Anti-il2 receptor gamma antigen-binding proteins

Abstract

The present invention provides an antibody and an antigen-binding fragment (e.g., a human antibody) that specifically bind to human IL2 receptor gamma (IL2Rγ). A method for treating or preventing a disease mediated by IL2Rγ (e.g., graft-versus-host disease) using the antibody and the fragment is also provided along with a method for preparing the antibody and the fragment.

Description

Technology Field

[0001] This application claims priority to U.S. provisional patent application No. 62 / 799,851 filed on February 1, 2019, the full text of which is incorporated herein by reference.

[0002] The present invention relates to an antibody that binds to an anti-IL-2 receptor gamma protein, and a method of use, for example, to treat or prevent a disease. Background Technology

[0003] The conventional cytokine receptor gamma chain (γc) was first identified as the third chain of the interleukin-2 (IL-2) receptor complex and named IL-2Rγ. The same subunit was identified as part of several other receptor complexes: IL-4, IL-7, IL-9, IL-15, and IL-21, and thus can be referred to as γc (the conventional cytokine receptor gamma chain). γc is involved in ligand binding as well as signal transduction by these cytokine receptors.

[0004] Binding of cytokines to their receptors activates the Janus kinase (JAK)-family proteins tyrosine kinases JAK1 and JAK3, triggering transphosphorylation of JAK1 and JAK3 on tyrosine. JAK1 associates with a specific α or β chain, and JAK3 associates with the receptor's γc. Phosphorylated JAK can subsequently activate transcriptional signaling and activating factor (STAT) proteins, which together form the JAK / STAT signaling pathway. Phosphorylation of STAT induces dimerization of STAT, which then adopts high-affinity DNA binding activity and translocates to the nucleus. Here, they act as transcription factors that induce the transcription of target genes.

[0005] γc gene ( IL2RGIL-2Rγ is located on chromosome Xq13. IL-2Rγ is mutated in patients with X-linked severe combination immunodeficiency (X-SCID). Patients with the said disease have profound immunodeficiency due to the absence of T, NK, and fully mature B cells.

[0006] IL-7, -9, and -15 are associated with psoriasis and rheumatoid arthritis (References: Pathak, The expanding role of IL-7 and thymic stromal lymphopoietin as therapeutic target for rheumatoid arthritis. Expert Opin Ther Targets. 18(5):581-94 (2014); Hughes-Austin et al. , Multiple cytokines and chemokines are associated with rheumatoid arthritis-related autoimmunity in first-degree relatives without rheumatoid arthritis: Studies of the Aetiology of Rheumatoid Arthritis (SERA), Ann Rheum Dis.;72(6):901-7 (2013); Dantas et al. , Increased Serum Interleukin-9 Levels in Rheumatoid Arthritis and Systemic Lupus Erythematosus: Pathogenic Role or Just an Epiphenomenon?, Dis Markers. 2015;2015:519638; Yang et al. , Therapeutic potential of IL-15 in rheumatoid arthritis, Hum Immunol. 2015 Nov;76(11):812-8; Lesiak et al., Are interleukin-15 and -22 a new pathogenic factor in pustular palmoplantar psoriasis?, Postepy Dermatol Alergol. 33(5):336-339 (2016); Raeber et al. , The role of cytokines in T-cell memory in health and disease, Immunol Rev. 283(1):176-193 (2018)).

[0007] IL-4 and IL-9 blockade was shown to improve asthma symptoms in mice (Reference: Generoso et al. , Prospects for Monoclonal Antibody Therapy in Pediatric Asthma, Curr Allergy Asthma Rep. 18(9):45 (2018); Tashkin & Wechsler, Role of eosinophils in airway inflammation of chronic obstructive pulmonary disease, Int J Chron Obstruct Pulmon Dis. 13:335-349 (2018); Buzney et al., Asthma and Atopic Dermatitis: A Review of Targeted Inhibition of Interleukin-4 and Interleukin-13 As Therapy for Atopic Disease, J Drugs Dermatol. 15(2):165-71 (2016); Lloyd & Harker, Epigenetic Control of Interleukin-9 in Asthma, N Engl J Med. 379(1):87-89 (2018); Neurath & Finotto, IL-9 signaling as key driver of chronic inflammation in mucosal immunity, Cytokine Growth Factor Rev. 29:93-9 (2016)).

[0008] IL-21 is associated with various inflammatory disorders, including Crohn's disease and rheumatoid arthritis. (Reference: Holm et al. , Evaluating IL-21 as a Potential Therapeutic Target in Crohn's Disease, Gastroenterol Res Pract. 2018:5962624 (2018); Dinesh & Rasool Multifaceted role of IL-21 in rheumatoid arthritis: Current understanding and future perspectives, J Cell Physiol. 233(5):3918-3928 (2018)).

[0009] Summary of the Invention

[0010] The present invention provides an isolated antigen-binding protein (e.g., a monospecific or multispecific antibody or an antigen-binding fragment thereof) characterized by one or more of the following: about 2.75 x 10⁶ to human IL2Rγ at 25°C -9 M to about 3.36 x 10 -7M's K D It binds to; approximately 6.42 x 10⁶ human IL2Rγ at 37°C -9 M to approximately 3.53 x 10 -7 M's K D Combined as; approximately 3.53 x 10 -7 K less than M D Combined with; at 25℃, Macaca facicularius ( Macaca fascicularis ) Approximately 3.18 x 10⁶ in IL-2Rγ -9 M to about 2.38 x 10 -7 M's K D It binds to; at 37°C, approximately 8.29 x 10⁶ to Macaca faciculariis IL-2Rγ -9 M to about 3.20 x 10 -7 M's K D Combine as; approximately 3.20 X 10 -7 K less than M D It binds to; approximately 2.45 x 10⁶ human IL2Rγ at 25°C -9 M to 1.20 X 10 -8 M's K D Combine as; approximately 1.20 X 10 -8 K less than M D It binds to; approximately 1.86 x 10⁶ human IL2Rγ at 37°C -11 M to approximately 3.00 x 10 -8 M's K D Combine as; approximately 3.00 X 10 -8 K less than M D It binds to; approximately 1.84 x 10⁶ in mouse IL2Rγ at 25°C -8 M, 3.76 X 10 -9 M, 1.08 X 10 -7 M, 2.17 X 10 -8 M, 6.02 X 10 -9 M or 7.93 X 10 -8 M's K D Binding or not binding detectably; approximately 5.59 x 10⁶ to mouse IL2Rγ at 37°C -8 M, 6.11 X 10-9 M, 3.87 X 10 -7 M, 5.16 X 10 -8 M, 8.70 X 10 -9 M or 2.15 X 10 -7 M's K D Binding as; without binding detectably; approximately 3.32 x 10⁶ to human IL2Rγ domain 1 at 25°C -9 M to about 1.97 x 10 -7 M's K D Binds to; does not bind detectably; approximately 4.13 x 10⁶ to human IL2Rγ domain 1 at 37°C -9 M to about 2.25 x 10 -7 M's K D Binding as; not binding detectably; approximately 2.91 x 10⁶ to human IL2Rγ domain 2 at 25°C -7 M to about 5.35 x 10 -10 of K D Without binding or detectably binding; approximately 1.14 x 10⁶ to human IL2Rγ domain 2 at 37°C -8 or about 1.27 x 10⁻⁶ -8 of K Dto bind to; not to bind detectably; to block STAT phosphorylation in T-cells induced by IL-2, IL-4, IL-7, IL-15 and / or IL-21; to block STAT phosphorylation in mast cells induced by IL-9; to reduce the number of human immune cells injected into mice; to reduce the levels of serum human cytokines and / or mouse serum cytokines in mice with human immune cells; not to bind detectably to mouse or rat IL2Rγ; to protect mice from body weight loss and / or death due to GvHD in a GvHD mouse model; to block the binding of hybrid receptors including IL2Rγ complexed with cytokine-specific receptor subunits from IL-2, IL-4, IL-7, IL-9, IL-15 and / or IL-21; and / or to reduce the number of CD45+ cells, B-cells, T-cells and / or NK cells (but optionally, e.g., neutrophils) in the blood or serum of subjects. An antibody and an antigen-binding fragment that specifically bind to IL2Rγ are variants of any antibody or fragment whose sequences are specifically presented herein, and are characterized by one or more of the characteristics presented above and form part of the present invention.

[0011] The present invention also provides an isolated antigen-binding protein, for example, which specifically binds to an epitope on IL2Rγ identical to a reference antibody or its antigen-binding fragment; (ii) an antibody or its antigen-binding fragment that competes with a reference antibody or its antigen-binding fragment for binding to an IL2Rγ polypeptide, wherein said reference antibody or its antigen-binding fragment comprises: (a) SEQ ID NOs 2, 18, 22, 38, 42, 58, 62, 77, 81, 97, 101, 115, 119, 134, 138, 152, 156, 170, 174, 186, 190, 198, 200, 208, 210, 216, 218, 234, 238, 254, 258, 272, 276, 284, 286, 294, 296, 311, 315, A heavy chain immunoglobulin comprising the amino acid sequences presented in 331, 335, 343, 345, 357, 361 and / or 376, or a heavy chain immunoglobulin comprising CDR-H1, CDR-H2 and CDR-H3 of the variable region thereof, or a variable region thereof; or a variant thereof; and / or (b) a light chain immunoglobulin comprising the amino acid sequences presented in SEQ ID NOs 10, 20, 30, 40, 50, 60, 70, 79, 89, 99, 109, 117, 127, 136, 146, 154, 164, 172, 182, 188, 226, 236, 246, 256, 266, 274, 304, 313, 323, 333, 353, 359, 368 and / or 378, or a light chain immunoglobulin comprising CDR-L1, CDR-L2 and CDR-L3 of a variable region thereof; or a variant thereof. In one embodiment of the present invention, a reference antibody or fragment is pre-bound to an IL2Rg antigen before adding an antigen-binding protein and evaluating for binding. In one embodiment of the present invention, an antigen-binding protein is pre-bound to an antigen before adding a reference antibody or fragment and evaluating for binding.

[0012] The present invention also provides an isolated antigen-binding protein (e.g., an antibody or an antigen-binding fragment thereof) comprising the following: (a) SEQ ID NOs 2, 18, 22, 38, 42, 58, 62, 77, 81, 97, 101, 115, 119, 134, 138, 152, 156, 170, 174, 186, 190, 198, 200, 208, 210, 216, 218, 234, 238, 254, 258, 272, 276, 284, 286, 294, 296, 311, 315, 331, 335, 343, 345, 357, 361 and / or a heavy chain immunoglobulin comprising the amino acid sequence presented in 376 or a heavy chain immunoglobulin comprising CDR-H1, CDR-H2 and CDR-H3 of the variable region thereof or the variable region thereof; or a variant thereof; and / or (b) a light chain immunoglobulin comprising the amino acid sequences presented in SEQ ID NOs 10, 20, 30, 40, 50, 60, 70, 79, 89, 99, 109, 117, 127, 136, 146, 154, 164, 172, 182, 188, 226, 236, 246, 256, 266, 274, 304, 313, 323, 333, 353, 359, 368 and / or 378, or a light chain immunoglobulin comprising CDR-L1, CDR-L2 and CDR-L3 of a variable region thereof; or a variant thereof.

[0013] One embodiment of the present invention is (a) at least 90% amino acid sequence identity with the amino acid sequences presented in SEQ ID NOs 2, 18, 22, 38, 42, 58, 62, 77, 81, 97, 101, 115, 119, 134, 138, 152, 156, 170, 174, 186, 190, 198, 200, 208, 210, 216, 218, 234, 238, 254, 258, 272, 276, 284, 286, 294, 296, 311, 315, 331, 335, 343, 345, 357, 361 and / or 376 (b) a heavy chain immunoglobulin or a variable region thereof comprising an amino acid sequence having at least 90% amino acid sequence identity with the amino acid sequences presented in SEQ ID NOs 10, 20, 30, 40, 50, 60, 70, 79, 89, 99, 109, 117, 127, 136, 146, 154, 164, 172, 182, 188, 226, 236, 246, 256, 266, 274, 304, 313, 323, 333, 353, 359, 368 and / or 378, comprising a light chain immunoglobulin or a variable region thereof. For example, in one embodiment of the present invention, the antigen-binding protein comprises: (a) the one presented in SEQ ID NOs 2, 18, 22, 38, 42, 58, 62, 77, 81, 97, 101, 115, 119, 134, 138, 152, 156, 170, 174, 186, 190, 198, 200, 208, 210, 216, 218, 234, 238, 254, 258, 272, 276, 284, 286, 294, 296, 311, 315, 331, 335, 343, 345, 357, 361 and / or 376 Includes amino acid sequences SEQ ID NOs 2, 18, 22, 38, 42, 58, 62, 77, 81, 97, 101, 115, 119, 134, 138, 152, 156, 170, 174, 186, 190, 198, 200, 208, 210, 216, 218,A heavy chain immunoglobulin or a variable region thereof comprising CDR-H1, CDR-H2, and CDR-H3 of the heavy chain immunoglobulin or its variable region having at least 90% amino acid sequence identity with the amino acid sequences presented in 234, 238, 254, 258, 272, 276, 284, 286, 294, 296, 311, 315, 331, 335, 343, 345, 357, 361, and / or 376; and / or (b) comprising the amino acid sequences presented in SEQ ID NOs 10, 20, 30, 40, 50, 60, 70, 79, 89, 99, 109, 117, 127, 136, 146, 154, 164, 172, 182, 188, 226, 236, 246, 256, 266, 274, 304, 313, 323, 333, 353, 359, 368 and / or 378, and comprising SEQ ID NOs 10, 20, 30, 40, 50, 60, 70, 79, 89, 99, 109, 117, 127, 136, 146, A light chain immunoglobulin or a variable region thereof comprising CDR-L1, CDR-L2, and CDR-L3 of the variable region thereof having at least 90% amino acid sequence identity with the amino acid sequences presented in 154, 164, 172, 182, 188, 226, 236, 246, 256, 266, 274, 304, 313, 323, 333, 353, 359, 368, and / or 378.

[0014] In an embodiment of the present invention, the antigen-binding protein comprises the following:

[0015] (i) Heavy chain set of CDR: CDR-H1 comprising the amino acid sequence presented in SEQ ID NO. 4; CDR-H2 comprising the amino acid sequence presented in SEQ ID NO. 6; and CDR-H3 comprising the amino acid sequence presented in SEQ ID NO. 8; and / or CDR-H1 comprising the amino acid sequence presented in SEQ ID NO. 24; CDR-H2 comprising the amino acid sequence presented in SEQ ID NO. 26; and CDR-H3 comprising the amino acid sequence presented in SEQ ID NO. 28; and / or CDR-H1 comprising the amino acid sequence presented in SEQ ID NO. 44; CDR-H2 comprising the amino acid sequence presented in SEQ ID NO. 46; and CDR-H3 comprising the amino acid sequence presented in SEQ ID NO. 48; and / or CDR-H1 comprising the amino acid sequence presented in SEQ ID NO. 64; CDR-H2 comprising the amino acid sequence presented in SEQ ID NO. 66; and CDR-H3 comprising the amino acid sequence presented in SEQ ID NO. 68; and / or CDR-H1 comprising the amino acid sequence presented in SEQ ID NO. 83; CDR-H2 comprising the amino acid sequence presented in SEQ ID NO. 85; and CDR-H3 comprising the amino acid sequence presented in SEQ ID NO. 87; and / or CDR-H1 comprising the amino acid sequence presented in SEQ ID NO. 103; CDR-H2 comprising the amino acid sequence presented in SEQ ID NO. 105; and CDR-H3 comprising the amino acid sequence presented in SEQ ID NO. 107; and / or CDR-H1 comprising the amino acid sequence presented in SEQ ID NO. 121; CDR-H2 comprising the amino acid sequence presented in SEQ ID NO. 123; and CDR-H3 comprising the amino acid sequence presented in SEQ ID NO. 125; and / or CDR-H1 comprising the amino acid sequence presented in SEQ ID NO. 140; CDR-H2 comprising the amino acid sequence presented in SEQ ID NO. 142; and CDR-H3 comprising the amino acid sequence presented in SEQ ID NO. 144; and / or CDR-H1 comprising the amino acid sequence presented in SEQ ID NO. 158; CDR-H2 comprising the amino acid sequence presented in SEQ ID NO. 160;and CDR-H3 comprising the amino acid sequence presented in SEQ ID NO. 162; and / or CDR-H1 comprising the amino acid sequence presented in SEQ ID NO. 176; CDR-H2 comprising the amino acid sequence presented in SEQ ID NO. 178; and CDR-H3 comprising the amino acid sequence presented in SEQ ID NO. 180; and / or CDR-H1 comprising the amino acid sequence presented in SEQ ID NO. 192; CDR-H2 comprising the amino acid sequence presented in SEQ ID NO. 194; and CDR-H3 comprising the amino acid sequence presented in SEQ ID NO. 196; and / or CDR-H1 comprising the amino acid sequence presented in SEQ ID NO. 202; CDR-H2 comprising the amino acid sequence presented in SEQ ID NO. 204; and CDR-H3 comprising the amino acid sequence presented in SEQ ID NO. 206; and / or CDR-H1 comprising the amino acid sequence presented in SEQ ID NO. 176; and CDR-H2 comprising the amino acid sequence presented in SEQ ID NO. 212; and CDR-H3 comprising the amino acid sequence presented in SEQ ID NO. 214; and / or CDR-H1 comprising the amino acid sequence presented in SEQ ID NO. 220; CDR-H2 comprising the amino acid sequence presented in SEQ ID NO. 222; and CDR-H3 comprising the amino acid sequence presented in SEQ ID NO. 224; and / or CDR-H1 comprising the amino acid sequence presented in SEQ ID NO. 240; CDR-H2 comprising the amino acid sequence presented in SEQ ID NO. 242; and CDR-H3 comprising the amino acid sequence presented in SEQ ID NO. 244; and / or CDR-H1 comprising the amino acid sequence presented in SEQ ID NO. 260; CDR-H2 comprising the amino acid sequence presented in SEQ ID NO. 262; and CDR-H3 comprising the amino acid sequence presented in SEQ ID NO. 264; and / or CDR-H1 comprising the amino acid sequence presented in SEQ ID NO. 278; and CDR-H2 comprising the amino acid sequence presented in SEQ ID NO. 280; and CDR-H3 comprising the amino acid sequence presented in SEQ ID NO. 282; and / or CDR-H1 comprising the amino acid sequence presented in SEQ ID NO. 288;CDR-H2 comprising the amino acid sequence presented in SEQ ID NO. 290; and CDR-H3 comprising the amino acid sequence presented in SEQ ID NO. 292; and / or CDR-H1 comprising the amino acid sequence presented in SEQ ID NO. 298; CDR-H2 comprising the amino acid sequence presented in SEQ ID NO. 300; and CDR-H3 comprising the amino acid sequence presented in SEQ ID NO. 302; and / or CDR-H1 comprising the amino acid sequence presented in SEQ ID NO. 317; CDR-H2 comprising the amino acid sequence presented in SEQ ID NO. 319; and CDR-H3 comprising the amino acid sequence presented in SEQ ID NO. 321; and / or CDR-H1 comprising the amino acid sequence presented in SEQ ID NO. 337; CDR-H2 comprising the amino acid sequence presented in SEQ ID NO. 399; and CDR-H3 comprising the amino acid sequence presented in SEQ ID NO. 341; and / or CDR-H1 comprising the amino acid sequence presented in SEQ ID NO. 347; CDR-H2 comprising the amino acid sequence presented in SEQ ID NO. 349; and CDR-H3 comprising the amino acid sequence presented in SEQ ID NO. 351; and / or CDR-H1 comprising the amino acid sequence presented in SEQ ID NO. 363; CDR-H2 comprising the amino acid sequence presented in SEQ ID NO. 66; and CDR-H3 comprising the amino acid sequence presented in SEQ ID NO. 366; and / or (ii) a light chain set of CDR: CDR-L1 comprising the amino acid sequence presented in SEQ ID NO. 12; CDR-L2 comprising the amino acid sequence presented in SEQ ID NO. 14; and CDR-L3 comprising the amino acid sequence presented in SEQ ID NO. 16; and / or CDR-L1 comprising the amino acid sequence presented in SEQ ID NO. 32; CDR-L2 comprising the amino acid sequence presented in SEQ ID NO. 34; and CDR-L3 comprising the amino acid sequence presented in SEQ ID NO. 36; and / or CDR-L1 comprising the amino acid sequence presented in SEQ ID NO. 52; CDR-L2 comprising the amino acid sequence presented in SEQ ID NO. 54; and CDR-L3 comprising the amino acid sequence presented in SEQ ID NO. 56;and / or CDR-L1 comprising the amino acid sequence presented in SEQ ID NO. 72; CDR-L2 comprising the amino acid sequence presented in SEQ ID NO. 54; and CDR-L3 comprising the amino acid sequence presented in SEQ ID NO. 75; and / or CDR-L1 comprising the amino acid sequence presented in SEQ ID NO. 91; CDR-L2 comprising the amino acid sequence presented in SEQ ID NO. 93; and CDR-L3 comprising the amino acid sequence presented in SEQ ID NO. 95; and / or CDR-L1 comprising the amino acid sequence presented in SEQ ID NO. 111; CDR-L2 comprising the amino acid sequence presented in SEQ ID NO. 54; and CDR-L3 comprising the amino acid sequence presented in SEQ ID NO. 113; and / or CDR-L1 comprising the amino acid sequence presented in SEQ ID NO. 129; CDR-L2 comprising the amino acid sequence presented in SEQ ID NO. 54; and CDR-L3 comprising the amino acid sequence presented in SEQ ID NO. 132; and / or CDR-L1 comprising the amino acid sequence presented in SEQ ID NO. 148; CDR-L2 comprising the amino acid sequence presented in SEQ ID NO. 54; and CDR-L3 comprising the amino acid sequence presented in SEQ ID NO. 150; and / or CDR-L1 comprising the amino acid sequence presented in SEQ ID NO. 166; CDR-L2 comprising the amino acid sequence presented in SEQ ID NO. 14; and CDR-L3 comprising the amino acid sequence presented in SEQ ID NO. 168; and / or CDR-L1 comprising the amino acid sequence presented in SEQ ID NO. 72; CDR-L2 comprising the amino acid sequence presented in SEQ ID NO. 54; and CDR-L3 comprising the amino acid sequence presented in SEQ ID NO. 184; and / or CDR-L1 comprising the amino acid sequence presented in SEQ ID NO. 72; CDR-L2 comprising the amino acid sequence presented in SEQ ID NO. 54; and CDR-L3 comprising the amino acid sequence presented in SEQ ID NO. 184; and / or CDR-L1 comprising the amino acid sequence presented in SEQ ID NO. 72; CDR-L2 comprising the amino acid sequence presented in SEQ ID NO. 54;and CDR-L3 comprising the amino acid sequence presented in SEQ ID NO. 184; and / or CDR-L1 comprising the amino acid sequence presented in SEQ ID NO. 72; CDR-L2 comprising the amino acid sequence presented in SEQ ID NO. 54; and CDR-L3 comprising the amino acid sequence presented in SEQ ID NO. 184; and / or CDR-L1 comprising the amino acid sequence presented in SEQ ID NO. 228; CDR-L2 comprising the amino acid sequence presented in SEQ ID NO. 230; and CDR-L3 comprising the amino acid sequence presented in SEQ ID NO. 232; and / or CDR-L1 comprising the amino acid sequence presented in SEQ ID NO. 248; CDR-L2 comprising the amino acid sequence presented in SEQ ID NO. 250; and CDR-L3 comprising the amino acid sequence presented in SEQ ID NO. 252; and / or CDR-L1 comprising the amino acid sequence presented in SEQ ID NO. 268; CDR-L2 comprising the amino acid sequence presented in SEQ ID NO. 54; and CDR-L3 comprising the amino acid sequence presented in SEQ ID NO. 270; and / or CDR-L1 comprising the amino acid sequence presented in SEQ ID NO. 72; CDR-L2 comprising the amino acid sequence presented in SEQ ID NO. 54; and CDR-L3 comprising the amino acid sequence presented in SEQ ID NO. 184; and / or CDR-L1 comprising the amino acid sequence presented in SEQ ID NO. 72; CDR-L2 comprising the amino acid sequence presented in SEQ ID NO. 54; and CDR-L3 comprising the amino acid sequence presented in SEQ ID NO. 84; and / or CDR-L1 comprising the amino acid sequence presented in SEQ ID NO. 306; CDR-L2 comprising the amino acid sequence presented in SEQ ID NO. 230; and CDR-L3 comprising the amino acid sequence presented in SEQ ID NO. 309; and / or CDR-L1 comprising the amino acid sequence presented in SEQ ID NO. 325; and CDR-L2 comprising the amino acid sequence presented in SEQ ID NO. 327; and CDR-L3 comprising the amino acid sequence presented in SEQ ID NO. 329; and / or CDR-L1 comprising the amino acid sequence presented in SEQ ID NO. 72;CDR-L2 comprising the amino acid sequence presented in SEQ ID NO. 54; and CDR-L3 comprising the amino acid sequence presented in SEQ ID NO. 184; and / or CDR-L1 comprising the amino acid sequence presented in SEQ ID NO. 72; CDR-L2 comprising the amino acid sequence presented in SEQ ID NO. 54; and CDR-L3 comprising the amino acid sequence presented in SEQ ID NO. 355; and / or CDR-L1 comprising the amino acid sequence presented in SEQ ID NO. 370; CDR-L2 comprising the amino acid sequence presented in SEQ ID NO. 372; and CDR-L3 comprising the amino acid sequence presented in SEQ ID NO. 374.;

[0016] In one embodiment of the present invention, the antigen-binding protein of the present invention comprises a heavy chain set of CDR and a light chain set of CDR as follows:

[0017] (i) a heavy chain variable region comprising CDR-H1 having the amino acid sequence presented in SEQ ID NO. 4; CDR-H2 having the amino acid sequence presented in SEQ ID NO. 6; and CDR-H3 having the amino acid sequence presented in SEQ ID NO. 8; and a light chain variable region comprising CDR-L1 having the amino acid sequence presented in SEQ ID NO. 12; CDR-L2 having the amino acid sequence presented in SEQ ID NO. 14; and CDR-L3 having the amino acid sequence presented in SEQ ID NO. 16; (ii) a heavy chain variable region comprising CDR-H1 having the amino acid sequence presented in SEQ ID NO. 24; CDR-H2 having the amino acid sequence presented in SEQ ID NO. 26; and CDR-H3 having the amino acid sequence presented in SEQ ID NO. 28; and CDR-L1 having the amino acid sequence presented in SEQ ID NO. 32; and CDR-L2 having the amino acid sequence presented in SEQ ID NO. 34; (iii) a light chain variable region comprising CDR-L3 having the amino acid sequence presented in SEQ ID NO. 36; (iii) a heavy chain variable region comprising CDR-H1 having the amino acid sequence presented in SEQ ID NO. 44; CDR-H2 having the amino acid sequence presented in SEQ ID NO. 46; and CDR-H3 having the amino acid sequence presented in SEQ ID NO. 48; and a light chain variable region comprising CDR-L1 having the amino acid sequence presented in SEQ ID NO. 52; CDR-L2 having the amino acid sequence presented in SEQ ID NO. 54; and CDR-L3 having the amino acid sequence presented in SEQ ID NO. 56; (iv) a heavy chain variable region comprising CDR-H1 having the amino acid sequence presented in SEQ ID NO. 64; CDR-H2 having the amino acid sequence presented in SEQ ID NO. 66; and CDR-H3 having the amino acid sequence presented in SEQ ID NO. 68; and CDR-L1 having the amino acid sequence presented in SEQ ID NO. 72; A light chain variable region comprising a CDR-L2 having the amino acid sequence presented in SEQ ID NO. 54; and a CDR-L3 having the amino acid sequence presented in SEQ ID NO. 75;(v) a heavy chain variable region comprising CDR-H1 having the amino acid sequence presented in SEQ ID NO. 83; CDR-H2 having the amino acid sequence presented in SEQ ID NO. 85; and CDR-H3 having the amino acid sequence presented in SEQ ID NO. 87; and a light chain variable region comprising CDR-L1 having the amino acid sequence presented in SEQ ID NO. 91; CDR-L2 having the amino acid sequence presented in SEQ ID NO. 93; and CDR-L3 having the amino acid sequence presented in SEQ ID NO. 95; (vi) a heavy chain variable region comprising CDR-H1 having the amino acid sequence presented in SEQ ID NO. 103; CDR-H2 having the amino acid sequence presented in SEQ ID NO. 105; and CDR-H3 having the amino acid sequence presented in SEQ ID NO. 107; and CDR-L1 having the amino acid sequence presented in SEQ ID NO. 111; and CDR-L2 having the amino acid sequence presented in SEQ ID NO. 54; (vi) a light chain variable region comprising CDR-L3 having the amino acid sequence presented in SEQ ID NO. 113; (vi) a heavy chain variable region comprising CDR-H1 having the amino acid sequence presented in SEQ ID NO. 121; CDR-H2 having the amino acid sequence presented in SEQ ID NO. 123; and CDR-H3 having the amino acid sequence presented in SEQ ID NO. 125; a light chain variable region comprising CDR-L1 having the amino acid sequence presented in SEQ ID NO. 129; CDR-L2 having the amino acid sequence presented in SEQ ID NO. 54; and CDR-L3 having the amino acid sequence presented in SEQ ID NO. 132; (vii) a heavy chain variable region comprising CDR-H1 having the amino acid sequence presented in SEQ ID NO. 140; CDR-H2 having the amino acid sequence presented in SEQ ID NO. 142; and CDR-H3 having the amino acid sequence presented in SEQ ID NO. 144; and CDR-L1 having the amino acid sequence presented in SEQ ID NO. 148; CDR-L2 containing the amino acid sequence presented in SEQ ID NO. 54;(viii) a light chain variable region comprising CDR-L3 having the amino acid sequence presented in SEQ ID NO. 150; (viii) a heavy chain variable region comprising CDR-H1 having the amino acid sequence presented in SEQ ID NO. 158; CDR-H2 having the amino acid sequence presented in SEQ ID NO. 160; and CDR-H3 having the amino acid sequence presented in SEQ ID NO. 162; and a light chain variable region comprising CDR-L1 having the amino acid sequence presented in SEQ ID NO. 166; CDR-L2 having the amino acid sequence presented in SEQ ID NO. 14; and CDR-L3 having the amino acid sequence presented in SEQ ID NO. 168; (ix) a heavy chain variable region comprising CDR-H1 having the amino acid sequence presented in SEQ ID NO. 176; CDR-H2 having the amino acid sequence presented in SEQ ID NO. 178; and CDR-H3 having the amino acid sequence presented in SEQ ID NO. 180; and CDR-L1 having the amino acid sequence presented in SEQ ID NO. 72; (x) a light chain variable region comprising CDR-L2 having the amino acid sequence presented in SEQ ID NO. 54; and CDR-L3 having the amino acid sequence presented in SEQ ID NO. 184; (x) a heavy chain variable region comprising CDR-H1 having the amino acid sequence presented in SEQ ID NO. 192; CDR-H2 having the amino acid sequence presented in SEQ ID NO. 194; and CDR-H3 having the amino acid sequence presented in SEQ ID NO. 196; and a light chain variable region comprising CDR-L1 having the amino acid sequence presented in SEQ ID NO. 72; CDR-L2 having the amino acid sequence presented in SEQ ID NO. 54; and CDR-L3 having the amino acid sequence presented in SEQ ID NO. 184; (xi) a heavy chain variable region comprising CDR-H1 having the amino acid sequence presented in SEQ ID NO. 202; CDR-H2 having the amino acid sequence presented in SEQ ID NO. 204; and CDR-H3 having the amino acid sequence presented in SEQ ID NO. 206; and CDR-L1 comprising the amino acid sequence presented in SEQ ID NO. 72;(xii) a light chain variable region comprising CDR-L2 having the amino acid sequence presented in SEQ ID NO. 54; and CDR-L3 having the amino acid sequence presented in SEQ ID NO. 184; (xii) a heavy chain variable region comprising CDR-H1 having the amino acid sequence presented in SEQ ID NO. 176; CDR-H2 having the amino acid sequence presented in SEQ ID NO. 212; and CDR-H3 having the amino acid sequence presented in SEQ ID NO. 214; and a light chain variable region comprising CDR-L1 having the amino acid sequence presented in SEQ ID NO. 72; CDR-L2 having the amino acid sequence presented in SEQ ID NO. 54; and CDR-L3 having the amino acid sequence presented in SEQ ID NO. 184; (xiii) a heavy chain variable region comprising CDR-H1 having the amino acid sequence presented in SEQ ID NO. 220; CDR-H2 having the amino acid sequence presented in SEQ ID NO. 222; and CDR-H3 having the amino acid sequence presented in SEQ ID NO. 224; (xiv) a light chain variable region comprising CDR-L1 having the amino acid sequence presented in SEQ ID NO. 228; CDR-L2 having the amino acid sequence presented in SEQ ID NO. 230; and CDR-L3 having the amino acid sequence presented in SEQ ID NO. 232; (xiv) a heavy chain variable region comprising CDR-H1 having the amino acid sequence presented in SEQ ID NO. 240; CDR-H2 having the amino acid sequence presented in SEQ ID NO. 242; and CDR-H3 having the amino acid sequence presented in SEQ ID NO. 244; and a light chain variable region comprising CDR-L1 having the amino acid sequence presented in SEQ ID NO. 248; CDR-L2 having the amino acid sequence presented in SEQ ID NO. 250; and CDR-L3 having the amino acid sequence presented in SEQ ID NO. 252; (xv) CDR-H1 having the amino acid sequence presented in SEQ ID NO. 260; CDR-H2 having the amino acid sequence presented in SEQ ID NO. 262; and a heavy chain variable region comprising a CDR-H3 having the amino acid sequence presented in SEQ ID NO. 264;(xvi) a light chain variable region comprising CDR-L1 having the amino acid sequence presented in SEQ ID NO. 268; CDR-L2 having the amino acid sequence presented in SEQ ID NO. 54; and CDR-L3 having the amino acid sequence presented in SEQ ID NO. 270; (xvi) a heavy chain variable region comprising CDR-H1 having the amino acid sequence presented in SEQ ID NO. 278; CDR-H2 having the amino acid sequence presented in SEQ ID NO. 280; and CDR-H3 having the amino acid sequence presented in SEQ ID NO. 282; and a light chain variable region comprising CDR-L1 having the amino acid sequence presented in SEQ ID NO. 72; CDR-L2 having the amino acid sequence presented in SEQ ID NO. 54; and CDR-L3 having the amino acid sequence presented in SEQ ID NO. 184; (xvii) CDR-H1 having the amino acid sequence presented in SEQ ID NO. 288; CDR-H2 having the amino acid sequence presented in SEQ ID NO. 290; (xviii) a heavy chain variable region comprising CDR-H3 having the amino acid sequence presented in SEQ ID NO. 292; CDR-L1 having the amino acid sequence presented in SEQ ID NO. 72; CDR-L2 having the amino acid sequence presented in SEQ ID NO. 54; and a light chain variable region comprising CDR-L3 having the amino acid sequence presented in SEQ ID NO. 184; (xviii) a heavy chain variable region comprising CDR-H1 having the amino acid sequence presented in SEQ ID NO. 298; CDR-H2 having the amino acid sequence presented in SEQ ID NO. 300; and CDR-H3 having the amino acid sequence presented in SEQ ID NO. 302; and a light chain variable region comprising CDR-L1 having the amino acid sequence presented in SEQ ID NO. 306; CDR-L2 having the amino acid sequence presented in SEQ ID NO. 230; and CDR-L3 having the amino acid sequence presented in SEQ ID NO. 309; (xix) a CDR-H1 having the amino acid sequence presented in SEQ ID NO. 317; CDR-H2 containing the amino acid sequence presented in SEQ ID NO. 319;and a heavy chain variable region comprising CDR-H3 comprising the amino acid sequence presented in SEQ ID NO. 321; and a light chain variable region comprising CDR-L1 comprising the amino acid sequence presented in SEQ ID NO. 325; CDR-L2 comprising the amino acid sequence presented in SEQ ID NO. 327; and CDR-L3 comprising the amino acid sequence presented in SEQ ID NO. 329; (xx) a heavy chain variable region comprising CDR-H1 comprising the amino acid sequence presented in SEQ ID NO. 337; CDR-H2 comprising the amino acid sequence presented in SEQ ID NO. 339; and CDR-H3 comprising the amino acid sequence presented in SEQ ID NO. 341; and a light chain variable region comprising CDR-L1 comprising the amino acid sequence presented in SEQ ID NO. 72; CDR-L2 comprising the amino acid sequence presented in SEQ ID NO. 54; and CDR-L3 comprising the amino acid sequence presented in SEQ ID NO. 184; (xxi) a CDR-H1 comprising the amino acid sequence presented in SEQ ID NO. 347; (xxii) a heavy chain variable region comprising CDR-H2 having the amino acid sequence presented in SEQ ID NO. 349; and CDR-H3 having the amino acid sequence presented in SEQ ID NO. 351; and a light chain variable region comprising CDR-L1 having the amino acid sequence presented in SEQ ID NO. 72; CDR-L2 having the amino acid sequence presented in SEQ ID NO. 54; and CDR-L3 having the amino acid sequence presented in SEQ ID NO. 355; (xxii) a heavy chain variable region comprising CDR-H1 having the amino acid sequence presented in SEQ ID NO. 363; CDR-H2 having the amino acid sequence presented in SEQ ID NO. 66; and CDR-H3 having the amino acid sequence presented in SEQ ID NO. 366; and a light chain variable region comprising CDR-L1 having the amino acid sequence presented in SEQ ID NO. 370; CDR-L2 having the amino acid sequence presented in SEQ ID NO. 372; and CDR-L3 having the amino acid sequence presented in SEQ ID NO. 374.;

[0018] A complex comprising the antigen-binding protein of the present invention bound to the IL2Rγ polypeptide or its antigen fragment is also part of the present invention.

