4-N-His ligand for binding to the human IL4RA-hFc antigen was tested by ELISA in order to investigate the activity of 20G10 H3L3 and 13E5 H4L4 in blocking ligand binding to the target antigen human IL4RA-hFc.

[228] ELISA plates were coated with human IL4RA-hFc and blocked before antibodies were added. An equal volume of human IL4-N-His (synthesized by Akeso, Inc.) was added, and the mixture was thoroughly mixed and incubated. After the plates were washed, mouse anti-His, HRP (acquired from CoWin Biosciences, Cat No. CW0285A) was added for incubation. The plates were subjected to another wash. The chromogenic reaction was initiated by the addition of TMB (Neogen, 308177) and then terminated. At the end of the reaction, the OD value at a wavelength of 450 nm was measured by a plate reader and analyzed and processed by SoftMax Pro 6.2.1. The results are shown in Table 11.

[229] By logistic regression of 4 absorbance parameters vs antibody concentration, the blocking EC50 of the antibodies was calculated. As shown in Figure 11, 20G10 H3L3 and 13E5 H4L4 are both capable of effectively blocking the binding of human IL4-N-His ligand to human IL4RA-hFc antigen in a dose-dependent manner. The 20G10 H3L3 and 13E5 H4L4 antibodies demonstrate superior activities to compete with human IL4-NHis for binding to human IL4RA-hFc compared to the reference antibody dupilumab for the same antigen. Table 11. Assay of activity of 20G10 H3L3, 13E5 H4L4 and dupilumab in Competition with human IL4-N-His for binding to human IL4RA-HFC Antibody dilution (μg / ml) Antigen: IL4RA-hFc (2 μg / ml) 20G10 H3L3 13E5 H4L4 Dupilumab 3 0.093 0.082 0.065 0.074 0.059 0.059 1:3 0.099 0.094 0.097 0.071 0.059 0.060 1:9 0.199 0.212 0.123 0.119 0.201 0.197 Petition 870260061493, dated 06 / 23 / 2026, pages 122 / 182 109 / 130 Antibody dilution (pg / ml) Antigen: IL4RA-hFc (2 pg / ml) 20G10 H3L3 13E5 H4L4 Dupilumab 1:27 0.701 0.693 0.554 0.594 0.853 0.948 1:81 0.948 1.001 0.944 0.976 1.241 1.287 1:243 1.118 1.131 1.137 1.200 1.443 1.400 1:729 1.210 1.180 1.252 1.269 1.534 1.441 0 1.295 1.274 1.328 1.349 1,559 1,482 IL4-N-his: 0.15 pg / ml Second mouse anti-His antibody, HRP (1:4000) EC50 (nM) 0.742 0.532 0.865 Example 8. Assay of the affinity constant of humanized antibodies 13E5 H1L1, 13E5 H2L2, 13E5 H3L3, 13E5 H4L2, 13E5 H4L4, 18H7 H1L1, 18H7 H2L2 and 18H7 H3L2 for human IL-4RA.

[230] Using the Fortebio molecular interaction instrument, the affinity constant of the humanized antibodies 13E5H 1L1, 13E5H 2L2, 13E5 H3L3, 13E5H 4L2, 13E5H 4L4, 18H7 H1L1, 18H7 H2L2, 18H7 H3L2 and dupilumab for binding to human IL-4RA was measured.

[231] 5 μg / ml of antigen was immobilized on the AMC sensor by 60 s incubation. The sensor was then equilibrated in PBST for 300 s and incubated for 120 s in antibodies at 0.39 to 25 nM (two-fold serial dilution) to bind the antibodies to the antigen immobilized on the sensor. The remaining antibodies were dissociated from the antigen by a 600-second incubation in PBST. The sensor was refreshed in 10 mM glycine, pH 1.7. Data were analyzed by 1:1 model fitting to obtain affinity constants.

[232] The affinity constants of the humanized antibodies 13E5 H4L4, 18H7 H1L1 and dupilumab (reference) for human IL4RA are shown in Table 12 and Figures 12-14. Table 12. Assay of the affinity constant of 13E5 H4L4, 18H7 H1L1 and dupilumab for human IL4RA. Name Kd(M) kon (1 / Ms) Error kon kdis (1 / s) Error kdis Rmax (nm) 13E5 H4L4 2.63E-11 5.56E + 06 1.60E + 1.46E-04 9.74E-06 0.1370-0.1667 Petition 870260061493, dated 06 / 23 / 2026, pages 123 / 182 110 / 130 Name Kd(M) kon (1 / Ms) Error kon kdis (1 / s) Error kdis Rmax (nm) 05 18H7 H1L1 3.09E-11 4.97E+06 1.94E+05 1.54E-04 1.33E-05 0.1026-0.1445 Dupilumab 1.14E-11 7.08E+06 2.15E+05 8.10E-05 1.13E-05 0.1325-0.2184 Kdó is the affinity constant; Kd= kdis / kon.

[233] The results show that humanized antibodies 13E5 H4L4, 18H7 H1L1, and human IL4RA have high target antigen binding capabilities, comparable to those of the reference antibody dupilumab.

[234] The affinity constants of the humanized antibodies 13E5 H1L1, 13E5 H2L2, 13E5 H3L3, 13E5 H4L2, 18H7 H2L2, 18H7 H3L2 and dupilumab (reference) for human IL-4RA are shown in Table 13 and Figures 15-21. Table 13. Affinity constant assay of 13E5 H1L1, 13E5 H2L2, 13E5 H3L3, 13E5 H4L2, 18H7 H2L2, 18H7 H3L2 and dupilumab for IL4RA HUMAN Antibody Kd(M) kon (1 / Ms) Error kon kdis (1 / s) Error kdis Rmax (nm) 13E5 H1L1 1.00E-11 5.78E + 06 1.94E + 05 5.79E-05 1.12E-05 0.1347-0.2008 13E5 H2L2 2.83E-11 2.44E + 06 9.77E + 04 6.90E-05 1.44E-05 0.1377-0.1944 13E5 H3L3 1.82E-11 2.79E + 06 1.46E + 05 5.09E-05 1.90E-05 0.0824-0.1332 13E5 H4L2 1.79E-11 1.78E + 07 1.16E + 06 3.18E-04 2.15E-05 0.0521-0.1012 18H7 H2L2 2.39E-11 6.47E + 06 2.63E + 05 1.54E-04 1.60E-05 0.0913-0.117 18H7 H3L2 1.71E-11 1.27E + 06 5.38E + 04 2.16E-05 1.44E-05 0.1731-0.3601 Dupilumab 1.17E-11 2.35E + 06 1.68E+05 2.75E-05 1.73E-05 0.2131-0.3131 Kdó is the affinity constant; Kd = kdis / kon.

[235] The result shows that the affinity of the humanized antibody The binding of 13E5 H1L1 to the antigen is superior to that of the reference antibody dupilumab; the dissociation rate constants kdis of 13E5 H1L1, 13E5 H2L2, 18H7 H2L2, and 18H7 H3L2 with human IL-4RA were lower than that of the reference antibody dupilumab, suggesting more stable binding of 13E5 H2L2 and 18H7 H2L2. Petition 870260061493, dated 06 / 23 / 2026, pp. 124 / 182 111 / 130 and 18H7 H3L2 for human IL-4RA. The association rate constants of 13E5 H1L1 and 13E5 H4L2 with the human IL-4RA antigen are higher than those of the reference antibody dupilumab, suggesting a faster binding of 13E5 H1L1 and 13E5 H4L2 to the human IL-4RA antigen than dupilumab. Example 9. Cellular bioactivity assay

[236] The cellular bioactivity of 13E5 H1L1, 13E5 H2L2, 13E5 H4L2, 13E5 H4L4, 18H7 H1L1 and 18H7 H2L2 to inhibit human IL-4 / IL-13-induced TF-1 cell proliferation was analyzed. The procedures are as follows.

