Anti- il2 receptor gamma antigen binding proteins

Abstract

Antibodies that bind to IL2 receptor gamma proteins and methods of using the same, e.g., to treat or prevent disease, are provided.SOLUTION: The present invention provides antibodies and antigen-binding fragments (e.g., human antibodies) that specifically bind to human IL2 receptor gamma (IL2R γ). Methods of using the antibodies and fragments to treat or prevent diseases mediated by IL2R γ (e.g., graft versus host disease) are also provided, along with methods of making the antibodies and fragments.SELECTED DRAWING: None

Description

[Technical Field]

[0001] This application claims the benefit of U.S. Provisional Patent Application No. 62 / 799,851, filed February 1, 2019, which is incorporated herein by reference in its entirety.

[0002] FIELD OF THE INVENTION The present invention relates to antibodies that bind to anti-IL2 receptor gamma protein and methods of using them, for example, to treat or prevent disease. [Background technology]

[0003] The common cytokine receptor gamma chain (γc) was first identified as the third chain of the interleukin-2 (IL-2) receptor complex and was designated IL-2Rγ. The same subunit has been identified as part of several other cytokine receptor complexes: IL-4, IL-7, IL-9, IL-15, and IL-21, and is therefore sometimes referred to as γc (common cytokine receptor gamma chain). γc is involved in ligand binding as well as signal transduction for these cytokine receptors.

[0004] Binding of a cytokine to its receptor activates the Janus kinase (JAK) family protein tyrosine kinases JAK1 and JAK3, triggering transphosphorylation on tyrosines of JAK1 and JAK3. JAK1 associates with a unique α or β chain and JAK3 with the receptor's γc. The phosphorylated JAKs can then activate signal transducer and activator of transcription (STAT) proteins, which together form the JAK / STAT signaling pathway. Phosphorylation of STATs triggers their dimerization, thereby acquiring high-affinity DNA-binding activity and translocating to the nucleus, where they act as transcription factors that induce the transcription of target genes.

[0005] The γc gene (IL2RG) is located on chromosome Xq13. IL-2Rγ is mutated in patients with X-linked severe combined immunodeficiency (X-SCID). Patients with this disease exhibit severe immunodeficiency due to a lack of T, NK, and fully mature B cells.

[0006] IL-7, -9 and -15 have been implicated in psoriasis and rheumatoid arthritis (Non-Patent Documents 1-6).

[0007] Blockade of IL-4 and IL-9 has been shown to improve asthma symptoms in mice (Non-Patent Documents 7 to 11).

[0008] IL-21 has been linked to various inflammatory disorders, including Crohn's disease and rheumatoid arthritis (Non-Patent Documents 12-13). [Prior art documents] [Non-patent literature]

[0009] [Non-Patent Document 1] 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) [Non-patent document 2] 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) [Non-patent document 3] 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 [Non-patent document 4] Yang et al., “Therapeutic potential of IL-15 in rheumatoid arthritis,” Hum Immunol. November 2015; 76(11): 812–8. [Non-Patent Document 5] Lesiak et al., “Are interleukin-15 and -22 a new pathogenic factor in pustular palmoplantar psoriasis?”, Postepy Dermatol Alergol.33(5):336–339 ​​(2016) [Non-patent document 6] Raeber et al., “The role of cytokines in T-cell memory in health and disease,” Immunol Rev. 283(1): pp. 176–193 (2018) [Non-Patent Document 7] Generoso et al., “Prospects for Monoclonal Antibody Therapy in Pediatric Asthma,” Curr Allergy Asthma Rep. 18(9):45 (2018) [Non-patent document 8] Tashkin & Wechsler, “Role of eosinophils in airway inflammation of chronic obstructive pulmonary disease”, Int J Chron Obstruct Pulmon Dis.13:335-349 (2018) [Non-Patent Document 9] 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): pp. 165–71 (2016) [Non-Patent Document 10] Lloyd & Harker, "Epigenetic Control of Interleukin-9 in Asthma", N Engl J Med.379(1):87-89 (2018) [Non-Patent Document 11] Neurath & Finotto, "IL-9 signaling as key driver of chronic inflammation in mucosal immunity", Cytokine Growth Factor Rev. 29:93-9 (2016) [Non-Patent Document 12] Holm et al., "Evaluating IL-21 as a Potential Therapeutic Target in Crohn's Disease," Gastroenterol Res Pract.2018:5962624 (2018) [Non-Patent Document 13] Dinesh & Rasool, “Multifaceted role of IL-21 in rheumatoid arthritis: Current understanding and future perspectives”, J Cell Physiol.233(5):3918~3928 (2018) Summary of the Invention [Means for solving the problem]

[0010] The present invention provides the following: -9 M ~ approx. 3.36×10 -7 K of MD binds to human IL2Rγ at approximately 6.42 × 10 at 37°C; -9 M ~ approx. 3.53×10 -7 K of M D or approximately 3.53 × 10 -7 K lower than M D at 25°C; -9 M ~ approx. 2.38×10 -7 K of M D binds to cynomolgus monkey (Macaca fascicularis) IL-2Rγ at 37°C; -9 M ~ approx. 3.20×10 -7 K of M D or approximately 3.20 x 10 -7 K lower than M D at 25°C; approximately 2.45 x 10 -9 M ~ approx. 1.20×10 -8 K of M D or approximately 1.20 × 10 -8 K lower than M D at 37°C; approximately 1.86 x 10 -11 M ~ approx. 3.00×10 -8 K of M D or about 3.00 × 10 -8 K lower than M D at 25°C; approximately 1.84 x 10 -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 K of M D or no detectable binding; approximately 5.59 x 10 -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 K of M D or no detectable binding; approximately 3.32 x 10 -9 M ~ approx. 1.97×10 -7 K of M D or no detectable binding to human IL2Rγ domain 1; -9 M ~ approx. 2.25×10 -7 K of M D or no detectable binding to human IL2Rγ domain 1; -7 M ~ approx. 5.35×10 -10 K D or no detectable binding to human IL2Rγ domain 2; -8 or approximately 1.27 x 10 -8 K Dor no detectable binding to human IL2Rγ domain 2; blocking STAT phosphorylation in T cells induced by IL-2, IL-4, IL7, IL-15, and / or IL-21; blocking STAT phosphorylation in mast cells induced by IL-9; reducing the number of human immune cells injected into mice; reducing serum human cytokine and / or mouse serum cytokine levels in mice bearing human immune cells; no detectable binding to mouse IL2Rγ or rat IL2Rγ; reducing body weight caused by GvHD in a GvHD mouse model. and / or reducing the number of CD45+ cells, B cells, T cells and / or NK cells (but optionally not, e.g., neutrophils) in the blood or serum of a subject. Antibodies and antigen-binding fragments thereof, e.g., monospecific or multispecific, whose sequences are variants of any of the antibodies or fragments specifically described herein and characterized by one or more of the traits described above, form part of the present invention.