[0019] The present invention also relates to an antigen-binding protein (e.g., an antibody or an antigen-binding fragment thereof) or its immunoglobulin chain (e.g., V H , V L A method for producing (HC or LC) is provided, said method comprising the following steps: (a) introducing one or more polynucleotides (or a vector containing said polynucleotides) encoding one or more immunoglobulin chains of said antigen-binding protein into a host cell (e.g., CHO); (b) culturing said host cell under conditions that may be favorable for the expression of said polynucleotides; and (c) optionally isolating the antigen-binding protein or immunoglobulin chain from said host cell and / or the medium in which said host cell grew. The antigen-binding protein or immunoglobulin chain that is the product of said method forms part of the present invention.

[0020] The present invention also provides a polypeptide comprising: (a) a heavy chain comprising the amino acid sequence presented in SEQ ID NOs 2, 18, 22, 38, 42, 58, 62, 77, 81, 97, 101, 115, 119, 134, 138, 152, 156, 170, 174, 186, 190, 198, 200, 208, 210, 216, 218, 234, 238, 254, 258, 272, 276, 284, 286, 294, 296, 311, 315, 331, 335, 343, 345, 357, 361 and / or 376 Immunoglobulin or CDR-H1, CDR-H2, and CDR-H3 of the variable region thereof, or variants thereof; and / or (b) a light chain immunoglobulin comprising the amino acid sequence presented in SEQ ID NOs 10, 20, 30, 40, 50, 60, 70, 79, 89, 99, 109, 117, 127, 136, 146, 154, 164, 172, 182, 188, 226, 236, 246, 256, 266, 274, 304, 313, 323, 333, 353, 359, 368 and / or 378, or CDR-L1, CDR-L2 and CDR-L3 of a variable region thereof, or a variant thereof, or (c) an amino acid sequence presented in a member selected from the group consisting of SEQ ID NOs 1-378, or a variant thereof. The present invention also provides a polynucleotide encoding one or more of the polypeptides or a vector (e.g., a plasmid) comprising the polynucleotide.

[0021] The present invention also relates to an antigen-binding protein (e.g., an antibody or an antigen-binding fragment thereof) or an immunoglobulin chain presented herein (e.g., V H , V L Provides a host cell (e.g., CHO cell) containing HC or LC) or a polypeptide or polynucleotide or a vector.

[0022] The present invention also provides a composition or kit comprising one or more of the antigen-binding proteins presented herein, combined with additional therapeutic agents (e.g., anti-inflammatory agents, anti-TNFα antibodies or binding proteins, infliximab, adalimumab, etanercept, golimumab, corticosteroids, prednisolone, methylprednisolone, anti-thymocyte globulin, alemtuzumab, dacluzumab, in vitro photophoresis, mycophenolate mofetil, sirolimus, pentostatin, mesenchymal stem cells, inolimomab, denilukin, or baciliximab).

[0023] The present invention further provides a pharmaceutical formulation comprising the antigen-binding protein (e.g., antibody or antigen-binding fragment thereof) presented herein and a pharmaceutically acceptable carrier and optionally additional therapeutic agents (e.g., anti-inflammatory agents, anti-TNFα antibody or binding protein, infliximab, adalimumab, etanercept, golimumab, corticosteroids, prednisolone, methylprednisolone, antithymocyte globulin, alemtuzumab, dacluzumab, in vitro photophoresis, mycophenolate mofetil, tacrolimus, cyclosporine, sirolimus, pentostatin, mesenchymal stem cells, inolimomab, denilukin, or basiliximab).

[0024] The present invention also provides a container or injection device (e.g., vial, syringe, pre-filled syringe or auto-injector) comprising the antigen-binding protein or composition (e.g., pharmaceutical formulation) presented herein.

[0025] The present invention also provides a method for administering an antigen-binding protein or a composition presented herein to a subject (e.g., a person), said method comprising the step of introducing said antigen-binding protein or composition into the body of said subject, for example, by injection (e.g., subcutaneous, intravenous, or intramuscular). The present invention also provides a method for treating or preventing an IL2Rγ-mediated disease or condition (e.g., graft-versus-host disease, organ transplant rejection, skin transplant rejection, heart transplant rejection, lung transplant rejection, kidney transplant rejection, liver transplant rejection, birdshot chorioretinopathy, multiple sclerosis, uveitis, autoimmune disease, type I diabetes mellitus, multiple sclerosis, rheumatoid arthritis, systemic lupus erythematosus, and / or myasthenia gravis), comprising the step of administering an effective amount of said antigen-binding protein or composition presented herein, for example, by injection.

[0026] The present invention also blocks STAT phosphorylation in peripheral blood mononuclear cells (e.g., T cells) induced by cytokines (e.g., IL-2, IL-4, IL-7, IL-15 and / or IL-21) in a subject; blocks STAT (e.g., STAT3) phosphorylation in mast cells induced by cytokines (e.g., IL-9); and reduces serum levels of interferon-gamma, tumor necrosis factor-alpha, IL-6, IL-8, IL-10 and / or mKC / GRO (e.g., in a subject receiving a graft); A method for blocking and / or reducing serum levels of JAK-STAT-mediated (e.g., STAT3) intracellular signaling induced by cytokines in the IL2Rγ family (e.g., IL-2, IL-4, IL-7, IL-9, IL-15 and / or IL-21) in CD45+ immune cells, NK cells, T-cells and / or B-cells (e.g., neutrophils), said method comprising the step of administering to said subject an effective amount of the anti-IL2Rγ antigen-binding protein, a composition thereof, or a formulation thereof as presented herein. In one embodiment of the present invention, the subject suffers from an IL2Rγ-mediated disease or condition, e.g., graft-versus-host disease, organ transplant rejection, β-islet cell graft rejection, skin transplant rejection, heart transplant rejection, lung transplant rejection, kidney transplant rejection, liver transplant rejection, shot chorioretinopathy, multiple sclerosis, uveitis, autoimmune disease, type I diabetes mellitus, multiple sclerosis, rheumatoid arthritis, systemic lupus erythematosus, myasthenia gravis, aplastic anemia, atopic dermatitis, asthma, mast cell activation disorder, mast cell activation syndrome (MCAS), systemic mastocytosis (SM) and / or mast cell leukemia (MCL). Brief explanation of the drawing

[0027] Fig. 1 (ab). Blocking of human (A) IL-2-, (B) IL-4-, (C) IL-7-, (D) IL-15-, and (E) IL-21-induced STAT phosphorylation in human CD4+ T cells by various concentrations of anti-IL-2R gamma antibodies H4H12857P, H4H12874P, H4H12886P, H4H12889P, and H4H12922P2; and antibodies REGN1945 and COMP1499. Fig. 2 Blocking of human IL-9-induced STAT3 phosphorylation in in vitro differentiated human mast cells by anti-IL-2R gamma antibodies H4H12874P, H4H12886P, H4H12889P, H4H12922P2; and antibodies COMP1499 and REGN1945. Fig. 3 (af) Percentage of initial body weight of mice with human PBMCs administered anti-IL2R gamma antibodies (E) H4H12889P and (F) H4H12922P2 and antibody (D) COMP1499 over time. (B) indicates a control experiment in mice without antibodies, (C) isotype control antibodies, or (A) mice without human PBMCs. The initiation of antibody injection on day 21 and the termination of antibody injection on day 59 are indicated by dashed lines. Fig. 4 This shows the survival rates over time in mice injected with anti-IL2R gamma antibodies H4H12889P and H4H12922P2, antibody COMP1499, and antibody REGN1945, and in mice not injected with any antibodies. The huPBMC group is not shown. Differences in animal survival rates relative to the isotype control antibody groups were analyzed by the Mantel-Cox log-rank test. A P value <0.05 was considered statistically significant. **, P value <0.0021; ****, P value <0.0001. The initiation of antibody injection on day 21 and the termination of antibody injection on day 59 are indicated by dashed lines. Fig. 5 (ad). Absolute human cell counts in blood at day 35 after huPBMC injection in mice that did not receive antibodies (IgG absence) or received REGN1945, COMP1499, or anti-IL2R gamma antibodies H4H12889P or H4H12922P2 ((A) human CD45 cells; (B) human T-cells; (C) human CD4 T-cells; and (D) human CD8 T-cells). Group “huPBMC absence” is not indicated; #, significantly different from group “huPBMC absence”; †, significantly different from group “huPBMC - IgG absence”; *, significantly different from group “huPBMCs - REGN1945”. Each symbol represents a mouse. Zero values ​​were arbitrarily changed to 0.01 for graphing purposes (log scale). Fig. 6 (ad) . Blood counts of human (A) CD45+ cells, (B) T cells, (C) CD4+ T cells, and (D) CD8+ T cells over time in mice administered anti-IL2R gamma antibody H4H12889P or H4H12922P2; or COMP1499 or isotype control antibody. The initiation of antibody injection on day 21 and the termination of antibody injection on day 59 are indicated by dashed lines. Fig. 7 (ai)Serum levels of human and mouse cytokines ((A) human interferon-gamma; (B) human TNFα; (C) human IL-6; (D) human IL-8; (E) human IL-10; (F) mouse TNFα; (G) mouse IL-6; (H) mouse KC / GRO; and (I) mouse IL-10) at day 42 after huPBMC injection in mice that received no antibodies (IgG absence), or received REGN1945, COMP1499, or anti-IL2R gamma antibodies H4H12889P or H4H12922P2, or in mice without any human PBMCs. #, significantly different from the “huPBMC absence” group; †, significantly different from the “huPBMC - IgG absence” group; *, significantly different from the “huPBMCs - REGN1945” group. Each symbol represents a mouse. Fig. 8 (ad) . Serum levels of (A) human IFN-γ, (B) human TNFα, (C) mouse TNFα, and (D) mouse IL-6 over time in mice administered anti-IL2R gamma antibodies H4H12889P or H4H12922P2; or COMP1499 or isotype control antibodies. Fig. 9 (ab) Levels of total human antibodies or CD45+ immune cells (A), NK cells (B), T cells (C), B cells (D), or neutrophils (E) in the blood of mice treated with various doses of the antibody REGN1945 or H4H12889P. Fig. 10 Experimental layout for in vivo skin graft rejection experiment. Fig. 11 . Time to onset of skin graft rejection in mice that did not receive any antibodies or were administered REGN1945 or H4H12889P. Fig. 12 . Time to complete rejection of skin grafts in mice that did not receive any antibodies, or were administered REGN1945 or H4H12889P. Fig. 13Total donor-specific IgG antibodies in non-engrafted or transplanted mice that have not received any antibodies or have received REGN1945 or H4H12889P. Specific details for implementing the invention

[0028] The present invention provides an antibody and an antigen-binding fragment thereof that specifically bind to human and Macassar faciculariis IL2Rγ and exhibit exceptional biological activity, particularly in relation to the blockade of cytokine-induced STAT phosphorylation in T-cells and the blockade of graft-versus-host disease in a mouse model applicable thereto.

[0029] According to the present invention, conventional molecular biology, microbiology, and recombinant DNA techniques within the scope of the art may be used. Such techniques are fully described in the literature. For example, the literature (Sambrook, Fritsch & Maniatis, Molecular Cloning: A Laboratory Manual, Second Edition (1989) Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY (herein "Sambrook, et al., 1989"); DNA Cloning: A Practical Approach, Volumes I and II (DN Glover ed. 1985); Oligonucleotide Synthesis (MJ Gait ed. 1984); Nucleic Acid Hybridization (BD Hames & SJ Higgins eds. (1985)); Transcription And Translation (BD Hames & SJ Higgins, eds. (1984)); Animal Cell Culture (RI Freshney, ed. (1986)); B. Perbal, A Practical Guide to Molecular Cloning (1984); et al. Refer to (eds.), Current Protocols in Molecular Biology, John Wiley & Sons, Inc. (1994).

[0030] IL-2Rγ

[0031] Interleukin-2 receptor subunit gamma is also known as CD132; the standard cytokine receptor γc-chain; IL-2RG; IL-2Rg; IL2R gamma; IL-2Rγ, IMD4; P64: SCIDX; or SCIDX1. IL2Rγ is a standard subunit of several interleukin receptors, including IL-2R, IL-4R, IL-7R, IL-9R, IL-15R, and IL21R.

[0032] In one embodiment of the present invention, human IL2Rγ is encoded by the nucleotide sequence presented under Genbank approval number NM_000206. In one embodiment of the present invention, human IL2Rγ comprises the amino acid sequence presented under Genbank approval number NP_000197.

[0033] antigen-binding protein

[0034] The present invention relates to the IL2Rγ protein or its antigen fragment ( for example The invention provides antigen-binding proteins that specifically bind to the extracellular domain of IL2Rγ, e.g., antibodies (e.g., human antibodies, monoclonal antibodies, and recombinant antibodies) and antigen-binding fragments thereof. Antigen-binding proteins that bind to epitopes on IL2Rγ identical to IL2Rγ, or that compete with IL2Rγ for binding to any antigen-binding protein presented herein, are also part of the invention.

[0035] The present invention also includes SEQ ID NOs 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 30, 32, 34, 36, 38, 40, 42, 44, 46, 48, 50, 52, 54, 56, 58, 60, 62, 64, 66, 68, 70, 72, 75, 77, 79, 81, 83, 85, 87, 89, 91, 93, 95, 97, 99, 101, 103, 105, 107, 109, 111, 113, 115, 117, 119, 121, 123, 125, 127, 129, 132, 134, 136, 138, 140, 142, 144, 146, 148, 150, 152, 154, 156, 158, 160, 162, 164, 166, 168, 170, 172, 174, 176, 178, 180, 182, 184, 186, 188, 190, 192, 194, 196, 198, 200, 202, 204, 206, 208, 210, 212, 214, 216, 218, 220, 222, 224, 226, 228, 230, 232, 234, 236, 238, 240, 242, 244, 246, 248, 250, 252, 254, 256, 258, 260, 262, 264, 266, 268, 270, 272, 274, 276, 278, 280, 282, 284, 286, 288, 290, 292, 294, 296, 298, 300, 302, 304, 306, 309, 311, 313, 315, Provides any polypeptide comprising the amino acid sequences presented in 317, 319, 321, 323, 325, 327, 329, 331, 333, 335, 337, 339, 341, 343, 345, 347, 349, 351, 353, 355, 357, 359, 361, 363, 366, 368, 370, 372, 374, 376 and / or 378 or variants thereof.Optionally, the polypeptide is fused to one or more other polypeptides, e.g., human Fc (e.g., human IgG, e.g., IgG1 or IgG4 (e.g., containing the S108P mutation)).

[0036] The term “antibody” as used herein refers to an immunoglobulin molecule comprising four polypeptide chains (i.e., “complete antibody molecule”) (e.g., IgG) consisting of two heavy chains (HC) and two light chains (LC) interconnected by disulfide bonds—e.g., H4H12857P; H4H12858P; H4H12859P; H4H12863P; H4H12874P; H4H12871P; H4H12884P; H4H12886P; H4H12889P; H4H12890P; H4H12899P; H4H12900P; H4H12908P; H4H12913P2; H4H12922P2; H4H12924P2; H4H12926P2; H4H12927P2; H4H12934P2; H4H13538P; H4H13541P; H4H13544P2; or H4H13545P2 is referred to. In one embodiment of the present invention, each antibody heavy chain (Hc) has a heavy chain variable region (“HCVR” or “V H ”) (e.g., SEQ ID NOs 2, 22, 42, 62, 81, 101, 119, 138, 156, 174, 190, 200, 210, 218, 238, 258, 276, 286, 296, 315, 335, 345 or 361 or variants thereof) and heavy chain invariant region (domain C H 1, C H 2 and C H Each antibody light chain (LC) comprises (including 3); and each antibody light chain comprises a light chain variable region (“LCVR” or “V L ”) (e.g., SEQ ID NOs 10, 30, 50, 70, 89, 109, 127, 146, 164, 182, 226, 246, 266, 304, 323, 353 or 368 or variants thereof) and light chain invariant region (CL Includes ). The above V H and V L The region can be further subdivided into a more conserved region called the Framework Region (FR) and a hypervariable region called the Intersecting Complementarity Decision Region (CDR). Each V H and V L It comprises three CDRs and four FRs aligned from amino terminus to carboxy terminus in the following order: FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4. In a specific embodiment of the present invention, the FRs of the antibody (or its antigen-binding fragment) are identical to the sequence of a human germ cell lineage, or are naturally or artificially modified.

[0037] Typically, the variable domains of heavy and light chain immunoglobulins also include three hypervariable regions, referred to as complementarity determining regions (CDRs), located in a relatively conserved framework region (FR). Generally, from the N-terminus to the C-terminus, both the light and heavy chain variable domains include FR1, CDR1, FR2, CDR2, FR3, CDR3, and FR4. In an embodiment of the present invention, the assignment of amino acids to each domain is based on the literature (Ref. Kabat, et al. ; National Institutes of Health, Bethesda, Md.; 5th ed.; NIH Publ. No. 91-3242 (1991); Kabat (1978) Adv. Prot. Chem. 32:1-75; Kabat, et al. , (1977) J. Biol. Chem. 252:6609-6616; Chothia, et al. , (1987) J Mol. Biol. 196:901-917 or Chothia, et al. The present invention follows the sequence definition of a protein of immunological interest in (1989) Nature 342:878-883). Accordingly, the present invention V H CDR and V LA antibody comprising a CDR and an antigen-binding fragment, and the V H and V L It comprises an amino acid sequence (or a variant thereof) as presented herein, and said CDR is as defined according to Cavat and / or Chotia.

[0038] The terms “antigen-binding portion” or “antigen-binding fragment,” such as those of antibodies or antigen-binding proteins as used herein, include any naturally occurring, enzymatically obtainable, synthetic or genetically modified polypeptides or glycoproteins that specifically bind to an antigen to form a complex. Non-limiting examples of antigen-binding fragments include: (i) a Fab fragment; (ii) an F(ab')2 fragment; (iii) an Fd fragment (a heavy chain portion of the Fab fragment cleaved with papain); (iv) an Fv fragment (V H or V L); and (v) single-stranded Fv (scFv) molecules. Other processed molecules, e.g., domain-specific antibodies, single-domain antibodies, domain-deleted antibodies, chimeric antibodies, CDR-grafted antibodies, diabodies, triabodidies, tetrabodies, minibodies, and small modular immunoagents (SMIPs) are also included within the expression “antigen-binding fragment” as used herein. In one embodiment of the invention, the antigen-binding fragment is H4H12857P; H4H12858P; H4H12859P; H4H12863P; H4H12874P; H4H12871P; H4H12884P; H4H12886P; H4H12889P; H4H12890P; H4H12899P; H4H12900P; H4H12908P; It includes three or more CDRs of H4H12913P2; H4H12922P2; H4H12924P2; H4H12926P2; H4H12927P2; H4H12934P2; H4H13538P; H4H13541P; H4H13544P2; or H4H13545P2 (e.g., CDR-H1, CDR-H2 and CDR-H3; or CDR-L1, CDR-L2 and CDR-L3).

[0039] In one embodiment of the present invention, the antigen-binding protein of the present invention (e.g., its antibody or antigen-binding fragment) comprises a combination of heavy chain CDRs (CDR-H1, CDR-H2, and CDR-H3) as presented in Table A below. H ( for example It includes heavy chain immunoglobulin containing , HC).

[0040] Table A

[0041]

[0042] Table B

[0043]

[0044] In one embodiment of the present invention, the antigen-binding protein of the present invention (e.g., an antibody or an antigen-binding fragment thereof) comprises a combination of heavy chain and light chain CDRs (CDR-H1, CDR-H2 and CDR-H3; and CDR-L1, CDR-L2 and CDR-L3) as presented in Table C below, V H ( for example , HC) and V L It includes heavy chain and light chain immunoglobulins, including (e.g., LC).

[0045] Table C

[0046]

[0047] The present invention is as follows V H and V L It includes an antigen-binding protein (e.g., an antibody or its antigen-binding fragment) comprising a polypeptide pair containing an amino acid sequence:

[0048] Sequence No. 2 and Sequence No. 10;

[0049] Sequence No. 22 and Sequence No. 30;

[0050] Sequence No. 42 and Sequence No. 50;

[0051] Sequence No. 62 and Sequence No. 70;

[0052] Sequence No. 81 and Sequence No. 89;

[0053] Sequence No. 101 and Sequence No. 109;

[0054] Sequence No. 119 and Sequence No. 127;

[0055] Sequence No. 138 and Sequence No. 146;

[0056] Sequence No. 156 and Sequence No. 164;

[0057] Sequence No. 174 and Sequence No. 182;

[0058] Sequence No. 190 and Sequence No. 182;

[0059] Sequence No. 200 and Sequence No. 182;

[0060] Sequence No. 210 and Sequence No. 182;

[0061] Sequence No. 218 and Sequence No. 226;

[0062] Sequence No. 238 and Sequence No. 246;

[0063] Sequence No. 258 and Sequence No. 266;

[0064] Sequence No. 276 and Sequence No. 182;

[0065] Sequence No. 286 and Sequence No. 182;

[0066] Sequence No. 296 and Sequence No. 304;

[0067] Sequence No. 315 and Sequence No. 323;

[0068] Sequence No. 335 and Sequence No. 182;

[0069] Sequence No. 345 and Sequence No. 353; or

[0070] Sequence No. 361 and Sequence No. 368;

[0071] The present invention comprises an antigen-binding protein (e.g., an antibody or an antigen-binding fragment thereof) comprising the following amino acid sequence pairs encoding HC and LC:

[0072] Sequence No. 18 and Sequence No. 20;

[0073] Sequence No. 38 and Sequence No. 40;

[0074] Sequence No. 58 and Sequence No. 60;

[0075] Sequence No. 77 and Sequence No. 79;

[0076] Sequence No. 97 and Sequence No. 99;

[0077] Sequence No. 115 and Sequence No. 117;

[0078] Sequence No. 134 and Sequence No. 136;

[0079] Sequence No. 152 and Sequence No. 154;

[0080] Sequence No. 170 and Sequence No. 172;

[0081] Sequence No. 186 and Sequence No. 188;

[0082] Sequence No. 198 and Sequence No. 188;

[0083] Sequence No. 208 and Sequence No. 188;

[0084] Sequence No. 216 and Sequence No. 188;

[0085] Sequence No. 234 and Sequence No. 236;

[0086] Sequence No. 254 and Sequence No. 256;

[0087] Sequence No. 272 ​​and Sequence No. 274;

[0088] Sequence No. 284 and Sequence No. 188;

[0089] Sequence No. 294 and Sequence No. 188;

[0090] Sequence No. 311 and Sequence No. 313;

[0091] Sequence No. 331 and Sequence No. 333;

[0092] Sequence No. 343 and Sequence No. 188;

[0093] Sequence No. 357 and Sequence No. 359; or

[0094] Sequence No. 376 and Sequence No. 378;

[0095] Embodiments of the present invention are also the corresponding V specifically presented herein. H , V L Immunoglobulin V comprising a variant amino acid sequence having at least 70% (e.g., 80%, 85%, 90%, 95%, 97%, or 99%) total amino acid sequence identity with the amino acid sequence of HC or LC. H and V L; or include antigen-binding proteins comprising HC and LC, e.g., anti-IL2Rγ antibody and its antigen-binding protein, wherein CDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2, and CDR-H3 of the immunoglobulin are not variants and comprise the amino acid sequences presented herein. Accordingly, in the above embodiment, the CDRs within the variant antigen-binding proteins are not variants themselves.

[0096] The present invention comprises a monoclonal composition comprising a monoclonal anti-IL2Rγ antigen-binding protein, e.g., an antibody and its antigen-binding fragment, and a plurality of isolated monoclonal antigen-binding proteins. The terms “monoclonal antibody” or “mAb” as used herein refer to members of a substantially homogeneous group of antibodies, that is, said antibody molecules comprising said group are identical in amino acid sequences, except for possible natural mutations that may be present in small amounts. In the composition, “a plurality” of said monoclonal antibodies and fragments refers to concentrations of said identical antibodies and fragments (i.e., in amino acid sequences, except for possible natural mutations that may be present in small amounts as discussed above) that are normally present in nature, e.g., in the blood of a host organism, e.g., a mouse or a human.

[0097] In an embodiment of the present invention, the anti-IL2Rγ antigen-binding protein, e.g., antibody or antigen-binding fragment, is e.g., type IgA ( for example , IgA1 or IgA2), IgD, IgE, IgG ( for example , comprising the heavy chain constant domain of IgG1, IgG2, IgG3, and IgG4 (e.g., including S228P and / or S108P mutations) or IgM. In embodiments of the present invention, antigen-binding proteins, e.g. Listen,The antibody or antigen-binding fragment contains, for example, a light chain constant domain of kappa or lambda. The present invention relates to an antigen-binding protein comprising a variable domain presented herein, connected to a heavy chain and / or light chain constant domain as described above, for example (e.g., H4H12857P; H4H12858P; H4H12859P; H4H12863P; H4H12874P; H4H12871P; H4H12884P; H4H12886P; H4H12889P; H4H12890P; H4H12899P; H4H12900P; H4H12908P; H4H12913P2; H4H12922P2; H4H12924P2; H4H12926P2; H4H12927P2; H4H12934P2; H4H13538P; Includes H4H13541P; H4H13544P2; or H4H13545P2).

[0098] The term “human” antigen-binding protein, such as antibody or antigen-binding fragment as used herein, comprises antibodies and fragments having variable and constant regions derived from immunoglobulin sequences of the human germline family, whether in human cells or in non-human cells, e.g., mouse cells. For example, refer to the literature (US8502018, US6596541, or US5789215). The human antibodies and antigen-binding fragments of the present invention, in embodiments of the present invention, for example, in CDR and particularly in CDR3, amino acid residues that are not encoded by the human germline family immunoglobulin sequence ( for example..., including those having mutations induced by in vitro random or site-specific mutagenesis or by in vivo somatic mutation. However, the term “human antibody” as used herein is not intended to include mAbs in which a CDR sequence derived from a germline of another mammalian species (e.g., mouse) is transplanted into a human FR sequence. The term includes non-human mammals or antibodies produced by recombination in cells of non-human mammals. The term is not intended to include antibodies isolated from or produced in human subjects. The present invention relates to a human antigen-binding protein (e.g., an antibody or an antigen-binding fragment thereof, e.g., H4H12857P; H4H12858P; H4H12859P; H4H12863P; H4H12874P; H4H12871P; H4H12884P; H4H12886P; H4H12889P; H4H12890P; H4H12899P; H4H12900P; H4H12908P; H4H12913P2; H4H12922P2; H4H12924P2; H4H12926P2; H4H12927P2; H4H12934P2; H4H13538P; H4H13541P; It includes H4H13544P2; or H4H13545P2).

[0099] The present invention comprises anti-IL2Rγ chimeric antigen-binding proteins, e.g., antibodies and antigen-binding fragments thereof and methods of using the same. A "chimeric antibody" as used herein is an antibody having a variable domain from a first antibody and a constant domain from a second antibody, wherein the first and second antibodies originate from different species. (References: e.g., US4816567; and Morrison et al. , (1984) Proc. Natl. Acad. Sci. USA 81: 6851-6855). The present invention is as presented herein ( for example, H4H12857P; H4H12858P; H4H12859P; H4H12863P; H4H12874P; H4H12871P; H4H12884P; H4H12886P; H4H12889P; H4H12890P; H4H12899P; H4H12900P; H4H12908P; H4H12913P2; H4H12922P2; H4H12924P2; H4H12926P2; H4H12927P2; H4H12934P2; H4H13538P; H4H13541P; H4H13544P2; or includes a chimeric antibody containing a variable domain (from H4H13545P2).

[0100] Terms such as antibody or antigen-binding fragment thereof, and “recombinant” antigen-binding protein, refer to molecules produced, expressed, isolated, or obtained by techniques or methods known in the art involving recombinant DNA techniques, including DNA splicing and transgenic expression. The terms include antibodies expressed in non-human mammals (including non-human transgenic mammals, e.g., transgenic mice), or in host cells (e.g., Chinese hamster ovary (CHO) cells) or cell expression systems, or antibodies isolated from a library of recombinant human antibodies. The present invention relates to a recombinant antigen-binding protein as presented herein (e.g., H4H12857P; H4H12858P; H4H12859P; H4H12863P; H4H12874P; H4H12871P; H4H12884P; H4H12886P; H4H12889P; H4H12890P; H4H12899P; H4H12900P; H4H12908P; H4H12913P2; H4H12922P2; H4H12924P2; H4H12926P2; H4H12927P2; H4H12934P2; H4H13538P; H4H13541P; H4H13544P2; or It includes H4H13545P2).

[0101] The antigen-binding fragment of the antibody comprises at least one variable domain in an embodiment of the invention. The variable domain may be a domain of any size or amino acid composition and will generally comprise at least one (e.g., 3) CDR that is adjacent to or forms a frame together with one or more framework sequences. V L V associated with the domain H In an antigen-binding fragment having a domain, V H and V L Domains can be located in any suitable alignment relative to one another. For example, the variable region is dimeric and V H -V H , V H -V L or V L -V L It may contain a dimer. Alternatively, the antigen-binding fragment of the antibody is a non-covalently bound monomeric V H and / or V L It may contain a domain.