[237] TF-1 cells (acquired from the American Type Culture Collection, Cat. No. CRL-2003) were cultured (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 a medium without GM-CSF, and counted. Cells were inoculated into 96-well plates at 20,000 cells / well. Treatment was administered as planned: final antibody concentrations were 0.05, 0.5, and 5 nM; three concentrations of 0.041, 0.41, and 4.1 nM were established for IL-4, and the antibody group employed 0.41 nM of IL-4; Three concentrations of 1.58, 15.8, and 79 nM were established for IL-13, and the antibody panel employed 15.8 nM of IL-13. After administration, the 96-well plates were incubated in a 5% carbon dioxide incubator at 37 °C for 72 h. After 72 hours, the CCK8 reagent was added according to the instructions of the CCK8 kit (purchased from Dojindo Laboratories, Japan, Cat No. CK04).The mixture was thoroughly mixed, incubated at 37 °C for 3–4 hours in a 5% carbon dioxide incubator, and the OD value at 450 nm was read. An OD vs. cell number curve was plotted by seeding diluted TF-1 cells serially in 96-well plates, adding CCK8 reagent, incubating the plates in a 5% carbon dioxide incubator at 37 °C for 3–4 hours, and reading the OD value at 450 nm. The cell numbers of the groups were calculated according to the OD value, and GraphPad Prism 5 was used for plotting. Petition 870260061493, dated 06 / 23 / 2026, pp. 125 / 182 112 / 130

[238] The reference antibody isotype was human anti-chicken egg lysozyme IgG (anti-HEL) derived from the variable region of the Fab F10.6.6 sequence. Affinity maturation increases the stability and plasticity of the Fv domain of anti-protein antibodies (Acierno et al., J Mol Biol., 2007, 374 (1): 13046). The isotype was synthesized by Akeso, Inc.

[239] Nanjing Genscript Biology was tasked with codon optimization and gene synthesis for the heavy and light chain genes (full sequence or variable region) of human IgG antibodies. With reference to Molecular Cloning: A Laboratory Manual (Second Edition), the heavy and light chain genes were subcloned into antibody heavy and light chain expression vectors (both were pcDNA3.1 vectors) for the mammalian expression system by standard molecular cloning techniques such as PCR, enzymatic digestion, DNA gel electrophoresis, ligation and transformation, colony PCR, or digestion and identification. The heavy and light chain genes of the recombinant expression vector were subsequently sequenced and analyzed (heavy and light chain sequences are presented in SEQ ID NOs: 122 and 123).After the sequence was verified as correct, endotoxin-free expression plasmids were prepared on a large scale, and the heavy and light chain plasmids were transiently co-transfected into HEK293 cells for recombinant antibody expression. After 7 days of culture, the cell culture medium was collected and purified by affinity using a Protein A (GE) column, and the quality of the resulting antibody sample was determined using SDS-PAGE and standard SEC-HPLC analytical techniques.

[240] The results are shown in Figures 22-27. As can be seen in Figures 22-27, both human IL-4 and human IL-13 are able to effectively promote TF-1 cell proliferation in a dose-dependent manner; compared with the reference isotype antibodies (human IgG), dupilumab, 13E5 H1L1, 13E5 H2L2, 13E5 H4L2, 13E5 H4L4, 18H7 Petition 870260061493, dated 06 / 23 / 2026, pp. 126 / 182 113 / 130 H1L1 and 18H7 H2L2 can specifically inhibit IL-4 and IL-13-induced TF-1 cell proliferation in a dose-dependent manner.

[241] The results show that 13E5 H1L1, 13E5 H2L2, 13E5 H4L2, 13E5 H4L4, 18H7 H1L1 and 18H7 H2L2 can specifically inhibit human IL-4 and human IL-13 induced TF-1 cell proliferation; antibodies 13E5 H1L1, 13E5 H4L4 and 18H7 H1L1 demonstrate activities comparable to the reference antibody dupilumab. Example 10. 13E5H4L4 and 18H7H1L1 inhibiting the upregulation of CD23 expression in PBMCS.

[242] This example aimed to examine the bioactivity of 13E5 H4L4 and 18H7 H1L1 to counteract the upregulation of CD23 expression on the surface of human PBMCs induced by human IL-4 and human IL-13 by means of flow cytometry. The procedures are as follows.

[243] Normal human peripheral blood (with heparin) was separated by Ficoll density gradient centrifugation to give fresh human PBMCs. After 3 centrifugations and washes, the cells were counted and the density adjusted to 2.5 χ 106 cells / ml. The cells were seeded in 96-well low-fixation plates at 200 μL of PBMCs per well (i.e., 500,000 cells / well); 25 μL of dupilumab antibodies, 13E5 H4L4 or 18H7 H1L1 (at final concentrations of 30, 3 and 0.3 nM, respectively) were added to each well, and the blank control reference and the human IgG isotype reference (at a final concentration of 30 nM) were set. The cells were incubated at room temperature for 30 min. After 30 min, 25 μI of human IL-4 (final concentration of 100 pM) or 25 μI 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, the PBMCs were separated and transferred to 1.5 ml EP tubes, supplemented with 500 μL of 1% PBSA, and centrifuged at 1000 χ² g for 5 min. The supernatant was discarded, and the residue was supplemented with 50 μL of CD23-PE antibody. Petition 870260061493, dated 06 / 23 / 2026, pp. 127 / 182 114 / 130 (diluted 50 times with 1% PBSA) and incubated on ice for 40 min. After incubation for 40 min, the system was supplemented with 1 ml of 1% PBSA and centrifuged at 1000 χ²g for 5 min before the supernatant was discarded. The cells were resuspended in 200 μL of 1% PBSA and transferred to a flow cytometry tube for assay.

[244] The results are shown in Figures 28 and 29.

[245] The results show that human IL-4 and human IL-13 can upregulate the CD23 expression level on the surface of human PBMCs, and 13E5 H4L4 and 18H7 H1L1 can specifically bind to human IL4RA, effectively blocking the upregulation of CD23 expression level by IL-4 and IL-13. Example 11. Effect of 13E5 H4L4 in the B-hIL4Ra mouse model with HDM-induced skin inflammation.

[246] The procedures are as follows: A B-hIL4Ra (background C57BL / 6) mouse skin inflammation model was established by induction with HDM (human dust mite allergen, Greer Laborct, lot No. 348717). Mice were divided into 6 groups of 7 mice each, including an isotype reference group (anti-HEL), a high-dose dupilumab group (80 mg / kg; commercially available dupilumab from Sanofi and Regeneron Pharmaceuticals) and a low-dose group (20 mg / kg; commercially available as Dupilumab from Sanofi and Regeneron Pharmaceuticals), a high-dose 13E5 H4L4 group (80 mg / kg) and a low-dose group (20 mg / kg). Treatment was administered by subcutaneous injection on D-1, D2, D5, and D8. In the normal group, the animal model was established by daily intradermal injection of normal saline solution.In the reference isotype group, the animal model was established with daily intradermal injection of HDM (37.5 μg χ² / 25 μI / day) for 7 days and daily intradermal injection of HDM (25 μg χ² / 25 μI / day) for 3 days. In the antibody treatment groups, the animal model was established with injection. Petition 870260061493, dated 06 / 23 / 2026, pages 128 / 182 115 / 130 daily intradermal injection of HDM (37.5 μg χ 2 / 25 μI / day) for 7 days and daily intradermal injection of HDM (25 μg χ 2 / 25 μI / day) for 3 days.