[0011] The present invention also provides isolated antigen-binding proteins, e.g., antibodies, that (i) specifically bind to the same epitope on IL2Rγ as a reference antibody or antigen-binding fragment thereof; or (ii) compete with the reference antibody or antigen-binding fragment thereof for binding to an IL2Rγ polypeptide. or an antigen-binding fragment thereof, wherein the reference antibody or antigen-binding fragment thereof is a heavy chain immunoglobulin comprising (a) an amino acid sequence set forth 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; or a variant thereof; or a heavy chain immunoglobulin comprising CDR-H1, CDR-H2 and CDR-H3 of the variable regions thereof. and / or (b) a light chain immunoglobulin or variable region thereof comprising CDR-L1, CDR-L2, and CDR-L3 of the light chain immunoglobulin or variable region thereof comprising the amino acid sequence set forth 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. In an embodiment of the invention, a reference antibody or fragment is pre-bound to the IL2Rg antigen before the antigen binding protein is added and assessed for binding. In an embodiment of the invention, the antigen binding protein is pre-bound to the antigen before the reference antibody or fragment is added and assessed for binding.

[0012] The present invention also provides a heavy chain immunoglobulin or a variable region thereof comprising CDR-H1, CDR-H2, and CDR-H3 of a heavy chain immunoglobulin or a variable region thereof comprising (a) an amino acid sequence set forth 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, and / or 376; or a variant thereof. and / or (b) an amino acid sequence set forth 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 and / or 378; or a variant thereof.

[0013] In embodiments of the invention, the antigen binding protein has (a) at least 90% amino acid sequence identity to the amino acid sequence set forth 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. and / or (b) a heavy chain immunoglobulin or a variable region thereof comprising an amino acid sequence having at least 90% amino acid sequence identity to the amino acid sequence set forth 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. For example, in embodiments of the invention, the antigen binding protein is selected from the group consisting of (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, 2 00, 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 or the amino acid sequences set forth 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, or a heavy chain immunoglobulin or variable region thereof, comprising CDR-H1, CDR-H2 and CDR-H3 of the heavy chain immunoglobulin or variable region thereof, comprising an amino acid sequence having at least 90% amino acid sequence identity to the amino acid sequence set forth in and / or (b) the amino acid sequence set forth 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 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 7, 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 or a variable region thereof comprising CDR-L1, CDR-L2 and CDR-L3 of the light chain immunoglobulin or variable region thereof having an amino acid sequence having at least 90% amino acid sequence identity to the amino acid sequence set forth in