[0102] In a specific embodiment, the antigen-binding fragment of the antibody may contain at least one variable domain covalently linked to at least one constant domain. Non-limiting exemplary configurations of variable and constant domains that may be found within the antigen-binding fragment of the antibody of the present invention include: (i) V H -C H 1; (ii) V H -C H 2; (iii) V H -C H 3; (iv) V H -C H 1-C H 2; (v) V H -C H 1-C H 2-C H 3; (vi) V H -C H 2-C H 3; (vii) V H -C L; (viii) V L -C H 1; (ix) V L -C H 2; (x) V L -CH3; (xi) V L -C H 1-C H 2; (xii) V L -C H 1-C H 2-C H 3; (xiii) V L -C H 2-C H 3; and (xiv) V L -C L In any configuration of variable and constant domains comprising any of the exemplary configurations listed above, the variable and constant domains may be directly connected to each other or connected by a complete hinge or linker region. The hinge region may consist of at least two amino acids (e.g., 5, 10, 15, 20, 40, 60, or more), which induce flexible or semi-flexible binding between adjacent variable and / or constant domains in a single polypeptide molecule. Furthermore, the antigen-binding fragments of the antibody of the present invention are each and / or one or more monomeric V H or V LThe invention may include homodimers or heterodimers (or other polymers) of any variable and invariant domain configuration listed above, non-covalently associated with the domain (e.g., by disulfide bond(s)). The invention relates to antigen-binding proteins presented herein, e.g., H4H12857P; H4H12858P; H4H12859P; H4H12863P; H4H12874P; H4H12871P; H4H12884P; H4H12886P; H4H12889P; H4H12890P; H4H12899P; H4H12900P; H4H12908P; H4H12913P2; H4H12922P2; H4H12924P2; H4H12926P2; It includes antigen-binding fragments of H4H12927P2; H4H12934P2; H4H13538P; H4H13541P; H4H13544P2; or H4H13545P2.

[0103] Antigen-binding proteins (e.g., antibodies and antigen-binding fragments) may be unispecific or multispecific (e.g., bispecific). Multispecific antigen-binding proteins are discussed further herein. The present invention specifically relates to the antigen-binding proteins presented herein (e.g., H4H12857P; H4H12858P; H4H12859P; H4H12863P; H4H12874P; H4H12871P; H4H12884P; H4H12886P; H4H12889P; H4H12890P; H4H12899P; H4H12900P; H4H12908P; H4H12913P2; H4H12922P2; H4H12924P2; H4H12926P2; H4H12927P2; H4H12934P2; H4H13538P; H4H13541P; H4H13544P2; or It includes unispecific and multispecific (e.g., bispecific) antigen-binding fragments comprising one or more variable domains from H4H13545P2).

[0104] The terms “specifically binds” or “binds specifically” refer, for example, to K during measurements by real-time label-free biolayer interferometric calibration at 25°C or 37°C, e.g., by the Octet® HTX biosensor, or by surface plasmon resonance, e.g., by BIACORE™, or by solution-affinity ELISA. D at least about 10 -7 M (e.g., 10 -8 M, 10 -9 M; 10 -10 M; 10 -11 M or 10 -12 Refers to an antigen-binding protein (e.g., an antibody or an antigen-binding fragment thereof) having binding affinity for an antigen such as the IL2Rγ protein, represented by M). The present invention comprises an antigen-binding protein that specifically binds to the IL2Rγ protein. In one embodiment of the present invention, the anti-IL2Rγ antigen-binding protein is a human and / or mouse and / or macaca facicularius ( Macaca fascicularis) and / or any K presented in Tables 3-1 to 3-12 for binding to rat IL2Rγ or its domains D Includes the value. “Anti-IL2R gamma” refers to an antigen-binding protein (or other molecule), for example, an antibody or its antigen-binding fragment that specifically binds to IL2R gamma.

[0105] “Isolated” antigen-binding proteins (e.g., antibodies or their antigen-binding fragments), polypeptides, polynucleotides, and vectors are at least partially free of other biological molecules of the origin of the cells or cell cultures from which they are produced. Such biological molecules include nucleic acids, proteins, other antibodies or antigen-binding fragments, lipids, carbohydrates, or other substances, e.g., cell debris and growth media. The isolated antigen-binding proteins may additionally be at least partially free of expression system components, such as biological molecules from host cells, or their growth media. Generally, the term “isolated” refers to the complete absence of such biological molecules (e.g., small or trace amounts of impurities may remain) or the absence of water, buffer, or salts, or a component of a pharmaceutical formulation comprising antigen-binding proteins (e.g., antibodies or antigen-binding fragments).

[0106] The present invention relates to the antigen-binding protein of the present invention ( for example , H4H12857P; H4H12858P; H4H12859P; H4H12863P; H4H12874P; H4H12871P; H4H12884P; H4H12886P; H4H12889P; H4H12890P; H4H12899P; H4H12900P; H4H12908P; H4H12913P2; H4H12922P2; H4H12924P2; H4H12926P2; H4H12927P2; H4H12934P2; H4H13538P; H4H13541P; H4H13544P2; or includes an antigen-binding protein, e.g., an antibody or an antigen-binding fragment that binds to the same epitope as the antigen-binding protein of H4H13545P2).

[0107] An antigen is, for example, a molecule to which an antibody binds, for example, a peptide (e.g., IL2R gamma or a fragment thereof (antigen fragment)). A specific region on the antigen that the antibody recognizes and binds to is called an epitope. An antigen-binding protein of the present invention (e.g., an antibody) that specifically binds to the antigen is part of the present invention.

[0108] The term “epitope” refers to an antigenic determinant (e.g., on IL2Rγ) that interacts with a specific antigen-binding site of an antigen-binding protein, known as a paratope, e.g., a variable region of an antibody molecule. A single antigen may have more than one epitope. Therefore, different antibodies may bind to different regions on the antigen and have different biological effects. The term “epitope” may also refer to a region on the antigen to which B and / or T cells respond and / or a region of the antigen bound by an antibody. Epitopes may be structurally or functionally limited. Functional epitopes are generally a subset of structural epitopes and contain residues that directly contribute to the affinity of the interaction. Epitopes may have linear or stereochemical structures, that is, they may be composed of non-linear amino acids. In certain embodiments, the epitope may comprise a crystalline group which is a chemically active surface group of a molecule, such as an amino acid, a sugar side chain, a phosphoryl group, or a sulfonyl group, and in certain embodiments, may have specific three-dimensional structural characteristics and / or specific charge characteristics. The epitope to which the antigen-binding protein of the present invention binds is IL2Rγ, for example , a fragment of human IL2Rγ, for example, may be included in the ectodomain, its domain 1 or domain 2. An antigen-binding protein of the present invention (e.g., an antibody) that binds to the epitope is part of the present invention.

[0109] Methods for determining the epitopes of antigen-binding proteins, e.g., antibodies, fragments, or polypeptides, include alanine scanning mutation analysis, peptide blot analysis (see Reineke (2004) Methods Mol. Biol. 248: 443-63), peptide cleavage analysis, crystallographic studies, and NMR analysis. Additionally, methods such as epitope excision, epitope extraction, and chemical modification of the antigen may also be used (see Tomer (2000) ProtTomer (2000) Prot. Sci. 9: 487-496). Another method that can be used to identify the amino acids within the polypeptide with which the antigen-binding protein (e.g., antibodies, fragments, or polypeptides) interacts is hydrogen / deuterium exchange detected by mass spectrometry. For example, refer to the literature (Ehring (1999) Analytical Biochemistry 267: 252-259; Engen and Smith (2001) Anal. Chem. 73: 256A-265A).

[0110] The present invention relates to IL2Rγ, for example, regarding binding to the variant IL2Rγ epitope as discussed herein, the antigen-binding proteins of the present invention, e.g., H4H12857P; H4H12858P; H4H12859P; H4H12863P; H4H12874P; H4H12871P; H4H12884P; H4H12886P; H4H12889P; H4H12890P; H4H12899P; H4H12900P; H4H12908P; H4H12913P2; H4H12922P2; H4H12924P2; H4H12926P2; H4H12927P2; H4H12934P2; H4H13538P; Includes H4H13541P; H4H13544P2; or an antigen-binding protein competing with H4H13545P2. As used herein, the term “competes” refers to an antigen-binding protein (e.g., an antibody or its antigen-binding fragment) that binds to an antigen (e.g., IL2Rγ) and inhibits or blocks the binding of another antigen-binding protein (e.g., an antibody or its antigen-binding fragment) to the antigen. Unless otherwise noted, the term also includes competition between two antigen-binding proteins in both orientations, e.g., an antibody, i.e., a first antibody that binds to the antigen and blocks binding by the second antibody, or vice versa. Thus, in embodiments of the present invention, competition occurs in one of the orientations. In certain embodiments, the first antigen-binding protein (e.g., an antibody) and the second antigen-binding protein (e.g., an antibody) may bind to the same epitope. Alternatively, the first and second antigen-binding proteins (e.g., antibodies) may bind to different, but, for example, overlapping or non-overlapping epitopes, such that, for example, one binding inhibits or blocks the binding of the second antibody through, for example, steric hindrance. Cross-competition between antigen-binding proteins (e.g., antibodies) can be measured by methods known in the art, for example, by real-time label-free biolayer interferometry assays.In addition, binding competition between anti-IL2Rγ antigen-binding proteins (e.g., monoclonal antibodies (mAbs)) can be determined using real-time label-free biolayer interferometry on the Octet RED384 biosensor (Pall ForteBio Corp.).

[0111] Typically, some modified antibody of the present invention or its antigen-binding fragment possesses the ability to specifically bind to IL2Rγ, and, for example, possesses at least 10% of its IL2Rγ binding activity (when compared to the parent antibody) when activity is expressed on a molar basis. Preferably, the antibody or antigen-binding fragment of the present invention possesses at least 20%, 50%, 70%, 80%, 90%, 95%, or 100% or more of IL2Rγ binding affinity compared to the parent antibody. Additionally, the antibody or antigen-binding fragment of the present invention is intended to include conserved or non-conserved amino acid substitutions (referred to as “conserved variants” or “function-conserved variants”) that do not substantially alter its biological activity.

[0112] polypeptides such as immunoglobulin chains ( for example , H4H12857P; H4H12858P; H4H12859P; H4H12863P; H4H12874P; H4H12871P; H4H12884P; H4H12886P; H4H12889P; H4H12890P; H4H12899P; H4H12900P; H4H12908P; H4H12913P2; H4H12922P2; H4H12924P2; H4H12926P2; H4H12927P2; H4H12934P2; H4H13538P; H4H13541P; H4H13544P2; or H4H13545P2 V H , V L “Variants” of , HC or LC or the CDR thereof comprising the amino acid sequence specifically presented herein are the reference amino acid sequence presented herein ( for example, arbitrary sequence number 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 30, 32, 34, 36, 38, 40, 42, 44, 46, 48, 50, 52, 54, 56, 58, 60, 62, 64, 66, 68, 70, 72, 75, 77, 79, 81, 83, 85, 87, 89, 91, 93, 95, 97, 99, 101, 103, 105, 107, 109, 111, 113, 115, 117, 119, 121, 123, 125, 127, 129, 132, 134, 136, 138, 140, 142, 144, 146, 148, 150, 152, 154, 156, 158, 160, 162, 164, 166, 168, 170, 172, 174, 176, 178, 180, 182, 184, 186, 188, 190, 192, 194, 196, 198, 200, 202, 204, 206, 208, 210, 212, 214, 216, 218, 220, 222, 224, 226, 228, 230, 232, 234, 236, 238, 240, 242, 244, 246, 248, 250, 252, 254, 256, 258, 260, 262, 264, 266, 268, 270, 272, 274, 276, 278, 280, 282, 284, 286, 288, 290, 292, 294, 296, 298, 300, 302, 304, 306, 309, 311, 313, 315, When compared with 317, 319, 321, 323, 325, 327, 329, 331, 333, 335, 337, 339, 341, 343, 345, 347, 349, 351, 353, 355, 357, 359, 361, 363, 366, 368, 370, 372, 374, 376, or 378) and by the BLAST algorithm, at least about 70-99.9% ( for exampleRefer to polypeptides containing identical or similar amino acid sequences (at least 70, 72, 74, 75, 76, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 99.5 or 99.9%); wherein the parameters of the algorithm are selected to grant maximum matching between each sequence over the entire length of each reference sequence (e.g., Expected threshold: 10; Word size: 3; Maximum matching in search range: 0; BLOSUM 62 matrix; Gap cost: Presence 11, Extension 1; Conditional composition score matrix adjustment).

[0113] Furthermore, variants of the polypeptide are immunoglobulin chains (e.g., H4H12857P; H4H12858P; H4H12859P; H4H12863P; H4H12874P; H4H12871P; H4H12884P; H4H12886P; H4H12889P; H4H12890P; H4H12899P; H4H12900P; H4H12908P; H4H12913P2; H4H12922P2; H4H12924P2; H4H12926P2; H4H12927P2; H4H12934P2; H4H13538P; H4H13541P; H4H13544P2; or H4H13545P2 V H , V L It may comprise a polypeptide such as , HC or LC or its CDR), and its amino acid sequence may comprise the amino acid sequence of a reference polypeptide specifically presented herein, except for one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) mutations, e.g., one or more missense mutations (e.g., conservative substitutions), non-sense mutations, deletions, or insertions. For example, the present invention comprises an immunoglobulin light chain (or V) having one or more of the said mutations, but comprising the amino acid sequence presented in SEQ ID NO. 10. L) variants and / or immunoglobulin heavy chains (or V) comprising the amino acid sequence presented in SEQ ID NO. 2 but having one or more of the said mutations H The anti-IL2Rγ antigen-binding protein comprises a variant thereof. In an embodiment of the invention, the anti-IL2Rγ antigen-binding protein comprises an immunoglobulin light chain variant comprising CDR-L1, CDR-L2 and CDR-L3 (wherein one or more of the CDRs (e.g., 1 or 2 or 3) have one or more mutations (e.g., conservative substitutions)) and / or an immunoglobulin heavy chain variant comprising CDR-H1, CDR-H2 and CDR-H3 (wherein one or more of the CDRs (e.g., 1 or 2 or 3) have one or more mutations (e.g., conservative substitutions)).

[0114] The following reference concerns BLAST algorithms commonly used for sequence analysis: BLAST ALGORITHMS: Altschul et al. (2005) FEBS J. 272(20): 5101-5109; Altschul, S.F., et al. , (1990) J. Mol. Biol. 215:403-410; Gish, W.; et al. , (1993) Nature Genet. 3:266-272; Madden, T.L.; et al. , (1996) Meth. Enzymol. 266:131-141; Altschul, S.F., et al. , (1997) Nucleic Acids Res. 25:3389-3402; Zhang, J.; et al. , (1997) Genome Res. 7:649-656; Wootton, J.C.; et al. , (1993) Comput. Chem. 17:149-163; Hancock, J.M. et al., (1994) Comput. Appl. Biosci. 10:67-70; ALIGNMENT SCORING SYSTEMS: Dayhoff, M. O., et al. , "A model of evolutionary change in proteins." in Atlas of Protein Sequence and Structure, (1978) vol. 5, suppl. 3. M. O. Dayhoff (ed.), pp. 345-352, Natl. Biomed. Res. Found., Washington, D.C.; Schwartz, R. M., et al. , "Matrices for detecting distant relationships." in Atlas of Protein Sequence and Structure, (1978) vol. 5, suppl. 3.'' M. O. Dayhoff (ed.), pp. 353-358, Natl. Biomed. Res. Found., Washington, D.C.; Altschul, S. F., (1991) J. Mol. Biol. 219:555-565; States, D. J., et al. , (1991) Methods 3:66-70; Henikoff, S., et al. , (1992) Proc. Natl. Acad. Sci. USA 89:10915-10919; Altschul, S. F., et al. , (1993) J. Mol. Evol. 36:290-300; ALIGNMENT STATISTICS: Karlin, S., et al. , (1990) Proc. Natl. Acad. Sci. USA 87:2264-2268; Karlin, S., et al. , (1993) Proc. Natl. Acad. Sci. USA 90:5873-5877; Dembo, A., et al., (1994) Ann. Prob. 22:2022-2039; and Altschul, SF "Evaluating the statistical significance of multiple distinct local alignments." in Theoretical and Computational Methods in Genome Research (S. Suhai, ed.), (1997) pp. 1-14, Plenum, NY

[0115] For example, “conservatively modified variants” or “conservative substitutions” of the immunoglobulin chain presented herein refer to variants in which one or more amino acids within the polypeptide are substituted with other amino acids having similar characteristics (e.g., charge, side chain size, hydrophobicity / hydrophilicity, backbone type, and rigidity, etc.). Such changes can often be made without significantly inhibiting the biological activity of the antibody or fragment. Those skilled in the art will recognize that, generally, a single amino acid substitution in the non-essential region of a polypeptide does not substantially alter biological activity (see literature: e.g., Watson). et al. (1987) Molecular Biology of the Gene, The Benjamin / Cummings Pub. Co., p. 224 (4 th Ed.)). Additionally, substitution of structurally or functionally similar amino acids is unlikely to significantly inhibit biological activity. The present invention comprises an anti-IL2Rγ antigen-binding protein comprising the above-mentioned conservatively modified variant immunoglobulin chain.

[0116] Examples of amino acid groups possessing side chains with similar chemical properties include 1) aliphatic side chains: glycine, alanine, valine, leucine, and isoleucine; 2) aliphatic-hydroxyl side chains: serine and threonine; 3) amide-containing side chains: asparagine and glutamine; 4) aromatic side chains: phenylalanine, tyrosine, and tryptophan; 5) basic side chains: lysine, arginine, and histidine; 6) acidic side chains: aspartate and glutamate; and 7) sulfur-containing side chains: cysteine ​​and methionine. Alternatively, a conservative substitution is any change having a positive value in the PAM250 log-likelihood matrix disclosed in the literature [Ref: Gonnet et al. (1992) Science 256: 1443-45].

[0117] For example, the anti-IL2Rγ antigen-binding protein presented herein, comprising a variant immunoglobulin chain, may exhibit one or more of the following properties:

[0118] · Approximately 2.75 x 10⁻⁶ at 25℃ -9 M to about 3.36 x 10 -7 M's K D Binds to human IL2Rγ (e.g., its fusions such as the myc-myc-His6 fusion);

[0119] · Approximately 6.42 x 10⁻⁶ at 37℃ -9 M to approximately 3.53 x 10 -7 M's K D Binding to human IL2Rγ (e.g., its fusions such as the myc-myc-His6 fusion) (or about 3.53 x 10⁻¹⁰ -7 K less than M D Combined as ;

[0120] · Approximately 3.18 x 10⁻⁶ at 25℃ -9 M to about 2.38 x 10 -7 M's K D Lo Macaca pasicularis ( Macaca fascicularis) binds to IL-2Rγ (e.g., its fusions such as myc-myc-His6 fusions);

[0121] · Approximately 8.29 x 10⁻⁶ at 37℃ -9 M to about 3.20 x 10 -7 M's K D Lo Macaca pasicularis ( Macaca fascicularis ) binds to IL-2Rγ (e.g., its fusions such as the myc-myc-His6 fusion) (or about 3.20 x 10⁻⁶ -7 M's K D Combined with);

[0122] · Approximately 2.45 x 10⁻⁶ at 25℃ -9 M to about 1.20 x 10 -8 M's K D Binds to human IL2Rγ (e.g., its fusion to the C-terminal mouse IgG2a Fc tag) (or about 1.20 x 10⁻⁶ -8 K less than M D Combined with);

[0123] · Approximately 1.86 x 10⁻⁶ at 37℃ -11 M to approximately 3.00 x 10 -8 M's K D Binds to human IL2Rγ (e.g., its fusion to the C-terminal mouse IgG2a Fc tag) (or about 3.00 x 10⁻⁶ -8 K less than M D Combined with);

[0124] · Approximately 1.84 x 10⁻⁶ at 25℃ -8 M, 3.76 X 10 -9 M, 1.08 X 10 -7 M, 2.17 X 10 -8 M, 6.02 X 10 -9 M or 7.93 X 10 -8 M's K D Binding to (or binding to or not binding to) mouse IL2Rγ (e.g., its fusions such as myc-myc-His6 fusions);

[0125] · Approximately 5.59 x 10⁻⁶ at 37℃ -8 M, 6.11 X 10 -9 M, 3.87 X 10 -7 M, 5.16 X 10 -8 M, 8.70 X 10 -9 M or 2.15 X 10 -7 M's K D Binding to (or binding to or not binding to) mouse IL2Rγ (e.g., its fusions such as myc-myc-His6 fusions);

[0126] · Approximately 3.32 x 10⁻⁶ at 25℃ -9 M to about 1.97 x 10 -7 M's K D Binds to human IL2Rγ domain 1 (e.g., its fusions such as myc-myc-His6 fusions) (binds or does not bind);

[0127] · Approximately 4.13 x 10⁻⁶ at 37℃ -9 M to about 2.25 x 10 -7 M's K D Binds to human IL2Rγ domain 1 (e.g., its fusions such as myc-myc-His6 fusions) (binds or does not bind);

[0128] · Approximately 2.91 x 10⁻⁶ at 25℃ -7 M to about 5.35 x 10 -10 M's K D Binds to human IL2Rγ domain 2 (e.g., its fusions such as myc-myc-His6 fusions) (binds or does not bind);

[0129] · Approximately 1.14 x 10⁻⁶ at 37℃ -8 M or approximately 1.27 x 10⁻⁶ -8 M's K D Binds to human IL2Rγ domain 2 (e.g., its fusion such as the myc-myc-His6 fusion);

[0130] · T-cells induced by, for example, IL-2 (e.g., at about 10 nM), IL-4 (e.g., at about 50 pM), IL-7 (e.g., at about 1 pM), IL-15 (e.g., at about 0.5 nM) and / or IL-21 (e.g., at about 50 pM) (e.g., human CD4 + Blocking STAT phosphorylation in T cells, for example, IC 50 is about 1 nM to about 0.5 nM;

[0131] · For example, IL-9 ( for example Blocking STAT phosphorylation in mast cells (e.g., differentiated human mast cells) induced by (at approximately 2 nM) and IC 50 It is approximately 4 x 10 -10 It's M;

[0132] · Reduction in the number of human immune cells (e.g., human PBMCs (peripheral blood mononuclear cells), e.g., human CD45+ cells, human T cells, human CD4+ T cells, and / or human CD8+ T cells) in mice (e.g., NOD-scid IL2r null (NSG) mice) after injection using human peripheral blood mononuclear cells (PBMCs);

[0133] · Mice after injection using human peripheral blood mononuclear cells (PBMC) ( for example Decrease in serum human cytokines (e.g., human IFN-, human TNFα, human IL-6, human IL-8 and / or human IL-10) and / or mouse cytokines (e.g., mouse TNFα, mouse IL-6, mouse KC / GRO and / or mouse IL-10) in NOD-scid IL2r null (NSG) mice;

[0134] · For example, competing with any one or more anti-IL2Rγ antibodies presented herein for binding to human IL-2Rγ on a cell surface (e.g., tagged with a C-terminal myc-myc-hexahistidine tag);

[0135] · For example, binding to the same epitope as any one or more anti-IL2Rγ antibodies presented herein on human IL2Rγ on a cell surface (e.g., tagged with a C-terminal myc-myc-hexahistidine tag);

[0136] · Mouse or rat IL2Rγ (e.g., 37 ℃ Not detectably coupled (when measured by Biacore);

[0137] · Protects mice from GvHD-induced weight loss and / or death in GvHD mouse models;

[0138] · Blocking the binding of hybrid receptors containing IL2Rγ complexed with a cytokine-specific receptor subunit to cytokines such as IL-2, IL-4, IL-7, IL-9, IL-15, and / or IL-21; and / or

[0139] · For example, when measuring luciferase expression in cells containing a luciferase gene operatively linked to a STAT3 response factor, for example Inhibits IL2Rγ intracellular signaling via the JAK-STAT pathway induced by IL2, IL4, IL7, IL9, IL15 and / or IL21 (e.g., in human B-lymphocyte cells or human natural killer cells).

[0140] Unless otherwise noted, “H4H12857P”; “H4H12858P”; “H4H12859P”; “H4H12863P”; “H4H12874P”; “H4H12871P”; “H4H12884P”; “H4H12886P”; “H4H12889P”; “H4H12890P”; “H4H12899P”; “H4H12900P”; “H4H12908P”; “H4H12913P2”; “H4H12922P2”; “H4H12924P2”; “H4H12926P2”; “H4H12927P2”; “H4H12934P2”; “H4H13538P”; “H4H13541P”; “H4H13544P2”; or “H4H13545P2” refers to an anti-IL2Rγ antigen-binding protein, e.g., an antibody and an antigen-binding fragment (including a multispecific antigen-binding protein), which is H4H12857P; H4H12858P; H4H12859P; H4H12863P; H4H12874P; H4H12871P; H4H12884P; H4H12886P; H4H12889P; H4H12890P; H4H12899P; H4H12900P; H4H12908P; H4H12913P2; H4H12922P2; H4H12924P2; H4H12926P2; H4H12927P2; H4H12934P2; H4H13538P; H4H13541P; H4H13544P2; or comprising the amino acid sequence specifically presented herein for H4H13545P2 (e.g., SEQ ID NO. 2, 18, 22, 38, 42, 58, 62, 77, 81, 97, 101, 115, 119, 134, 138, 152, 156, 170, 174, 186, 190, 198, 200, 208, 210, 216, 218, 234, 238, 254, 258, 272, 276, 284, 286, 294, 296, 311, 315, 331, 335, 343, 345, 357, 361, or 376). Immunoglobulin heavy chain or its variable region (V H) (or variants thereof), and / or H4H12857P; H4H12858P; H4H12859P; H4H12863P; H4H12874P; H4H12871P; H4H12884P; H4H12886P; H4H12889P; H4H12890P; H4H12899P; H4H12900P; H4H12908P; H4H12913P2; H4H12922P2; H4H12924P2; H4H12926P2; H4H12927P2; H4H12934P2; H4H13538P; H4H13541P; H4H13544P2; or an immunoglobulin light chain or a variable region thereof (V) comprising an amino acid sequence specifically presented herein for H4H13545P2 (e.g., SEQ ID NOs 10, 20, 30, 40, 50, 60, 70, 79, 89, 99, 109, 117, 127, 136, 146, 154, 164, 172, 182, 188, 226, 236, 246, 256, 266, 274, 304, 313, 323, 333, 353, 359, 368, or 378). L Each comprising ) (or a variant thereof); or this comprising a heavy chain or V comprising its CDR (CDR-H1 (or a variant thereof), CDR-H2 (or a variant thereof) and CDR-H3 (or a variant thereof)). H and / or a light chain or V comprising its CDR (CDR-L1 (or its variant), CDR-L2 (or its variant) and CDR-L3 (or its variant)) L Includes. In one embodiment of the present invention, V H is linked to an IgG constant heavy chain domain, e.g., a human IgG constant heavy chain domain (e.g., IgG1 or IgG4 (e.g., containing S228P and / or S108P mutations)) and / or V LIt is linked to a light chain invariant domain, e.g., a human light chain invariant domain (e.g., a lambda or kappa invariant light chain domain). Any of the above-mentioned immunoglobulin chains (e.g., V H , V L Polynucleotides encoding one or more of , HC and / or LC form part of the present invention.

[0141] The present invention comprises a “neutralizing” or “antagonist” anti-IL2Rγ antigen-binding protein (e.g., an antibody or antigen-binding fragment) comprising a molecule that inhibits the activity of IL2Rγ to any detectable degree (e.g., binding of a hybrid receptor comprising IL2Rγ complexed with a cytokine-specific receptor subunit from binding to cytokines such as IL-2, IL-4, IL-7, IL-9, IL-15 and / or IL-21).

[0142] The antibody and antigen-binding fragment of the present invention (e.g., H4H12857P; H4H12858P; H4H12859P; H4H12863P; H4H12874P; H4H12871P; H4H12884P; H4H12886P; H4H12889P; H4H12890P; H4H12899P; H4H12900P; H4H12908P; H4H12913P2; H4H12922P2; H4H12924P2; H4H12926P2; H4H12927P2; H4H12934P2; H4H13538P; H4H13541P; H4H13544P2; or H4H13545P2) comprises immunoglobulin chains (and variants thereof) comprising amino acid sequences specifically presented herein, as well as cellular and in vitro post-translation modifications of the above antibody or fragment. For example, the present invention comprises antibodies and fragments in which one or more asparagine, serine and / or threonine residues are glycosylated, one or more asparagine residues are deamidated, one or more residues (e.g., Met, Trp and / or His) are oxidized, and N-terminal glutamine is pyroglutamate (pyroE) and / or C-terminal lysine or other amino acids are deleted, as well as antibodies and antigen-binding fragments that specifically bind to IL2Rγ and include heavy chain and / or light chain amino acid sequences presented herein.

[0143] The present invention provides a container (e.g., a plastic or glass vial having a cap or chromatography column, a hollow needle or a syringe cylinder) which is the anti-IL2Rγ antigen-binding protein of the present invention, e.g., H4H12857P; H4H12858P; H4H12859P; H4H12863P; H4H12874P; H4H12871P; H4H12884P; H4H12886P; H4H12889P; H4H12890P; H4H12899P; H4H12900P; H4H12908P; H4H12913P2; H4H12922P2; H4H12924P2; H4H12926P2; H4H12927P2; Includes H4H12934P2; H4H13538P; H4H13541P; H4H13544P2; or H4H13545P2.

[0144] The present invention also provides an injection device comprising one or more antigen-binding proteins (e.g., antibodies or antigen-binding fragments) that specifically bind to IL2Rγ, for example, H4H12857P; H4H12858P; H4H12859P; H4H12863P; H4H12874P; H4H12871P; H4H12884P; H4H12886P; H4H12889P; H4H12890P; H4H12899P; H4H12900P; H4H12908P; H4H12913P2; H4H12922P2; H4H12924P2; H4H12926P2; H4H12927P2; H4H12934P2; H4H13538P; H4H13541P; H4H13544P2; or includes H4H13545P2, or a pharmaceutical formulation thereof. The injection device may be packaged in a kit. The injection device is a device that introduces a substance into a subject's body via a parenteral route, e.g., intravitreal, intramuscular, subcutaneous, or intravenous. For example, the injection device may be a syringe or auto-injector (e.g., pre-filled with a pharmaceutical formulation) comprising a cylinder or barrel for holding a fluid to be injected (e.g., containing an antibody or fragment or a pharmaceutical formulation thereof); a needle for perforating the skin, blood vessel, or other tissue for injecting the fluid; and a plunger for pushing the fluid out of the cylinder and through the needle bore.

[0145] The present invention further comprises the anti-IL2Rγ antigen-binding protein of the present invention, e.g., H4H12857P; H4H12858P; H4H12859P; H4H12863P; H4H12874P; H4H12871P; H4H12884P; H4H12886P; H4H12889P; H4H12890P; H4H12899P; H4H12900P; H4H12908P; H4H12913P2; H4H12922P2; H4H12924P2; H4H12926P2; H4H12927P2; H4H12934P2; H4H13538P; H4H13541P; H4H13544P2; Alternatively, a method for administering H4H13545P2 to a subject is provided, said method comprises, for example, introducing an antigen-binding protein into the body of a subject (e.g., a person) parenterally. For example, said method comprises puncturing the subject's body with a syringe needle and injecting the antigen-binding protein into the subject's body, for example, the subject's vein, artery, eye, muscle tissue, or subcutaneous tissue.

[0146] Polynucleotide and method for preparing the same

[0147] Polynucleotides are DNA and RNA. The present invention relates, for example, to H4H12857P; H4H12858P; H4H12859P; H4H12863P; H4H12874P; H4H12871P; H4H12884P; H4H12886P; H4H12889P; H4H12890P; H4H12899P; H4H12900P; H4H12908P; H4H12913P2; H4H12922P2; H4H12924P2; H4H12926P2; H4H12927P2; H4H12934P2; H4H13538P; H4H13541P; optionally linked to a promoter or other expression regulatory sequence. H4H13544P2; or immunoglobulin V of H4H13545P2 H , V LIt includes any polynucleotide of the present invention encoding , CDR-H, CDR-L, HC, or LC.For example, the present invention relates to SEQ ID NOs 1, 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 23, 25, 27, 29, 31, 33, 35, 37, 39, 41, 43, 45, 47, 49, 51, 53, 55, 57, 59, 61, 63, 65, 67, 69, 71, 73, 74, 76, 78, 80, 82, 84, 86, 88, 90, 92, 94, 96, 98, 100, 102, 104, 106, 108, 110, 112, 114, 116, 118, 120, 122, 124, 126, 128, 130, 131, 133, 135, 137, 139, 141, 143, 145, 147, 149, 151, 153, 155, 157, 159, 161, 163, 165, 167, 169, 171, 173, 175, 175, 177, 179, 181, 183, 185, 187, 189, 191, 193, 195, 197, 199, 201, 203, 205, 207, 209, 211, 213, 215, 217, 219, 221, 223, 225, 227, 229, 231, 233, 235, 237, 239, 241, 243, 245, 247, 249, 251, 253, 255, 257, 259, 261, 263, 265, 267, 269, 271, 273, 275, 277, 279, 281, 283, 285, 287, 289, 291, 293, 295, 297, 299, 301, 303, 305, 307, Provides any polynucleotide (e.g., DNA) comprising the nucleotide sequences presented in 308, 310, 312, 314, 316, 318, 320, 322, 324, 326, 328, 330, 332, 334, 336, 338, 340, 342, 344, 346, 348, 350, 352, 354, 356, 358, 360, 362, 364, 365, 367, 369, 371, 373, 375, or 377.In one embodiment of the present invention, the polynucleotide of the present invention is fused to a secretion signal sequence. The polynucleotide encoded by said polynucleotide is also within the scope of the present invention.