[247] The epidermal thickness of mice was measured to investigate the effect of 13E5 H4L4 on epidermal thickness inhibition in the B-hIL4Ra mouse skin inflammation model. Table 14. Dosage and regimen Group n Animal model Treatment Normal group 7 Normal saline solution, 25 μI / day on D0-D9, intradermal injection, daily Normal saline solution, subcutaneous injection, D-1, D2, D5 and D8 hIgG4 (i.e., anti-HEL) 7 HDM, 37.5 μg χ 2 / 25 μI / day, D0-D6; 25 μg χ² / 25 μl / day, D7-D9, daily intradermal injection Anti-HEL, 80 mg / kg, subcutaneous injection, D-1, D2, D5 and D8 Dupilumab 80 mg / kg 7 Dupilumab, 80 mg / kg, subcutaneous injection, D-1, D2, D5 and D8 Dupilumab, 20 mg / kg 7 Dupilumab, 80 mg / kg, subcutaneous injection, D-1, D2, D5 and D8 13E5 H4L4, 80 mg / kg 7 13E5 H4L4, 80 mg / kg, subcutaneous injection, D-1, D2, D5 and D8 13E5 H4L4, 20 mg / kg 7 13E5 H4L4, 20 mg / kg, subcutaneous injection, D-1, D2, D5 and D8

[248] Note: D0 is the first day of model establishment. Normal saline and HDM were administered to the upper right back and lower right back, respectively. The results are shown in Figure 30. Compared to the hIgG4 isotype reference antibody, 13E5 H4L4 at different doses can effectively inhibit epidermal thickening, and the blood concentration of 13E5 H4L4 is higher than that of dupilumab at 80 mg / kg, which corresponds to efficacy.

[249] Pathological sections are shown in Figure 31: in the B-hIL4Ra mouse skin inflammation model established by 37.5 μg + 25 μg HDM intradermal injection, the epidermal thickness in the model group is significantly thickened compared to that of the normal group, Petition 870260061493, dated 06 / 23 / 2026, pp. 129 / 182 116 / 130 Epidermal thickening in mice can be significantly inhibited by dupilumab 80 mg / kg and 13E5 H4L4 with subcutaneous injections of 80 mg / kg with a good dose-response relationship. 13E5 H4L4 80 mg / kg is slightly superior to dupilumab 80 mg / kg.

[250] Preferred embodiments of the present invention have been described above in detail, but the present invention is not limited to embodiments. Those skilled in the art may make various equivalent modifications or substitutions without violating the spirit of the present invention. These equivalent modifications or substitutions are included within the scope defined by the claims of the present application. Sequence Listing

[251] 13E5 heavy chain variable region: GAGGTGCAGCTGCAGCAGAGCGGACCAGCTGGTGAAGGC CTGGCGCCTCTGTGAAGATCAGCTGTAAGACCTCCGGCTACACCTTCACA GAGTATACAATCCACTGGGTGAAGCAGAACCACGGCAAGAGCCTGGAGTG GATCGGCGGCATCAATCCTAACCAATGCCAGCCAGCCAGCCAACT TCAAGGGCAAGGCCACCCTGACAGTGGACAAGAGCTCCTCTACCGCCTAT ATGGAGCTGAGGTCTCTGACAAGCGAGGACTCCGCCGTGTACTATTGCGC CAGAGTGCGGAGAGGCATGGATTACTGGGGCCAGGGCACCTCCGTGACA GTGAGCTCC (SEQ ID NO: 1); and EVQLQQSGPELVKPGASVKISCKTSGYTFTEYTIHWVKQNHGKS LEWIGGINPNNGGTVYNQNFKGKATLTVDKSSSTAYMELRSLTSEDSAVYYCA RVRRGMDYWGQGTSVTVSS (SEQ ID: 2).

[252] Light chain variable region 13E5: GACATCGTGATGACCCAGTCCCACAAGTTTATGTCCACATCT GTGGGCGACAGGGTGTCCATCACCCTGTAAGGCCTCTCAGGATGTGACCAC AGCCGTGGCCTGGTACCAGCAGAAGCCAGGCCAGTCTCCCAAGCTGCTG Petition 870260061493, of 23 / 06 / 2026, p. 130 / 182 117 / 130 CTCTGGCAGCGGCACAGATTTCACCTTTACAATCAAGCTCCGTGCAGGCAG AGGACCTGGCCGTGTACTATTGCCAGCAGCACTACTCTGCCCCTTGGACC TTCGGCGGAGGAACAAACCTGGAGATCAAG (SEQ ID NO: 3); and DIVMTQSHKFMSTSVGDRVSITCCASQDVTTAVAWYQQKPGQS PKLLIYSASYRYTGVPDRFTGSGSGTDFTFTISSVQAEDLAVYYCQQHYSAPW TFGGGTNLEIK (SEQ ID NO: 4).

[253] 18H7 heavy chain variable region: GATGTGAAGCTGGTGGAGTCCGGCGGCGACCTGGTGAACCT GGGCGGAAGCCTGAAGCTGAGCTGTGCCGCCAGCGGCTTCACATTTTCCT CCAGCTACATGAGCTGGGTGAGGCAGACCCGAGAGGAGACTGGAGCT GGTGGCCGCCATCAACAGCAGAGGAGGAGACTGGAGCT TGAAGGGCAGATTCCACCATCAGCAGGGACAACGCCAAGAACACCCTGTAC CTGCAGATGTCCGGCCTGAAGACAGAGGACAGCCCTGTACTACTGCAC CAGGCAGAGGGGCAACTACGTGGGCGCCATGGACTACTGGGGCCAGGG CACAAGCGTGACCGTGAGCC (SEQ ID NOQ: 5); and DVKLVESGGDLVNLGGSLKLSCAASGTFFSSSYMSWVRQTPER RLELVAAINSNGGKTYYPDTVKGRFTISRDNAKNTLYLQMSGLKTEDTALYYC TRQRGNYVGAMDYWGQGTSVTVSS (SEQ ID NO: 6).

[254] Light chain variable region 18H7: GACATCGTGATGACACAGTCCCACAAGTTTATGTCCACATCC GTGGGCGATAGGGTGTCCATCACATGCAAGGCCAGCCAGGACGTGAGCA CAGCCGTGGTGTGGTACCAGCAGAAGCCTGGCCAGAGCCCCACCCTGCT GATCTACTCCGCCAGCTACAGGTACACAGGCGTGCCTGACAGATTCACAG GCTCCGGCAGCGGCACCGATTTCACCTTTACCATCTCCTCCGTGCAGGCC GAGGATCTGGCCGTGTACTACTGCCACCAGTACTACGGCAGCCCCCCCAC ATTCGGCGGCGGAACAAAGCTGGAGATCAAG (SEQ ID NO: 7); e DIVMTQSHKFMSTSVGDRVSITCKASQDVSTAVVWYQQKPGQS PTLLIYSASYRYTGVPDRFTGSGSGTDFTFTISSVQAEDLAVYYCHQYYGSPP Petition: 870260061493, on 06 / 23 / 2026, page. 131 / 182 118 / 130 TFGGGTKLEIK (SEQ ID NO: 8).

[255] 13E5 CDR: HCDR1: GYTFTEYT (SEQ ID NO: 9); HCDR2: INPNNGGT (SEQ ID NO: 10); HCDR3: ARVRRGMDY (SEQ ID NO: 11); LCDR1: QDVTTA (SEQ ID NO: 12); LCDR2: SAS (SEQ ID NO: 13); e LCDR3: QQHYSAPWT (SEQ ID NO: 14).