[0014] In an embodiment of the invention, the antigen binding protein comprises: (i) a heavy chain CDR set: CDR-H1 comprising the amino acid sequence set forth in SEQ ID NO: 4; CDR-H2 comprising the amino acid sequence set forth in SEQ ID NO: 6; and CDR-H3 comprising the amino acid sequence set forth in SEQ ID NO: 8; and / or CDR-H1 comprising the amino acid sequence set forth in SEQ ID NO: 24; CDR-H2 comprising the amino acid sequence set forth in SEQ ID NO: 26; and CDR-H3 comprising the amino acid sequence set forth in SEQ ID NO: 28; and / or CDR-H1 comprising the amino acid sequence set forth in SEQ ID NO: 44; CDR-H2 comprising the amino acid sequence set forth in SEQ ID NO: 46; and CDR-H3 comprising the amino acid sequence set forth in SEQ ID NO: 48; and / or CDR-H1 comprising the amino acid sequence set forth in SEQ ID NO: 64; CDR-H2 comprising the amino acid sequence set forth in SEQ ID NO: 66; and CDR-H3 comprising the amino acid sequence set forth in SEQ ID NO: 68; and / or CDR-H1 comprising the amino acid sequence set forth in SEQ ID NO: 83; CDR-H2 comprising the amino acid sequence set forth in SEQ ID NO: 85; and CDR-H3 comprising the amino acid sequence set forth in SEQ ID NO: 87; and / or CDR-H1 comprising the amino acid sequence set forth in SEQ ID NO: 103; CDR-H2 comprising the amino acid sequence set forth in SEQ ID NO: 105; and CDR-H3 comprising the amino acid sequence set forth in SEQ ID NO: 107; and / or CDR-H1 comprising the amino acid sequence set forth in SEQ ID NO: 121; CDR-H2 comprising the amino acid sequence set forth in SEQ ID NO: 123; and CDR-H3 comprising the amino acid sequence set forth in SEQ ID NO: 125; and and / or CDR-H1 comprising the amino acid sequence set forth in SEQ ID NO: 140; CDR-H2 comprising the amino acid sequence set forth in SEQ ID NO: 142; and CDR-H3 comprising the amino acid sequence set forth in SEQ ID NO: 144; and / or CDR-H1 comprising the amino acid sequence set forth in SEQ ID NO: 158; CDR-H2 comprising the amino acid sequence set forth in SEQ ID NO: 160; and CDR-H3 comprising the amino acid sequence set forth in SEQ ID NO: 162; and / or CDR-H1 comprising the amino acid sequence set forth in SEQ ID NO: 176; CDR-H2 comprising the amino acid sequence set forth in SEQ ID NO: 178; and CDR-H3 comprising the amino acid sequence set forth in SEQ ID NO: 180; and / or CDR-H1 comprising the amino acid sequence set forth in SEQ ID NO: 192; CDR-H2 comprising the amino acid sequence set forth in SEQ ID NO: 194; and CDR-H3 comprising the amino acid sequence set forth in SEQ ID NO: 196; and / or CDR-H1 comprising the amino acid sequence set forth in SEQ ID NO: 202; and CDR-H2; and CDR-H3 comprising the amino acid sequence set forth in SEQ ID NO: 206; and / or CDR-H1 comprising the amino acid sequence set forth in SEQ ID NO: 176; CDR-H2 comprising the amino acid sequence set forth in SEQ ID NO: 212; and CDR-H3 comprising the amino acid sequence set forth in SEQ ID NO: 214; and / or CDR-H1 comprising the amino acid sequence set forth in SEQ ID NO: 220; CDR-H2 comprising the amino acid sequence set forth in SEQ ID NO: 222; and CDR-H3 comprising the amino acid sequence set forth in SEQ ID NO: 224; and / or CDR-H1 comprising the amino acid sequence set forth in SEQ ID NO: 240 CDR-H1 comprising the amino acid sequence set forth in SEQ ID NO: 242; and CDR-H3 comprising the amino acid sequence set forth in SEQ ID NO: 244; and / or CDR-H1 comprising the amino acid sequence set forth in SEQ ID NO: 260; CDR-H2 comprising the amino acid sequence set forth in SEQ ID NO: 262; and CDR-H3 comprising the amino acid sequence set forth in SEQ ID NO: 264; and / or CDR-H1 comprising the amino acid sequence set forth in SEQ ID NO: 278; CDR-H2 comprising the amino acid sequence set forth in SEQ ID NO: 280; and CDR-H3 comprising the amino acid sequence set forth in SEQ ID NO: 282 and / or CDR-H1 comprising the amino acid sequence set forth in SEQ ID NO: 288; CDR-H2 comprising the amino acid sequence set forth in SEQ ID NO: 290; and CDR-H3 comprising the amino acid sequence set forth in SEQ ID NO: 292; and / or CDR-H1 comprising the amino acid sequence set forth in SEQ ID NO: 298; CDR-H2 comprising the amino acid sequence set forth in SEQ ID NO: 300; and CDR-H3 comprising the amino acid sequence set forth in SEQ ID NO: 302; and / or CDR-H1 comprising the amino acid sequence set forth in SEQ ID NO: 317; CDR-H2 comprising the amino acid sequence set forth in SEQ ID NO: 319; and and CDR-H3 comprising the amino acid sequence set forth in SEQ ID NO: 321; and / or CDR-H1 comprising the amino acid sequence set forth in SEQ ID NO: 337; CDR-H2 comprising the amino acid sequence set forth in SEQ ID NO: 339; and CDR-H3 comprising the amino acid sequence set forth in SEQ ID NO: 341; and / or CDR-H1 comprising the amino acid sequence set forth in SEQ ID NO: 347; CDR-H2 comprising the amino acid sequence set forth in SEQ ID NO: 349; and CDR-H3 comprising the amino acid sequence set forth in SEQ ID NO: 351; and / or CDR-H1 comprising the amino acid sequence set forth in SEQ ID NO: 363; CDR-H2 comprising the amino acid sequence set forth in SEQ ID NO: 66; and CDR-H3 comprising the amino acid sequence set forth in SEQ ID NO: 366; and / or (ii) a light chain CDR set: CDR-L1 comprising the