[0148] Generally, a "promoter" or "promoter sequence" is a DNA regulatory region capable of binding to RNA polymerase in a cell (e.g., directly or through other promoter-bound proteins or substances) and initiating the transcription of an coding sequence. The promoter may be operatively linked to other expression regulatory sequences, including enhancer and repressor sequences, and / or to the polynucleotides of the present invention. Promoters that may be used to regulate gene expression include the cytomegalovirus (CMV) promoter (U.S. Patents No. 5,385,839 and 5,168,062), the SV40 early promoter region (Reference: Benoist, et al. , (1981) Nature 290:304-310), promoter contained in the 3' long terminal repeat of Rous sarcoma virus (Reference: Yamamoto, et al. , (1980) Cell 22:787-797), herpes thymidine kinase promoter (Reference: Wagner, et al. , (1981) Proc. Natl. Acad. Sci. USA 78:1441-1445), regulatory sequence of metallothionein gene (Reference: Brinster, et al. , (1982) Nature 296:39-42); prokaryotic expression vectors, e.g., beta-lactamase promoter (Reference: VIIIa-Komaroff, et al. , (1978) Proc. Natl. Acad. Sci. USA 75:3727-3731), or tac Promoter (Reference: DeBoer, et al., (1983) Proc. Natl. Acad. Sci. USA 80:21-25; also "Useful proteins from recombinant bacteria" in Scientific American (1980) 242:74-94); and promoter elements from yeast or other fungi, for example, Gal4 Promoters include, but are not limited to, ADC (alcohol dehydrogenase) promoters, PGK (phosphoglycerol kinase) promoters or alkaline phosphatase promoters.

[0149] A polynucleotide encoding a polypeptide is “operatorily linked” to a promoter or other expression regulatory sequence in a cell or other expression system, whereby the sequence directs RNA polymerase-mediated transcription of the coding sequence into RNA, preferably mRNA, and then the mRNA is RNA spliced ​​(if it contains introns) and optionally decoded into a protein encoded by the coding sequence.

[0150] The present invention is V H and V L It includes a set of polynucleotides comprising the following polynucleotide pairs encoding:

[0151] Sequence No. 1 and Sequence No. 9;

[0152] Sequence No. 21 and Sequence No. 29;

[0153] Sequence No. 41 and Sequence No. 49;

[0154] Sequence No. 61 and Sequence No. 69;

[0155] Sequence No. 80 and Sequence No. 88;

[0156] Sequence No. 100 and Sequence No. 108;

[0157] Sequence No. 118 and Sequence No. 126;

[0158] Sequence No. 137 and Sequence No. 145;

[0159] Sequence No. 155 and Sequence No. 163;

[0160] Sequence No. 173 and Sequence No. 181;

[0161] Sequence No. 189 and Sequence No. 181;

[0162] Sequence No. 199 and Sequence No. 181;

[0163] Sequence No. 209 and Sequence No. 181;

[0164] Sequence No. 217 and Sequence No. 225;

[0165] Sequence No. 237 and Sequence No. 245;

[0166] Sequence No. 257 and Sequence No. 265;

[0167] Sequence No. 275 and Sequence No. 181;

[0168] Sequence No. 285 and Sequence No. 181;

[0169] Sequence No. 295 and Sequence No. 303;

[0170] Sequence No. 314 and Sequence No. 322;

[0171] Sequence No. 334 and Sequence No. 181;

[0172] Sequence No. 344 and Sequence No. 352; or

[0173] Sequence No. 360 and Sequence No. 367;

[0174] The present invention comprises a polynucleotide comprising the following set of polynucleotides encoding CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3:

[0175] Sequence numbers 3, 5, 7, 11, 13 and 15;

[0176] Sequence numbers 23, 25, 27, 31, 33 and 35;

[0177] Sequence numbers 43, 45, 47, 51, 53 and 55;

[0178] Sequence numbers 63, 65, 67, 71, 73 and 74;

[0179] Sequence numbers 82, 84, 86, 90, 92 and 94;

[0180] Sequence numbers 102, 104, 106, 110, 73 and 112;

[0181] Sequence numbers 120, 122, 124, 128, 130 and 131;

[0182] Sequence numbers 139, 141, 143, 147, 73 and 149;

[0183] Sequence numbers 157, 159, 161, 165, 13 and 167;

[0184] Sequence numbers 175, 177, 179, 71, 73 and 183;

[0185] Sequence numbers 191, 193, 195, 71, 73 and 183;

[0186] Sequence numbers 201, 203, 205, 71, 73 and 183;

[0187] Sequence numbers 175, 211, 213, 71, 73 and 183;

[0188] Sequence numbers 219, 221, 223, 227, 229 and 231;

[0189] Sequence numbers 239, 241, 243, 247, 249 and 251;

[0190] Sequence numbers 259, 261, 263, 267, 73 and 269;

[0191] Sequence numbers 277, 279, 281, 71, 73 and 183;

[0192] Sequence numbers 287, 289, 291, 71, 73 and 183;

[0193] Sequence numbers 297, 299, 301, 305, 307 and 308;

[0194] Sequence numbers 316, 318, 320, 324, 326 and 328;

[0195] Sequence numbers 336, 338, 340, 71, 73 and 183;

[0196] Sequence numbers 346, 348, 350, 71, 73 and 354; or

[0197] Sequence numbers 362, 364, 365, 369, 371 and 373;

[0198] The present invention comprises a polynucleotide set including the following polynucleotide pairs encoding HC and LC:

[0199] Sequence No. 17 and Sequence No. 19;

[0200] Sequence No. 37 and Sequence No. 39;

[0201] Sequence No. 57 and Sequence No. 59;

[0202] Sequence No. 76 and Sequence No. 78;

[0203] Sequence No. 96 and Sequence No. 98;

[0204] Sequence No. 114 and Sequence No. 116;

[0205] Sequence No. 133 and Sequence No. 135;

[0206] Sequence No. 151 and Sequence No. 153;

[0207] Sequence No. 169 and Sequence No. 171;

[0208] Sequence No. 185 and Sequence No. 187;

[0209] Sequence No. 197 and Sequence No. 187;

[0210] Sequence No. 207 and Sequence No. 187;

[0211] Sequence No. 215 and Sequence No. 187;

[0212] Sequence No. 233 and Sequence No. 235;

[0213] Sequence No. 253 and Sequence No. 255;

[0214] Sequence No. 271 and Sequence No. 273;

[0215] Sequence No. 283 and Sequence No. 187;

[0216] Sequence No. 293 and Sequence No. 187;

[0217] Sequence No. 310 and Sequence No. 312;

[0218] Sequence No. 330 and Sequence No. 332;

[0219] Sequence No. 342 and Sequence No. 187;

[0220] Sequence No. 356 and Sequence No. 358; or

[0221] Sequence No. 375 and Sequence No. 377.

[0222] The present invention comprises a polynucleotide encoding an immunoglobulin polypeptide chain whose nucleotide sequence is specifically a variant of those presented herein. The “variant” of the polynucleotide is such that the parameters of the algorithm have the maximum correspondence between each sequence along the full length of each reference sequence ( for example Refers to a polynucleotide containing a nucleotide sequence that is at least about 70-99.9% (e.g., 70, 72, 74, 75, 76, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 99.5, 99.9%) identical to the reference nucleotide sequence presented herein when compared by a BLAST algorithm selected to provide: , expected threshold: 10; word size: 28; maximum match within search range: 0; BLOSUM 62 matrix; gap cost: extension 1, extension -2; conditional composition score matrix adjustment). In one embodiment of the present invention, a variant of the nucleotide sequence specifically presented herein comprises one or more of one or more nucleotides ( for example, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12) point mutations, insertions (e.g., in-frame insertions), or deletions (e.g., in-frame deletions). In one embodiment of the present invention, the mutations may be missense or nonsense mutations. In one embodiment of the present invention, the variant polynucleotide is incorporated into an anti-IL2Rγ antigen-binding protein, i.e., the protein encodes an immunoglobulin polypeptide capable of possessing specific binding to IL2Rγ.

[0223] Eukaryotic and prokaryotic host cells, including mammalian cells, can be used as hosts for the expression of anti-IL2Rγ antigen-binding proteins (e.g., antibodies or their antigen-binding fragments). Such host cells are widely known in the art, and many cells are available from the American Type Culture Collection (ATCC). These host cells include, in particular, Chinese hamster ovary (CHO) cells, NSO, SP2 cells, HeLa cells, baby hamster kidney (BHK) cells, monkey kidney (COS) cells, human hepatocellular carcinoma cells (e.g., Hep G2), A549 cells, 3T3 cells, HEK-293 cells, and numerous other cell lines. Mammalian host cells include human, mouse, rat, dog, monkey, pig, goat, cattle, horse, and hamster cells. Other cell lines that can be used include insect cell lines (e.g., Spodopthera prucipida ( Spodoptera frugiperda ) or Trichoplocyanis ( Trichoplusia ni )), amphibian cells, bacterial cells, plant cells, and fungal cells. Fungal cells are, for example, Pichia ( Pichia ), Pikia Pastoris( Pichia pastoris ), Pikia Finlandica( Pichia finlandica ), Pichia trehalophila( Pichia trehalophila ), Pikia Cocclamae ( Pichia koclamae ), Pychia membranaefaciens( Pichia membranaefaciens ), Pikia Minuta( Pichia minuta )(Ogataea Minuta( Ogataea minuta ), Pikia Lindnery( Pichia lindneri )), Pikia Opuntiae( Pichia opuntiae ), Pikia thermotolerans( Pichia thermotolerans ), Pikia Salictaria( Pichia salictaria ), Pikia Gourcum( Pichia guercuum ), Pikia Piperi ( Pichia pijperi ), Pikia stiftis( Pichia stiptis ), Pikia Metanolica( Pichia methanolica ), Pichia species ( Pichia sp. ), Saccharomyces cerevisiae( Saccharomyces cerevisiae ), Saccharomyces species ( Saccharomyces sp.), *Hansenula polymorpha* ( Hansenula polymorpha ), Cluiberomyces species ( Kluyveromyces sp.), Cluiberomyces lactis ( Kluyveromyces lactis ), Candida albicans( Candida albicans ), Aspergillus nidulans( Aspergillus nidulans ), Aspergillus niger( Aspergillus niger ), Aspergillus oryzae( Aspergillus oryzae ), Trichoderma Re-essay( Trichoderma reesei ), Chrysosporium lucnowens ( Chrysosporium lucknowense ), Fusarium species ( Fusarium sp.), Fusarium graminum ( Fusarium gramineum ), Fusarium Venenatum( Fusarium venenatum ), Piscomitrella Patens( Physcomitrella patens ) and Neurospora Crasa( Neurospora crassa It includes yeast and filamentous fungal cells comprising ). The present invention relates to an antigen-binding protein, the V thereof. H , V L, HC, LC or CDR (or variants thereof), e.g., H4H12857P; H4H12858P; H4H12859P; H4H12863P; H4H12874P; H4H12871P; H4H12884P; H4H12886P; H4H12889P; H4H12890P; H4H12899P; H4H12900P; H4H12908P; H4H12913P2; H4H12922P2; H4H12924P2; H4H12926P2; H4H12927P2; H4H12934P2; H4H13538P; H4H13541P; It comprises an isolated host cell (e.g., a CHO cell or any type of host cell described above) comprising H4H13544P2; or H4H13545P2; and / or a polynucleotide encoding one or more of the immunoglobulins thereof (e.g., as discussed herein).

[0224] The present invention also relates to the antigen-binding proteins of the present invention (e.g., antibodies or antigen-binding fragments thereof), e.g., H4H12857P; H4H12858P; H4H12859P; H4H12863P; H4H12874P; H4H12871P; H4H12884P; H4H12886P; H4H12889P; H4H12890P; H4H12899P; H4H12900P; H4H12908P; H4H12913P2; H4H12922P2; H4H12924P2; H4H12926P2; H4H12927P2; H4H12934P2; H4H13538P; H4H13541P; H4H13544P2; or cells expressing IL2Rγ or an antigen fragment or fusion thereof (e.g., His6, Fc and / or myc) bound by H4H13545P2, wherein the cells are located within the body of the subject or in vitro.

[0225] Additionally, the present invention also provides a complex comprising an anti-IL2Rγ antigen-binding protein, e.g., an antibody or its antigen-binding fragment, as described herein, which is complexed with an IL2Rγ polypeptide or its antigen fragment or its fusion and / or complexed with a secondary antibody or its antigen-binding fragment (e.g., a detectably labeled secondary antibody) that specifically binds to an anti-IL2Rγ antibody or fragment. In embodiments of the present invention, the complex is in vitro (e.g., immobilized on a solid substrate) or in the body of a subject.

[0226] Recombinant anti-IL2Rγ antigen-binding proteins, e.g., the antibody and antigen-binding fragment described herein, can also be produced in an E.C.L. / T7 expression system. In the above embodiment, the anti-IL2Rγ antibody immunoglobulin molecule of the present invention (e.g., H4H12857P; H4H12858P; H4H12859P; H4H12863P; H4H12874P; H4H12871P; H4H12884P; H4H12886P; H4H12889P; H4H12890P; H4H12899P; H4H12900P; H4H12908P; H4H12913P2; H4H12922P2; H4H12924P2; H4H12926P2; H4H12927P2; H4H12934P2; H4H13538P; H4H13541P; H4H13544P2; or HC, LC, V of H4H13545P2 H and / or V L Polynucleotides encoding (or its CDR) can be inserted into pET-based plasmids and this. Coli ( E. coliIt can be expressed in a ) / T7 system. For example, the present invention comprises a method for expressing an antibody or its antigen-binding fragment or its immunoglobulin chain in a host cell (e.g., a bacterial host cell such as E. coli, e.g., BL21 or BL21DE3), said method also comprising a polynucleotide encoding an immunoglobulin chain that is operatively linked to a T7 promoter ( for example, Sequence number 1, 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 23, 25, 27, 29, 31, 33, 35, 37, 39, 41, 43, 45, 47, 49, 51, 53, 55, 57, 59, 61, 63, 65, 67, 69, 71, 73, 74, 76, 78, 80, 82, 84, 86, 88, 90, 92, 94, 96, 98, 100, 102, 104, 106, 108, 110, 112, 114, 116, 118, 120, 122, 124, 126, 128, 130, 131, 133, 135, 137, 139, 141, 143, 145, 147, 149, 151, 153, 155, 157, 159, 161, 163, 165, 167, 169, 171, 173, 175, 175, 177, 179, 181, 183, 185, 187, 189, 191, 193, 195, 197, 199, 201, 203, 205, 207, 209, 211, 213, 215, 217, 219, 221, 223, 225, 227, 229, 231, 233, 235, 237, 239, 241, 243, 245, 247, 249, 251, 253, 255, 257, 259, 261, 263, 265, 267, 269, 271, 273, 275, 277, 279, 281, 283, 285, 287, 289, 291, 293, 295, 297, 299, 301, 303, 305, 307, 308, The method comprises the step of expressing T7 RNA polymerase in a cell comprising a nucleotide sequence in one or more of 310, 312, 314, 316, 318, 320, 322, 324, 326, 328, 330, 332, 334, 336, 338, 340, 342, 344, 346, 348, 350, 352, 354, 356, 358, 360, 362, 364, 365, 367, 369, 371, 373, 375, or 377; or a variant thereof.For example, in an embodiment of the invention, a bacterial host cell, e.g., E. coli. lac It contains a polynucleotide encoding a T7 RNA polymerase gene operatively linked to a promoter, and the expression of the polymerase and said chain is induced by incubating the host cell with IPTG (isopropyl-beta-D-thiogalactopyranoside). See literature (US4952496 and US5693489 or Studier & Moffatt, Use of bacteriophage T7 RNA polymerase to direct selective high-level expression of cloned genes, J. Mol. Biol. 1986 May 5;189(1): 113-30).

[0227] Several methods for manufacturing recombinant antibodies are known in the art. One example of a method for the recombinant production of antibodies is described in the literature (US4816567).

[0228] Transformation may be by any known method for introducing polynucleotides into host cells. Methods for introducing heterogeneous polynucleotides into mammalian cells are widely known in the art and include dextran-mediated transfection, calcium phosphate precipitation, polybrane-mediated transfection, protoplast fusion, electroporation, encapsulation of polynucleotide(s) within liposomes, biolistic injection, and microinjection of DNA into the nucleus. Additionally, nucleic acid molecules may be introduced into mammalian cells by viral vectors. Methods for transforming cells are widely known in the art. For example, see U.S. Patents No. 4399216; No. 4912040; No. 4740461 and No. 4959455. Accordingly, the present invention comprises a recombinant method for producing an anti-IL2Rγ antigen-binding protein, such as an antibody or an antigen-binding fragment or an immunoglobulin chain thereof, wherein the method comprises (i) a light chain and / or heavy chain immunoglobulin of an antigen-binding protein to a host cell, e.g., H4H12857P; H4H12858P; H4H12859P; H4H12863P; H4H12874P; H4H12871P; H4H12884P; H4H12886P; H4H12889P; H4H12890P; H4H12899P; H4H12900P; H4H12908P; H4H12913P2; H4H12922P2; H4H12924P2; H4H12926P2; H4H12927P2; H4H12934P2; H4H13538P; H4H13541P; H4H13544P2; or one or more polynucleotides encoding H4H13545P2 ( for example, Sequence number 1, 9, 17, 19, 21, 29, 37, 39, 41, 49, 57, 59, 61, 69, 76, 78, 80, 88, 96, 98, 100, 108, 114, 116, 118, 126, 133, 135, 137, 145, 151, 153, 155, 163, 169, 171, 173, 181, 185, 187, 189, 197, 199, 207, 209, 215, 217, 225, 233, 235, 237, 245, A step of introducing a nucleotide sequence comprising one or more of 253, 255, 257, 265, 271, 273, 275, 283, 285, 293, 295, 303, 310, 312, 314, 322, 330, 332, 334, 342, 344, 352, 356, 358, 360, 367, 375, or 377; or a variant thereof, wherein, for example, said polynucleotide is in a vector and / or is incorporated into a host cell chromosome and / or is operatively linked to a promoter; (ii) a host cell (e.g., CHO or Pikia ( Pichia ) or Pikia Pastoris( Pichia pastorisThe method comprises the steps of: (iii) culturing the host cell and / or optionally isolating the antigen-binding protein (e.g., antibody or antigen-binding fragment) from the host cell and / or the medium in which the host cell was grown. When producing an antigen-binding protein (e.g., antibody or antigen-binding fragment) comprising more than one immunoglobulin chain, for example, an antibody comprising two heavy-chain immunoglobulins and two light-chain immunoglobulins, the co-expression of the chains in a single host cell induces the association of the chains, for example, within the cell or on the cell surface, or outside the cell when said chains are secreted, to form the antigen-binding protein (e.g., antibody or antigen-binding fragment). The method of the present invention comprises methods in which only heavy-chain immunoglobulin or only light-chain immunoglobulin, or both (e.g., any of those discussed herein including mature fragments and / or variable domains thereof) are expressed in the cell. The above single chain is useful as an intermediate in the expression of, for example, an antibody or antigen-binding fragment comprising the above chain. For example, the present invention also comprises an anti-IL2Rγ antigen-binding protein, e.g., an antibody and its antigen-binding fragment, which is a product of the manufacturing method presented herein and optionally a purification method presented herein.

[0229] In one embodiment of the present invention, an anti-IL2Rγ antigen-binding protein, for example A method for preparing an antibody or an antigen-binding fragment thereof includes, for example, a method of purifying an antigen-binding protein by column chromatography, precipitation, and / or filtration. As discussed, the product of said method also forms part of the present invention.

[0230] Production of human antibodies

[0231] The anti-IL2Rγ antibody of the present invention may be a complete human antibody. Methods for producing monoclonal antibodies comprising a complete human monoclonal antibody are known in the art. Any of these known methods may be used to produce a human antibody that specifically binds to human IL2Rγ in connection with the content of the present invention.

[0232] For example, using VELOCIMMUNE™ technology or any other similar known method for generating a complete monoclonal antibody, a high-affinity chimeric antibody for IL2Rγ having a human variable region and a mouse constant region is initially isolated. As in the experimental section below, said antibody is characterized and selected for desired features including affinity, ligand blocking activity, selectivity, epitopes, etc. If necessary, the mouse constant region is replaced with a desired human constant region, e.g., wild-type or modified IgG1 or IgG4, to generate a complete human anti-IL2Rγ antibody. While the selected constant region may vary depending on the specific application, high-affinity antigen binding and target-specific features remain in the variable region. In certain cases, the complete human anti-IL2Rγ antibody is isolated directly from antigen-positive B cells. For example, refer to US 6,596,541, Regeneron Pharmaceuticals, VELOCIMMUNE®.

[0233] Anti-IL2Rγ antibody containing Fc variant

[0234] According to a specific embodiment of the present invention, an anti-IL2Rγ antibody is provided comprising an Fc domain containing one or more mutations that enhance or reduce antibody binding to an FcRn receptor at acidic pH compared to, for example, neutral pH. For example, the present invention relates to C of the Fc domain. H 2 or a C H3. An anti-IL2Rγ antibody containing a mutation within the region, wherein the mutation(s) increase the affinity of the Fc domain for FcRn in an acidic environment (e.g., in an endosome where the pH is in the range of about 5.5 to about 6.0). Such mutation may result in an increase in the serum half-life of the antibody when administered to animals.

[0235] Non-limiting examples of the above Fc variation include, for example, variations at the following positions:

[0236] · 250 (e.g., E or Q);

[0237] · 250 and 428 (e.g., L or F);

[0238] · 252 (e.g., L / Y / F / W or T),

[0239] · 254 (e.g., S or T), and / or

[0240] · 256 (e.g., S / R / Q / E / D or T);

[0241] and / or variations at the following locations:

[0242] · 428 and / or 433 (e.g., H / L / R / S / P / Q or K), and / or

[0243] · 434 (e.g. , H / F or Y);

[0244] and / or variations at the following locations:

[0245] · 250 and / or 428;

[0246] and / or variations at the following locations:

[0247] · 307 or 308 (e.g. , 308F, V308F), and / or

[0248] · 434.

[0249] In one embodiment of the present invention, the modification includes the following:

[0250] · 428L (e.g. , M428L) and 434S (e.g. , N434S) variant;

[0251] · 428L, 259I ( for example, V259I), and 308F (e.g. , V308F) Variant;

[0252] · 433K (e.g. , H433K) and 434 (e.g. , 434Y) Variation;

[0253] · 252, 254, and 256 ( for example, 252Y, 254T, and 256E) variants;

[0254] · 250Q and 428L variants (e.g. , T250Q and M428L); and / or

[0255] · 307 and / or 308 variations (e.g., , 308F or 308P).

[0256] For example, the present invention comprises an anti-IL2Rγ antibody comprising an Fc domain comprising one or more pairs or groups of mutations selected from the group consisting of the following:

[0257] · 250Q and 248L (e.g., T250Q and M248L);

[0258] · 252Y, 254T, and 256E (e.g., M252Y, S254T, and T256E);

[0259] · 428L and 434S (e.g., M428L and N434S); and

[0260] · 433K and 434F (e.g., H433K and N434F).

[0261] In one embodiment of the present invention, the heavy chain invariant domain is 4, comprising S228P and / or S108P mutations. Literature (Angal et al. A single amino acid substitution abolishes the heterogeneity of chimeric mouse / human (IgG4) antibody, Mol Immunol. 1993 Jan;30(1):105-108).

[0262] All possible combinations of the above-mentioned Fc domain mutations and other mutations within the antibody variable domains described herein are considered within the scope of the present invention.

[0263] The anti-IL2Rγ antibody of the present invention may include a modified Fc domain having reduced effector function. As used herein, the "modified Fc domain having reduced effector function" is modified, mutated, or truncated relative to the naturally occurring wild-type Fc domain, and a molecule containing said modified Fc relative to a comparison factor molecule containing the wild-type, naturally occurring version of the Fc portion causes apoptosis ( for example It means any Fc portion of an immunoglobulin that exhibits a reduction in severity or degree of at least one effect selected from the group consisting of ADCC and / or CDC), complement activation, phagocytosis, and opsonization. In certain embodiments, the “modified Fc domain having reduced effector function” is an Fc domain having reduced or weakened binding to an Fc receptor (e.g., FcγR).

[0264] In a specific embodiment of the present invention, the modified Fc domain is a variant IgG1 Fc or a variant IgG4 Fc comprising substitutions within the hinge region. For example, the modified Fc for use in connection with the present invention may comprise the variant IgG1 Fc, wherein at least one amino acid in the IgG1 Fc hinge region is replaced with a corresponding amino acid from the IgG2 Fc hinge region. Alternatively, the modified Fc for use in connection with the present invention may comprise the variant IgG4 Fc, wherein at least one amino acid in the IgG4 Fc hinge region is replaced with a corresponding amino acid from the IgG2 Fc hinge region. Non-limiting exemplary modified Fc regions that may be used in connection with the present invention are disclosed in U.S. Patent Application Publication No. 2014 / 0243504, and functionally equivalent variants of the modified Fc regions presented herein, as well as the full text of the disclosure thereof, are incorporated by reference.

[0265] Other modified Fc domains and Fc modifications that may be used in connection with the content of the present invention include any modifications as disclosed in US2014 / 0171623; US8697396; US2014 / 0134162; and WO2014 / 043361 (the full text of which is incorporated herein by reference). Methods for constructing antibodies or other antigen-binding fusion proteins comprising modified Fc domains as described herein are known in the art.

[0266] Multispecific antigen-binding protein

[0267] The present invention comprises an anti-IL2Rγ antigen-binding protein, e.g., an antibody and an antigen-binding fragment thereof, a method of using said antigen-binding protein, and a method of preparing said antigen-binding protein. The term “anti-IL2Rγ” or “anti-IL2R-gamma” antigen-binding protein, e.g., an antibody or an antigen-binding fragment, comprises at least one first antigen-binding domain that specifically binds to IL2Rγ ( for example , H4H12857P; H4H12858P; H4H12859P; H4H12863P; H4H12874P; H4H12871P; H4H12884P; H4H12886P; H4H12889P; H4H12890P; H4H12899P; H4H12900P; H4H12908P; H4H12913P2; H4H12922P2; H4H12924P2; H4H12926P2; H4H12927P2; H4H12934P2; H4H13538P; H4H13541P; H4H13544P2; or comprises a multispecific (e.g., bispecific or biparatopic) molecule comprising an antigen-binding domain from H4H13545P2) and at least one second antigen-binding domain that binds to a different antigen or epitope in IL2Rγ, which is different from the first antigen-binding domain. In an embodiment of the invention, the first and second epitopes overlap. In another embodiment of the invention, the first and second epitopes do not overlap.

[0268] Multispecific binding refers to binding to two or more different epitopes that may be on the same or different antigens. Multispecific includes bispecific, trispecific, and quadrspecific.

[0269] “H4H12857P”; “H4H12858P”; “H4H12859P”; “H4H12863P”; “H4H12874P”; “H4H12871P”; “H4H12884P”; “H4H12886P”; “H4H12889P”; “H4H12890P”; “H4H12899P”; “H4H12900P”; “H4H12908P”; “H4H12913P2”; “H4H12922P2”; “H4H12924P2”; “H4H12926P2”; “H4H12927P2”; “H4H12934P2”; “H4H13538P”; “H4H13541P”; “H4H13544P2”; or “H4H13545P2” respectively “H4H12857P”; “H4H12858P”; “H4H12859P”; “H4H12863P”; “H4H12874P”; “H4H12871P”; “H4H12884P”; “H4H12886P”; “H4H12889P”; “H4H12890P”; “H4H12899P”; “H4H12900P”; “H4H12908P”; “H4H12913P2”; “H4H12922P2”; “H4H12924P2”; HCDR and LCDR of “H4H12926P2”; “H4H12927P2”; “H4H12934P2”; “H4H13538P”; “H4H13541P”; “H4H13544P2”; or “H4H13545P2”, V H and V L , or a multispecific molecule including HC and LC, for example, an antibody or antigen-binding fragment, and one or more antigen-binding domains that bind to different epitopes.

[0270] In one embodiment of the present invention, an antigen-binding domain that specifically binds to IL2Rγ, which may be included in a multispecific molecule, comprises the following:

[0271] (1)

[0272] (i) a heavy chain variable domain (V) comprising CDR-H1, CDR-H2, and CDR-H3 from an immunoglobulin heavy chain comprising an amino acid sequence selected from SEQ ID NOs 2, 22, 42, 62, 81, 101, 119, 138, 156, 174, 190, 200, 210, 218, 238, 258, 276, 286, 296, 315, 335, 345, and 361 (or variants thereof) H ) sequence, and

[0273] (ii) a light chain variable domain (V) comprising CDR-L1, CDR-L2, and CDR-L3 from an immunoglobulin light chain comprising an amino acid sequence selected from SEQ ID NOs 10, 30, 50, 70, 89, 109, 127, 146, 164, 182, 226, 246, 266, 304, 323, 353, and 368 (or variants thereof) L ) sequence; or,

[0274] (2)

[0275] (i) a heavy chain variable domain (V) comprising an amino acid sequence selected from SEQ ID NOs 2, 22, 42, 62, 81, 101, 119, 138, 156, 174, 190, 200, 210, 218, 238, 258, 276, 286, 296, 315, 335, 345 and 361 (or variants thereof). H ); and

[0276] (ii) a light chain variable domain (V) comprising an amino acid sequence selected from SEQ ID NOs 10, 30, 50, 70, 89, 109, 127, 146, 164, 182, 226, 246, 266, 304, 323, 353 and 368 (or variants thereof) L ); and

[0277] One or more antigen-binding domains that bind to different epitopes.

[0278] In one embodiment of the present invention, the bispecific antigen-binding fragment is a first scFv having binding specificity for a first epitope (e.g., IL2Rγ) ( for example , H4H12857P; H4H12858P; H4H12859P; H4H12863P; H4H12874P; H4H12871P; H4H12884P; H4H12886P; H4H12889P; H4H12890P; H4H12899P; H4H12900P; H4H12908P; H4H12913P2; H4H12922P2; H4H12924P2; H4H12926P2; H4H12927P2; H4H12934P2; H4H13538P; H4H13541P; H4H13544P2; or V in H4H13545P2 H and V L It includes a second scFv having binding specificity for a second different epitope (including) and a second scFv. For example, in one embodiment of the invention, the first and second scFvs are a linker, for example, a peptide linker (e.g., (GGGGS) n (Here, n is, for example, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10) is connected by a GS linker (sequence number 386)).

[0279] Other specific antigen-binding fragments are H4H12857P; H4H12858P; H4H12859P; H4H12863P; H4H12874P; H4H12871P; H4H12884P; H4H12886P; H4H12889P; H4H12890P; H4H12899P; H4H12900P; H4H12908P; H4H12913P2; H4H12922P2; H4H12924P2; H4H12926P2; H4H12927P2; H4H12934P2; H4H13538P; H4H13541P; H4H13544P2; or includes F(ab)2 of a specific IgG antibody comprising the heavy and light chain CDRs of another antibody that binds to H4H13545P2 and a different epitope.

[0280] Immunoconjugate

[0281] The present invention comprises an antibody or antigen-binding fragment conjugated to an anti-IL2Rγ antigen-binding protein, for example, another moiety, for example, a therapeutic moiety (“immunoconjugate”). In embodiments of the present invention, the anti-IL2Rγ antigen-binding protein, for example, an antibody or antigen-binding fragment, is conjugated to any additional therapeutic agent presented herein. The term “immunoconjugate” as used herein refers to an antibody or antigen-binding fragment that is chemically or biologically conjugated to an antigen-binding protein, for example, another antigen-binding protein, a drug, a radioactive agent, a reporter moiety, an enzyme, a peptide, a protein, or a therapeutic agent.

[0282] Administration and Treatment

[0283] The present invention provides a method for treating or preventing an IL2Rγ-mediated disease or pathological condition in a subject, and said method comprises a therapeutically effective amount of anti-IL2Rg antigen-binding protein (H4H12857P; H4H12858P; H4H12859P; H4H12863P; H4H12874P; H4H12871P; H4H12884P; H4H12886P; H4H12889P; H4H12890P; H4H12899P; H4H12900P; H4H12908P; H4H12913P2; H4H12922P2; H4H12924P2; H4H12926P2; H4H12927P2; H4H12934P2; It includes administering H4H13538P; H4H13541P; H4H13544P2; or H4H13545P2) to the subject.

[0284] “IL2Rγ-mediated disease or condition” refers to any disease or condition whose symptoms are mediated by the activity of cytokines IL-2, IL-4, IL-7, IL-9, IL-15, and IL-21 and / or receptors binding to cytokines; for example, includes autoimmunity and / or inflammation mediated by said cytokines and / or receptors. For example, IL2Rγ-mediated disease or condition includes graft-versus-host disease (GvHD), organ transplant rejection (e.g., skin graft (skin graft)), β-islet cell graft, heart transplant, lung transplant, kidney transplant and / or liver transplant), shotgun chorioretinopathy, multiple sclerosis, uveitis, autoimmune diseases (e.g., diabetes mellitus I, multiple sclerosis, rheumatoid arthritis, systemic lupus erythematosus, and myasthenia gravis), aplastic anemia; atopic dermatitis; asthma; and mast cell activation disorders (e.g., mast cell activation syndrome (MCAS), systemic mastocytosis (SM), or mast cell leukemia (MCL)).

[0285] The present invention also relates to an antigen-binding protein (e.g., an antibody or an antigen-binding fragment thereof) that specifically binds to IL2Rγ, e.g., H4H12857P; H4H12858P; H4H12859P; H4H12863P; H4H12874P; H4H12871P; H4H12884P; H4H12886P; H4H12889P; H4H12890P; H4H12899P; H4H12900P; H4H12908P; H4H12913P2; H4H12922P2; H4H12924P2; H4H12926P2; H4H12927P2; H4H12934P2; H4H13538P; A method for administering H4H13541P; H4H13544P2; or H4H13545P2 to a subject having, for example, an IL2Rγ-mediated disease or condition, wherein the method comprises, for example, introducing an antigen-binding protein into the subject's body by injection.