[256] 18H7 CDR: HCDR1: GFTFSSSY (SEQ ID NO: 15); HCDR2: INSNGGKT (SEQ ID NO: 16); HCDR3: TRQRGNYVGAMDY (SEQ ID NO: 17); LCDR1: QDVSTA (SEQ ID NO: 18); LCDR2: SAS (SEQ ID NO: 19); and LCDR3: HQYYGSPPT (SEQ ID NO: 20).

[257] Variable region of heavy chain 13E5 H1: CAGGTGCAGCTGCAGCAGTCCGGAGCAGGTGGTGAAGC CAGGAGCCAGCGTGAAGATCTCCTGTAAGACCTCTGGCTACACCTTCACA GAGTATACAATCCACTGGGTGAAGCAGGCACACGGACAGAGCCTGGAGT GGATCGGCGGCATCAACCCTAACAATGGCGGCACCGTGTACAATCAGAAG TTTCAGGGCAAGGCCACCCTGACAGTGGACAAGTCTACCAGCACAGCCTA TATGGAGCTGAGGTCCCTGACCTCTGAGGACACAGCCGTGTACTATTGCG CCCGGGTGCGGAGAGGCATGGATTACTGGGGCCAGGGCACCTCCGTGAC AGTGAGCTCC (SEQ ID NO: 21); and QVQLQQSGAEVVKPGASVKISCKTSGYTFTEYTIHWVKQAHGQ SLEWIGGINPNNGGTVYNQKFQGKATLTVDKSTSTAYMELRSLTSEDTAVYYC ARVRRGMDYWGQGTSVTVSS (SEQ ID NO: 22).

[258] Variable region of the 13E5 L1 light chain: Petition 870260061493, dated 06 / 23 / 2026, pp. 132 / 182 119 / 130 GACATCCAGATGACCCAGTCTCCTAAGTCTCTGAGCACATCC GTGGGCGACCGGGTGACCATCACATGTAGAGCCAGCCAGGATGTGACCA CAGCAGTGGCATGGTACCAGCAGAAGCCTGGCAAGTCCCCTAAGCTGCTG CTCTGGCAGCGGCACAGACTTCACCTTTACAATCAGCTCCGTGCAGCCAG AGGATCTGGCCACCTACTATTGCCAGCAGCACTACAGCGCCCCATGGACC TTTGGCGGAGGAACAAACCTGGAGATCAAG (SEQ ID NO: 23); e DIQMTQSPKSLSTSVGDRVTITCRASQDVTTAVAWYQQKPGKS PKLLIYSASYRYTGVPSRFSGSGSGTDFTFTISSVQPEDLATYYCQHYSAPW TFGGGTNLEIK (SEQ ID NO: 24).

[259] Heavy chain variable region 13E5 H2: CAGGTGCAGCTGGTGCAGTCCGGAGCAGAGGTGGTGAAGC CAGGAGCCAGCGTGAAGGTGTCCTGTAAGACCTCTGGCTACACCTTCACA GAGTATACAATCCACTGGGTGCGGCAGGCACCAGGACAGTCTCTGGAGTG GATCGGCGGCATCAACCCTAACAATGGGGCCACCAGATCCA TTCAGGGCAAGGTGACCCTGACAGTGGACAAGTCCACCTCTACAGCCTAT ATGGAGCTGAGCTCCCTGAGGTCTGAGGACAGCCGTGTACTATTGCGC CCGCGTGCGGAGAGGCATGGATTACTGGGGCCAGGGCACCAGCGTGACA GTGTCTAGC (SEQ ID NO: 25); and QVQLVQSGAEVVKPGASVKVSCCTGYTFTEYTIHWVRQAPGQ SLEWIGGINPNNGGTNYNQFQGKVTLTVDKSTSTAYMELSSLEDTAVYY CARVRRGMDYWGQGTSVTVSS (SEQ ID NO: 26).

[260] Light chain variable region 13E5 L2: GACATCCAGATGACCCAGAGCCCTAGCTCCCTGAGCGCCTC CGTGGGCGACAGGGTGACCATCACATGTAGAGCCTCCCAGGATGTGACC ACAGCAGTGGCATGGTACCAGCAGAAGCCAGGCAAGGCCCCTAAGCTGC TGATCTACTCCGCCTCTAGCAGGTATACCGGAGTGCCCTCTGCTCTGGTC GCAGCGGCTCCGGCACAGACTTTACCCTGACAATCTCCCTCTGTGCAGCCA Petition 870260061493, of 23 / 06 / 2026, p. 133 / 182 120 / 130 GAGGATCTGGCCACATACTATTGCCAGCAGCACTATTCTGCCCCCTGGAC CTTTGGCGGCGGCACAAACCTGGAGATCAAG (SEQ ID NO: 27); e DIQMTQSPSSLSASVGDRVTITCRASQDVTTAVAWYQQKPGKA PKLLIYSASSRYTGVPSRFSGSGSGTDFTLTISSVQPEDLATYYCQQHYSAPW TFGGGTNLEIK (SEQ ID NO: 28).

[261] Heavy chain variable region 13E5 H3: CAGGTGCAGCTGGTGCAGTCCGGAGCAGGGTGGTGAAGC CAGGAGCCAGCGTGAAGGTGTCCTGTAAGGCCTCTGGCTACACCTTCACA GAGTATACCATCCACTGGGTGCGGCAGGCAGCACCAGGAGGGACTGGAGT GGATCGGCGGCATCAACCCTAACAATGGCGCCCAGAAT TTTCAGGGCAGGGTGACCATCACAGTGGACAAGTCCACCTCTACAGCCTA TATGGAGCTGAGCTCCCTGAGGTCTGAGGACACCGCCGTGTACTATTGCG CCCGCGTGCGGAGAGGCATGGATTACTGGGGCCAGGGCACCAGCGTGAC AGTGTCTAGC (SEQ ID NO: 29); and QVQLVQSGAEVVKPGASVKVSCKASGYTFTEYTIHWVRQAPGQ GLEWIGGINPNNGGTNYAQKFQGRVTITVDKSTAYMELSSLRSEDTAVYYC ARVRRGMDYWGQGTSVTVSS (SEQ ID NO: 30).

[262] Light chain variable region 13E5 L3: GACATCCAGATGACCCAGAGCCCTAGCTCCCTGAGCGCCTC CGTGGGCGACAGGGTGACCATCACATGTAGAGCCTCCCAGGATGTGACC ACAGCCCTGGCATGGTACCAGCAGAAGCCAGGCAAGGCCCCTAAGCTGC GCAGCGGCTCCGGCACAGACTTTACCCTGACAATCTCCCTCTCTGCAGCCA GAGGATTTCGCCACATACTATTGCCAGCAGCACTATTCTGCCCCCTGGAC CTTTGGCGGCGGCACAAACCTGGAGATCAAG (SEQ ID NO: 31); and DIQMTQSPSSLSASVGDRVTITCRASQDVTTALAWYQQKPGKA PKLLIYSASSLYTGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQHYSAPW TFGGGTNLEIK (SEQ ID NO: 32). Petition 870260061493, of 23 / 06 / 2026, p. 134 / 182 121 / 130

[263] Heavy chain variable region 13E5 H4: CAGGTGCAGCTGGTGCAGTCCGGAGCAGAGGTGGTGAAGC CAGGAGCCAGCGTGAAGGTGTCCTGTAAGACCTCTGGCTACACCTTCACA GAGTATACAATCCACTGGGTGCGGCAGGCACCAGGACAGTCTCTGGAGTG GATCGGCGGCATCAACCCTAACAATGGGGCCACCATCAGTGAGTTGTT TCAGGGCAAGGTGACCCTGACAGTGGACAAGTCCACCTCTACAGCCTATA TGGAGCTGAGCTCCCTGAGGTCTGAGGACAGCCGTGTACTATTGCGCC CGCGTGCGGAGAGGCATGGATTACTGGGGCCAGGCACCAGCGTGACAG TGTCTAGC (SEQ ID NO: 33); e QVQLVQSGAEVVKPGASVKVSCKTSGYTFTEYTIHWVRQAPGQ SLEWIGGINPNNGGTVYNQFQGKVTLTVDKSTSTAYMELSSLEDTAVYC ARVRRGMDYWGQGTSVTVSS (SEQ ID NO: 34 SEQ).