amino acid sequence set forth in SEQ ID NO: 12; CDR-L2 comprising the amino acid sequence set forth in SEQ ID NO: 14; and CDR-L3 comprising the amino acid sequence set forth in SEQ ID NO: 16; and / or CDR-L1 comprising the amino acid sequence set forth in SEQ ID NO: 32; CDR-L2 comprising the amino acid sequence set forth in SEQ ID NO: 34; and CDR-L3 comprising the amino acid sequence set forth in SEQ ID NO: 36; and / or CDR-L1 comprising the amino acid sequence set forth in SEQ ID NO: 52; CDR-L2 comprising the amino acid sequence set forth in SEQ ID NO: 54; and CDR-L3 comprising the amino acid sequence set forth in SEQ ID NO: 56; and / or CDR-L1 comprising the amino acid sequence set forth in SEQ ID NO: 72; CDR-L2 comprising the amino acid sequence set forth in SEQ ID NO: 54; and CDR-L3 comprising the amino acid sequence set forth in SEQ ID NO: 75; and / or CDR-L1 comprising the amino acid sequence set forth in SEQ ID NO: 91; CDR-L2 comprising the amino acid sequence set forth in SEQ ID NO: 93; and CDR-L3 comprising the amino acid sequence set forth in SEQ ID NO: 95; and / or CDR-L1 comprising the amino acid sequence set forth in SEQ ID NO: 111; CDR-L2 comprising the amino acid sequence set forth in SEQ ID NO: 54; and CDR-L3 comprising the amino acid sequence set forth in SEQ ID NO: 113; and / or CDR-L1 comprising the amino acid sequence set forth in SEQ ID NO: 129 CDR-L1 comprising the amino acid sequence set forth in SEQ ID NO: 54; CDR-L2 comprising the amino acid sequence set forth in SEQ ID NO: 54; and CDR-L3 comprising the amino acid sequence set forth in SEQ ID NO: 132; and / or CDR-L1 comprising the amino acid sequence set forth in SEQ ID NO: 148; CDR-L2 comprising the amino acid sequence set forth in SEQ ID NO: 54; and CDR-L3 comprising the amino acid sequence set forth in SEQ ID NO: 150; and / or CDR-L1 comprising the amino acid sequence set forth in SEQ ID NO: 166; CDR-L2 comprising the amino acid sequence set forth in SEQ ID NO: 14; and CDR-L3 comprising the amino acid sequence set forth in SEQ ID NO: 168; and / or CDR-L1 comprising the amino acid sequence set forth in SEQ ID NO: 72; CDR-L2 comprising the amino acid sequence set forth in SEQ ID NO: 54; and CDR-L3 comprising the amino acid sequence set forth in SEQ ID NO: 184 CDR-L3; and / or CDR-L1 comprising the amino acid sequence set forth in SEQ ID NO: 72; CDR-L2 comprising the amino acid sequence set forth in SEQ ID NO: 54; and CDR-L3 comprising the amino acid sequence set forth in SEQ ID NO: 184; and / or CDR-L1 comprising the amino acid sequence set forth in SEQ ID NO: 72; CDR-L2 comprising the amino acid sequence set forth in SEQ ID NO: 54; and CDR-L3 comprising the amino acid sequence set forth in SEQ ID NO: 184; and / or CDR-L1 comprising the amino acid sequence set forth in SEQ ID NO: 72; CDR-L2 comprising the amino acid sequence set forth in SEQ ID NO: 54; and CDR-L3 comprising the amino acid sequence set forth in SEQ ID NO: 184; and / or CDR-L1 comprising the amino acid sequence set forth in SEQ ID NO: 228; CDR-L2 comprising the amino acid sequence set forth in SEQ ID NO: 230; and CDR-L3 comprising the amino acid sequence set forth in SEQ ID NO: 232; and / or CDR-L1 comprising the amino acid sequence set forth in SEQ ID NO: 248; CDR-L2 comprising the amino acid sequence set forth in SEQ ID NO: 250; and CDR-L3 comprising the amino acid sequence set forth in SEQ ID NO: 252; and / or CDR-L1 comprising the amino acid sequence set forth in SEQ ID NO: 268 CDR-L1 comprising the amino acid sequence set forth in SEQ ID NO: 54; CDR-L2 comprising the amino acid sequence set forth in SEQ ID NO: 54; and CDR-L3 comprising the amino acid sequence set forth in SEQ ID NO: 270; and / or CDR-L1 comprising the amino acid sequence set forth in SEQ ID NO: 72; CDR-L2 comprising the amino acid sequence set forth in SEQ ID NO: 54; and CDR-L3 comprising the amino acid sequence set forth in SEQ ID NO: 184; and / or CDR-L1 comprising the amino acid sequence set forth in SEQ ID NO: 72; CDR-L2 comprising the amino acid sequence set forth in SEQ ID NO: 54; and CDR-L3 comprising the amino acid sequence set forth in SEQ ID NO: 184; and / or CDR-L1 comprising the amino acid sequence set forth in SEQ ID NO: 306; CDR-L2 comprising the amino acid sequence set forth in SEQ ID NO: 230; and CDR-L3 comprising the amino acid sequence set forth in SEQ ID NO: 309; and / or CDR-L1 comprising the amino acid sequence set forth in SEQ ID NO: 325; CDR-L2 comprising the amino acid sequence set forth in SEQ ID NO: 327; and CDR-L3 comprising the amino acid sequence set forth in SEQ ID NO: 329; and / or CDR-L1 comprising the amino acid sequence set forth in SEQ ID NO: 72; CDR-L2 comprising the amino acid sequence set forth in SEQ ID NO: 54;and CDR-L3 comprising the amino acid sequence set forth in SEQ ID NO: 184; and / or CDR-L1 comprising the amino acid sequence set forth in SEQ ID NO: 72; CDR-L2 comprising the amino acid sequence set forth in SEQ ID NO: 54; and CDR-L3 comprising the amino acid sequence set forth in SEQ ID NO: 355; and / or CDR-L1 comprising the amino acid sequence set forth in SEQ ID NO: 370; CDR-L2 comprising the amino acid sequence set forth in SEQ ID NO: 372; and CDR-L3 comprising the amino acid sequence set forth in SEQ ID NO: 374; Includes:

[0015] In an embodiment of the invention, the antigen binding protein of the invention comprises a set of heavy chain CDRs and a set of light chain CDRs as follows: (i) a heavy chain variable region comprising CDR-H1 having the amino acid sequence set forth in SEQ ID NO: 4; CDR-H2 having the amino acid sequence set forth in SEQ ID NO: 6; and CDR-H3 having the amino acid sequence set forth in SEQ ID NO: 8; and a light chain variable region comprising CDR-L1 having the amino acid sequence set forth in SEQ ID NO: 12; CDR-L2 having the amino acid sequence set forth in SEQ ID NO: 14; and CDR-L3 having the amino acid sequence set forth in SEQ ID NO: 16; (ii) a heavy chain variable region comprising CDR-H1 having the amino acid sequence set forth in SEQ ID NO: 24; CDR-H2 having the amino acid sequence set forth in SEQ ID NO: 26; and CDR-H3 having the amino acid sequence set forth in SEQ ID NO: 28; and a light chain variable region comprising CDR-L1 having the amino acid sequence set forth in SEQ ID NO: 32; CDR-L2 having the amino acid sequence set forth in SEQ ID NO: 34; and CDR-L3 having the amino acid sequence set forth in SEQ ID NO: 36; (iii) a heavy chain variable region comprising CDR-H1 having the amino acid sequence set forth in SEQ ID NO: 44; CDR-H2 having the amino acid sequence set forth in SEQ ID NO: 46; and CDR-H3 having the amino acid sequence set forth in SEQ ID NO: 48; and a light chain variable region comprising CDR-L1 having the amino acid sequence set forth in SEQ ID NO: 52; CDR-L2 having the amino acid sequence set forth in SEQ ID NO: 54; and CDR-L3 having the amino acid sequence set forth in SEQ ID NO: 56; (iv) a CDR-H1 having the amino acid sequence set forth in SEQ ID NO: 64; and a CDR-L3 having the amino acid sequence set forth in SEQ ID NO: 66 and a light chain variable region comprising a CDR-L1 comprising the amino acid sequence set forth in SEQ ID NO: 91; a CDR-L2 comprising the amino acid sequence set forth in SEQ ID NO: 93; and a CDR-L3 comprising the amino acid sequence set forth in SEQ ID NO: 95; (v) a heavy chain variable region comprising a CDR-H1 comprising the amino acid sequence set forth in SEQ ID NO: 83; a CDR-H2 comprising the amino acid sequence set forth in SEQ ID NO: 85; and a CDR-H3 comprising the amino acid sequence set forth in SEQ ID NO: 87; and a light chain variable region comprising a CDR-L1 comprising the amino acid sequence set forth in SEQ ID NO: 91; a CDR-L2 comprising the amino acid sequence set forth in SEQ ID NO: 93; and a CDR-L3 comprising the amino acid sequence set forth in SEQ ID NO: 95; (vi) a heavy chain variable region comprising a CDR-H1 comprising the amino acid sequence set forth in SEQ ID NO: 103; a CDR-H2 comprising the amino acid sequence set forth in SEQ ID NO: 105; and a CDR-H3 comprising the amino acid sequence set forth in SEQ ID NO: 107; and a CDR-L1 comprising the amino acid sequence set forth in SEQ ID NO: 111; a CDR-L2 comprising the amino acid sequence set forth in SEQ ID NO: 54; and a CDR-L3 comprising the amino acid sequence set forth in SEQ ID NO: 95; (vi) a light chain variable region comprising a CDR-L3 comprising the amino acid sequence set forth in SEQ ID NO: 113; (vii) a heavy chain variable region comprising a CDR-H1 comprising the amino acid sequence set forth in SEQ ID NO: 121; a CDR-H2 comprising the amino acid sequence set forth in SEQ ID NO: 123; and a CDR-H3 comprising the amino acid sequence set forth in SEQ ID NO: 125; and a light chain variable region comprising a CDR-L1 comprising the amino acid sequence set forth in SEQ ID NO: 129; a CDR-L2 comprising the amino acid sequence set forth in SEQ ID NO: 54; and a CDR-L3 comprising the amino acid sequence set forth in SEQ ID NO: 132; (vii) a light chain variable region comprising a CDR-L1 comprising the amino acid sequence set forth in SEQ ID NO: 140; a heavy chain variable region comprising a CDR-H1 comprising the amino acid sequence set forth in SEQ ID NO: 142; a CDR-H2 comprising the amino acid sequence set forth in SEQ ID NO: 142; and a CDR-H3 comprising the amino acid sequence set forth in SEQ ID NO: 144; and a light chain variable region comprising a CDR-L1 comprising the amino acid sequence set forth in SEQ ID NO: 148; a CDR-L2 comprising the amino acid sequence set forth in SEQ ID NO: 54; and a CDR-L3 comprising the amino acid sequence set forth in SEQ ID NO: 150; (viii) a CDR-H1 comprising the amino acid sequence set forth in SEQ ID NO: 158; and a CDR-H2 comprising the amino acid sequence set forth in SEQ ID NO: 160;and a CDR-H3 comprising the amino acid sequence set forth in SEQ ID NO: 162; and a light chain variable region comprising a CDR-L1 comprising the amino acid sequence set forth in SEQ ID NO: 166; a CDR-L2 comprising the amino acid sequence set forth in SEQ ID NO: 14; and a CDR-L3 comprising the amino acid sequence set forth in SEQ ID NO: 168; (ix) a heavy chain variable region comprising a CDR-H1 comprising the amino acid sequence set forth in SEQ ID NO: 176; a CDR-H2 comprising the amino acid sequence set forth in SEQ ID NO: 178; and a CDR-H3 comprising the amino acid sequence set forth in SEQ ID NO: 180; and a light chain variable region comprising a CDR-L1 comprising the amino acid sequence set forth in SEQ ID NO: 166; a CDR-L2 comprising the amino acid sequence set forth in SEQ ID NO: 14; and a CDR-L3 comprising the amino acid sequence set forth in (x) a light chain variable region comprising a CDR-L1 comprising the amino acid sequence set forth in SEQ ID NO: 72; a CDR-L2 comprising the amino acid sequence set forth in SEQ ID NO: 54; and a CDR-L3 comprising the amino acid sequence set forth in SEQ ID NO: 184; (x) a heavy chain variable region comprising a CDR-H1 comprising the amino acid sequence set forth in SEQ ID NO: 192; a CDR-H2 comprising the amino acid sequence set forth in SEQ ID NO: 194; and a CDR-H3 comprising the amino acid sequence set forth in SEQ ID NO: 196; and a CDR-L1 comprising the amino acid sequence set forth in SEQ ID NO: 72; a CDR-L2 comprising the amino acid sequence set forth in SEQ ID NO: 54; and and CDR-L3 comprising the amino acid sequence set forth in SEQ ID NO: 184; (xi) a heavy chain variable region comprising CDR-H1 comprising the amino acid sequence set forth in SEQ ID NO: 202; CDR-H2 comprising