[0286] GvHD is a condition that can occur after allogeneic transplantation. For example, in GvHD, donated bone marrow or peripheral blood stem cells may recognize the recipient's body as foreign material, and the donated cells / bone marrow attack the body. GvHD can occur, for example, after hematopoietic cell transplantation (HCT; e.g., in subjects suffering from acute myeloid leukemia (AML) and / or myelodysplastic syndrome or myeloproliferative neoplasms), blood transfusion, thymectomy, or in patients with thymoma. Types of GvHD include steroid-refractory GvHD, acute graft-versus-host disease (aGvHD), and chronic graft-versus-host disease (cGvHD). Allogeneic transplant recipients may experience either aGvHD or cGvHD, or both, or neither. The present invention comprises a method for treating or preventing GvHD (of any type) in a subject, wherein the method comprises administering a therapeutically effective amount of anti-IL2Rγ antigen-binding protein to the subject.

[0287] Symptoms of aGvHD may include a skin rash or redness of the skin (signs of aGvHD of the skin); yellowing of the skin and / or eyes, and abnormal blood test results (signs of aGvHD of the liver); nausea, vomiting, diarrhea, or abdominal cramps (signs of aGvHD of the gastrointestinal tract or "intestines"); and / or increased dryness / irritation of the eyes (signs of GvHD of the eyes).

[0288] Symptoms of cGvHD may include a rash, raised or discolored areas, thickening or tightening of the skin (signs of cutaneous cGvHD); abdominal swelling, yellowing of the skin and / or eyes, abnormal blood test results (signs of liver cGvHD); dry eyes or changes in vision (signs of ocular cGvHD); dry mouth, white spots in the mouth, pain or sensitivity to spicy foods (signs of oral cGvHD); shortness of breath or changes visible on a chest X-ray (signs of lung cGvHD, dry cough); difficulty swallowing, pain when swallowing, or weight loss (signs of gastrointestinal or “intestinal” cGvHD); fatigue, muscle weakness, or pain (signs of nerve and muscle cGvHD); and / or increased need to urinate (frequent urination), burning or bleeding during urination, vaginal dryness / tightness, or penile dysfunction (signs of genitourinary system, bladder, or reproductive organ cGvHD).

[0289] Organ transplant rejection is the rejection of a transplanted organ by the recipient's immune system. Hyperacute rejection occurs within minutes after transplantation, acute rejection occurs within one week to three months after transplantation, and chronic rejection occurs over several years. Transplanted organs include, for example, solid organs, such as skin, pancreas, kidney, liver, heart, and lung. The present invention comprises a method for treating or preventing organ transplantation (of any type) in a subject, said method comprising administering a therapeutically effective amount of anti-IL2Rγ antigen-binding protein to the subject.

[0290] Scattered chorioretinopathy is a rare form of posterior uveitis, which is inflammation of the uvea, the part of the eye that provides most of the blood supply to the retina. Scattered chorioretinopathy can be caused by autoimmunity. Symptoms of Scattered chorioretinopathy may include night blindness, color vision problems, sensitivity to bright light, seeing flashing lights, visual distortion, eye pain, and loss of depth perception and / or peripheral vision. The present invention comprises a method for treating or preventing Scattered chorioretinopathy or uveitis in a subject, said method comprising administering a therapeutically effective amount of anti-IL2Rγ antigen-binding protein to the subject by intravitreal administration, e.g., intravitreal injection.

[0291] The present invention also provides a method for treating or preventing any autoimmune disease or pathological condition by inhibiting IL2Rγ. Blocking the signaling of one or more cytokines from the Bc family may be beneficial to patients suffering from autoimmunity due to their inhibitory effects on the secretion of inflammatory cytokines and the production of autoantibodies. Multiple sclerosis (MS) is a disease of the brain and spinal cord (central nervous system (CNS)) in which the immune system attacks myelin sheaths of nerve fibers, causing communication problems between the brain and the rest of the body. Ultimately, the nerves themselves may deteriorate or suffer permanent damage as a result of the disease. Rheumatoid arthritis (RA) is an autoimmune disease in which the body's immune system attacks the joints. It generates inflammation that thickens the tissues surrounding the inside of the joint (synovium), causing swelling and pain inside and around the joint. Psoriasis is an autoimmune disease that exhibits primary symptoms affecting the skin. Inflammation can also affect the joints, blood vessels, and eyes of people with psoriasis. Type 1 diabetes is an autoimmune disease in which the immune system attacks and destroys insulin-producing cells in the pancreas. Consequently, the pancreas produces almost no insulin. Systemic lupus erythematosus (SLE) is a systemic autoimmune disease that occurs when the body's immune system attacks its own tissues and organs. The inflammation caused by lupus can affect many different body systems, including joints, skin, kidneys, blood cells, the brain, heart, and lungs. Myasthenia gravis is an autoimmune disease in which antibodies block receptors for acetylcholine at the neuromuscular junction, preventing muscles from contracting. In most individuals with myasthenia gravis, this is caused by antibodies against the acetylcholine receptor itself. However, antibodies against other proteins, such as the muscle-specific kinase (MuSK) protein, can also induce impaired transmission at the neuromuscular junction.The present invention comprises a method for treating or preventing an autoimmune disorder or pathological condition (e.g., multiple sclerosis or any other central nervous system inflammation, rheumatoid arthritis, psoriasis, type I diabetes mellitus, systemic lupus erythematosus and / or myasthenia gravis) in a subject, the method comprising the step of administering a therapeutically effective amount of an anti-IL2R antigen-binding protein to the subject.

[0292] Anti-IL2Rg antigen-binding protein for treating or preventing IL2Rγ-mediated diseases or conditions, for example An effective or therapeutically effective amount of an antibody or antigen-binding fragment refers to an amount of antigen-binding protein sufficient to alleviate one or more signs and / or symptoms of a disease or pathological condition in a treated subject, whether by inducing regression or elimination of signs and / or symptoms or by inhibiting the progression of said signs and / or symptoms. In one embodiment of the present invention, an effective or therapeutically effective amount of anti-IL2Rγ antigen-binding protein is about 0.05-50 mg / kg body weight. The dosage may vary depending on the age and size of the subject to be administered, the target disease, the pathological condition, the route of administration, etc. In a specific embodiment, a second dose or a plurality of subsequent doses of antigen-binding protein are administered in an amount that is approximately equal to, less than, or greater than that of the initial dose, following the initial dose, wherein the subsequent doses are separated into at least 1 to 3 days; at least 1 week, at least 2 weeks; at least 3 weeks; at least 4 weeks; at least 5 weeks; at least 6 weeks; at least 7 weeks; at least 8 weeks; at least 9 weeks; at least 10 weeks; at least 12 weeks; or at least 14 weeks.

[0293] As used herein, the term "subject" refers to, for example, mammals requiring prevention and / or treatment of IL2Rγ-mediated disease (e.g., rats, mice, cats, dogs, cattle, sheep, horses, goats, rabbits), preferably humans. The subject may have IL2Rγ-mediated disease or may have a predisposition to develop said disease.

[0294] The “prevention” of IL2Rγ-mediated disease or pathological condition refers to the use of the anti-IL2Rγ antigen-binding protein of the present invention, which involves administering the protein to a subject prior to the onset of symptoms of a disease or pathological condition within the subject’s body to stop the onset of said symptoms.

[0295] Combinations and pharmaceutical formulations

[0296] The present invention provides a composition comprising an anti-IL2Rγ antigen-binding protein combined with one or more components; a method of using the same and a method of preparing said composition. A pharmaceutical formulation comprising an anti-IL2Rγ antigen-binding protein and a pharmaceutically acceptable carrier or excipient is part of the present invention.

[0297] Anti-IL2Rγ antigen-binding proteins, e.g., antibodies and their antigen-binding fragments (e.g., H4H12857P; H4H12858P; H4H12859P; H4H12863P; H4H12874P; H4H12871P; H4H12884P; H4H12886P; H4H12889P; H4H12890P; H4H12899P; H4H12900P; H4H12908P; H4H12913P2; H4H12922P2; H4H12924P2; H4H12926P2; H4H12927P2; H4H12934P2; H4H13538P; H4H13541P; To prepare pharmaceutical formulations of H4H13544P2 (or H4H13545P2), the antigen-binding protein is mixed with a pharmaceutically acceptable carrier or excipient. For example, the literature (Remington's Pharmaceutical Sciences and US Pharmacopeia: National Formulary, Mack Publishing Company, Easton, Pa. (1984); Hardman, et al. (2001) Goodman and Gilman's The Pharmacological Basis of Therapeutics, McGraw-Hill, New York, NY; Gennaro (2000) Remington: The Science and Practice of Pharmacy, Lippincott, Williams, and Wilkins, New York, NY; Avis, et al. (eds.) (1993) Pharmaceutical Dosage Forms: Parenteral Medications, Marcel Dekker, NY; Lieberman, et al. (eds.) (1990) Pharmaceutical Dosage Forms: Tablets, Marcel Dekker, NY; Lieberman, et al.(eds.) (1990) Pharmaceutical Dosage Forms: Disperse Systems, Marcel Dekker, NY; Weiner and Kotkoskie (2000) Excipient Toxicity and Safety, Marcel Dekker, Inc., New York, NY. In one embodiment of the present invention, the pharmaceutical formulation is sterile. The composition is part of the present invention.

[0298] The pharmaceutical formulation of the present invention comprises an anti-IL2Rγ antigen-binding protein and a pharmaceutically acceptable carrier comprising, for example, water, a buffer, a preservative and / or a detergent.

[0299] The scope of the present invention is anti-IL2Rγ antigen-binding proteins, e.g., antibodies or antigen-binding fragments thereof (e.g., H4H12857P; H4H12858P; H4H12859P; H4H12863P; H4H12874P; H4H12871P; H4H12884P; H4H12886P; H4H12889P; H4H12890P; H4H12899P; H4H12900P; H4H12908P; H4H12913P2; H4H12922P2; H4H12924P2; H4H12926P2; H4H12927P2; H4H12934P2; H4H13538P; H4H13541P; It includes a dried, e.g., freeze-dried composition comprising H4H13544P2; or H4H13545P2), or a pharmaceutical formulation thereof comprising a pharmaceutically acceptable carrier but substantially water-free.

[0300] In a further embodiment of the present invention, the anti-IL2Rγ antigen-binding protein described herein, for example, antibody or its antigen-binding fragment (e.g., H4H12857P; H4H12858P; H4H12859P; H4H12863P; H4H12874P; H4H12871P; H4H12884P; H4H12886P; H4H12889P; H4H12890P; H4H12899P; H4H12900P; H4H12908P; H4H12913P2; H4H12922P2; H4H12924P2; H4H12926P2; H4H12927P2; H4H12934P2; H4H13538P; H4H13541P; H4H13544P2; or Additional therapeutic agents administered to subjects in combination with H4H13545P2 are referenced in the literature (see: Physicians' Desk Reference 2003 (Thomson Healthcare; 57 th It is administered to the subject according to the edition (Nov. 1, 2002).

[0301] The method of administration of anti-IL2Rγ antigen-binding protein or a composition thereof may vary. Routes of administration include parenteral, non-parenteral, oral, rectal, transmucosal, intestinal, parenteral; intramuscular, subcutaneous, intradermal, intramedullary, intrathecal, direct intraventricular, intravenous, intraperitoneal, intranasal, intraocular, inhalation, aspiration, local, skin, intraocular, intravitreal, transcutaneous, or intra-arterial.

[0302] The present invention relates to an anti-IL2Rγ antigen-binding protein, for example, an antibody or an antigen-binding fragment thereof (e.g., H4H12857P; H4H12858P; H4H12859P; H4H12863P; H4H12874P; H4H12871P; H4H12884P; H4H12886P; H4H12889P; H4H12890P; H4H12899P; H4H12900P; H4H12908P; H4H12913P2; H4H12922P2; H4H12924P2; H4H12926P2; H4H12927P2; H4H12934P2; H4H13538P; H4H13541P; A method for administering H4H13544P2 (or H4H13545P2) to a subject is provided, said method comprising the step of introducing said protein or a pharmaceutical formulation thereof into the subject's body. For example, in one embodiment of the present invention, said method comprises the step of puncturing the subject's body with a syringe needle and injecting said antigen-binding protein or a pharmaceutical formulation thereof into the subject's body, for example, the subject's eye, vein, artery, muscle tissue, or subcutaneous tissue.

[0303] The present invention provides a container (e.g., a plastic or glass vial having a cap or chromatography column, a hollow needle or a syringe cylinder) which is an anti-IL2Rγ antigen-binding protein, e.g., an antibody or an antigen-binding fragment thereof (e.g., H4H12857P; H4H12858P; H4H12859P; H4H12863P; H4H12874P; H4H12871P; H4H12884P; H4H12886P; H4H12889P; H4H12890P; H4H12899P; H4H12900P; H4H12908P; H4H12913P2; H4H12922P2; H4H12924P2; H4H12926P2; It includes a pharmaceutical formulation comprising H4H12927P2; H4H12934P2; H4H13538P; H4H13541P; H4H13544P2; or H4H13545P2) or a pharmaceutically acceptable carrier thereof.

[0304] The present invention relates to an anti-IL2Rγ antigen-binding protein combined with one or more additional therapeutic agents, e.g., the antibody of the present invention or an antigen-binding fragment thereof (e.g., H4H12857P; H4H12858P; H4H12859P; H4H12863P; H4H12874P; H4H12871P; H4H12884P; H4H12886P; H4H12889P; H4H12890P; H4H12899P; H4H12900P; H4H12908P; H4H12913P2; H4H12922P2; H4H12924P2; H4H12926P2; H4H12927P2; H4H12934P2; It includes a combination comprising H4H13538P; H4H13541P; H4H13544P2; or H4H13545P2). The anti-IL2Rγ antigen-binding protein and additional therapeutic agents may be present in a single composition or in separate compositions. For example, in an embodiment of the present invention, the additional therapeutic agent is an immunosuppressive drug. In embodiments of the present invention, additional therapeutic agents are anti-TNFα antibodies or binding proteins (e.g., infliximab, adalimumab, etanercept, or golimumab), tacrolimus, cyclosporine, corticosteroids, prednisolone, methylprednisolone, antithymocyte globulin, alemtuzumab, daclizumab, in vitro photophoresis, mycophenolate mofetil, sirolimus, pentostatin, mesenchymal stem cells, inolimomab, denilukin, multispecific (e.g., two-specific) antibodies binding to BCMA (B-cell maturation antigen) and CD3 or antigen-binding fragments thereof and / or basiliximab.

[0305] Anti-IL2Rγ antigen-binding proteins combined with additional therapeutic agents, e.g., H4H12857P; H4H12858P; H4H12859P; H4H12863P; H4H12874P; H4H12871P; H4H12884P; H4H12886P; H4H12889P; H4H12890P; H4H12899P; H4H12900P; H4H12908P; H4H12913P2; H4H12922P2; H4H12924P2; H4H12926P2; H4H12927P2; H4H12934P2; H4H13538P; H4H13541P; A method for treating or preventing IL2Rγ-mediated disease in subjects requiring treatment or prevention by administering H4H13544P2 or H4H13545P2 is part of the present invention.

[0306] The term “associated with” indicates that the antibody of the present invention or its antigen-binding fragment may be formulated as a single composition, for example, for co-delivery, together with another agent, such as an anti-IL2Rγ antigen-binding protein, e.g., methotrexate, or may be formulated separately into two or more compositions (e.g., a kit containing each component). Components administered in association may be administered to a subject at a time different from when other components are administered; for example, each administration may be administered non-co-simultaneously (e.g., separately or sequentially) at regular intervals over a given period. Separate components administered in association may also be administered sequentially during the same administration period, even if they are essentially co-administrations. Furthermore, separate components administered in association may be administered to a subject via the same route or different routes.

[0307] Examples

[0308] The following examples are presented to provide those skilled in the art with a complete disclosure and description of the manufacturing method and the use of the method and composition of the invention, and are not intended to limit the scope of the invention by the inventors.

[0309] Example 1: Identification and isolation of anti-IL2Rγ antibody.

[0310] The anti-IL2Rγ antibody was obtained by immunizing VELOCIMMUNE® mice (i.e., processed mice containing DNA encoding the variable regions of the human immunoglobulin heavy chain and kappa light chain) with an IL2Rγ protein immunogen (ecto domain) containing the extracellular sequence of IL2Rγ.

[0311] Specifically, the immunogen, human IL2Rg ecto-mmh, included the following:

[0312] · Amino acids (1-240): Human IL2Rg ecto(L23-A262 of NP_000197.1), and

[0313] · Amino acids (241-268): Myc-Myc-hexahistidine tag (underlined);

[0314] Containing the following amino acid sequence:

[0315] LNTTILTPNGNEDTTADFFLTTMPTDSLSVSTLPLPEVQCFVFNVEYMNCTWNSSSEPQPTNLTLHYWYKNSDNDKVQKCSHYLFSEEITSGCQLQKKEIHLYQTFVVQLQDPREPRRRQA TQMLKLQNLVIPWAPENLTLHKLSESQLELNWNNRFLNHCLEHLVQYRTDWDHSWTEQSVDYRHKFSLPSVDGQKRYTFRVRSRFNPLCGSAQHWSEWSHPIHWGSNTSKENPFLFALEA EQKLISEEDLGGEQKLISEEDLHHHHHH

[0316] (Sequence No. 379)

[0317] *Expressed along with the mROR signal sequence

[0318] Antibody immune responses were monitored by IL2Rγ-specific immunoassays. Complete human anti-IL2Rγ antibodies were isolated and purified.

[0319] Table 1-1

[0320]

[0321] Table 1-2

[0322]

[0323] The amino acid sequences of the heavy and light immunoglobulin chains of the anti-IL2Rγ antibody are presented below (CDR is highlighted; variable regions are in bold).

[0324] H4H12857P

[0325] Heavy chain (sequence number 311)

[0326] EVQLVESGGGVVRPGGSLRLSCAAS GFTFDD FDMSWVRQGPGKGLEWVSG INWHGSST GYADSVKGRFTISRDNAKNSLYLQMSSLRAEDTALYHC VRGGTIVGATTPLDY WGQGTLVTVSS ASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVE VHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK

[0327] Light chain (sequence number 313)

[0328] DIQMTQSPSSLSASVGDRVTMTCRAS RTISSY LSWYQQKSGKVPNLLIF GAS SLQSGVPSRFSASGSGTDFTLISSLQPEDFATYYC QQSYSSPLT FGGGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC

[0329] H4H12858P

[0330] Heavy chain (sequence number 331)

[0331] EVQLVESGGDLVQPGGSLRLSCTAS GFIFRNYA MNWVRQAPGKGLEWLSG ILGSNDNT YYVDSVKGRFTISRDNSSRNTLYLQMNSLRAEDSAVYYC AKGDAGGFDY WGQGTLVTVSS ASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK

[0332] Light chain (sequence number 333)

[0333] DVVMTQSPLSLPVILGQPASISCRSS QSLVSSDGNTY LNWFQQRPGQSPRRLIY KVS NRDSGVPDRFSGSGSGTDFTLKISRVEAEDVGAYYC MQGSYWPPT FGQGTKLEIK RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC

[0334] H4H12859P

[0335] Heavy chain (Sequence No. 18)

[0336] QVQLVQSGAEVKKPGASVRVSCKAS GYTFTDYD IHWVRQAPGHGLEWMGW INPNSGGT NYAQKFQGRVTMTRDTSISTVYMDLSRLRSDDTAVYYC ARADYSSSYYYYGMDV WGQGTTVTVSS ASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPAPEFLGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK

[0337] Light chain (sequence number 20)

[0338] DIVMTQSPDSLAVSLGERATINCKSS QSVLYSSKNKNY LSWYQQKPGQPPKLLIY WAS TREFGVPDRFSGRGSGTDFTLTISSLQAEDVAVYYC QQYYTTPYT FGQGTKLEIK RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC

[0339] H4H12863P

[0340] Heavy chain (sequence number 38)

[0341] QVQLVESGGGVVQPGRSLRLSCTAS GFTFRSYD MYWVRQAPGKGLEWVSV ITYDGNNK YYADSVKGRFTISRDNSKNTLFLQMSSLRPEDTAVYYC AKRGLIWVGESFDY WGQGTLVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPAPEFLGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK

[0342] Light chain (sequence number 40)

[0343] DIQMTQSPSTLSASVGDRVTITCRAS QSINSW LAWYQQKPGKAPNLLIY KAS SLESGVPSRFSGSGSGTEFTLTISSLQPDDFATYYC QQYKSYSWT FGQGTKVEIK RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC

[0344] H4H12874P

[0345] Heavy chain (sequence number 58)

[0346] QVQLVESGGGVVQPGRSLRLSCAAS GFNFRNFG MHWVRQAPGKGLEWVAG ILYDGSSK YYADSVKDRFTISRDNSKNTLFLQMNSLRAEDTAMYYC AKEEDTAMVPFDS WGPGTLVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPAPEFLGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK

[0347] Light chain (sequence number 60)

[0348] DIQLTQSPSFLSASVGDRVTITCWAS QGISSY LAWYQQKPGKAPTLLIY AAS TLQSGVPSRFSGSGSGTEFTLTISSLQPEDFASYYC QQLKSYPLT FGGGTKVEIK RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC

[0349] H4H12871P

[0350] Heavy chain (sequence number 376)

[0351] QVQLQESGPGLVKPSQTLSLTCTVS GGSITSGGYY WSWIRQYPGQGLEWIGY IYYSGKT YYNPFSFTSRITISVDTSKKQFSLKMSSVTAADTAVYYC ARAGFTSSNGWFDP WGQGTLVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPAPEFLGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK

[0352] Light chain (sequence number 378)

[0353] DIQMTQSPSSLSASVGDRVTITCRAS QNIRSY LNWYQQKPGKAPKLLIY SAS SLQSGVPSRFSGSGSGTDFTLTISSLQPEDFPTYYC QQTYSSPWT FGPGTKVEIK RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC

[0354] H4H12884P

[0355] Heavy chain (Sequence No. 77)

[0356] QVQLQESGPGLVKPSQTLSLTCTVS GGSISSGGYY WSWIRQHPGKGLEWIGF IYYSGKT YYNPSLKSRLTISVDTSKSQFSLKLRSVTAADTAVYYC ARLGYTNSAGWFDP WGQGTLVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPAPEFLGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK

[0357] Light chain (sequence number 79)

[0358] DIQMTQSPSSLSASVGDRVTITCRAS QSISSY LNWYQQKPGKAPNLLIY AAS SLQSGVPSRFSGSGSGTDFTLTISSLQPEDLATYYC QQSYTTPFT FGPGTKVDIK RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC

[0359] H4H12886P

[0360] Heavy chain (Sequence No. 97)

[0361] EVQLVESGGGLVKPGGSLRLSCAAS GFTFSTAW MSWVRQSPGRGLEWVGR MKSKTDGGTT FYAAPVKGRFTISRDDSKNTLYLQMNSLKTEDTAVYYC TTGLVPAFYKYYGVDV WGQGTTVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPAPEFLGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK

[0362] Light chain (sequence number 99)

[0363] DIQMTQSPSSLSASVGDRITITCQAS QDITNY LNWYQQKPGKAPNLLIY DAS NLVTGVPSRFSGSGSGTDFTFTILSLQPEDIATYYC QQYDSLLT FGPGTKVDIK RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC

[0364] H4H12889P

[0365] Heavy chain (Sequence No. 357)

[0366] EVQLVESGGGLVQPGGSLRLSCAAS GFIFSSYE MHWVRQAPGKGLEWISY ISSSGTTI YYADSVKGRFTISRDNAKNSLYLHMNSLRAEDTAVYYC TRARITGTFDVFDI WGQGTMVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPAPEFLGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK

[0367] Light chain (sequence number 359)

[0368] DIQMTQSPSSLSASVGDRVTITCRAS QSISSY LNWYQQKPGKAPKLLIF AAS NLQSGVPSRFSGSRSGTDFTLTISSLQPEDFATYYC QQNYNIPYT FGQGTKLEIK RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC

[0369] H4H12890P

[0370] Heavy chain (sequence number 115)

[0371] EVQLVESGGGLVQPGGSLRLSCAAS GFTFNNYA MHWVRQAPGKGLEYVSS ISSSGGST YYEDSVKGRFTISRDNSKNTLYLQMGSLRAEDMAVYYC ARSFYGSGTYYDTFDM WGQGTMVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPAPEFLGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK

[0372] Light chain (sequence number 117)

[0373] DIQMTQSPSSLSASIGDRVTITCRAS QSISRY LNWYQQKPGKAPKLLIY AAS SLQSGVPSRFSASGSGTDFTLTISSLQPEDFATYYC QQSYSTPFT FGQGTKLEIK RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC

[0374] H4H12899P

[0375] Heavy chain (Sequence No. 134)

[0376] QVQLVESGGDLVKPGGSLRLSCATS GFTFSDFY MTWIRQAPGKGLEWISY ISNSGSIV KYADSVKGRFTISRDNAKNSLYLQMNSLRAEDTAIYYC ARFYGDR WGQGTLVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPAPEFLGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK

[0377] Light chain (sequence number 136)

[0378] DIQLTQSPSFLSASVGDRVTITCWAS QGISTF LAWYQQKPGKAPKLLIY AAS TLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYHC QQLNNYPWT FGQGTKVEIK RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC

[0379] H4H12900P

[0380] Heavy chain (sequence number 152)

[0381] QVQLVESGGGLVKPGGSLRLSCEAS GFTFNDFY MTWIRQAPGKGLEWIAY ISKSGDKM RYADSVKGRFSTSRDNAKNSLSLQMNSLRAEDTAVYYC ARFYGDI WGQGTLVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPAPEFLGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK

[0382] Light chain (sequence number 154)

[0383] DIQLTQSPSFLSASVGDRVTITCWAS QDISSF LVWYQQKPGKAPNLLIY AAS ALQSGVPSRFSGSGSGTEFTLTISSLQPEDFASYYC EQLNNYPWT FGQGTKVEIK RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC

[0384] H4H12908P

[0385] Heavy chain (Sequence No. 170)

[0386] EVQLVESGGRLVQPGGSLRLSCEAS GFTFSNYG MTWVRQAPGKGLEWVSV ISGSDNRK YYAESVKGRFTISRDNSKNTLYLQMNSSLRAEDTAVYYC AKLGYSRSSKDFYYGMDV WGQGTTVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPAPEFLGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK

[0387] Light chain (sequence number 172)

[0388] DIVMTQSPDSLAVSLGERATINCKSS QSVLYNSNNRNY LVWYQQKPGQSPKLLIY WAS TRESGVPDRFSGSGSGTDFTLTISSLQAEDVAVYYC QQYYNVPYT FGQGTKLEIK RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC

[0389] H4H12913P2

[0390] Heavy chain (Sequence No. 186)

[0391] EVQLVESGGGVVRPGGSLRLSCAAS GFTFDDYG MSWVRQAPGKGLEWISS INRNGGSA DYADSVKGRFTISRDNAKNSLFLQMSSLRAEDTALYHC ASGEFRFDY WGQGTLVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPAPEFLGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK

[0392] Light chain (sequence number 188)

[0393] DIQMTQSPSSLSASVGDRVTITCRAS QSISSY LNWYQQKPGKAPKLLIY AAS SLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYC QQSYSTPPIT FGQGTRLEIK RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC

[0394] H4H12922P2

[0395] Heavy print (Sequence No. 343)

[0396] QVQLVESGGGVVKPGGSLRLSCAAS GFTFSNSG IHWVRQAPGKGLEWVAL ISYAGSNK YYADSVKGRFTISRDNSKNTLSLQMNSLRAEDTAVYYC AKEVWTGTYDSFDM WGRGTMVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPAPEFLGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK

[0397] Light chain (sequence number 188)

[0398] DIQMTQSPSSLSASVGDRVTITCRAS QSISSY LNWYQQKPGKAPKLLIY AAS SLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYC QQSYSTPPIT FGQGTRLEIK RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC

[0399] H4H12924P2

[0400] Heavy print (Sequence No. 198)

[0401] EVQLVESGGGLVQPGRSLRLSCAAS GFTLEDYA MHWVRQAPGKGLEWVSG ISWNRGST GYADSVKGRFTISRDNAKNSLYLQMTSLRAEDTALYYC AKGFYSMDV WGQGTTVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPAPEFLGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK

[0402] Light chain (sequence number 188)

[0403] DIQMTQSPSSLSASVGDRVTITCRAS QSISSY LNWYQQKPGKAPKLLIY AAS SLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYC QQSYSTPPIT FGQGTRLEIK RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC

[0404] H4H12926P2

[0405] Heavy chain (sequence number 208)

[0406] QVQLQQSGPGLVKPSQTLSLTCAIS GDSVSSNIAA WNWIRLSPSRGLEWLGR TFFRSTWFY DYSLSVKGRITINPDTSKNQFSLHLNSVTPEDAAVYYC ARTGRRWSLDY WGQGTLVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPAPEFLGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK

[0407] Light chain (sequence number 188)

[0408] DIQMTQSPSSLSASVGDRVTITCRAS QSISSY LNWYQQKPGKAPKLLIY AAS SLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYC QQSYSTPPIT FGQGTRLEIK RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC

[0409] H4H12927P2

[0410] Heavy chain (sequence number 216)

[0411] EVQLVESGGGVVRPGGSLRLSCATS GFTFDDYG MSWVRQVPGKGLEWVSS VNRNGGTT DYADSVKGRFTISRDNAKRSLFLQMNSLRAEDTALYHC ATGELFFDY WGQGTLVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPAPEFLGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK

[0412] Light chain (sequence number 188)

[0413] DIQMTQSPSSLSASVGDRVTITCRAS QSISSY LNWYQQKPGKAPKLLIY AAS SLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYC QQSYSTPPIT FGQGTRLEIK RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC

[0414] H4H12934P2

[0415] Heavy chain (Sequence No. 234)

[0416] QVQLVQSGAEVKKPGASVKVSCKAS GYTFTGHY MHWVRQAPGQGLEWMGW IYPHSGHT NYAKRFQGRVTMTRDTSITTAYMELIRLRSDDTAVYYC ARRSGRSWYFDL WGRGTLVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPAPEFLGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK

[0417] Light chain (sequence number 236)

[0418] EIVLTQSPGTLSLSPGERATLSCRAS QSVSSSY LAWYQQKPGQAPRLLIY GAS SRATGIPDRFSGSGSGTDFTLTISRLEPEDFAVYYC QQYGSSPWT FGQGTKVEIK RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC

[0419] H4H13538P

[0420] Heavy chain (sequence number 254)

[0421] EVQLVESGGGLVQPGGSLGLSCAAS GFTFSNYA MSWVRQAPGKGLEWVSA VSGGGGGT YYADSVKGRFTISRDNSKNTVLLQMNSLRAEDTAVYYC ARGRTGGLDY WGPGTLVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPAPEFLGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK

[0422] Light chain (sequence number 256)

[0423] DVVMTQSPLSLPVIFGQPASISCRSS QSLVDSDGNTY LNWLQQRPGQSPRRLIY EVS NRDSGVPDRFSGSGSGTDFTLTISRVEAEDVGIYYC MQGTRWPPT FGGGTKVEIK RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC

[0424] H4H13541P

[0425] Heavy chain (Sequence No. 272)

[0426] EVQLVESGGGVVRPGGSLRLSCAAS GFIFDDYD MSWVRQPPGRGLEWVSG IDWFGGTR GYADSMKGRFTISRDNAKNSLYLQMNSLRVEDTAFYYC ARGGAIVGAVTPFDY WGQGTLVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPAPEFLGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK

[0427] Light chain (sequence number 274)

[0428] DIQMTQSPSSLSASVGNRVTLSCRAS QSINTY LSWYQQRPGKAPKLLIY AAS SLQSGVPSRFSGSGAGTDFTLTISSLQPEDFATYYC QQSYSAPLT FGGGTKVEIK RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC

[0429] H4H13544P2

[0430] Heavy chain (Sequence No. 284)

[0431] QLQLQESGPGLVKPSETLSLTCTVS GGSISIKNYY WGWIRQPPGKGLEWIGS IYYSGTT YYNPSLKSRVTISVDTSKNQFSLKLSSVTAADTAVYHC ARHGYSYGHGWFDP WGQGTLVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPAPEFLGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK

[0432] Light chain (sequence number 188)

[0433] DIQMTQSPSSLSASVGDRVTITCRAS QSISSY LNWYQQKPGKAPKLLIY AAS SLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYC QQSYSTPPIT FGQGTRLEIK RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC

[0434] H4H13545P2

[0435] Heavy chain (sequence number 294)

[0436] QVQLQQSGPGLVKPSQTLSLTCDIS GDSVSSNIAT WNWIRQSPSRGLEWLGR TYYRSKWYK DYAVSVKSRITINPDTSKNQFSLQVNSVTPEDTAVYYC ARMTGPRYYFEY WGQGTLVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVE VHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK

[0437] Light chain (sequence number 188)

[0438] DIQMTQSPSSLSASVGDRVTITCRAS QSISSY LNWYQQKPGKAPKLLIY AAS SLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYC QQSYSTPPIT FGQGTRLEIK RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC

[0439] The antibodies mentioned in these examples are those having an immunoglobulin chain having the amino acid sequence specifically described in Example 1.

[0440] Example 2: Surface plasmon resonance coupling assay.