[264] Light chain variable region 13E5 L4: GACATCCAGATGACCCAGAGCCCTAGCTCCCTGAGCGCCTC CGTGGGCGACAGGGTGACCATCACATGTAGAGCCTCCCAGGATGTGACC ACAGCAGTGGCATGGTACCAGCAGAAGCCAGGCAAGGCCCCTAAGCTGC TGATCTACTCCGCCTCTTAcAGGTATACCGGAGTGCCATCTCGGTTCTCTG GCAGCGGCTCCGGCACAGACTTTACCCTGACAATCTCCTCTGTGCAGCCA GAGGATCTGGCCACATACTATTGCCAGCAGCACTATTCTGCCCCCTGGAC CTTTGGCGGCGGCACAAACCTGGAGATCAAG (SEQ ID NO: 35); and DIQMTQSPSSLSASVGDRVTITCRASQDVTTAVAWYQQKPGKA PKLLIYSASYRYTGVPSRFSGSGSGTDFTLTISSVQPEDLATYYCQQHYSAPW TFGGGTNLEIK (SEQ ID NO: 36).

[265] Variable region of heavy chain 18H7 H1: GACGTGCAGCTGGTGGAGAGCGGCGGCGGCCTGGTGCAGC TGGGCGGCTCCCTGAGGCTGTCTTGTGCAGCCAGCGGCTTCACCTTTAGC TCCTCTTACATGTCTTGGGTGCGGCAGACACCCGAGAAGAGACTGGAGCT GGTGGCCGCCATCAACTCTAATGGCGGCAAGACCTACTATGCCGACAGCG Petition 870260061493, dated 06 / 23 / 2026, pages 135 / 182 122 / 130 TGAAGGGCAGGTTTACCATCTCCCGCGATAACTCTAAGAATACACTGTATC TGCAGATGAGCTCCCTGAGAGCCGAGGACCGCCGTGTACTATTGCACA CGGCAGAGAGGCAACTACGTGGGCGCCATGGATTATTGGGGCCAGGGCA CCAGCGTGACAGTGTCTAGC (SEQ ID NO: 37); and DVQLVESGGGLVQLGGSLRLSCAASGTFFSSSYMSWVRQTPE KRLELVAAINSNGGKTYYADSVKGRFTISRDNSKNTLYLQMSSLRAEDTAVYY CTRQRGNYVGAMDYWGQGTSVTVSS (SEQ ID NO: 38).

[266] Light chain variable region 18H7 L1: GACATCCAGATGACCCAGTCTCCCAGCTCCCTGTCCACATCT GTGGGCGACCGGGTGACCATCACCTGTAAGGCCTCTCAGGATGTGAGCA CCGCCGTGGTGGTACCAGCAGAAGCCAGGCAAGAGCCCCAAGCTGCT GATCTATAGCCTCCTACCG GCAGCGGCTCCGGCACAGACTTCACCTTTACAATCTCTAGGGTGCAGCCA GAGGATATCGCCACATACTATTGCCACCAGTACTATGGCAGCCCTCCCAC CTTCGGCGGCGGCACAAAGCTGGAGATCAAG (SEQ ID NO: 39); and IQMTQSPSSLSTSVGDRVTITCKASQDVSTAVVWYQQKPGKSP CLLIYSASYRYTGVPSRFSGSGSGTDFTFTISSVQPEDIATYYCHQYYGSPPTF GGGTKLEIK (SEQ ID NO: 40).

[267] Heavy chain variable region 18H7 H2: GAGGTGCAGCTGGTGGAGAGCGGCGGCGGCCTGGTGCAGC CCGGCGGCTCCCTGAGGCTGTCTTGTGCCGCCAGCGGCTTCACCTTTAGC TCCTCTTACATGTCTTGGGTGCGGCAGGCACCTGGCAAGAGACTGGAGCT GGTGGCCGCCATCAACTCTAATGAGGCCAGGCCGACCAGCT TGAAGGGCAGGTTTACCATCTCCCGCGATAACTCTAAGAATACACTGTATC TGCAGATGAGCTCCCTGAGAGCCGAGGACCGCCGTGTACTATTGCACA CGGCAGAGAGGCAACTACGTGGGCGCCATGGATTATTGGGGCCAGGGCA CCAGCGTGACAGTGTCTAGC (SEQ ID NO: 41); and EVQLVESGGGLVQPGGSLRLSCAASGTFFSSSYMSWVRQAPG Petition 870260061493, of 23 / 06 / 2026, p. 136 / 182 123 / 130 KRLELVAAINSNGGKTYADVKGRFTISRDNSKNTLYLQMSSLRAEDTAVYY CTRQRGNYVGAMDYWGQGTSVTVSS (SEQ ID NO: 42).

[268] Light chain variable region 18H7 L2: GACATCCAGATGACCCAGTCTCCAAGCTCCCTGTCCGCCTCT GTGGGCGACAGGGTGACCATCACATGTCAGGCCTCTCAGGATGTGAGCA CAGCCGTGGTGGTACCAGCAGAAGCCAGGCAAGAGCCCCAAGCTGCT GATCTATAGCGCCTCCTACCT CAGCGGCTCCGGCACAGACTTCACCTTTACAATCTCTAGCCCTGCAGCCAG AGGATATCGCCACCTACTATTGCCACCAGTACTATGGCAGCCCTCCACCT TCGGCGGCGGCACAAAGCTGGAGATCAAG (SEQ ID NO: 43); and DIQMTQSPSSLSASVGDRVTITCQASQDVSTAVVWYQQKPGKS PKLLIYSASYLYTGVPSRFSGSGSGTDFTFTISSLQPEDIATYYCHQYYGSPPT FGGGTKLEIK (SEQ ID NO: 44).

[269] Heavy chain variable region 18H7 H3: GAGGTGCAGCTGGTGGAGAGCGGCGGCGGCCTGGTGCAGC CCGGCGGCTCCCTGCGGCTGTCTTGTGCCGCCAGCGGCTTCACCTTTAG CTCCTCTTACATGTCCTGGGTGAGGCAGGCACCTGGCAAGGGACTGGAGT ACGTGAGCGCCATCAACTCTAATGACGACTGACTGACTGCTGCTGCT GTGAAGGGCAGGTTTACCATCAGCCGCGATAACTCCAAGAATACACTGTA CCTGCAGATGAGCTCCCTGAGGGCAGAGGACCGCCGTGTACTATTGCA CACGGCAGAGAGGCAACTACGTGGGCGCCATGGATTATTGGGGCCAGGG CACCTCCGTGACAGTGTCTATTGGGGGCCAGGG CACCTCCGTGACAGTGTCTATTGCAQ: ID NO 45); and EVQLVESGGGLVQPGGSLRLSCAASGFTFSSSYMSWVRQAPG KGLEYVSAINSNGGKTYYADSVKGRFTISRDNSKNTLYLQMSSLRAEDTAVYY CTRQRGNYVGAMDYWGQGTSVTVSS (SEQ ID NO: 46).