the amino acid sequence set forth in SEQ ID NO: 204; and CDR-H3 comprising the amino acid sequence set forth in SEQ ID NO: 206; and a light chain variable region comprising CDR-L1 comprising the amino acid sequence set forth in SEQ ID NO: 72; CDR-L2 comprising the amino acid sequence set forth in SEQ ID NO: 54; and CDR-L3 comprising the amino acid sequence set forth in SEQ ID NO: 184; (xii) a light chain variable region comprising CDR-H1 comprising the amino acid sequence set forth in SEQ ID NO: 176 a heavy chain variable region comprising a CDR-H1 comprising the amino acid sequence set forth in SEQ ID NO: 212; a CDR-H2 comprising the amino acid sequence set forth in SEQ ID NO: 212; and a CDR-H3 comprising the amino acid sequence set forth in SEQ ID NO: 214; and a light chain variable region comprising a CDR-L1 comprising the amino acid sequence set forth in SEQ ID NO: 72; a CDR-L2 comprising the amino acid sequence set forth in SEQ ID NO: 54; and a CDR-L3 comprising the amino acid sequence set forth in SEQ ID NO: 184; (xiii) a CDR-H1 comprising the amino acid sequence set forth in SEQ ID NO: 220; and a CDR-H2 comprising the amino acid sequence set forth in SEQ ID NO: 222;and a heavy chain variable region comprising a CDR-H3 comprising the amino acid sequence set forth in SEQ ID NO: 224; and a CDR-L1 comprising the amino acid sequence set forth in SEQ ID NO: 228; SEQ ID NO: (xiv) a light chain variable region comprising a CDR-H1 comprising the amino acid sequence set forth in SEQ ID NO: 240; a CDR-H2 comprising the amino acid sequence set forth in SEQ ID NO: 242; and a CDR-H3 comprising the amino acid sequence set forth in SEQ ID NO: 244; and a CDR-L1 comprising the amino acid sequence set forth in SEQ ID NO: 248; a CDR-L2 comprising the amino acid sequence set forth in SEQ ID NO: 250; and a CDR-L3 comprising the amino acid sequence set forth in SEQ ID NO: 252. (xv) a heavy chain variable region comprising a CDR-H1 comprising the amino acid sequence set forth in SEQ ID NO: 260; a CDR-H2 comprising the amino acid sequence set forth in SEQ ID NO: 262; and a CDR-H3 comprising the amino acid sequence set forth in SEQ ID NO: 264; and a light chain variable region comprising a CDR-L1 comprising the amino acid sequence set forth in SEQ ID NO: 268; a CDR-L2 comprising the amino acid sequence set forth in SEQ ID NO: 54; and a CDR-L3 comprising the amino acid sequence set forth in SEQ ID NO: 270; (xvi) a CDR-H1 comprising the amino acid sequence set forth in SEQ ID NO: 278; and a CDR-L3 comprising the amino acid sequence set forth in SEQ ID NO: 280 (xvii) a heavy chain variable region comprising a CDR-H1 comprising the amino acid sequence set forth in SEQ ID NO: 288; a CDR-H2 comprising the amino acid sequence set forth in SEQ ID NO: 290; and a CDR-H3 comprising the amino acid sequence set forth in SEQ ID NO: 292; and a light chain variable region comprising a CDR-L1 comprising the amino acid sequence set forth in SEQ ID NO: 72; a CDR-L2 comprising the amino acid sequence set forth in SEQ ID NO: 54; and a CDR-L3 comprising the amino acid sequence set forth in SEQ ID NO: 184; (xvii) a heavy chain variable region comprising a CDR-H1 comprising the amino acid sequence set forth in SEQ ID NO: 288; a CDR-H2 comprising the amino acid sequence set forth in SEQ ID NO: 290; and a CDR-H3 comprising the amino acid sequence set forth in SEQ ID NO: 292; and (xviii) a light chain variable region comprising a CDR-L1 comprising the amino acid sequence set forth in SEQ ID NO: 72; a CDR-L2 comprising the amino acid sequence set forth in SEQ ID NO: 54; and a CDR-L3 comprising the amino acid sequence set forth in SEQ ID NO: 184; (xviii) a heavy chain variable region comprising a CDR-H1 comprising the amino acid sequence set forth in SEQ ID NO: 298; a CDR-H2 comprising the amino acid sequence set forth in SEQ ID NO: 300; and a CDR-H3 comprising the amino acid sequence set forth in SEQ ID NO: 302; and a CDR-L1 comprising the amino acid sequence set forth in SEQ ID NO: 306; and a CDR-L2 comprising the amino acid sequence set forth in SEQ ID NO: 230;and a light chain variable region comprising a CDR-L1 comprising the amino acid sequence set forth in SEQ ID NO: 309; (xix) a heavy chain variable region comprising a CDR-H1 comprising the amino acid sequence set forth in SEQ ID NO: 317; a CDR-H2 comprising the amino acid sequence set forth in SEQ ID NO: 319; and a CDR-H3 comprising the amino acid sequence set forth in SEQ ID NO: 321; and a light chain variable region comprising a CDR-L1 comprising the amino acid sequence set forth in SEQ ID NO: 325; a CDR-L2 comprising the amino acid sequence set forth in SEQ ID NO: 327; and a CDR-L3 comprising the amino acid sequence set forth in SEQ ID NO: 329; (xx) a heavy chain variable region comprising a CDR-H1 comprising the amino acid sequence set forth in SEQ ID NO: 337; a CDR-H2 comprising the amino acid sequence set forth in SEQ ID NO: 339; and a CDR-H3 comprising the amino acid sequence set forth in SEQ ID NO: 341; and a CDR-L1 comprising the amino acid sequence set forth in SEQ ID NO: 72; a CDR-L2 comprising the amino acid sequence set forth in SEQ ID NO: 54; and an amino acid sequence set forth in SEQ ID NO: 184 (xxi) a light chain variable region comprising a CDR-H1 comprising the amino acid sequence set forth in SEQ ID NO: 347; a CDR-H2 comprising the amino acid sequence set forth in SEQ ID NO: 349; and a CDR-H3 comprising the amino acid sequence set forth in SEQ ID NO: 351; and a light chain variable region comprising a CDR-L1 comprising the amino acid sequence set forth in SEQ ID NO: 72; a CDR-L2 comprising the amino acid sequence set forth in SEQ ID NO: 54; and a CDR-L3 comprising the amino acid sequence set forth in SEQ ID NO: 355; (xxii) a heavy chain variable region comprising a CDR-H1 comprising the amino acid sequence set forth in SEQ ID NO: 363; a CDR-H2 comprising the amino acid sequence set forth in SEQ ID NO: 66; and a CDR-H3 comprising the amino acid sequence set forth in SEQ ID NO: 366; and a light chain variable region comprising a CDR-L1 comprising the amino acid sequence set forth in SEQ ID NO: 370; a CDR-L2 comprising the amino acid sequence set forth in SEQ ID NO: 372; and a CDR-L3 comprising the amino acid sequence set forth in SEQ ID NO: 374.