[0441] Dissociation rate constant for binding of IL-2Rγ reagent to purified anti-IL2Rγ monoclonal antibody ( k d ) was determined using the real-time surface plasmon resonance-based Viacore 4000 biosensor platform. All binding studies were performed at 25°C and 37°C using two development buffers, (i) 1.9 mM NaH2PO4, 8.1 mM Na2HPO4, 2.7 mM KCl, 137 mM NaCl, 0.03% NaN3, 0.05% v / v surfactant Tween-20, pH 7.4 (PBS-T-pH 7.4), and (ii) 8.8 mM NaH2PO4, 1.2 mM Na2HPO4, 2.7 mM KCl, 137 mM NaCl, 0.03% NaN3, 0.05% v / v surfactant Tween-20, pH 6.0 (PBS-T-pH 6.0). The surface of the above CM5 Viacor sensor was derivatized by amine coupling with a monoclonal mouse anti-human Fc antibody [GE, # BR-1008-39] and used to capture an anti-IL2Rγ monoclonal antibody co-expressed with human IgG4 Fc. All IL2Rγ reagents were expressed with a C-terminal myc-myc-hexahistidine tag (hereinafter referred to with the -MMH suffix). Human IL2Rγ extracellular domain (hIL-2Rg-MMH; SEQ ID NO. 379) expressed with a C-terminal myc-myc-hexahistidine tag at different concentrations or Macaca facicularis ( Macaca fascicularis The IL2Rγ extracellular domain (mfIL-2Rg-MMH; SEQ ID NO. 380) was prepared in PBS-T-pH 7.4 developing buffer (100 nM - 11.11 nM; 3-fold serial dilution) and injected at a flow rate of 30 μL / min for 4 minutes. Dissociation of the bound IL-2Rg-MMH was performed in PBS-T-pH 7.4 or PBS-T-pH 6.0 developing buffer for 6 minutes.

[0442] Dissociation rate constant among two developing buffers ( k d ) was determined by fitting a real-time binding sensorgram to a 1:1 binding model using Scrubber 2.0c curve-fitting software. The values ​​of the dissociation rates for the binding of anti-hemojuvelin mAbs to hIL-2RG-MMH and mfIL-2RG-MMH at 25°C and 37°C in PBS-T-pH 7.4 and PBS-T-pH 6.0 are shown in Tables 2-1 to 2-8.

[0443] Table 2-1

[0444]

[0445] Table 2-2

[0446]

[0447] Table 2-3

[0448]

[0449] Table 2-4

[0450]

[0451] Table 2-5

[0452]

[0453] Table 2-6

[0454]

[0455] Table 2-7

[0456]

[0457] Table 2-8

[0458]

[0459] Example 3: Bonding dynamics.

[0460] Equilibrium dissociation constant (K) for IL-2Rγ binding to purified anti-IL2Rγ monoclonal antibody DThe values ​​were determined using a Viacore 4000 instrument equipped with a real-time surface plasmon resonance biosensor. All binding studies were performed at 25°C and 37°C in a development buffer of 10 mM HEPES, 150 mM NaCl, 3 mM EDTA, and 0.05% v / v surfactant Tween-20 (HBS-ET). The anti-IL2Rγ monoclonal antibody was captured by first derivatizing the Viacore sensor surface with amine coupling with a monoclonal mouse anti-human Fc antibody (GE, # BR-1008-39).

[0461] Binding studies were performed on the following IL-2Rγ reagents:

[0462] · Amino acid (1-240): Human IL2Rg ecto (NP_000197.1 L23-A262)

[0463] Amino acids (241-268): Myc-Myc-hexahistidine tag (underlined)

[0464] A human IL2Rγ extracellular domain expressed with a C-terminal myc-myc-hexahistidine tag (hIL-2Rg-MMH; SEQ ID NO. 379) comprising the following amino acid sequence:

[0465] LNTTILTPNGNEDTTADFFLTTMPTDSLSVSTLPLPEVQCFVFNVEYMNCTWNSSSEPQPTNLTLHYWYKNSDNDKVQKCSHYLFSEEITSGCQLQKKEIHLYQTFVVQLQDPREPRRRQA TQMLKLQNLVIPWAPENLTLHKLSESQLELNWNNRFLNHCLEHLVQYRTDWDHSWTEQSVDYRHKFSLPSVDGQKRYTFRVRSRFNPLCGSAQHWSEWSHPIHWGSNTSKENPFLFALEA EQKLISEEDLGGEQKLISEEDLHHHHHH

[0466] *Expressed along with the mROR signal sequence

[0467] Amino acids (1-240); Macama pasicularis ( Macaca fascicularis) IL2Rg ecto (L23-A262 of XP_005593949.1)

[0468] Amino acids (241-268): Myc-Myc-hexahistidine tag (underlined)

[0469] Macama facicularis (including a C-terminal myc-myc-hexahistidine tag (mfIL-2Rg-MMH; SEQ ID NO. 380) and having the following amino acid sequence Macaca fascicularis ) IL2Rγ extracellular domain:

[0470] LNTTILTPNGNEDATTDFFLTSMPTDSLSVSTLPLPEVQCFVFNVEYMNCTWNSSSEPQPTNLTLHYWYKNSDNDKVQKCSHYLFSEEITSGCQLQKKEIHLYQTFVVQLQDPREPRRRQA TQMLKLQNLVIPWAPENLTLRKLSESQLELNWNNRFLNHCLEHLVQYRTDWDHSWTEQSVDYRHKFSLPSVDGQKRYTFRVRSRFNPLCGSAQHWSEWSHPIHWGSNSSKENPFLFALEA EQKLISEEDLGGEQKLISEEDLHHHHHH

[0471] Amino acid (1-240): Human IL2Rg ecto (L23-A262 of NP_000197.1)

[0472] Amino acids (241-473): Mouse IgG2a Fc tag (underlined)

[0473] A human IL2Rγ extracellular domain expressed with a C-terminal mouse IgG2a Fc tag (hIL-2Rg-mFc SEQ NO. 381) containing the following amino acid sequence:

[0474] LNTTILTPNGNEDTTADFFLTTMPTDSLSVSTLPLPEVQCFVFNVEYMNCTWNSSSEPQPTNLTLHYWYKNSDNDKVQKCSHYLFSEEITSGCQLQKKEIHLYQTFVVQLQDPREPRRRQA TQMLKLQNLVIPWAPENLTLHKLSESQLELNWNNRFLNHCLEHLVQYRTDWDHSWTEQSVDYRHKFSLPSVDGQKRYTFRVRSRFNPLCGSAQHWSEWSHPIHWGSNTSKENPFLFALEA EPRGPTIKPCPPCKCPAPNLLGGPSVFIFPPKIKDVLMISLSPIVTCVVVDVSEDDPDVQISWFVNNVEVHTAQTQTHREDYNSTLRVVSALPIQHQDWMSGKEFKCKVNNKDLPA PIERTISKPKGSVRAPQVYVLPPPEEEMMTKKQVTLTCMVTDFMPEDIYVEWTNNGKTELNYKNTEPVLDSDGSYFMYSKLRVEKKNWVERNSYSCSVVHEGLHNHHTTKSFSRTPGK

[0475] *Expressed along with the mROR signal sequence

[0476] Amino acid (1-131): Human IL2Rg domain 1 (L23-I153 of NP_000197.1)

[0477] Amino acids (132-159): Myc-Myc-hexahistidine tag (underlined)

[0478] The D1 domain of a human IL-2Rγ extracellular domain expressed with a C-terminal myc-myc-hexahistidine tag (hIL-2Rg_D1-MMH; SEQ ID NO. 382) containing the following amino acid sequence:

[0479] LNTTILTPNGNEDTTADFFLTTMPTDSLSVSTLPLPEVQCFVFNVEYMNCTWNSSSEPQPTNLTLHYWYKNSDNDKVQKCSHYLFSEEITSGCQLQKKEIHLYQTFVVQLQDPREPRRQATQMLKLQNLVI EQKLISEEDLGGEQKLISEEDLHHHHHH

[0480] *Expressed along with the mROR signal sequence

[0481] Amino acid (1-88): Human IL2Rg domain 2 (P154-S241 of NP_000197.1)

[0482] Amino acids (89-116): Myc-Myc-hexahistidine tag (underlined)

[0483] The D2 domain of a human IL2Rγ extracellular domain expressed with a C-terminal myc-myc-hexahistidine tag (hIL-2Rg_D2-MMH; SEQ ID NO. 383) comprising the following amino acid sequence:

[0484] PWAPENLTLHKLSESQLELNWNNRFLNHCLEHLVQYRTDWDHSWTEQSVDYRHKFSLPSVDGQKRYTFRVRSRFNPLCGSAQHWSEWS EQKLISEEDLGGEQKLISEEDLHHHHHH

[0485] *Expressed along with the mROR signal sequence

[0486] Amino acid (1-241): Mouse IL2Rg ecto (W23-A263 of NP_038591.1)

[0487] Amino acids (242-269): Myc-Myc-hexahistidine tag (underlined) containing the following amino acid sequence

[0488] A mouse IL2Rγ extracellular domain expressed with a C-terminal myc-myc-hexahistidine tag (mIL-2Rg-MMH; SEQ ID NO. 384) comprising the following amino acid sequence:

[0489] WSSKVLMSSANEDIKADLILTSTAPEHLSAPTLPLPEVQCFVFNIEYMNCTWNSSSEPQATNLTLHYRYKVSDNNTFQECSHYLFSKEITSGCQIQKEDIQLYQTFVVQLQDPQKPQRRA VQKLNLQNLVIPRAPENLTLSNLSESQLELRWKSRHIKERCLQYLVQYRSNRDRSWTELIVNHEPRFSLPSVDELKRYTFRVRSRYNPICGSSQQWSKWSQPVHWGSHTVEENPSLFALEA EQKLISEEDLGGEQKLISEEDLHHHHHH

[0490] Amino acids (1-240): Rat IL2Rg ecto (W23-A262 of NP_543165.1)

[0491] Amino acids (241-268): Myc-Myc-hexahistidine tag (underlined)

[0492] C-terminal myc-myc-hexahistidine tag (hIL-2Rg-MMH; SEQ ID NO. 385) including

[0493] Rat IL2Rγ extracellular domain expressed together with and containing the following amino acid sequence:

[0494] WSSKVLMSSGNEDTKSDLLLTSMDLKHLSVPTLPLPEVQCFVFNVEYMNCTWNSSSEPQPTNLTMHYRYKGSDNNTFQECSHYLFSKEITSGCQIQKEDIQLYQTFVVQLQDPQKPQRRA EQKLNLQNLVIPWAPENLTLYNLSESQVELRWKSRYIERCLQYLVQYRSNRDRSWTEQIVDHEPRFSLPSVDEQKLYTFRVRSRFNPICGSTQQWSKWSQPIHWGSHTAEENPSLFALEA EQKLISEEDLGGEQKLISEEDLHHHHHH

[0495] *Expressed along with the mROR signal sequence

[0496] IL2Rγ reagents at different concentrations were prepared in HBS-ET development buffer (100 nM–6.25 nM; 4-fold serial dilution or 50 nM–3.125 nM; 4-fold serial dilution for hIL-2Rg-mFc) and injected onto the surface of anti-human Fc-captured anti-IL2Rγ monoclonal antibodies for 4 minutes at a flow rate of 30 μL / min. The dissociation of the monoclonal antibody-bound IL2Rγ reagent was monitored in HBS-ET development buffer for 8 to 10 minutes. Kinetic binding ( k a ) and Harry ( k d The ) rate constant was determined by fitting the real-time sensorgram to a 1:1 coupled model using Scrubber 2.0c curve fitting software. Coupled dissociation equilibrium constant ( K D ) and the dissociation half-life (t½) were calculated from the kinetic rate constants as follows:

[0497] K D (M) = , and t½ (min) =

[0498] The kinetic parameters for the binding of various IL-2Rγ reagents to different IL2Rγ monoclonal antibodies at 25°C and 37°C are shown in Tables 3-1 to 3-14.

[0499] Table 3-1

[0500]

[0501] Table 3-2

[0502]

[0503] Table 3-3

[0504]

[0505] Table 3-4

[0506]

[0507] Table 3-5

[0508]

[0509] Table 3-6

[0510]

[0511] Table 3-7

[0512]

[0513] Table 3-8

[0514]

[0515] Table 3-9

[0516]

[0517] Table 3-10

[0518]

[0519] Table 3-11

[0520]

[0521] Table 3-12

[0522]

[0523] Table 3-13

[0524]

[0525] Table 3-14

[0526]

[0527] Example 4: Octet Cross-Competition Between Different Anti-IL-2Rγ Monoclonal Antibodies

[0528] Binding competition among panels of anti-IL2Rγ monoclonal antibodies was determined using real-time label-free biolayer interferorefractography on the Octet HTX biosensor platform (Pall ForteBio Corp.). The entire experiment was performed at 25°C in a buffer of 10 mM HEPES, 150 mM NaCl, 3 mM EDTA, and 0.05% v / v surfactant Tween-20, 1 mg / mL BSA, pH 7.4 (HBS-EBT) using a plate shaking rate of 1000 rpm. To evaluate whether two antibodies compete with each other for binding to their respective epitopes on the extracellular domain of human IL2Rγ expressed with a C-terminal myc-myc-hexahistidine tag (hIL-2Rg-MMH; SEQ ID NO. 379), ~0.27 nM hIL-2Rg-MMH was captured by immersing an anti-penta-His antibody-coated octet biosensor tip (Fortebio Inc, # 18-5122) in a well containing 10 μg / mL hIL-2Rg-MMH for 3 minutes. The antigen-captured biosensor tip was then saturated with the first anti-IL2Rγ monoclonal antibody (subsequently referred to as mAb-1) by immersing it in a well containing 50 μg / mL of mAb-1 for 300 seconds. The biosensor tip was subsequently immersed in a well containing 50 μg / mL of the second anti-IL2Rγ monoclonal antibody (subsequently referred to as mAb-2) for 240 seconds. The biosensor tip was washed in HBS-ETB buffer at each experimental step. Real-time binding reactions were monitored throughout the entire experimental process, and binding reactions were recorded at the end of each step. The binding reactions of mAb-2 to mAb-1 and pre-conjugated hIL-2Rg-MMH were compared, and the competitive / non-competitive behavior of the different anti-IL2Rγ monoclonal antibodies was determined as shown in Table 4-1.

[0529] Table 4-1

[0530]

[0531]

[0532]

[0533] Example 5: Flow cytometry analysis of STAT phosphorylation in human CD4+ T cells (human PBMC).

[0534] To evaluate the in vitro characteristics of the IL2Rγ antibody of the present invention, CD4 induced by IL-2, IL-4, IL-7, IL-15, and IL-21 + Their ability to block T cell activation is based on flow cytometry (BD TM It was measured by the Phosflow test. BD TM Phosflow analyzes cell signaling in individual cell subpopulations through the simultaneous analysis of intracellular phosphoproteins (e.g., STAT proteins) and cell surface markers. Using the above technology, human CD4 upon stimulation with cytokines derived from the gamma c family + STAT phosphorylation in T cells was analyzed.

[0535] Human peripheral blood mononuclear cells (PBMCs) were isolated from fresh whole blood (BioreclammationIVT) by density gradient centrifugation. K2 EDTA whole blood was X-VIVO TM It was diluted 1:1 in Medium 15 (Lonza), added to a SepMate tube (StemCell) containing FicollPaquePLUS (Healthcare), and centrifuged to isolate PBMC. The layer containing PBMC was transferred to a new tube and washed twice with DPBS (Life Technologies). The PBMC was subsequently ~5.0 x 10⁶ 6 X-VIVO at a concentration of cells / mL TM 15. The cells were resuspended in medium, dispensed into 96-well plates (50 uL cells / well; ~250,000 cells / well), and incubated at 37°C for 2 hours before adding cytokines and antibodies.

[0536] Serial dilution (1:5) of the antibody is preheated X-VIVO TM 15. It was prepared in medium and added to cells (50 uL) at a final antibody concentration starting from 400 nM. The fixed cytokine concentration was preheated in X-VIVO TM 15 mediums were prepared and added to cells (100 uL) at final concentrations of 1 pM for IL-7 (R&D Systems), 50 pM for IL-4 (R&D Systems) and IL-21 (eBioscience), 0.5 nM for IL-15 (R&D Systems), and 10 nM for IL-2 (R&D Systems); and a final volume of 200 uL per well.

[0537] For the cytokine dose response, each cytokine serial dilution (1:5) is also X-VIVO preheated to a final cytokine concentration starting from 5 nM for IL-4, IL-7, and IL-21, or from 50 nM for IL-2 and IL-15. TM It was prepared in medium 15. First, 50 uL of X-VIVO TM Medium 15 was added to the cells, followed by the addition of 100 µL of serial dilution of cytokines to a total volume of 200 µL per well. After the addition of cytokines and antibodies to the cells, they were incubated at 37°C for 15 minutes to enable PBMC activation (STAT phosphorylation). Subsequent stimulation was introduced by adding 200 µL of warmed Cytofix (Bd) to each well, and the cells were incubated at 37°C for 10 minutes (fixation step). The cells were then washed twice with staining buffer (BD) and maintained overnight at 4°C. The next day, the cells were centrifuged and permeated by slowly adding 100 µL of cold permeation buffer III (BD) to the pellet. The cells were incubated at 4°C for 30 minutes and then washed twice with staining buffer. CD4 used to measure STAT phosphorylation +To enable the analysis of T cell populations, cells were stained with a mixture of human FcR binding inhibitor (eBioscience; 1 / 10), anti-CD33-PE (BD; 1 / 200), anti-CD4-PacificBlue (BD; 1 / 200), anti-CD3-PECy7 (BD; 1 / 200), and related anti-phospho-STAT-AlexaFluor647 (BD), prepared in staining buffer:

[0538] - Anti-phosphoSTAT3 (1 / 10): Against IL-21-stimulated cells,

[0539] - Anti-phosphoSTAT5 (1 / 20): Against cells stimulated with IL-2, IL-7, and IL-15,

[0540] - Anti-phosphoSTAT6 (1 / 10): Against IL-4 stimulated cells.

[0541] The samples were kept at room temperature in a dark room for 1 hour. The cells were subsequently centrifuged and washed twice with staining buffer. Sample data were acquired on an LSR Fortessa X-20 cell analyzer using HTS adhesion (Bd). Data analysis was performed using FlowJo X software (Tree Star, OR). CD4 + T cells are intact cells, singlets, CD33 - , CD3 + , CD4 + It was identified as; STAT phosphorylation was analyzed within the above cell population (MFI = mean fluorescence intensity).

[0542] Both H4H12889P and H4H12922P2 similarly and efficiently blocked STAT phosphorylation induced by all cytokines (IL-2, IL-4, IL-7, IL-15, and IL-21) tested in the assay, while H4H12874P, H4H12886P, H4H12857P, and the comparator antibody COMP1499 (anti-IL2Rγ antibody CP.B8, see US2002 / 0028202) only partially blocked or did not block cytokine-induced STAT phosphorylation.

[0543] Table 5-1

[0544]

[0545] Refer to Fig. 1(ae), where the level of STAT phosphorylation is determined at each concentration of the tested antibody.

[0546] Example 6: In vitro Flow cytometry analysis of STAT3 phosphorylation in differentiated human mast cells.

[0547] To evaluate the in vitro characteristics of the IL2Rγ antibodies of the present invention, their ability to block human mast cell activation induced by IL-9 was measured by flow cytometry (BDTM Phosflow assay). The inventors used the above technique to [in response to] stimulation using human IL-9 In vitro STAT3 phosphorylation was observed in differentiated human mast cells.

[0548] Briefly, human mast cells were cultured for 6 weeks in bone marrow CD133 in StemSpan serum-free medium supplemented with human SCF, IL-6, and IL-3. + It was produced in vitro from striatal cells.

[0549] Human mast cells are ~4.0 x 10 6 X-VIVO at a concentration of cells / mL TM15. The cells were resuspended in medium, dispensed into 96-well plates (50 uL of cells / well; ~200,000 cells / well), and incubated at 37°C for 2 hours before the addition of cytokines and antibodies.

[0550] Serial dilution (1:5) of the antibody is preheated X-VIVO TM 15. It was prepared in medium and added to cells (50 µL) at a final antibody concentration starting from 400 nM. The fixed IL-9 (R&D) concentration was preheated in X-VIVO TM It was prepared in 15 medium and added to cells (100 uL) at a final concentration of 2 nM and a final volume of 200 uL per well.

[0551] For the cytokine dose response, a serial dilution (1:5) of IL-9 was also preheated to a final concentration starting from 100 nM in X-VIVO TM It was prepared in medium 15. First, 50 uL of X-VIVO TM 15. Medium was added to the cells, followed by the addition of 100 µL of serial dilution of cytokine to a total volume of 200 µL per well.

[0552] After the addition of cytokines and antibodies to the cells, they were incubated at 37°C for 15 minutes to enable mast cell activation (measured by STAT3 phosphorylation). Subsequently, stimulation was introduced by adding 200 µL of warmed Cytofix (BD) to each well, and the cells were incubated at 37°C for 10 minutes (fixation step). The cells were then washed twice with staining buffer (BD) and maintained overnight at 4°C. The next day, the cells were centrifuged and permeated by slowly adding 100 µL of cold permeation buffer III (BD) to the pellet. The cells were incubated at 4°C for 30 minutes and then washed twice with staining buffer. Mast cells were then stained with a mixture of human FcR binding inhibitor (eBioscience; 1 / 10), anti-c-kit-PE (BD; 1 / 100), and anti-phospho-STAT3-AlexaFluor647 (BD; 1 / 10) prepared in staining buffer.

[0553] Samples were kept at room temperature in a dark room for 1 hour. The cells were subsequently centrifuged and washed twice with staining buffer. Sample data were acquired on an LSR Fortessa X-20 cell analyzer using HTS adhesion (Bd). Data analysis was performed using FlowJo X software (Tree Star, OR). Mast cells were classified into intact cells, singlets, and c-Kit cells. + It was identified as; STAT3 phosphorylation was analyzed within the above cell population (MFI = mean fluorescence intensity).

[0554] Both H4H12889P and H4H12922P2 similarly and efficiently blocked STAT3 phosphorylation induced by IL-9.

[0555] Table 6-1

[0556]

[0557] Also refer to Figure 2, where the IL-9-induced STAT phosphorylation level is determined at each concentration of the tested antibody.

[0558] Example 7: In vivo model to evaluate the blocking activity of IL-2R gamma antibody as a therapeutic treatment; monoclonal antibody test in a xenograft acute graft-versus-host disease model.

[0559] To determine the effects of the anti-IL2Rγ antibodies of the present invention, H4H12889P and H4H12922P2, together with the comparative factor IL-2Rγ antibody COMP1499 in a relevant in vivo model, a xenograft acute graft-versus-host disease (GvHD) study was conducted. Briefly, to induce GvHD in mice, human peripheral blood mononuclear cells (huPBMCs) were induced into NOD- scid IL2rγ 널 It was injected into (NSG) mice (Jackson Lab). Upon engraftment, human immune cells recognize the mouse host as a xenograft and enhance a vigorous immune response against its tissues.

[0560] In the above experiment, NSG mice (Jackson Lab) were retroorbitally injected with 10 million huPBMCs (ReachBio) resuspended in DPBS (10 million cells / 100 µL; 5 groups of 10 mice each). Briefly, human PBMCs were thawed on the day of injection in IMDM medium (Irvine Scientific) supplemented with 10% FBS (Seradigm) and incubated at 37°C for 2 hours in the supplemented medium. The cells were then washed in DPBS (Life Technologies) and resuspended at 10 million cells / 100 µL for injection. The control group (10 mice) was retroorbitally injected with 100 µL of PBS. Four groups of huPBMC-engrafted NSG mice were administered 25 mg / kg of H4H12889P, H4H12922P2, COMP1499, or isotype control antibody (REGN1945; human anti- Felis domesticusFel d1 antibody (IgG4 (S108P) / kappa)) was injected subcutaneously. The experiment was terminated on day 161 after huPBMC engraftment by sacrificing the remaining mice. The experimental administration and treatment protocols for the mouse groups are shown in Table 7-1.

[0561] Table 7-1

[0562]

[0563] Throughout the entire experimental period, mice were monitored twice a week for body weight loss and mortality (to evaluate the effect of therapeutic antibodies on survival rates). Serum mouse and human cytokine levels, as well as human cell engraftment in the blood, were evaluated at different time points as shown in Table 7-2.

[0564] Table 7-2

[0565]

[0566] Throughout the entire experiment, mice were monitored twice a week for body weight loss (Fig. 3 (af); % of initial body weight on the day of huPBMC engraftment and mortality (Fig. 4; to evaluate the effect of therapeutic antibodies on survival rate). Animals showing a body weight loss of 20% of their initial body weight were euthanized.

[0567] Blood samples from mice were collected in Microtainer tubes (BD, Cat# 3659740) at different time points after huPBMC injection, and human cell engraftment was evaluated by observing the absolute number of human cells in the blood via flow cytometry. Briefly, 50 µL of each blood sample was incubated in ACK lysis buffer (Gibco) at room temperature for 5 minutes to lyse red blood cells. The cells were then washed in DPBS, stained with a live / dead fixable dead stain (Invitrogen), washed in MACS buffer (Miltenyi Biotec), and human CD45 + Cells, T cells, CD4 + T cells and CD8 + T cells were labeled with a mixture of anti-human CD45, anti-human CD3, anti-human CD4, and anti-human CD8 [BD] diluted to 1 / 50 in a mixture of antibodies used for T cell identification (excellent staining buffer [BD] with human and mouse Fc inhibitor antibodies [eBioscience and BD, respectively]). Finally, samples were washed in MACS buffer, immobilized in BD CytoFix (BD), and subsequently resuspended in MACS buffer containing CountBright beads (Life Technologies) to count the absolute cell count in each sample. Sample data were acquired on an LSR Fortessa X-20 cell analyzer using HTS adhesion (BD). Data analysis was performed using FlowJo X software (Tree Star, OR). Human CD45 + T cells are living cells, single-stranded, CD45 + It was identified as and CD4 in the above group + T cells and CD8 + T cells additionally each CD3 + , CD4 + and CD3 + , CD8+ It was identified as.

[0568] Table 7-3

[0569]

[0570] As an example, the absolute number of human cells in the blood on day 35 after huPBMC injection is shown in Fig. 5 (AD). The number of human CD45+ cells, T cells, CD4+ T cells, and CD8+ T cells in the blood over a certain period is shown in Fig. 6 (AD).

[0571] Serum from mice was collected on different dates after huPBMC injection, and serum levels of mouse and human cytokines were evaluated. Briefly, whole blood was collected in microtainer tubes (BD, Cat# 365967) and allowed to clot undisturbed at room temperature for at least 30 minutes. The clotted blood and cells were pelleted by centrifugation at 15,000 xg for 10 minutes at 4°C. The designated serum from the obtained supernatant was transferred to clear plates, and cytokine concentrations in the serum were measured using two pro-inflammation (mouse and human) multiplex immunoassay kits (Meso Scale Discovery) according to the manufacturer's instructions. Plates were washed with PBS containing 0.05% (w / v) Tween-20 (Life Technologies). Electrochemiluminescence was read immediately on an MSD Spector instrument. Data analysis was performed using FlowJo X software (Tree Star, OR).

[0572] Table 7-4

[0573]

[0574] Table 7-5

[0575]

[0576] In addition, as an example, serum human and mouse cytokine levels on day 42 after huPBMC injection are shown in Fig. 7 (ai). Serum levels of human IFN-γ, human TNFα, mouse TNFα, and mouse IL-6 over a period of time are shown in Fig. 8 (ad).

[0577] The above in vivo study demonstrated the efficacy of the anti-IL2Rγ antibodies, H4H12889P and H4H12922P2, when administered therapeutically in a model of graft-versus-host disease. Both H4H12889P and H4H12922P2, excluding COMP1499, efficiently blocked the onset of GvHD in mice. Mice therapeutically treated with either of these two antibodies were protected from body weight loss and death, which was associated with a sharp decline in both mouse and human serum cytokine levels and blood human T cell counts. See Tables 7-3, 7-4, and 7-5.

[0578] Example 8: Biopsy using NK92 / hIL7R / STAT3-Luc and Ramos.2G6.4C10 / STAT3-Luc cells.

[0579] The IL2Rγ family of cytokines IL-2, IL-4, IL-7, IL-9, IL-15, and IL-21 signal via the JAK-STAT (Janus kinase - signaling factor and transcriptional activator) pathway (Reference: Rochman et al., New insights into the regulation of T cells by gamma(c) family cytokines. Nat Rev Immunol. 2009 Jul;9(7):480-90). To evaluate the inhibition of cytokine signaling by anti-IL2Rγ antibodies, a biopsy was developed using NK-92 cells (human natural killer cell line, ATCC) stably expressing a luciferase reporter (STAT3-Luc; SABiosciences, # CLS-6028L). NK-92 endogenously expressed ligand-selective receptors mediating the signaling of IL2Rγ and IL-2, IL-9, IL-15, and IL-21. To also evaluate the regulation of IL-7 signaling, NK-92 cells were transfected with a lentivirus containing human IL-7R, and cells stably expressing it were selected and maintained in G418. The obtained cell line is referred to as NK-92 / hIL7R / STAT3-Luc. To test the regulation of IL-4-mediated signaling, the STAT3-luc reporter was transduced into Ramos.2G6.4C10 (human B-lymphocyte cell line, ATCC) cells endogenously expressing IL2Rγ and IL-4R receptors, and the obtained cell line is referred to as Ramos.2G6.4C10 / STAT3-Luc.

[0580] The anti-IL2γ antibody of the present invention was tested for inhibition of human IL-2 (hIL-2), human IL-7 (hIL-7), human IL-9 (hIL-9), human IL-15 (hIL-15), or human IL-21 (hIL-21) signaling by seeding 20,000 NK-92 / hIL7R / STAT3-Luc cells per well in growth medium (prepared according to ATCC guidelines, but without IL-2) in 96-well plates and incubated overnight at 37°C in 5% CO2. On the next day, the anti-IL2Rγ antibody or isotype control was diluted from 500-0.008 nM in assay buffer (+ sample-containing buffer alone without test molecules), added to the cells, and incubated for 30 minutes. After incubation, the ligand was added to the cells at the following final concentrations: 30 pM hIL-2, 50 pM hIL-7, 20 pM hIL-9, 60 pM or 100 pM hIL-15, or 5 pM or 3 pM hIL-21. Dose-dependent activity was determined using serial dilutions of the ligand added to the cells at concentrations ranging from 10 nM to 0.2 pM (+ sample-containing buffer alone without ligand). After incubation at 37°C for 5 hours in 5% CO2, luciferase activity was measured using OneGlo™ reagent (Promega, # E6031) and a Victor™ X multi-labeled plate reader (Perkin Elmer).

[0581] To test the anti-IL2g antibody of the present invention for the inhibition of human IL-4 (hIL-4) signaling, Ramos.2G6.4C10 / STAT3-Luc cells were seeded in growth medium (prepared according to ATCC guidelines) at a density of 100,000 cells per well in 96-well plates. The anti-IL2Rγ antibody or isotype control was serially diluted from 500–0.008 nM in assay buffer (buffer containing the sample alone without the test molecule), added to the cells, and incubated for 20 minutes. After incubation, hIL-4 was added to the cells at a final concentration of 250 pM or 200 pM. Dose-dependent activation was determined using serial dilutions of hIL-4 (buffer containing the sample alone without the ligand) at concentrations ranging from 10 nM to 0.2 pM added to the cells. After overnight incubation at 37°C in 5% CO2, luciferase activity was measured using OneGlo™ reagent (Promega, # E6031) and a Victor™ X multi-labeled plate reader (Perkin Elmer).

[0582] The above results were analyzed using non-linear regression (4-parameter logistic regression) with Prism 5 software (GraphPad) to EC 50 and IC 50 The value was obtained. The percentage of inhibition was calculated along with the RLU value using the following mathematical formula:

[0583]

[0584] In the above mathematical formula, “RLU 기준선 ” is the luminescence value from cells treated with a fixed amount of ligand without antibodies, and “RLU 억제 ” is the minimum immunoluminescence value of cell origin treated with a dose-response of a specific antibody at a specific ligand concentration, and “RLU 배경 " is the luminescence value from cells treated without any ligand or antibody.

[0585] Table 8-1

[0586]

[0587] Table 8-2

[0588]

[0589] The 23 anti-IL2γ antibodies of the present invention were tested for their ability to inhibit signal transduction by the IL2Rγ family of cytokines using bioassays. As shown in Table 8-1, 19 of the 23 anti-IL2γ antibodies inhibited IL2Rγ activation to varying degrees, and as shown in Table 8-2, 4 of the 23 anti-IL2γ antibodies did not show inhibition of IL2Rγ activation by ligands.

[0590] Example 9: Cell binding analysis by flow cytometry using NK-92, Zurkat, NIH / 3T3, MC / 9, and HEK293 cells.

[0591] To evaluate the binding of anti-IL2Rγ antibodies to human and mouse IL-2Rγ expressed on cells, flow cytometry analysis was performed using cell lines endogenously expressing IL-2Rγ: NK-92 (human natural killer cell line), Zurkat (human T-lymphocyte cell line), and MC / 9 (mouse mast cell line). NIH / 3T3 (mouse fibroblast) and HEK293 (human embryonic kidney) cell lines were included as negative controls.