[270] Variable region of the 18H7 L3 light chain: GACATCCAGATGACCCAGTCTCCAAGCTCCCTGTCCGCCTCT GTGGGCGACAGGGTGACCATCACATGTCAGGCCTCTCAGGATGTGAGCA Petition 870260061493, dated 06 / 23 / 2026, pp. 137 / 182 124 / 130 CAGCCCTGGCCTGGTACCAGCAGAAGCCAGGCAAGGCCCCCAAGCTGCT GATCTATAGCGCCTCCAACCTGGAGACCGGCGTGCCTAGCAGATTCTCTG GCAGCGGCTCCGGCACAGACTTCACCTTTACAATCTCTAGCCTGCAGCCA GAGGATATCGCCACCTACTATTGCCACCAGTACTATGGCAGCCCTCCCAC CTTCGGCGGCGGCACAAAGCTGGAGATCAAG (SEQ ID NO: 47); and DIQMTQSPSSLSASVGDRVTITCQASQDVSTALAWYQQKPGKA PKLLIYSASNLETGVPSRFSGSGSGTDFTFTISSLQPEDIATYYCHQYYGSPPT FGGGTKLEIK (SEQ ID NO: 48).

[271] 13E5 heavy chain structure region: FR-H1: EVQLQQSGPELVKPGASVKISCKTS (SEQ ID NO: 49); FR-H2: IHWVKQNHGKSLEWIGG (SEQ ID NO: 50); FR-H3: VYNQNFKGKATLTVDKSSSTAYMELRSLTSEDSAVYYC (SEQ ID NO: 51); e FR-H4: WGQGTSVTVSS (SEQ ID NO: 52).

[272] Região de estrutura de cadia level 13E5: FR-L1: DIVMTQSHKFMSTSVGDRVSITCKAS (SEQ ID NO: 53); FR-L2: VAWYQQKPGQSPKLLIY (SEQ ID NO: 54); FR-L3: YRYTGVPDRFTGSGSGTDFTFTISSVQAEDLAVYYC (SEQ ID NO: 55); e FR-L4: FGGGTNLEIK (SEQ ID NO: 56).

[273] Região de estrutura de cadia pesada 18H7: FR-H1: DVKLVESGGDLVNLGGSLKLSCAAS (SEQ ID NO: 57); FR-H2: MSWVRQTPERRLELLVAA (SEQ ID NO: 58); FR-H3: YYPDTVKGRFTISRDNAKNTLYLQMSGLKTEDTALYYC (SEQ ID NO: 59); e FR-H4: WGQGTSVTVSS (SEQ ID NO: 60).

[274] Regimen of construction at 18H7 level: FR-L1: DIVMTQSHKFMSTSVGDRVSITCKAS (SEQ ID NO: 61); Petition: 870260061493, on 06 / 23 / 2026, page. 138 / 182 125 / 130 FR-L2: VVWYQQKPGQSPTLLIY (SEQ ID NO:62); FR-L3: YRYTGVPDRFTGSGSGTDFTFTISSVQAEDLAVYYC (SEQ ID NO: 63); e FR-L4: FGGGTKLEIK (SEQ ID NO: 64).

[275] Região de estrutura 13E5 H1: FR-H1: QVQLQQSGAEVVKPGASVKISCKTS (SEQ ID NO: 65); FR-H2: IHWVKQAHGQSLEWIGG (SEQ ID NO: 66); FR-H3: VYNQKFQGKATLTVDKSTSTAYMELRSLTSEDTAVYYC (SEQ ID NO: 67); e FR-H4: WGQGTSVTVSS (SEQ ID NO: 68).

[276] Região de estrutura 13E5 L1: FR-L1: DIQMTQSPKSLSTSVGDRVTITCRAS (SEQ ID NO: 69); FR-L2: VAWYQQKPGKSPKLLIY (SEQ ID NO: 70); FR-L3: YRYTGVPSRFSGSGSGTDFTFTISSVQPEDLATYYC (SEQ ID NO: 71); e FR-L4: FGGGTNLEIK (SEQ ID NO: 72).

[277] Installation 13E5 H2: FR-H1: QVQLVQSGAEVVKPGASVKVSCKTS (SEQ ID NO: 73); FR-H2: IHWVRQAPGQSLEWIGG (SEQ ID NO: 74); FR-H3: NYNQKFQGKVTLTVDKSTSTAYMELSSLRSEDTAVYYC (SEQ ID NO: 75); e FR-H4: WGQGTSVTVSS (SEQ ID NO: 76).

[278] Região de estrutura 13E5 L2: FR-L1: DIQMTQSPSSSLSASVGDRVTITCRAS (SEQ ID NO: 77); FR-L2: VAWYQQKPGKAPKLLIY (SEQ ID NO: 78); FR-L3: SRYTGVPSRFSGSGSGTDFTLTISSVQPEDLATYYC (SEQ ID NO: 79); e FR-L4: FGGGTNLEIK (SEQ ID NO: 80). Petition: 870260061493, on 06 / 23 / 2026, page. 139 / 182 126 / 130

[279] Região de estrutura 13E5 H3: FR-H1: QVQLVQSGAEVVKPGASVKVSCKAS (SEQ ID NO: 81); FR-H2: IHWVRQAPGQGLEWIG (SEQ ID NO: 82); FR-H3: NYAQKFQGRVTITVDKSTSTAYMELSSLRSEDTAVYYC (SEQ ID NO: 83); e FR-H4: WGQGTSVTVSS (SEQ ID NO: 84).

[280] Installation replacement 13E5 L3: FR-L1: DIQMTQSPSSSLSASVGDRVTITCRAS (SEQ ID NO: 85); FR-L2: LAWYQQKPGKAPKLLIY (SEQ ID NO: 86); FR-L3: SLYTGVPSRFSGSGSGTDFTLTISSLQPEDFATYYC (SEQ ID NO: 87); e FR-L4: FGGGTNLEIK (SEQ ID NO: 88).

[281] Região de estrutura 13E5 H4: FR-H1: QVQLVQSGAEVVKPGASVKVSCKTS (SEQ ID NO: 89); FR-H2: IHWVRQAPGQSLEWIGG (SEQ ID NO: 90); FR-H3: VYNQKFQGKVTLTVDKSTSTAYMELSSLRSEDTAVYYC (SEQ ID NO: 91); e FR-H4: WGQGTSVTVSS (SEQ ID NO: 92).

[282] Região de estrutura 13E5 L4: FR-L1: DIQMTQSPSSSLSASVGDRVTITCRAS (SEQ ID NO: 93); FR-L2: VAWYQQKPGKAPKLLIY (SEQ ID NO: 94); FR-L3: YRYTGVPSRFSGSGSGTDFTLTISSVQPEDLATYYC (SEQ ID NO: 95); e FR-L4: FGGGTNLEIK (SEQ ID NO: 96).

[283] Replacement of framework 18H7 H1: FR-H1: DVQLVESGGGLVQLGGGSLRLSCAAS (SEQ ID NO: 97); FR-H2: MSWVRQTPEKRLELLVAA (SEQ ID NO: 98); FR-H3: YYADSVKGRFTISRDNSKNTLYLQMSSLRAEDTAVYYC Petition: 870260061493, on 06 / 23 / 2026, page. 140 / 182 127 / 130 (SEQ ID NO: 99); e FR-H4: WGQGTSVTVSS (SEQ ID NO: 100).

[284] Installation system 18H7 L1: FR-L1: DIQMTQSPSSLSTSVGDRVTITCKAS (SEQ ID NO: 101); FR-L2: VVWYQQKPGKSPKLLIY (SEQ ID NO: 102); FR-L3: YRYTGVPSRFSGSGSGTDFTFTISSVQPEDIATYYC (SEQ ID NO: 103); e FR-L4: FGGGTKLEIK (SEQ ID NO: 104).