[0016] A complex comprising an antigen-binding protein of the invention bound to an IL2Rγ polypeptide or an antigenic fragment thereof is also part of the present invention.

[0017] The present invention also provides an antigen-binding protein (e.g., an antibody or antigen-binding fragment thereof) or an immunoglobulin chain thereof (e.g., a V H , V L The present invention provides methods for making an antigen binding protein (HC or LC) comprising: (a) introducing into a host cell (e.g., a CHO cell) one or more polynucleotides encoding one or more immunoglobulin chains of said antigen binding protein (or vectors comprising such polynucleotides); (b) culturing the host cell under conditions favorable for expression of the polynucleotides; and (c) optionally isolating the antigen binding protein or immunoglobulin chain from the host cell and / or the medium in which the host cell is grown. The antigen binding protein or immunoglobulin chain that is the product of such a method also forms part of the present invention.

[0018] The present invention also provides a heavy chain immunoglobulin or variable region thereof comprising (a) CDR-H1, CDR-H2, and CDR-H3 of a heavy chain immunoglobulin or variable region thereof comprising the amino acid sequence set forth 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, or a variant thereof; and / or (b) or (c) an amino acid sequence set forth in a member selected from the group consisting of SEQ ID NOs: 1-378, or a variant thereof. The present invention also provides polynucleotides encoding one or more of such polypeptides or vectors (e.g., plasmids) comprising such polynucleotides.

[0019] The present invention also provides an antigen binding protein (e.g., an antibody or antigen-binding fragment thereof) or immunoglobulin chain (e.g., a V H , V L , HC or LC) or polypeptide or polynucleotide or vector.

[0020] The present invention also provides compositions or kits comprising one or more of the antigen binding proteins (e.g., antibodies or antigen-binding fragments thereof) described herein, optionally in combination with an additional therapeutic agent (e.g., an anti-inflammatory agent, an anti-TNFα antibody or binding protein, infliximab, adalimumab, etanercept, golimumab, corticoids, prednisolone, methylprednisolone, antithymocyte globulin, alemtuzumab, daclizumab, extracorporeal photopheresis, mycophenolate mofetil, sirolimus, pentostatin, mesenchymal stem cells, inolimomab, denileukin, or basiliximab).

[0021] The present invention further provides pharmaceutical formulations comprising an antigen binding protein (e.g., an antibody or antigen-binding fragment thereof) described herein and a pharmaceutically acceptable carrier, and, optionally, an additional therapeutic agent (e.g., an anti-inflammatory agent, an anti-TNFα antibody or binding protein, infliximab, adalimumab, etanercept, golimumab, a corticoid, prednisolone, methylprednisolone, antithymocyte globulin, alemtuzumab, daclizumab, extracorporeal photopheresis, mycophenolate mofetil, tacrolimus, cyclosporine, sirolimus, pentostatin, mesenchymal stem cells, inolimomab, denileukin, or basiliximab).

[0022] The invention also provides a method for the preparation of an antigen-binding protein or composition (e.g., a pharmaceutical formulation) described herein. a container or injection device (e.g., a vial, syringe, pre-filled syringe, or autoinjector) containing the

[0023] The present invention also provides methods of administering an antigen binding protein or composition described herein to a subject (e.g., a human), comprising introducing, e.g., injecting (e.g., subcutaneously, intravenously, or intramuscularly), the antigen binding protein or composition into the subject's body. The present invention also provides methods of treating or preventing an IL2Rγ mediated disease or condition (e.g., graft versus host disease, organ transplant rejection, skin graft rejection, heart transplant rejection, lung transplant rejection, kidney transplant rejection, liver transplant rejection, shattered chorioretinopathy, multiple sclerosis, uveitis, autoimmune disease, type 1 diabetes, multiple sclerosis, rheumatoid arthritis, systemic lupus erythematosus, and / or myasthenia gravis) in a subject in need thereof, comprising administering, e.g., injecting, an effective amount of an antigen binding protein or composition described herein.

[0024] The present invention also relates to methods for blocking cytokine (e.g., IL-2, IL-4, IL-7, IL-15 and / or IL-21)-induced STAT phosphorylation in peripheral blood mononuclear cells (e.g., T cells); for blocking cytokine (e.g., IL-9)-induced STAT (e.g., STAT3) phosphorylation in mast cells; for reducing serum levels of interferon-gamma, tumor necrosis factor-alpha, IL-6, IL-8, IL-10 and / or mKC / GRO (e.g., in transplanted subjects); and for inhibiting cytokine (e.g., IL-2, IL-4, IL-7, IL-15 and / or IL-21)-induced STAT phosphorylation in mast cells (e.g., IL-9). and / or for reducing serum levels of CD45+ immune cells, NK cells, T cells and / or B cells (e.g., excluding neutrophils) in a subject, the method comprising administering to the subject an effective amount of an anti-IL2Rγ antigen binding protein, or a composition thereof, or a formulation thereof, as described herein. In embodiments of the invention, the subject is suffering from an IL2Rγ mediated disease or condition, such as graft versus host disease, organ transplant rejection, b-pancreatic islet cell transplant rejection, skin graft rejection, heart transplant rejection, lung transplant rejection, kidney transplant rejection, liver transplant rejection, shattered chorioretinopathy, multiple sclerosis, uveitis, autoimmune disease, type 1 diabetes, 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 drawings]