[0592] For flow cytometry analysis, cells were pre-incubated with mouse IgG at 100 µg / ml for 15 minutes at room temperature (RT) to block antibody binding to Fc receptors. The anti-IL2Rγ antibody and isotype control antibody of the present invention were administered at 0.5–1 x 10⁶ at 10 µg / ml for 30–45 minutes at RT in PBS containing 1% FBS (calcium and magnesium-free) for Zurcat, NIH / 3T3, and HEK293 cells, or in growth medium (prepared according to ATCC guidelines) for NK-92 and MC / 9 cells. 6Cells / each cell type was used as a well. Cells were washed and incubated on ice for 30 minutes with an anti-human antibody conjugated to allophycocyanin (APC) (Jackson ImmunoResearch, #109-136-170). Cells were washed and BD CytoFix TM The cells were immobilized using (BD biosciences, # 554655) and analyzed on an IQue® (Intellicyt®) flow cytometer or an Accuri (BD) flow cytometer. An unstained control with the secondary antibody alone was also included for all cell lines. The results were analyzed using ForeCyt® (IntelliCyt®) software to determine the mean geometric fluorescence (MFI) for viable cells. The binding rate was calculated by normalizing the MFI of the test samples by the MFI of the unstained samples.

[0593] As shown in Table 9-1, 19 of the 23 anti-IL2Rg antibodies of the present invention tested at 10 µg / ml demonstrated binding to Zurcat and NK-92 cells, with binding rates of 1–19 and 1–94, respectively. The anti-IL2Rγ antibodies demonstrated binding to NIH / 3T3 and MC / 9 cells, with binding rates of 1–13 and 1, respectively. The human isotype control antibody, REGN1945, and the secondary sole control condition showed binding rates of 1–13 in all tested cell lines.

[0594] As shown in Table 9-2, four of the 23 anti-IL2Rγ antibodies of the present invention tested at 10 µg / ml demonstrated binding to NK-92 cells with binding ratios of 1-37 and binding to HEK293 cells with binding ratios of 1-3. The human isotype control antibody, REGN1945, and the second only control condition showed binding ratios of 1-2 to NK-92 and HEK293.

[0595] Table 9-1

[0596]

[0597] Table 9-2

[0598]

[0599] Example 10: In vivo immunosuppression experiment to evaluate the effect of the anti-IL2Rγ antibody H4H12889P on a blood immune cell population.

[0600] Experimental procedure. Velocigene® (VG) background mice (C57BL / 6NTac (75%) / 129S6SvEvTac (25%)) from Regeneron Velocigene® breeding colonies genetically modified to replace the endogenous IL2RG ectodomain with the corresponding human sequence were administered or not administered the isotype control (REGN1945) or H4H12889P at a dose of 10 mg / kg or 25 mg / kg at a frequency of 2 times per week for 3 weeks (total 6 doses).

[0601] Table 10-1

[0602]

[0603] Analysis of immune cell populations by flow cytometry over a certain period. The total number of immune cells, B cells, T cells, NK cells, and neutrophils in peripheral blood was analyzed at various time points (once a week) via flow cytometry to evaluate the effect of H4H12889P on the absolute number of these cell types. Briefly, at each time point, blood samples of mouse origin were collected in microtainer tubes containing K2EDTA [BD #365974], and 30–75 µL of each blood sample was incubated in erythrocyte lysis buffer [Sigma #R7757] at room temperature for 5 minutes to lyse the erythrocytes. If necessary, a second round of lysis was performed. The cells were subsequently washed in DPBS [Gibco #14190-144], stained for 20 minutes with LIVE / DEAD™ immobilizable near-IR dead cell stain [Invitrogen #L34962] diluted 1:500 in DPBS, washed again in DPBS, and then blocked with purified anti-mouse CD16 / CD32 (Fc Shield) [Tonbo Biosciences, #70-0161-M001] diluted 1:50 in MACS buffer [Auto-MACS Development Buffer; Miltenyi Biotec, #130-091-221]. Subsequently, the cells were stained for cell surface markers by adding a mixture of fluorescently labeled antibodies (listed in Table 2) diluted in BD Horizon Brilliant Staining Buffer [BD #566349] to CD45 +Cells, T cells, B cells, NK cells, and neutrophils were identified. Finally, samples were washed in MACS buffer, fixed in BD CytoFix [BD #554655] diluted 1:4 in DPBS, washed in MACS buffer prior to acquisition, and resuspended. Sample data were acquired on a FACSSymphony A5 analyzer using HTS adhesion [Bd]. The fixed volume of each sample was developed. Data analysis was performed using FlowJo v10 software [Tree Star, Or]. CD45 + Immune cells are single-line, viable cells, CD45 + It was identified as; within the above population, T cells additionally CD3 + It was identified as, and B cells CD3 - CD19 + It was identified as, and NK cells CD3 - CD19 - NKp46 + It was identified as and neutrophils are F4 / 80 - Ly6G + It was determined as follows. The number of cells / mL blood for each sample was calculated using the absolute number of each cell type developed through the analyzer, the sample volume development, and the volume of the originally stained blood.

[0604] Table 10-2.

[0605]

[0606] Analysis of serum therapeutic antibody levels over a specific period by antigen capture ELISA. Serum levels of IL2Rγ antibody or isotype control antibody were measured once weekly using a human total IgG platinum ELISA kit. Standard curves from H4H12889P and REGN1945 were generated by serially diluting each antibody in 0.5% BSA solution in PBS to obtain values ​​ranging from 1.56 to 100 ng / mL. Absorbance at 450 nm was measured on a SpectraMax M5 plate reader [Molecular Devices]. Data analysis was performed using Prism 8.1.2 [GraphPad].

[0607] Results Summary and Conclusion. Treatment with H4H12889P (10 mg / kg and 25 mg / kg) resulted in total CD45 in blood + While the numbers of immune cells (Fig. 9 (a)), NK cells (Fig. 9 (b)), T cells (Fig. 9 (c)), and B cells (Fig. 9 (d)) were significantly reduced, the number of neutrophils (Fig. 9 (E)) was unaffected. After the 3-week administration period ended, the serum concentration of H4H12889P decreased over time. The aforementioned decrease in the concentration of H4H12889P corresponds to total CD45 + It was associated with a continuous increase in the number of immune cells (Fig. 9 (a)), NK cells (Fig. 9 (b)), T cells (Fig. 9 (c)), and B cells (Fig. 9 (d)). By the end of the study, all of these populations had returned to the observed levels of pretreatment and mitosan, as well as to the levels observed in untreated or REGN1945 (isotype control) mice.

[0608] Example 11: In vivo skin graft rejection model for evaluating the blocking activity of IL2Rγ antibody H4H12889P.

[0609] Experimental Procedure .BALB / cJ mice obtained from The Jackson Laboratory (Bar Harbor, Me) were used as skin graft donors, and MHC-mismatched Velocigene® (VG) background mice (C57BL / 6NTac (75%) / 129S6SvEvTac (25%)) from Regeneron Velocigene® breeding colonies, genetically modified to replace the endogenous IL2RG ectodomain with the corresponding human sequence, were used as recipients. Skin grafts were obtained from the tails of the donor mice. They were descalded using forceps and punched with a 10 mm diameter biopsy punch. VG mice (humanized for IL2Rγ) used as graft recipients were either administered or not administered the isotype control (REGN1945) or H4H12889P subcutaneously at a dose of 25 mg / kg at a frequency of twice a week, starting 3 weeks prior to transplantation and continuing until rejection. The recipient, with the surgical site shaved, was anesthetized with nasal isoflurane and administered an analgesic (buprenorphine-delayed release) (ZooPharm). The shaved dorsal area was cleaned by applying povidone iodine and alcohol. The graft bed was created midway between the dorsal and ventral sides of the mouse by pinching the skin with forceps and then excising the skin using a sterile 10 mm diameter biopsy skin punch. The graft was then placed on the graft bed and covered with an adhesive band secured to the skin with two sterile surgical staples. Aseptic technique was maintained throughout the entire procedure. After 5 days, the band and staples were removed, and monitoring continued.

[0610] Table 11-1

[0611]

[0612] The experimental layout is shown in Fig. 10.

[0613] Monitoring of skin graft rejection.Monitoring of skin grafts included the following criteria: (1) Skin grafts that failed to form adequate angiogenesis were considered technical failures and excluded from the analysis. These grafts exhibited scabbing and contraction several hours after band removal. (2) At subsequent time points, “scabbing” and contraction of the graft were used as indicators of graft rejection. The point of complete rejection was recorded as Day 1 when 100% of the graft tissue necrotized (Fig. 12). The onset of rejection was recorded as Day 1 when signs of rejection (i.e., skin flushing) were present (Fig. 11). Significance was determined by Log-Rank (Mantel-Cox) with Bonferroni correction (adjusted p Value 0.005, K=9).

[0614] Detection of donor-specific antibodies by flow cytometry. Blood was sampled at day 56 after transplantation to evaluate the formation of donor-specific antibodies (Fig. 13).

[0615] CT26.WT (ATCC® CRL-2638™) cells were cultured in tissue culture flasks until 80% confluence was reached. The cells were washed with 1X DPBS, incubated at room temperature for 5 minutes, and dissociated with TrypLE Express reagent (Gibco) by washing the flask thoroughly with RPMI 1640 medium. Subsequently, the cells were centrifuged (500 g (10 min) and resuspended 4 µg / ml of Fc block (Tonbo) in 1:50 diluted 1X DPBS at room temperature for 15 minutes to 5 million cells / ml. The suspension was dispensed into 384-well V-bottom plates at 250,000 cells / well (50 µL).

[0616] 50 µl of serially diluted samples from transplanted mice, non-engrafted wild-type VG mice (C57BL / 6NTac (75%) / 129S6SvEvTac (25%)), and wild-type BALB / cJ mice obtained from The Jackson Laboratory were added to each well and incubated at 37°C for 45 minutes. After washing twice with MACS buffer (500g, 4 min), the cells were resuspended in 50 µl of LIVE / DEAD™ Blue Dead Cell Stain Kit (Invitrogen) diluted 1:500 in 1 X DPBS at a total volume of 500 µl per well and incubated at room temperature for 15 minutes. After centrifuging at 500 g for 4 minutes, the supernatant was discarded, and the cells were resuspended in 25 µl of Fc block (Tonbo) and incubated at 4°C for 15 minutes. Subsequently, 25 µl of 2X antibody cocktail (Table 11-2) was added, and the cells were incubated at 4°C for 25 minutes. The cells were washed in MACS buffer after centrifugation (500 g, 4 minutes) by adding 100 µl of MACS™ buffer to each well. The cells were fixed by resuspending them in 100 µl of Cytofix™ fixation buffer (BD) diluted 1:4 in 1X DPBS and incubated at 4°C for 15 minutes. Subsequently, the samples were centrifuged, resuspended in MACS buffer, and the fixative was discarded. Cells were acquired on BD Fortessa X-20. The acquired events were analyzed by FlowJo (Bd). MFI was induced from double-line separated cells (FSC-H, FSC-A) and subsequently was live / dead dye negative. The plotted results are median fluorescence intensity values ​​at a 1 / 512 dilution of the sample serum.

[0617] Table 11-2

[0618]

[0619] Results Summary and Conclusion.In a skin graft model (BALB / cJ vs. VG mice), treatment with H4H12889P (anti-IL2Rγ Ab) delayed the onset of skin graft rejection and improved overall skin graft survival. Treatment with H4H12889P also prevented the production of donor-specific antibodies in the said graft model.