[285] Região de estrutura 18H7 H2: FR-H1: EVQLVESGGGGLVQPGGSLRLSCAAS (SEQ ID NO: 105); FR-H2: MSWVRQAPGKRLELLVAA (SEQ ID NO: 106); FR-H3: YYADSVKGRFTISRDNSKNTLYLQMSSLRAEDTAVYYC (SEQ ID NO: 107); e FR-H4: WGQGTSVTVSS (SEQ ID NO: 108).

[286] Installation system 18H7 L2: FR-L1: DIQMTQSPSSLSASVGDRVTITCQAS (SEQ ID NO: 109); FR-L2: VVWYQQKPGKSPKLLIY (SEQ ID NO: 110); FR-L3: YLYTGVPSRFSGSGSGTDFTFTISSLQPEDIATYYC(SEQ) ID NO: 111); e FR-L4: FGGGTKLEIK (SEQ ID NO: 112).

[287] Região de estrutura 18H7 H3: FR-H1: EVQLVESGGGLVQPGGSLRLSCAAS (SEQ ID NO: 113); FR-H2: MSWVRQAPGKGLEYVSA (SEQ ID NO: 114); FR-H3: YYADSVKGRFTISRDNSKNTLYLQMSSLRAEDTAVYYC (SEQ ID NO: 115); e FR-H4: WGQGTSVTVSS (SEQ ID NO: 116).

[288] Installation system 18H7 L3: FR-L1: DIQMTQSPSSLSASVGDRVTITCQAS (SEQ ID NO: 117); Petition: 870260061493, on 06 / 23 / 2026, page. 141 / 182 128 / 130 FR-L2: LAWYQQKPGKAPKLLIY (SEQ ID NO: 118); FR-L3: NLETGVPSRFSGSGSGTDFTFTISSLQPEDIATYYC (SEQ ID NO: 119); e FR-L4: FGGGTKLEIK (SEQ ID NO: 120).

[289] Sequence of etiqueta mFc: PRGPTIKPCPPCKCPAPNLLGGPSVFIFPPKIKDVLMISLSPIVTC WVDVSEDDPDVQISWFVNNVEVHTAQTQTHREDYNSTLRWSALPIQHQDW MSGKEFKCKVNNKDLPAPIERTISKPKGSVRAPQVYVLPPPEEEETKKQVTLT CMVTDFMPEDIYVEWTNNGKTELNYKNTEPVLDSDGSYFMYSKLRVEKKNW VERNSYSCSVVHEGLHNHHTTKSFSRTPGK (SEQ ID NO: 121).

[290] Sequence of catheterization of hIgG: EVQLEQSGAELMKPGASVKISCKATGYTFTTYWIEWIKQRPGHS LEWIGEILPGSDSTYYNEKVKGKVTFTADASSNTAYMQLSLSLTSEDSAVYCA RGDGFYVYWGQGTTLTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYF PEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNV DHKPSNTKVDKRVESKYGPPCPPCPAPEFLGGPSVFLFPKPKDTLMISRTPE VTCWVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRWSVLTVL HQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKN QVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDK SRWQEGNVFSCSVMHEALHNHYTQKSLSLGK (SEQ ID NO: 122).

[291] Sequência de chain leve hIgG: DIELTQSPATLSVTPGDSVSLSCRASQSISNNLHWYQQKSHESP RLLIKYTSQSMSGIPSRFSGSGSGTDFTLSINSVETEDFGVYFCQQSGSWPRT FGGGTKLDIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKV DNALQSGNSQESVTEQDSKDSTYSLSTLTLSKADYEKHKVYACEVTHQGLS SPVTKSFNRGEC (SEQ ID NO: 123).

[292] VAB 16F3-1 VH-2: EVQLVESGGGLVQPGRSLRLSCEASGFTFDDYAMHWVRQAPG Petition 870260061493, de 23 / 06 / 2026, pág. 142 / 182 129 / 130 KGLEWVSGLSRTSVSIGYADSVKGRFTISRDNAKNSLYLEMNSLRPEDTALYY CAKWGTRGYFDYWGQGTLVTVSS (SEQ ID NO: 124).

[293] 16F3-1 VL: DIQMTQSPSSVSASVGDRVTITCRASQDISIWLAWYQQSPGKAP KLLINVASRLQSGVPSRFSGSGSGTDFTLTINSLQPEDFVTYYCQQANSFPITF GQGTRLATK (SEQ ID NO: 125).

[294] Variable heavy chain region 20G 10H3: CAGGTGACACTGAAGGAGTCCGGCCCAACCCTGGTGAAGCC CACCCAGACACTGACCCTGACATGTACCTTCAGCGGCTTTTCTCTGAGCAC ATCCGGCATGGGAGTGGGATGGATCAGACAGCCCCCTGGCAAGGCCCTG GAGTGGCTGGCCCTGATCTGGTGGGCCGACGATAAGAGGTACTCTACCA GCCTGAAGTCCCGCCTGACAATCTCCAAGGACACCTCTAAGAACCAGGTG GTGCTGACAATCACCAATGTGGACCCCGTGGATACAGCCACCTACTATTG CGCCCGGATCACAAGAGGCAACTCTGCCATGGATTTTTGGGCCAGGGCA CATCTGTGACCGTGAGCTCC (SEQ ID NO: 126); and QVTLKESGPTLVKPTQTLTLTCTFSGFSLSTSGMGVGWIRQPPG KALEWLALIWWADDKRYSTSLKSRLTISKDTSKNQVVLTITNVDPVDTATYYCA RITRGNSAMDFWGQGTSVTVSS (SEQ ID NO: 127).

[295] Variable light chain region 20G 10L3: GACATCCAGATGACCCAGTCTCCTAGCTCCCTGTCCGCCTCT GTGGGCGATAGGGTGACCATCACATGTAGAGCCTCTGAGAACGTGTACAG CTATCTGAATTGGTACCAGCAGAAGCCCGGCAAGGCCCCTAAGCTGCTGA TCTATAACGCCAAGAGCCTGCAGTCCGGAGTGCCAAGCCGGTTCAGCGG CTCCGGCTCTGGCACCGACTTTACCCTGACAATCTCTAGCCTGCAGCCAG AGGATTTCGCCACATACTATTGCCAGCACCACTACGGCATCCCCTGGACC TTCGGCGGCGGCACAAAGCTGGAGATCAAG (SEQ ID NO: 128); and DIQMTQSPSSLSASVGDRVTITCRASENVYSYLNWYQQKPGKA PKLLIYNAKSLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQHHYGIPWT Petition 870260061493, dated 06 / 23 / 2026, pp. 143 / 182 130 / 130 FGGGTKLEIK (SEQ ID NO: 129).

[296] 20G10 CDR: HCDR1: GFSLSTSGMG (SEQ ID NO: 130); HCDR2: IWWADDK (SEQ ID NO: 131); HCDR3: ARITRGNSAMDF (SEQ ID NO: 132); LCDR1: ENVYSY (SEQ ID NO: 133); LCDR2: NAK (SEQ ID NO: 134); and LCDR3: QHHYGIPWT (SEQ ID NO: 135).

[297] 20G 10H3 structure region: FR-H1: QVTLKESGPTLVKPTQTLTLTCTFS (SEQ ID NO: 136); FR-H2: VGWIRQPPGKALEWLAL (SEQ ID NO: 137); FR-H3: RYSTSLKSRLTISKDTSKNQVVLTITNVDPVDTATYYC (SEQ ID NO: 138); e FR-H4: WGQGTSVTVSS (SEQ ID NO: 139).

[298] Região da estrutura 20G 10L3: FR-L1: DIQMTQSPSSSLSASVGDRVTITCRAS (SEQ ID NO: 140); FR-L2: LNWYQQKPGKAPKLLIY (SEQ ID NO: 141); FR-L3: SLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYC (SEQ ID NO: 142); e FR-L4: FGGGTKLEIK (SEQ ID NO: 143).