Claims

Claim 1 Isolated antigen-binding protein specifically binding to IL2Rγ or its antigen fragment, characterized by one or more of the following: approximately 2.75 x 10⁶ to the extracellular domain of human IL2Rγ at 25°C -9 M to about 3.36 x 10 -7 M, approx. 2.45 x 10⁻⁶ -9 M to about 1.20 x 10 -8 M; or about 1.20 X 10 -8 K less than M D Binds to; approximately 6.42 x 10⁶ human IL2Rγ extracellular domain at 37°C -9 M to approximately 3.53 x 10 -7 M, approx. 1.86 X 10 -11 M to approximately 3.00 x 10 -8 M; approx. 3.00 X 10 -8 Less than M or approximately 3.53 x 10 -7 K less than M D Combined as; · Macaca facicularius at 25℃ ( Macaca fascicularis ) Approximately 3.18 x 10⁶ in the extracellular domain of IL-2Rγ -9 M to about 2.38 x 10 -7 M's K D Binds to the IL-2Rγ extracellular domain of Macaca facicularius at 37°C, approximately 8.29 x 10⁶ -9 M to about 3.20 x 10 -7 M's K D Combine as; approximately 3.20 X 10 -7 M's K D Binds to; · Approximately 1.84 x 10⁶ in the extracellular domain of mouse IL2Rγ at 25°C -8 M, 3.76 X 10 -9 M, 1.08 X 10 -7 M, 2.17 X 10 -8 M, 6.02 X 10 -9 M or 7.93 X 10 -8 M's K D Binds to or; does not bind detectably; · Approx. 5.59 x 10⁶ to the mouse IL2Rγ extracellular domain at 37°C -8 M, 6.11 X 10 -9 M, 3.87 X 10 -7 M, 5.16 X 10 -8 M, 8.70 X 10 -9 M or 2.15 X 10 -7 M's K D Binds to or; does not bind detectably; · Approximately 3.32 x 10⁶ to human IL2Rγ domain 1 at 25°C -9 M to about 1.97 x 10 -7 M's K D Binds or does not bind detectably; · Approximately 4.13 x 10⁶ to human IL2Rγ domain 1 at 37°C -9 M to about 2.25 x 10 -7 M's K D Binds to or; does not bind detectably; · Approximately 2.91 x 10⁶ to human IL2Rγ domain 2 at 25°C -7 M to about 5.35 x 10 -10 M's K D Binds to or; does not bind detectably; · Approximately 1.14 x 10⁶ to human IL2Rγ domain 2 at 37°C -8 M to about 1.27 x 10 -8 M's K D Binds to; does not bind detectably; · does not bind detectably to mouse or rat IL2Rγ; · blocks STAT phosphorylation in T-cells induced by IL-2, IL-4, IL-7, IL-15, and / or IL-21; · blocks STAT phosphorylation in mast cells induced by IL-9; · reduces the number of human peripheral blood mononuclear cells (PBMCs) and / or human cytokines in the blood or serum of immunodeficient mice injected with said cells; · protects mice from body weight loss and / or death caused by GvHD in a GvHD mouse model; · blocks the binding of hybrid receptors, including IL2Rγ complexed with a cytokine-specific receptor subunit, to IL-2, IL-4, IL-7, IL-9, IL-15, and / or IL-21; · Inhibits intracellular IL2Rγ signaling via the JAK-STAT pathway induced by IL-2, IL-4, IL-7, IL-9, IL-15, and / or IL-21; · H4H12857P; H4H12858P; H4H12859P; H4H12863P; H4H12874P; H4H12871P; H4H12884P; H4H12886P; H4H12889P; H4H12890P; H4H12899P; H4H12900P; H4H12908P; H4H12913P2; H4H12922P2; H4H12924P2; H4H12926P2; H4H12927P2; H4H12934P2; H4H13538P; H4H13541P; H4H13544P2; or specifically binds to an epitope on IL2Rγ identical to the reference antibody or its antigen-binding fragment, which is H4H13545P2; · H4H12857P; H4H12858P; H4H12859P; H4H12863P; H4H12874P; H4H12871P; H4H12884P; H4H12886P; H4H12889P; H4H12890P; H4H12899P; H4H12900P; H4H12908P; H4H12913P2; H4H12922P2; H4H12924P2; H4H12926P2;Competing for binding to IL2Rγ polypeptide or its antigen fragment with a reference antibody that is H4H12927P2; H4H12934P2; H4H13538P; H4H13541P; H4H13544P2; or H4H13545P2, or its antigen-binding fragment, and / or reducing CD45+ cells, B-cells, T-cells, and / or NK cells in blood or serum.; Claim 2 In claim 1, an antigen-binding protein that specifically binds to IL2Rγ or its antigen-binding fragment, which is an antibody or its antigen-binding fragment. Claim 3 In paragraph 2, an antigen-binding protein that specifically binds to IL2Rγ or its antigen-binding fragment, which is an antibody. Claim 4 An isolated antigen-binding protein that specifically binds to IL2Rγ or an antigen fragment thereof, comprising the following: (a) SEQ ID NOs 2, 18, 22, 38, 42, 58, 62, 77, 81, 97, 101, 115, 119, 134, 138, 152, 156, 170, 174, 186, 190, 198, 200, 208, 210, 216, 218, 234, 238, 254, 258, 272, 276, 284, 286, 294, 296, 311, 315, 331, 335, 343, 345, 357, 361 or A heavy chain immunoglobulin comprising the amino acid sequence presented in 376 or a heavy chain immunoglobulin comprising CDR-H1, CDR-H2, and CDR-H3 of the variable region thereof or the variable region thereof; or a variant thereof; and / or (b) a light chain immunoglobulin comprising the amino acid sequence presented in SEQ ID NOs 10, 20, 30, 40, 50, 60, 70, 79, 89, 99, 109, 117, 127, 136, 146, 154, 164, 172, 182, 188, 226, 236, 246, 256, 266, 274, 304, 313, 323, 333, 353, 359, 368 or 378, or a light chain immunoglobulin comprising CDR-L1, CDR-L2 and CDR-L3 of a variable region thereof; or a variant thereof. Claim 5 In any one of claims 1 to 4, an antigen-binding protein that specifically binds to IL2Rγ or an antigen fragment thereof, comprising: (a) SEQ ID NOs 2, 18, 22, 38, 42, 58, 62, 77, 81, 97, 101, 115, 119, 134, 138, 152, 156, 170, 174, 186, 190, 198, 200, 208, 210, 216, 218, 234, 238, 254, 258, 272, 276, 284, 286, 294, 296, 311, 315, 331, 335, 343, 345, A heavy chain immunoglobulin or a variable region thereof comprising an amino acid sequence having at least 90% amino acid sequence identity with the amino acid sequence presented in 357, 361, or 376; and / or (b) a light chain immunoglobulin or a variable region thereof comprising an amino acid sequence having at least 90% amino acid sequence identity with the amino acid sequence presented in SEQ ID NOs 10, 20, 30, 40, 50, 60, 70, 79, 89, 99, 109, 117, 127, 136, 146, 154, 164, 172, 182, 188, 226, 236, 246, 256, 266, 274, 304, 313, 323, 333, 353, 359, 368 or 378. Claim 6 In any one of claims 1 to 5, an antigen-binding protein that specifically binds to IL2Rγ or an antigen-binding fragment thereof, comprising: (a) SEQ ID NOs 2, 18, 22, 38, 42, 58, 62, 77, 81, 97, 101, 115, 119, 134, 138, 152, 156, 170, 174, 186, 190, 198, 200, 208, 210, 216, 218, 234, 238, 254, 258, 272, 276, 284, 286, 294, 296, 311, 315, 331, 335, 343, 345, The amino acid sequence presented in 357, 361, or 376, comprising the amino acid sequence presented in SEQ ID NO. 2, 18, 22, 38, 42, 58, 62, 77, 81, 97, 101, 115, 119, 134, 138, 152, 156, 170, 174, 186, 190, 198, 200, 208, 210, 216, 218, 234, 238, 254, 258, 272, 276, 284, 286, 294, 296, 311, 315, 331, 335, 343, 345, 357, 361, or 376 A heavy chain immunoglobulin comprising an amino acid sequence having at least 90% amino acid sequence identity with the sequence, or a heavy chain immunoglobulin comprising CDR-H1, CDR-H2, and CDR-H3 of the variable region thereof, or the variable region thereof;and / or (b) comprising the amino acid sequences presented in SEQ ID NO. 10, 20, 30, 40, 50, 60, 70, 79, 89, 99, 109, 117, 127, 136, 146, 154, 164, 172, 182, 188, 226, 236, 246, 256, 266, 274, 304, 313, 323, 333, 353, 359, 368 or 378, and comprising SEQ ID NO. 10, 20, 30, 40, 50, 60, 70, 79, 89, 99, 109, 117, 127, 136, 146, A light chain immunoglobulin comprising an amino acid sequence having at least 90% amino acid sequence identity with the amino acid sequences presented in 154, 164, 172, 182, 188, 226, 236, 246, 256, 266, 274, 304, 313, 323, 333, 353, 359, 368, or 378, or a light chain immunoglobulin comprising CDR-L1, CDR-L2, and CDR-L3 of the variable region thereof, or a variable region thereof.; Claim 7 In any one of claims 1 to 6, an antigen-binding protein that specifically binds to IL2Rγ or an antigen fragment thereof, comprising: (i) CDR-H1 comprising the amino acid sequence presented in SEQ ID NO. 4; CDR-H2 comprising the amino acid sequence presented in SEQ ID NO. 6; and CDR-H3 comprising the amino acid sequence presented in SEQ ID NO. 8; and / or CDR-H1 comprising the amino acid sequence presented in SEQ ID NO. 24; CDR-H2 comprising the amino acid sequence presented in SEQ ID NO. 26; and CDR-H3 comprising the amino acid sequence presented in SEQ ID NO. 28; and / or CDR-H1 comprising the amino acid sequence presented in SEQ ID NO. 44; CDR-H2 comprising the amino acid sequence presented in SEQ ID NO. 46; and CDR-H3 comprising the amino acid sequence presented in SEQ ID NO. 48; and / or CDR-H1 comprising the amino acid sequence presented in SEQ ID NO. 64; CDR-H2 comprising the amino acid sequence presented in SEQ ID NO. 66; and CDR-H3 comprising the amino acid sequence presented in SEQ ID NO. 68; and / or CDR-H1 comprising the amino acid sequence presented in SEQ ID NO. 83; CDR-H2 comprising the amino acid sequence presented in SEQ ID NO. 85; and CDR-H3 comprising the amino acid sequence presented in SEQ ID NO. 87; and / or CDR-H1 comprising the amino acid sequence presented in SEQ ID NO. 103; CDR-H2 comprising the amino acid sequence presented in SEQ ID NO. 105; and CDR-H3 comprising the amino acid sequence presented in SEQ ID NO. 107; and / or CDR-H1 comprising the amino acid sequence presented in SEQ ID NO. 121; CDR-H2 comprising the amino acid sequence presented in SEQ ID NO. 123; and CDR-H3 comprising the amino acid sequence presented in SEQ ID NO. 125; and / or CDR-H1 comprising the amino acid sequence presented in SEQ ID NO. 140; CDR-H2 comprising the amino acid sequence presented in SEQ ID NO. 142; and CDR-H3 comprising the amino acid sequence presented in SEQ ID NO. 144;and / or CDR-H1 comprising the amino acid sequence presented in SEQ ID NO. 158; CDR-H2 comprising the amino acid sequence presented in SEQ ID NO. 160; and CDR-H3 comprising the amino acid sequence presented in SEQ ID NO. 162; and / or CDR-H1 comprising the amino acid sequence presented in SEQ ID NO. 176; CDR-H2 comprising the amino acid sequence presented in SEQ ID NO. 178; and CDR-H3 comprising the amino acid sequence presented in SEQ ID NO. 180; and / or CDR-H1 comprising the amino acid sequence presented in SEQ ID NO. 192; CDR-H2 comprising the amino acid sequence presented in SEQ ID NO. 194; and CDR-H3 comprising the amino acid sequence presented in SEQ ID NO. 196; and / or CDR-H1 comprising the amino acid sequence presented in SEQ ID NO. 202; CDR-H2 comprising the amino acid sequence presented in SEQ ID NO. 204; and CDR-H3 comprising the amino acid sequence presented in SEQ ID NO. 206; and / or CDR-H1 comprising the amino acid sequence presented in SEQ ID NO. 176; CDR-H2 comprising the amino acid sequence presented in SEQ ID NO. 212; and CDR-H3 comprising the amino acid sequence presented in SEQ ID NO. 214; and / or CDR-H1 comprising the amino acid sequence presented in SEQ ID NO. 220; CDR-H2 comprising the amino acid sequence presented in SEQ ID NO. 222; and CDR-H3 comprising the amino acid sequence presented in SEQ ID NO. 224; and / or CDR-H1 comprising the amino acid sequence presented in SEQ ID NO. 240; CDR-H2 comprising the amino acid sequence presented in SEQ ID NO. 242; and CDR-H3 comprising the amino acid sequence presented in SEQ ID NO. 244; and / or CDR-H1 comprising the amino acid sequence presented in SEQ ID NO. 260; CDR-H2 comprising the amino acid sequence presented in SEQ ID NO. 262; and CDR-H3 comprising the amino acid sequence presented in SEQ ID NO. 264; and / or CDR-H1 comprising the amino acid sequence presented in SEQ ID NO. 278; CDR-H2 comprising the amino acid sequence presented in SEQ ID NO. 280;and CDR-H3 comprising the amino acid sequence presented in SEQ ID NO. 282; and / or CDR-H1 comprising the amino acid sequence presented in SEQ ID NO. 288; CDR-H2 comprising the amino acid sequence presented in SEQ ID NO. 290; and CDR-H3 comprising the amino acid sequence presented in SEQ ID NO. 292; and / or CDR-H1 comprising the amino acid sequence presented in SEQ ID NO. 298; CDR-H2 comprising the amino acid sequence presented in SEQ ID NO. 300; and CDR-H3 comprising the amino acid sequence presented in SEQ ID NO. 302; and / or CDR-H1 comprising the amino acid sequence presented in SEQ ID NO. 317; CDR-H2 comprising the amino acid sequence presented in SEQ ID NO. 319; and CDR-H3 comprising the amino acid sequence presented in SEQ ID NO. 321; and / or CDR-H1 comprising the amino acid sequence presented in SEQ ID NO. 337; CDR-H2 comprising the amino acid sequence presented in SEQ ID NO. 399; and CDR-H3 comprising the amino acid sequence presented in SEQ ID NO. 341; and / or CDR-H1 comprising the amino acid sequence presented in SEQ ID NO. 347; CDR-H2 comprising the amino acid sequence presented in SEQ ID NO. 349; and CDR-H3 comprising the amino acid sequence presented in SEQ ID NO. 351; and / or CDR-H1 comprising the amino acid sequence presented in SEQ ID NO. 363; CDR-H2 comprising the amino acid sequence presented in SEQ ID NO. 66; and CDR-H3 comprising the amino acid sequence presented in SEQ ID NO. 366; and / or (ii) CDR-L1 comprising the amino acid sequence presented in SEQ ID NO. 12; CDR-L2 comprising the amino acid sequence presented in SEQ ID NO. 14; and CDR-L3 comprising the amino acid sequence presented in SEQ ID NO. 16; and / or CDR-L1 comprising the amino acid sequence presented in SEQ ID NO. 32; CDR-L2 comprising the amino acid sequence presented in SEQ ID NO. 34; and CDR-L3 comprising the amino acid sequence presented in SEQ ID NO. 36; and / or CDR-L1 comprising the amino acid sequence presented in SEQ ID NO. 52;CDR-L2 comprising the amino acid sequence presented in SEQ ID NO. 54; and CDR-L3 comprising the amino acid sequence presented in SEQ ID NO. 56; and / or CDR-L1 comprising the amino acid sequence presented in SEQ ID NO. 72; CDR-L2 comprising the amino acid sequence presented in SEQ ID NO. 54; and CDR-L3 comprising the amino acid sequence presented in SEQ ID NO. 75; and / or CDR-L1 comprising the amino acid sequence presented in SEQ ID NO. 91; CDR-L2 comprising the amino acid sequence presented in SEQ ID NO. 93; and CDR-L3 comprising the amino acid sequence presented in SEQ ID NO. 95; and / or CDR-L1 comprising the amino acid sequence presented in SEQ ID NO. 111; CDR-L2 comprising the amino acid sequence presented in SEQ ID NO. 54; and CDR-L3 comprising the amino acid sequence presented in SEQ ID NO. 113; and / or CDR-L1 comprising the amino acid sequence presented in SEQ ID NO. 129; CDR-L2 comprising the amino acid sequence presented in SEQ ID NO. 54; and CDR-L3 comprising the amino acid sequence presented in SEQ ID NO. 132; and / or CDR-L1 comprising the amino acid sequence presented in SEQ ID NO. 148; CDR-L2 comprising the amino acid sequence presented in SEQ ID NO. 54; and CDR-L3 comprising the amino acid sequence presented in SEQ ID NO. 150; and / or CDR-L1 comprising the amino acid sequence presented in SEQ ID NO. 166; CDR-L2 comprising the amino acid sequence presented in SEQ ID NO. 14; and CDR-L3 comprising the amino acid sequence presented in SEQ ID NO. 168; and / or CDR-L1 comprising the amino acid sequence presented in SEQ ID NO. 72; CDR-L2 comprising the amino acid sequence presented in SEQ ID NO. 54; and CDR-L3 comprising the amino acid sequence presented in SEQ ID NO. 184; and / or CDR-L1 comprising the amino acid sequence presented in SEQ ID NO. 228; CDR-L2 comprising the amino acid sequence presented in SEQ ID NO. 230; and CDR-L3 comprising the amino acid sequence presented in SEQ ID NO. 232;and / or CDR-L1 comprising the amino acid sequence presented in SEQ ID NO. 248; CDR-L2 comprising the amino acid sequence presented in SEQ ID NO. 250; and CDR-L3 comprising the amino acid sequence presented in SEQ ID NO. 252; and / or CDR-L1 comprising the amino acid sequence presented in SEQ ID NO. 268; CDR-L2 comprising the amino acid sequence presented in SEQ ID NO. 54; and CDR-L3 comprising the amino acid sequence presented in SEQ ID NO. 270; and / or CDR-L1 comprising the amino acid sequence presented in SEQ ID NO. 306; CDR-L2 comprising the amino acid sequence presented in SEQ ID NO. 230; and CDR-L3 comprising the amino acid sequence presented in SEQ ID NO. 309; and / or CDR-L1 comprising the amino acid sequence presented in SEQ ID NO. 325; and CDR-L2 comprising the amino acid sequence presented in SEQ ID NO. 327; and CDR-L3 comprising the amino acid sequence presented in SEQ ID NO. 329; and / or CDR-L1 comprising the amino acid sequence presented in SEQ ID NO. 72; CDR-L2 comprising the amino acid sequence presented in SEQ ID NO. 54; and CDR-L3 comprising the amino acid sequence presented in SEQ ID NO. 355; and / or CDR-L1 comprising the amino acid sequence presented in SEQ ID NO. 370; CDR-L2 comprising the amino acid sequence presented in SEQ ID NO. 372; and CDR-L3 comprising the amino acid sequence presented in SEQ ID NO. 374.; Claim 8 An antigen-binding protein that specifically binds to IL2Rγ or an antigen fragment thereof, comprising one or more members selected from the group consisting of the following in any one of claims 1 to 7: (i) a heavy chain variable region comprising CDR-H1 having an amino acid sequence presented in SEQ ID NO. 4; CDR-H2 having an amino acid sequence presented in SEQ ID NO. 6; and CDR-H3 having an amino acid sequence presented in SEQ ID NO. 8; and a light chain variable region comprising CDR-L1 having an amino acid sequence presented in SEQ ID NO. 12; CDR-L2 having an amino acid sequence presented in SEQ ID NO. 14; and CDR-L3 having an amino acid sequence presented in SEQ ID NO. 16; (ii) a heavy chain variable region comprising CDR-H1 having an amino acid sequence presented in SEQ ID NO. 24; CDR-H2 having an amino acid sequence presented in SEQ ID NO. 26; and CDR-H3 having an amino acid sequence presented in SEQ ID NO. 28; (iii) a light chain variable region comprising CDR-L1 having the amino acid sequence presented in SEQ ID NO. 32; CDR-L2 having the amino acid sequence presented in SEQ ID NO. 34; and CDR-L3 having the amino acid sequence presented in SEQ ID NO. 36; (iii) a heavy chain variable region comprising CDR-H1 having the amino acid sequence presented in SEQ ID NO. 44; CDR-H2 having the amino acid sequence presented in SEQ ID NO. 46; and CDR-H3 having the amino acid sequence presented in SEQ ID NO. 48; and a light chain variable region comprising CDR-L1 having the amino acid sequence presented in SEQ ID NO. 52; CDR-L2 having the amino acid sequence presented in SEQ ID NO. 54; and CDR-L3 having the amino acid sequence presented in SEQ ID NO. 56; (iv) CDR-H1 having the amino acid sequence presented in SEQ ID NO. 64; and CDR-H2 having the amino acid sequence presented in SEQ ID NO. 66; and a heavy chain variable region comprising a CDR-H3 having the amino acid sequence presented in SEQ ID NO. 68;(v) a light chain variable region comprising CDR-L1 having the amino acid sequence presented in SEQ ID NO. 72; CDR-L2 having the amino acid sequence presented in SEQ ID NO. 54; and CDR-L3 having the amino acid sequence presented in SEQ ID NO. 75; (v) a heavy chain variable region comprising CDR-H1 having the amino acid sequence presented in SEQ ID NO. 83; CDR-H2 having the amino acid sequence presented in SEQ ID NO. 85; and CDR-H3 having the amino acid sequence presented in SEQ ID NO. 87; and a light chain variable region comprising CDR-L1 having the amino acid sequence presented in SEQ ID NO. 91; CDR-L2 having the amino acid sequence presented in SEQ ID NO. 93; and CDR-L3 having the amino acid sequence presented in SEQ ID NO. 95; (vi) CDR-H1 having the amino acid sequence presented in SEQ ID NO. 103; and CDR-H2 having the amino acid sequence presented in SEQ ID NO. 105; (vii) a heavy chain variable region comprising CDR-H3 having the amino acid sequence presented in SEQ ID NO. 107; a light chain variable region comprising CDR-L1 having the amino acid sequence presented in SEQ ID NO. 111; CDR-L2 having the amino acid sequence presented in SEQ ID NO. 54; and CDR-L3 having the amino acid sequence presented in SEQ ID NO. 113; (vii) a heavy chain variable region comprising CDR-H1 having the amino acid sequence presented in SEQ ID NO. 121; CDR-H2 having the amino acid sequence presented in SEQ ID NO. 123; and CDR-H3 having the amino acid sequence presented in SEQ ID NO. 125; a light chain variable region comprising CDR-L1 having the amino acid sequence presented in SEQ ID NO. 129; CDR-L2 having the amino acid sequence presented in SEQ ID NO. 54; and CDR-L3 having the amino acid sequence presented in SEQ ID NO. 132; (viii) a CDR-H1 having the amino acid sequence presented in SEQ ID NO. 140; CDR-H2 containing the amino acid sequence presented in SEQ ID NO. 142;and a heavy chain variable region comprising CDR-H3 comprising the amino acid sequence presented in SEQ ID NO. 144; and a light chain variable region comprising CDR-L1 comprising the amino acid sequence presented in SEQ ID NO. 148; CDR-L2 comprising the amino acid sequence presented in SEQ ID NO. 54; and CDR-L3 comprising the amino acid sequence presented in SEQ ID NO. 150; (ix) a heavy chain variable region comprising CDR-H1 comprising the amino acid sequence presented in SEQ ID NO. 158; CDR-H2 comprising the amino acid sequence presented in SEQ ID NO. 160; and CDR-H3 comprising the amino acid sequence presented in SEQ ID NO. 162; and a light chain variable region comprising CDR-L1 comprising the amino acid sequence presented in SEQ ID NO. 166; CDR-L2 comprising the amino acid sequence presented in SEQ ID NO. 14; and CDR-L3 comprising the amino acid sequence presented in SEQ ID NO. 168; (x) a CDR-H1 comprising the amino acid sequence presented in SEQ ID NO. 176; A heavy chain variable region comprising CDR-H2 having the amino acid sequence presented in SEQ ID NO. 178; and CDR-H3 having the amino acid sequence presented in SEQ ID NO. 180; and a light chain variable region comprising CDR-L1 having the amino acid sequence presented in SEQ ID NO. 72; CDR-L2 having the amino acid sequence presented in SEQ ID NO. 54; and CDR-L3 having the amino acid sequence presented in SEQ ID NO. 184; (xi) a heavy chain variable region comprising CDR-H1 having the amino acid sequence presented in SEQ ID NO. 192; CDR-H2 having the amino acid sequence presented in SEQ ID NO. 194; and CDR-H3 having the amino acid sequence presented in SEQ ID NO. 196; and CDR-L1 having the amino acid sequence presented in SEQ ID NO. 72; and CDR-L2 having the amino acid sequence presented in SEQ ID NO. 54; and a light chain variable region comprising a CDR-L3 having the amino acid sequence presented in SEQ ID NO. 184; (xii) a CDR-H1 having the amino acid sequence presented in SEQ ID NO. 202;(xiii) a heavy chain variable region comprising CDR-H2 having the amino acid sequence presented in SEQ ID NO. 204; and CDR-H3 having the amino acid sequence presented in SEQ ID NO. 206; and CDR-L1 having the amino acid sequence presented in SEQ ID NO. 72; CDR-L2 having the amino acid sequence presented in SEQ ID NO. 54; and CDR-L3 having the amino acid sequence presented in SEQ ID NO. 184; (xiii) a heavy chain variable region comprising CDR-H1 having the amino acid sequence presented in SEQ ID NO. 176; CDR-H2 having the amino acid sequence presented in SEQ ID NO. 212; and CDR-H3 having the amino acid sequence presented in SEQ ID NO. 214; and CDR-L1 having the amino acid sequence presented in SEQ ID NO. 72; and CDR-L2 having the amino acid sequence presented in SEQ ID NO. 54; and a light chain variable region comprising CDR-L3 having the amino acid sequence presented in SEQ ID NO. 184; (xiv) a heavy chain variable region comprising CDR-H1 having the amino acid sequence presented in SEQ ID NO. 220; CDR-H2 having the amino acid sequence presented in SEQ ID NO. 222; and CDR-H3 having the amino acid sequence presented in SEQ ID NO. 224; and a light chain variable region comprising CDR-L1 having the amino acid sequence presented in SEQ ID NO. 228; CDR-L2 having the amino acid sequence presented in SEQ ID NO. 230; and CDR-L3 having the amino acid sequence presented in SEQ ID NO. 232; (xv) a heavy chain variable region comprising CDR-H1 having the amino acid sequence presented in SEQ ID NO. 240; CDR-H2 having the amino acid sequence presented in SEQ ID NO. 242; and CDR-H3 having the amino acid sequence presented in SEQ ID NO. 244; A light chain variable region comprising: CDR-L1 having the amino acid sequence presented in SEQ ID NO. 248; CDR-L2 having the amino acid sequence presented in SEQ ID NO. 250; and CDR-L3 having the amino acid sequence presented in SEQ ID NO. 252;(xvi) a heavy chain variable region comprising CDR-H1 having the amino acid sequence presented in SEQ ID NO. 260; CDR-H2 having the amino acid sequence presented in SEQ ID NO. 262; and CDR-H3 having the amino acid sequence presented in SEQ ID NO. 264; and a light chain variable region comprising CDR-L1 having the amino acid sequence presented in SEQ ID NO. 268; CDR-L2 having the amino acid sequence presented in SEQ ID NO. 54; and CDR-L3 having the amino acid sequence presented in SEQ ID NO. 270; (xvii) a heavy chain variable region comprising CDR-H1 having the amino acid sequence presented in SEQ ID NO. 278; CDR-H2 having the amino acid sequence presented in SEQ ID NO. 280; and CDR-H3 having the amino acid sequence presented in SEQ ID NO. 282; and CDR-L1 having the amino acid sequence presented in SEQ ID NO. 72; and CDR-L2 having the amino acid sequence presented in SEQ ID NO. 54; and a light chain variable region comprising CDR-L3 having the amino acid sequence presented in SEQ ID NO. 184; (xviii) a heavy chain variable region comprising CDR-H1 having the amino acid sequence presented in SEQ ID NO. 288; CDR-H2 having the amino acid sequence presented in SEQ ID NO. 290; and CDR-H3 having the amino acid sequence presented in SEQ ID NO. 292; and a light chain variable region comprising CDR-L1 having the amino acid sequence presented in SEQ ID NO. 72; CDR-L2 having the amino acid sequence presented in SEQ ID NO. 54; and CDR-L3 having the amino acid sequence presented in SEQ ID NO. 184; (xix) a heavy chain variable region comprising CDR-H1 having the amino acid sequence presented in SEQ ID NO. 298; CDR-H2 having the amino acid sequence presented in SEQ ID NO. 300; and CDR-H3 having the amino acid sequence presented in SEQ ID NO. 302; and CDR-L1 having the amino acid sequence presented in SEQ ID NO. 306; CDR-L2 containing the amino acid sequence presented in SEQ ID NO. 230;and a light chain variable region comprising CDR-L3 having the amino acid sequence presented in SEQ ID NO. 309; (xx) a heavy chain variable region comprising CDR-H1 having the amino acid sequence presented in SEQ ID NO. 317; CDR-H2 having the amino acid sequence presented in SEQ ID NO. 319; and CDR-H3 having the amino acid sequence presented in SEQ ID NO. 321; and a light chain variable region comprising CDR-L1 having the amino acid sequence presented in SEQ ID NO. 325; CDR-L2 having the amino acid sequence presented in SEQ ID NO. 327; and CDR-L3 having the amino acid sequence presented in SEQ ID NO. 329; (xxi) a heavy chain variable region comprising CDR-H1 having the amino acid sequence presented in SEQ ID NO. 337; CDR-H2 having the amino acid sequence presented in SEQ ID NO. 339; and CDR-H3 having the amino acid sequence presented in SEQ ID NO. 341; A light chain variable region comprising CDR-L1 having the amino acid sequence presented in SEQ ID NO. 72; CDR-L2 having the amino acid sequence presented in SEQ ID NO. 54; and CDR-L3 having the amino acid sequence presented in SEQ ID NO. 184; (xxii) a heavy chain variable region comprising CDR-H1 having the amino acid sequence presented in SEQ ID NO. 347; CDR-H2 having the amino acid sequence presented in SEQ ID NO. 349; and CDR-H3 having the amino acid sequence presented in SEQ ID NO. 351; and a light chain variable region comprising CDR-L1 having the amino acid sequence presented in SEQ ID NO. 72; CDR-L2 having the amino acid sequence presented in SEQ ID NO. 54; and CDR-L3 having the amino acid sequence presented in SEQ ID NO. 355; (xxii) CDR-H1 having the amino acid sequence presented in SEQ ID NO. 363; and CDR-H2 having the amino acid sequence presented in SEQ ID NO. 66; and a heavy chain variable region comprising a CDR-H3 having the amino acid sequence presented in SEQ ID NO. 366; and a CDR-L1 having the amino acid sequence presented in SEQ ID NO. 370;A light chain variable region comprising a CDR-L2 having the amino acid sequence presented in SEQ ID NO. 372; and a CDR-L3 having the amino acid sequence presented in SEQ ID NO. 374.; Claim 9 Antigen-binding protein, which is an antibody or antigen-binding fragment that specifically binds to IL2Rγ or its antigen fragment, comprising: a heavy chain variable region comprising the amino acid sequence presented in SEQ ID NO. 2; a light chain variable region comprising the amino acid sequence presented in SEQ ID NO. 10; a heavy chain variable region comprising the amino acid sequence presented in SEQ ID NO. 22; a light chain variable region comprising the amino acid sequence presented in SEQ ID NO. 30; a heavy chain variable region comprising the amino acid sequence presented in SEQ ID NO. 42; a light chain variable region comprising the amino acid sequence presented in SEQ ID NO. 50; a heavy chain variable region comprising the amino acid sequence presented in SEQ ID NO. 62; a light chain variable region comprising the amino acid sequence presented in SEQ ID NO. 70; a heavy chain variable region comprising the amino acid sequence presented in SEQ ID NO. 81; a light chain variable region comprising the amino acid sequence presented in SEQ ID NO. 89; a heavy chain variable region comprising the amino acid sequence presented in SEQ ID NO. 101; and a light chain variable region comprising the amino acid sequence presented in SEQ ID NO. 109; A heavy chain variable region comprising the amino acid sequence presented in SEQ ID NO. 119; and a light chain variable region comprising the amino acid sequence presented in SEQ ID NO. 127; a heavy chain variable region comprising the amino acid sequence presented in SEQ ID NO. 138; and a light chain variable region comprising the amino acid sequence presented in SEQ ID NO. 146; a heavy chain variable region comprising the amino acid sequence presented in SEQ ID NO. 156; and a light chain variable region comprising the amino acid sequence presented in SEQ ID NO. 164; a heavy chain variable region comprising the amino acid sequence presented in SEQ ID NO. 174; and a light chain variable region comprising the amino acid sequence presented in SEQ ID NO. 182; a heavy chain variable region comprising the amino acid sequence presented in SEQ ID NO. 190; and a light chain variable region comprising the amino acid sequence presented in SEQ ID NO. 182; a heavy chain variable region comprising the amino acid sequence presented in SEQ ID NO. 200; and a light chain variable region comprising the amino acid sequence presented in SEQ ID NO. 182;A heavy chain variable region comprising the amino acid sequence presented in SEQ ID NO. 210; and a light chain variable region comprising the amino acid sequence presented in SEQ ID NO. 182; a heavy chain variable region comprising the amino acid sequence presented in SEQ ID NO. 218; and a light chain variable region comprising the amino acid sequence presented in SEQ ID NO. 226; a heavy chain variable region comprising the amino acid sequence presented in SEQ ID NO. 238; and a light chain variable region comprising the amino acid sequence presented in SEQ ID NO. 246; a heavy chain variable region comprising the amino acid sequence presented in SEQ ID NO. 258; and a light chain variable region comprising the amino acid sequence presented in SEQ ID NO. 266; a heavy chain variable region comprising the amino acid sequence presented in SEQ ID NO. 276; and a light chain variable region comprising the amino acid sequence presented in SEQ ID NO. 182; a heavy chain variable region comprising the amino acid sequence presented in SEQ ID NO. 286; and a light chain variable region comprising the amino acid sequence presented in SEQ ID NO. 182; and a heavy chain variable region comprising the amino acid sequence presented in SEQ ID NO. 296; and a light chain variable region comprising the amino acid sequence presented in SEQ ID NO. 304; a heavy chain variable region comprising the amino acid sequence presented in SEQ ID NO. 315; a light chain variable region comprising the amino acid sequence presented in SEQ ID NO. 323; a heavy chain variable region comprising the amino acid sequence presented in SEQ ID NO. 335; a light chain variable region comprising the amino acid sequence presented in SEQ ID NO. 182; a heavy chain variable region comprising the amino acid sequence presented in SEQ ID NO. 345; a light chain variable region comprising the amino acid sequence presented in SEQ ID NO. 353; and / or a heavy chain variable region comprising the amino acid sequence presented in SEQ ID NO. 361; and a light chain variable region comprising the amino acid sequence presented in SEQ ID NO. 368.; Claim 10 Antigen-binding protein that is an antibody or antigen-binding fragment specifically binding to IL2Rγ or its antigen fragment comprising the following: heavy chain immunoglobulin comprising the following amino acid sequence: QVQLVQSGAEVKKPGASVRVSCKASGYTFTDYDIHWVRQAPGHGLEWMGWINPNSGGTNYAQKFQGRVTMTRDTSISTVYMDLSRLRSDDTAVYYCARADYSSSYYYYGMDVWGQGTTVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESK YGPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTI SKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK (SEQ ID NO: 18); and light chain immunoglobulin comprising the following amino acid sequence: DIVMTQSPDSLAVSLGERATINCKSSQSVLYSSKNKNYLSWYQQKPGQPPKLLIYWASTREFGVPDRFSGRGSGTDFTLTISSLQAEDVAVYYCQQYYTTPYTFGQGTKLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC(SEQ ID No. 20);Heavy chain immunoglobulin containing the following amino acid sequence: QVQLVESGGGVVQPGRSLRLSCTASGFTFRSYDMYWVRQAPGKGLEWVSVITYDGNNKYYADSVKGRFTISRDNSKNTLFLQMSSLRPEDTAVYYCAKRGLIWVGESFDYWGQGTLVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKY GPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTIS KAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK (SEQ ID NO: 38); and light chain immunoglobulin comprising the following amino acid sequence: DIQMTQSPSTLSASVGDRVTITCRASQSINSWLAWYQQKPGKAPNLLIYKASSLESGVPSRFSGSGSGTEFTLTISSLQPDDFATYYCQQYKSYSWTFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID No. 40);Heavy chain immunoglobulin containing the following amino acid sequence: QVQLVESGGGVVQPGRSLRLSCAASGFNFRNFGMHWVRQAPGKGLEWVAGILYDGSSKYYADSVKDRFTISRDNSKNTLFLQMNSLRAEDTAMYYCAKEEDTAMVPFDSWGPGTLVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKY GPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTIS KAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK (SEQ ID NO: 58); and light chain immunoglobulin comprising the following amino acid sequence: DIQLTQSPSFLSASVGDRVTITCWASQGISSYLAWYQQKPGKAPTLLIYAASTLQSGVPSRFSGSGSGTEFTLTISSLQPEDFASYYCQQLKSYPLTFGGGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID No. 60);Heavy chain immunoglobulin containing the following amino acid sequence: QVQLQESGPGLVKPSQTLSLTCTVSGGSISSGGYYWSWIRQHPGKGLEWIGFIYYSGKTYYNPSLKSRLTISVDTSKSQFSLKLRSVTAADTAVYYCARLGYTNSAGWFDPWGQGTLVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESK YGPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTI SKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK (SEQ ID NO: 77); and a light chain immunoglobulin comprising the following amino acid sequence: DIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPNLLIYAASSLQSGVPSRFSGSGSGTDFTLTISSLQPEDLATYYCQQSYTTPFTFGPGTKVDIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID No. 79);Heavy chain immunoglobulin containing the following amino acid sequence: EVQLVESGGGLVKPGGSLRLSCAASGFTFSTAWMSWVRQSPGRGLEWVGRMKSKTDGGTTFYAAPVKGRFTISRDDSKNTLYLQMNSLKTEDTAVYYCTTGLVPAFYKYYGVDVWGQGTTVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVES KYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTI SKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK (SEQ ID NO: 97); and light chain immunoglobulin comprising the following amino acid sequence: DIQMTQSPSSLSASVGDRITITCQASQDITNYLNWYQQKPGKAPNLLIYDASNLVTGVPSRFSGSGSGTDFTFTILSLQPEDIATYYCQQYDSLLTFGPGTKVDIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC(SEQ ID No. 99);Heavy chain immunoglobulin containing the following amino acid sequence: EVQLVESGGGLVQPGGSLRLSCAASGFTFNNYAMHWVRQAPGKGLEYVSSISSSGGSTYYEDSVKGRFTISRDNSKNTLYLQMGSLRAEDMAVYYCARSFYGSGTYYDTFDMWGQGTMVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESK YGPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTI SKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK (SEQ ID NO: 115); and light chain immunoglobulin comprising the following amino acid sequence: DIQMTQSPSSLSASIGDRVTITCRASQSISRYLNWYQQKPGKAPKLLIYAASSLQSGVPSRFSASGSGTDFTLTISSLQPEDFATYYCQQSYSTPFTFGQGTKLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID No. 117);Heavy chain immunoglobulin containing the following amino acid sequence: QVQLVESGGDLVKPGGSLRLSCATSGFTFSDFYMTWIRQAPGKGLEWISYISNSGSIVKYADSVKGRFTISRDNAKNSLYLQMNSLRAEDTAIYYCARFYGDRWGQGTLVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPP CPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISK AKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK (SEQ ID NO: 134); and light chain immunoglobulin comprising the following amino acid sequence: DIQLTQSPSFLSASVGDRVTITCWASQGISTFLAWYQQKPGKAPKLLIYAASTLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYHCQQLNNYPWTFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID No. 136);Heavy chain immunoglobulin containing the following amino acid sequence: QVQLVESGGGLVKPGGSLRLSCEASGFTFNDFYMTWIRQAPGKGLEWIAYISKSGDKMRYADSVKGRFSTSRDNAKNSLSLQMNSLRAEDTAVYYCARFYGDIWGQGTLVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPP CPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISK AKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK (SEQ ID NO: 152); and light chain immunoglobulin comprising the following amino acid sequence: DIQLTQSPSFLSASVGDRVTITCWASQDISSFLVWYQQKPGKAPNLLIYAASALQSGVPSRFSGSGSGTEFTLTISSLQPEDFASYYCEQLNNYPWTFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID No. 154);Heavy chain immunoglobulin containing the following amino acid sequence: EVQLVESGGRLVQPGGSLRLSCEASGFTFSNYGMTWVRQAPGKGLEWVSVISGSDNRKYYAESVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAKLGYSRSSKDFYYGMDVWGQGTTVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVES KYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTI SKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK (SEQ ID NO: 170); and light chain immunoglobulin comprising the following amino acid sequence: DIVMTQSPDSLAVSLGERATINCKSSQSVLYNSNNRNYLVWYQQKPGQSPKLLIYWASTRESGVPDRFSGSGSGTDFTLTISSLQAEDVAVYYCQQYYNVPYTFGQGTKLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC(SEQ ID No. 172);하기의 아미노산 서열을 포함하는 중쇄 면역글로불린:EVQLVESGGGVVRPGGSLRLSCAASGFTFDDYGMSWVRQAPGKGLEWISSINRNGGSADYADSVKGRFTISRDNAKNSLFLQMSSLRAEDTALYHCASGEFRFDYWGQGTLVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK(서열번호 186);and a light chain immunoglobulin comprising the following amino acid sequence: DIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAASSLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQSYSTPPITFGQGTRLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID No. 188) and a heavy chain comprising the following amino acid sequence Immunoglobulin:EVQLVESGGGLVQPGRSLRLSCAASGFTLEDYAMHWVRQAPGKGLEWVSGISWNRGSTGYADSVKGRFTISRDNAKNSLYLQMTSLRAEDTALYYCAKGFYSMDVW GQGTTVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGP PCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISK AKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK (SEQ ID NO: 198); and light chain immunoglobulin comprising the following amino acid sequence: DIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAASSLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQSYSTPPITFGQGTRLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID No. 188);and heavy chain immunoglobulin containing the following amino acid sequence: QVQLQQSGPGLVKPSQTLSLTCAISGDSVSSNIAAWNWIRLSPSRGLEWLGRTFFRSTWFYDYSLSVKGRITINPDTSKNQFSLHLNSVTPEDAAVYYCARTGRRWSLDYWGQGTLVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKY GPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTIS KAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK (SEQ ID NO: 208); and light chain immunoglobulin comprising the following amino acid sequence: DIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAASSLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQSYSTPPITFGQGTRLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID No. 188);Heavy chain immunoglobulin containing the following amino acid sequence: EVQLVESGGGVVRPGGSLRLSCATSGFTFDDYGMSWVRQVPGKGLEWVSSVNRNGGTTDYADSVKGRFTISRDNAKRSLFLQMNSLRAEDTALYHCATGELFFDYWGQGTLVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGP PCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISK AKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK (SEQ ID NO: 216); and light chain immunoglobulin comprising the following amino acid sequence: DIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAASSLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQSYSTPPITFGQGTRLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID No. 188);Heavy chain immunoglobulin containing the following amino acid sequence: QVQLVQSGAEVKKPGASVKVSCKASGYTFTGHYMHWVRQAPGQGLEWMGWIYPHSGHTNYAKRFQGRVTMTRDTSITTAYMELIRLRSDDTAVYYCARRSGRSWYFDLWGRGTLVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYG PPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTIS KAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK (SEQ ID NO: 234); and light chain immunoglobulin comprising the following amino acid sequence: EIVLTQSPGTLSLSPGERATLSCRASQSVSSSYLAWYQQKPGQAPRLLIYGASSRATGIPDRFSGSGSGTDFTLTISRLEPEDFAVYYCQQYGSSPWTFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID No. 236);Heavy chain immunoglobulin containing the following amino acid sequence: EVQLVESGGGLVQPGGSLGLSCAASGFTFSNYAMSWVRQAPGKGLEWVSAVSGGGGGTYYADSVKGRFTISRDNSKNTVLLQMNSLRAEDTAVYYCARGRTGGLDYWGPGTLVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGP PCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISK AKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK (SEQ ID NO: 254); and light chain immunoglobulin comprising the following amino acid sequence: DVVMTQSPLSLPVIFGQPASISCRSSQSLVDSDGNTYLNWLQQRPGQSPRRLIYEVSNRDSGVPDRFSGSGSGTDFTLTISRVEAEDVGIYYCMQGTRWPPTFGGGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID No. 256);Heavy chain immunoglobulin containing the following amino acid sequence: EVQLVESGGGVVRPGGSLRLSCAASGFIFDDYDMSWVRQPPGRGLEWVSGIDWFGGTRGYADSMKGRFTISRDNAKNSLYLQMNSLRVEDTAFYYCARGGAIVGAVTPFDYWGQGTLVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESK YGPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTI SKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK (SEQ ID NO: 272); and light chain immunoglobulin comprising the following amino acid sequence: DIQMTQSPSSLSASVGNRVTLSCRASQSINTYLSWYQQRPGKAPKLLIYAASSLQSGVPSRFSGSGAGTDFTLTISSLQPEDFATYYCQQSYSAPLTFGGGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID No. 274);Heavy chain immunoglobulin containing the following amino acid sequence: QLQLQESGPGLVKPSETLSLTCTVSGGSISIKNYYWGWIRQPPGKGLEWIGSIYYSGTTYYNPSLKSRVTISVDTSKNQFSLKLSSVTAADTAVYHCARHGYSYGHGWFDPWGQGTLVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESK YGPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTI SKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK (SEQ ID NO: 284); and light chain immunoglobulin comprising the following amino acid sequence: DIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAASSLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQSYSTPPITFGQGTRLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID No. 188);Heavy chain immunoglobulin containing the following amino acid sequence: QVQLQQSGPGLVKPSQTLSLTCDISGDSVSSNIATWNWIRQSPSRGLEWLGRTYYRSKWYKDYAVSVKSRITINPDTSKNQFSLQVNSVTPEDTAVYYCARMTGPRYYFEYWGQGTLVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESK YGPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTI SKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK (SEQ ID NO: 294); and light chain immunoglobulin comprising the following amino acid sequence: DIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAASSLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQSYSTPPITFGQGTRLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID No. 188);Heavy chain immunoglobulin containing the following amino acid sequence: EVQLVESGGGVVRPGGSLRLSCAASGFTFDDFDMSWVRQGPGKGLEWVSGINWHGSSTGYADSVKGRFTISRDNAKNSLYLQMSSLRAEDTALYHCVRGGTIVGATTPLDYWGQGTLVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESK YGPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTI SKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK (SEQ ID NO: 311); and light chain immunoglobulin comprising the following amino acid sequence: DIQMTQSPSSLSASVGDRVTMTCRASRTISSYLSWYQQKSGKVPNLLIFGASSLQSGVPSRFSASGSGTDFTLIISSLQPEDFATYYCQQSYSSPLTFGGGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID No. 313);Heavy chain immunoglobulin containing the following amino acid sequence: EVQLVESGGDLVQPGGSLRLSCTASGFIFRNYAMNWVRQAPGKGLEWLSGILGSNDNTYYVDSVKGRFTISRDNSRNTLYLQMNSLRAEDSAVYYCAKGDAGGFDYWGQGTLVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGP PCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISK AKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK (SEQ ID NO: 331); and light chain immunoglobulin comprising the following amino acid sequence: DVVMTQSPLSLPVILGQPASISCRSSQSLVSSDGNTYLNWFQQRPGQSPRRLIYKVSNRDSGVPDRFSGSGSGTDFTLKISRVEAEDVGAYYCMQGSYWPPTFGQGTKLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID No. 333);Heavy chain immunoglobulin containing the following amino acid sequence: QVQLVESGGGVVKPGGSLRLSCAASGFTFSNSGIHWVRQAPGKGLEWVALISYAGSNKYYADSVKGRFTISRDNSKNTLSLQMNSLRAEDTAVYYCAKEVWTGTYDSFDMWGRGTMVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKY GPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTIS KAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK (SEQ ID NO: 343); and light chain immunoglobulin comprising the following amino acid sequence: DIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAASSLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQSYSTPPITFGQGTRLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID No. 188);Heavy chain immunoglobulin containing the following amino acid sequence: EVQLVESGGGLVQPGGSLRLSCAASGFIFSSYEMHWVRQAPGKGLEWISYISSSGTTIYYADSVKGRFTISRDNAKNSLYLHMNSLRAEDTAVYYCTRARITGTFDVFDIWGQGTMVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKY GPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTIS KAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK (SEQ ID NO: 357); and light chain immunoglobulin comprising the following amino acid sequence: DIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIFAASNLQSGVPSRFSGSRSGTDFTLTISSLQPEDFATYYCQQNYNIPYTFGQGTKLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID No. 359);and / or heavy chain immunoglobulin comprising the following amino acid sequence: QVQLQESGPGLVKPSQTLSLTCTVSGGSITSGGYYWSWIRQYPGQGLEWIGYIYYSGKTYYNPSFTSRITISVDTSKKQFSLKMSSVTAADTAVYYCARAGFTSSNGWFDPWGQGTLVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESK YGPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTI SKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK (SEQ ID NO: 376); and a light chain immunoglobulin comprising the following amino acid sequence: DIQMTQSPSSLSASVGDRVTITCRASQNIRSYLNWYQQKPGKAPKLLIYSASSLQSGVPSRFSGSGSGTDFTLTISSLQPEDFPTYYCQQTYSSPWTFGPGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID No. 378).; Claim 11 In any one of claims 1 to 10, a multispecific antigen-binding protein. Claim 12 A complex comprising an antigen-binding protein of any one of claims 1 to 11, bound to an IL2Rγ polypeptide or an antigen fragment thereof. Claim 13 A method for producing an antigen-binding protein or an immunoglobulin chain thereof according to any one of claims 1 to 11, the method comprising: (a) introducing one or more polynucleotides encoding the immunoglobulin chain of the antigen-binding protein into a host cell; (b) culturing the host cell under conditions that may be favorable for the expression of the polynucleotides; and (c) optionally isolating the antigen-binding protein or the immunoglobulin chain from the host cell and / or from the medium in which the host cell was grown. Claim 14 In paragraph 13, the method wherein the host cell is a Chinese hamster ovary cell. Claim 15 An antigen-binding protein or immunoglobulin chain that is the product of the method of claim 13 or 14. Claim 16 Polypeptide comprising: (a) a heavy chain comprising the amino acid sequence presented in SEQ NOs 2, 18, 22, 38, 42, 58, 62, 77, 81, 97, 101, 115, 119, 134, 138, 152, 156, 170, 174, 186, 190, 198, 200, 208, 210, 216, 218, 234, 238, 254, 258, 272, 276, 284, 286, 294, 296, 311, 315, 331, 335, 343, 345, 357, 361 and / or 376 Immunoglobulin or CDR-H1, CDR-H2, and CDR-H3 of a variable region thereof; or a variant thereof; and / or (b) light chain immunoglobulin or CDR-L1, CDR-L2, and CDR-L3 of a variable region thereof comprising the amino acid sequences presented in SEQ ID NOs 10, 20, 30, 40, 50, 60, 70, 79, 89, 99, 109, 117, 127, 136, 146, 154, 164, 172, 182, 188, 226, 236, 246, 256, 266, 274, 304, 313, 323, 333, 353, 359, 368, and / or 378; or a variant thereof; or, (c) an amino acid sequence presented in a member selected from the group consisting of SEQ ID NO. 1-385 or a variant thereof. Claim 17 A polynucleotide encoding one or more polypeptides of paragraph 16. Claim 18 A vector containing the polynucleotide of claim 17. Claim 19 A host cell comprising an antigen-binding protein, immunoglobulin chain, polypeptide, polynucleotide, and / or vector according to any one of claims 1 to 11 and claims 15 to 18. Claim 20 A composition or kit comprising one or more antigen-binding proteins of any one of claims 1 to 11 and 15, optionally combined with additional therapeutic agents. Claim 21 A pharmaceutical formulation comprising an antigen-binding protein of any one of claims 1 to 11 and 15, a pharmaceutically acceptable carrier or excipient, and optionally additional therapeutic agents. Claim 22 A composition or kit or formulation in combination with an additional therapeutic agent which is an anti-inflammatory agent, as described in paragraph 20 or 21. Claim 23 A composition, kit, or formulation according to claim 20 or 21, combined with an additional therapeutic agent which is one or more members selected from the group consisting of anti-TNFα antibody or binding protein, infliximab, adalimumab, etanercept, golimumab, corticosteroids, prednisolone, methylprednisolone, antithymocyte globulin, alemtuzumab, daclizumab, tacrolimus, cyclosporine, in vitro photophoresis, mycophenolate mofetil, sirolimus, pentostatin, mesenchymal stem cells, inolimomab, denilukin, and basiliximab. Claim 24 A container or injection device comprising an antigen-binding protein or composition or formulation of any one of claims 1 to 11, 15, 20, 21, 22, or 23. Claim 25 A method for administering an antigen-binding protein, composition, or formulation of any one of claims 1 to 11, 15, 20, 21, 22, or 23 to a subject, comprising injecting said antigen-binding protein, composition, or formulation into the body of said subject. Claim 26 A method for treating or preventing an IL2Rγ-mediated disease or condition in a subject requiring such treatment, comprising administering an effective amount of an antigen-binding protein, composition, or formulation according to any one of claims 1 to 11, 15, 20, 21, 22, or 23. Claim 27 In claim 26, the above IL2Rγ-mediated disease or condition is graft-versus-host disease, organ transplant rejection, β-islet cell graft rejection, skin transplant rejection, heart transplant rejection, lung transplant rejection, kidney transplant rejection, liver transplant rejection, shot chorioretinopathy, multiple sclerosis, uveitis, autoimmune disease, type I diabetes mellitus, multiple sclerosis, rheumatoid arthritis, systemic lupus erythematosus, myasthenia gravis, atopic dermatitis, asthma, mast cell activation disorder, mast cell activation syndrome (MCAS), systemic mastocytosis (SM) and / or mast cell leukemia (MCL). Claim 28 A method according to any one of claims 25 to 27, wherein the antigen-binding protein is administered into the body of the subject by injection, subcutaneously, intravenously, or intramuscularly. Claim 29 A method for reducing serum levels of interferon-gamma, tumor necrosis factor-alpha, IL-6, IL-8, IL-10 and / or mKC / GRO, comprising administering an effective amount of an antigen-binding protein, composition, or formulation of any one of claims 1 to 11, 15, 20, 21, 22, or 23 to a subject, wherein the subject comprises: - blocking STAT phosphorylation induced by cytokinesis in peripheral blood mononuclear cells; - blocking STAT phosphorylation induced by cytokinesis in mast cells; - reducing serum levels of interferon-gamma, tumor necrosis factor-alpha, IL-6, IL-8, IL-10 and / or mKC / GRO; - blocking JAK-STAT-mediated intracellular signaling induced by cytokinesis in the ILRγ family and / or reducing serum levels of CD45+ immune cells, NK cells, T-cells and / or B-cells. Claim 30 In paragraph 29, a method in which the subject suffers from an IL2Rγ-mediated disease or pathological condition. Claim 31 In claim 30, the above IL2Rγ-mediated disease or condition is graft-versus-host disease, organ transplant rejection, β-islet cell graft rejection, skin transplant rejection, heart transplant rejection, lung transplant rejection, kidney transplant rejection, liver transplant rejection, shotgun chorioretinopathy, multiple sclerosis, uveitis, autoimmune disease, type I diabetes mellitus, multiple sclerosis, rheumatoid arthritis, systemic lupus erythematosus, myasthenia gravis, atopic dermatitis, asthma, mast cell activation disorder, mast cell activation syndrome (MCAS), systemic mastocytosis (SM) and / or mast cell leukemia (MCL).

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