Claims

1. ANTIBODY or an antigen-binding fragment thereof that binds to IL4RA, characterized in that: (1) the antibody comprises: an HCDR1, comprising or consisting of the sequence set forth in SEQ ID NO: 130, an HCDR2, comprising or consisting of the sequence set forth in SEQ ID NO: 131, and an HCDR3, comprising or consisting of the sequence set forth in SEQ ID NO: 132, and the antibody further comprises: an LCDR1, comprising or consisting of the sequence set forth in SEQ ID NO: 133, an LCDR2, comprising or consisting of the sequence set forth in SEQ ID NO: 134, and an LCDR3, comprising or consisting of the sequence set forth in SEQ ID NO:

135.

2. ANTIBODY, according to claim 1, characterized in that IL4RA is a human IL4RA.

3. ANTIBODY, according to claim 1, characterized by comprising: (i) a variable heavy chain region comprising or consisting of: the amino acid sequence set forth in SEQ ID NO: 127, or a sequence having at least 80% sequence identity with the sequence set forth in SEQ ID NO: 127, and (ii) a variable light chain region comprising or consisting of: the amino acid sequence set forth in SEQ ID NO: 129, or Petition 870260061493, dated 06 / 23 / 2026, page 145 / 182 2 / 6 a sequence having at least 80% sequence identity with the sequence set forth in SEQ ID NO:

129.

4. ANTIBODY, according to any one of claims 1 to 3, characterized in that the antibody is a humanized antibody, a chimeric antibody, or a multispecific antibody.

5. ANTIBODY, according to claim 4, characterized in that the constant region of the antibody heavy chain is a C region of the Ig gamma-4 chain of GenBank accession number: P01861.1; the constant region of the light chain is a C region of the Ig kappa chain of GenBank accession number: P01834.

6. ANTIBODY, according to any one of claims 1 to 5, characterized in that the antigen-binding fragment is selected from Fab, Fab', F(ab')2, Fv, Fab / c, single-chain antibody, and bivalent antibody.

7. ISOLATED POLYNUCLEOTIDE, characterized by encoding the antibody, as defined in claim 1.

8. HOST CELL, characterized by comprising the isolated polynucleotide, as defined in claim 7.

9. METHOD FOR PREPARING THE ANTIBODY or antigen-binding fragment thereof, as defined in any one of claims 1 to 6, characterized by comprising culturing the host cell, as defined in claim 8.

10. ANTIBODY CONJUGATE, characterized by comprising the antibody or the antigen-binding fragment thereof, as defined in any one of claims 1 to 6, and a conjugate portion coupled thereto.

11. CONJUGATE, according to claim 10, characterized in that the conjugate portion is selected from a purification label, a cytotoxic agent, a detectable marker, a radioisotope, a luminescent substance, a colored substance, an enzyme or polyethylene glycol.

12. MULTISPECIFIC ANTIBODY, characterized by comprising the antibody or antigen-binding fragment thereof, as defined in any one of claims 1 to 6, and an antibody or antigen-binding fragment against another antigen and / or another antigenic epitope.

13. FUSION PROTEIN, characterized by comprising the antibody or antigen-binding fragment thereof, as defined in any one of claims 1 to 6.

14. PHARMACEUTICAL COMPOSITION, characterized by comprising the antibody or antigen-binding fragment thereof, as defined in any one of claims 1 to 6, the antibody conjugate, as defined in any one of claims 10 to 11, the multispecific antibody, as defined in claim 12, or the fusion protein, as defined in claim 13, and a pharmaceutically acceptable carrier and / or excipient.

15. COMPOSITION, according to claim 14, characterized in that the pharmaceutical composition is in a dosage form suitable for oral administration to the gastrointestinal (GI) tract; or the pharmaceutical composition is in a dosage form suitable for subcutaneous injection, intradermal injection, intravenous injection, intramuscular injection, or intralesional injection.

16. COMPOSITION, according to claim 15, characterized in that the dosage form is selected from tablets, capsules, pills, powders, granules, emulsions, microemulsions, solutions, suspensions, syrups and elixirs. Petition 870260061493, dated 06 / 23 / 2026, pp. 147 / 182 4 / 6 17. KIT, characterized by comprising the antibody or antigen-binding fragment thereof, as defined in any one of claims 1 to 6, the antibody conjugate, as defined in any one of claims 10 to 11, the multispecific antibody, as defined in claim 12, or the fusion protein, as defined in claim 13.

18. KIT, according to claim 17, characterized in that the kit further comprises a second antibody that specifically recognizes the antibody or the antigen-binding fragment thereof, as defined in any one of claims 1 to 6, the antibody conjugate, as defined in any one of claims 10 to 11, the multispecific antibody, as defined in claim 12, or the fusion protein, as defined in claim 13.

19. USE OF AN ANTIBODY or antigen-binding fragment thereof, as defined in any one of claims 1 to 6, antibody conjugate, as defined in any one of claims 10 to 11, multispecific antibody, as defined in claim 12, or fusion protein, as defined in claim 13, characterized in being in the preparation of a kit for detecting the presence or level of human IL-4RA in a sample.

20. USE OF AN ANTIBODY or antigen-binding fragment thereof, as defined in any one of claims 1 to 6, antibody conjugate, as defined in any one of claims 10 to 11, multispecific antibody, as defined in claim 12, or fusion protein, as defined in claim 13, characterized by being in the preparation of a medicament selected from: a medicament for blocking the binding of human IL-4RA to IL-13, a medicament for blocking the activity of human IL-4RA or negatively regulating the level of human IL-4RA, and a medicament for blocking a cellular biological response mediated by the binding of human IL-4 or human IL-13 to IL-4RA.

21. USE, according to claim 20, characterized in that the human IL-4RA ligand is human IL-4 or human IL-13.

22. USE OF AN ANTIBODY or antigen-binding fragment thereof, as defined in any one of claims 1 to 6, of antibody conjugate, as defined in any one of claims 10 to 11, of multispecific antibody, as defined in claim 12, or of fusion protein, as defined in claim 13, characterized by being in the preparation of a medicament for the prevention and / or treatment and / or adjuvant treatment and / or diagnosis of an allergic disease, a tumor, an autoimmune disease, a skin infection, tissue fibrosis, rhinosinusitis, nasal polyps, chronic obstructive pulmonary disease.

23. USE, according to claim 22, characterized by the allergic disease being selected from atopic dermatitis, allergic rhinitis, asthma and allergy.

24. USE, according to claim 23, characterized by atopic dermatitis including moderate and severe atopic dermatitis.

25. Hybridoma cell, characterized by having the China Center for Type Culture Collection accession number CCTCC No: C202010.

26. MONOCLONAL ANTIBODY, characterized by being secreted by the hybridoma cell, as defined in claim 25.

27. USE OF A KIT comprising the antibody or antigen-binding fragment thereof, as defined in any of claims 1 to 6, of the antibody conjugate, as defined in Petition 870260061493, dated 06 / 23 / 2026, p. 149 / 182 6 / 6 any of claims 10 to 11, of the multispecific antibody, as defined in claim 12, or of the fusion protein, as defined in claim 13, characterized by being in the preparation of a medicament for the prevention and / or treatment and / or adjuvant treatment of an allergic disease, a tumor, an autoimmune disease, a skin infection, tissue fibrosis, rhinosinusitis, nasal polyps, chronic obstructive pulmonary disease, wherein preferably, the allergic disease is selected from atopic dermatitis, allergic rhinitis, asthma and allergy and, more preferably, atopic dermatitis includes moderate and severe atopic dermatitis.

Images