[0025] [Figure 1A]Figure 1(A) Blockade 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. [Figure 1B] Figure 1(B) shows blockade 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. [Figure 1C] Figure 1(C) shows blockade 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. [Figure 1D] Figure 1(D) shows blockade 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. [Figure 1E] Figure 1(E) shows blockade 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. [Figure 2] Blockade 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. [Figure 3] Figure 3 (A-F) shows the percentage of initial body weight over time for mice with human PBMCs administered anti-IL2R gamma antibodies (E) H4H12889P and (F) H4H12922P2 and antibody (D) COMP1499. Also shown are control experiments in mice that received (B) no antibody, (C) an isotype control antibody, or (A) no human PBMCs. The start of antibody injections on day 21 and the end of antibody injections on day 59 are indicated by dashed lines. [Figure 4] Figure 1 shows survival over time of mice injected with anti-IL2R gamma antibodies H4H12889P and H4H12922P2, antibody COMP1499, antibody REGN1945, and no antibody. The no-huPBMC group is not depicted. Differences in animal survival compared to the isotype control antibody group were analyzed by the Mantel-Cox log-rank test. A P value of <0.05 was considered statistically significant. **, P value <0.0021; ****, P value <0.0001. The start of antibody injection on day 21 and the end of antibody injection on day 59 are indicated by dashed lines. [Figure 5]Figure 5 (A-D) shows absolute human cell counts in the blood at day 35 after huPBMC injection in mice that received no antibody (no IgG) or that received REGN1945, COMP1499, or the 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 "no huPBMC" is not shown; #, significantly different from group "no huPBMC"; †, significantly different from group "huPBMC-no IgG"; *, significantly different from group "huPBMC-REGN1945". Each symbol represents a mouse. The value of 0 was arbitrarily shifted by a value of 0.01 for graphing purposes (logarithmic scale). [Figure 6] Figure 6 (A-D) shows 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 antibodies H4H12889P or H4H12922P2; or COMP1499 or an isotype control antibody. The start of antibody injection on day 21 and the end of antibody injection on day 59 are indicated by dashed lines. [Figure 7-1]Figure 7(A) shows 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 antibody (no IgG), or that received REGN1945, COMP1499, or anti-IL2R gamma antibodies H4H12889P or H4H12922P2, or mice with no human PBMCs. #, significantly different from group "no huPBMCs"; †, significantly different from group "huPBMC-no IgG"; *, significantly different from group "huPBMC-REGN1945." Each symbol represents a mouse. Figure 7(B) shows 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 antibody (no IgG), or that received REGN1945, COMP1499, or anti-IL2R gamma antibodies H4H12889P or H4H12922P2, or mice with no human PBMCs. #, significantly different from group "no huPBMCs"; †, significantly different from group "huPBMC-no IgG"; *, significantly different from group "huPBMC-REGN1945." Each symbol represents a mouse. [Figure 7-2]Figure 7(C) shows 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 antibody (no IgG), or that received REGN1945, COMP1499, or anti-IL2R gamma antibodies H4H12889P or H4H12922P2, or mice with no human PBMCs. #, significantly different from group "no huPBMCs"; †, significantly different from group "huPBMC-no IgG"; *, significantly different from group "huPBMC-REGN1945." Each symbol represents a mouse. Figure 7(D) shows 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 antibody (no IgG), or that received REGN1945, COMP1499, or anti-IL2R gamma antibodies H4H12889P or H4H12922P2, or mice with no human PBMCs. #, significantly different from group "no huPBMCs"; †, significantly different from group "huPBMC-no IgG"; *, significantly different from group "huPBMC-REGN1945." Each symbol represents a mouse. Figure 7(E) shows 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 antibody (no IgG), or that received REGN1945, COMP1499, or anti-IL2R gamma antibodies H4H12889P or H4H12922P2, or in mice with no human PBMCs.#, significantly different from group "no huPBMC"; †, significantly different from group "huPBMC-no IgG"; *, significantly different from group "huPBMC-REGN1945". Each symbol represents a mouse. [Figure 7-3] Figure 7(F) shows 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 antibody (no IgG), or that received REGN1945, COMP1499, or anti-IL2R gamma antibodies H4H12889P or H4H12922P2, or mice without human PBMCs. #, significantly different from group "no huPBMCs"; †, significantly different from group "huPBMC-no IgG"; *, significantly different from group "huPBMC-REGN1945." Each symbol represents a mouse. Figure 7(G) shows 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 antibody (no IgG), or that received REGN1945, COMP1499, or anti-IL2R gamma antibodies H4H12889P or H4H12922P2, or mice without human PBMCs. #, significantly different from group "no huPBMCs"; †, significantly different from group "huPBMC-no IgG"; *, significantly different from group "huPBMC-REGN1945." Each symbol represents a mouse. [Figure 7-4]Figure 7(H) shows 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 antibody (no IgG), or that received REGN1945, COMP1499, or anti-IL2R gamma antibodies H4H12889P or H4H12922P2, or mice with no human PBMCs. #, significantly different from group "no huPBMCs"; †, significantly different from group "huPBMC-no IgG"; *, significantly different from group "huPBMC-REGN1945." Each symbol represents a mouse. Figure 7(I) shows 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 antibody (no IgG), or that received REGN1945, COMP1499, or anti-IL2R gamma antibodies H4H12889P or H4H12922P2, or mice with no human PBMCs. #, significantly different from group "no huPBMCs"; †, significantly different from group "huPBMC-no IgG"; *, significantly different from group "huPBMC-REGN1945." Each symbol represents a mouse. [Figure 8] Figure 8 (A-D) shows 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 an isotype control antibody. [Figure 9A] Figure 9(A) shows the 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 antibody REGN1945 or H4H12889P. [Figure 9B] Figure 9(B) shows the 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 antibody REGN1945 or H4H12889P. [Figure 9C] Figure 9(C) shows the 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 antibody REGN1945 or H4H12889P. [Figure 9D] Figure 9(D) shows the 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 antibody REGN1945 or H4H12889P. [Figure 9E] Figure 9(E) shows the 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 antibody REGN1945 or H4H12889P. [Figure 10] Experimental design for in vivo skin graft rejection experiments. [Figure 11] Time to onset of skin graft rejection in mice that received no antibody or received REGN1945 or H4H12889P. [Figure 12] Time to complete rejection of skin grafts in mice that received no antibody or received REGN1945 or H4H12889P. [Figure 13] Total donor-specific IgG antibodies in non-transplanted or transplanted mice that received no antibody or received REGN1945 or H4H12889P. DETAILED DESCRIPTION OF THE INVENTION

[0026] The present invention provides antibodies and antigen-binding fragments thereof that specifically bind to human and cynomolgus IL2Rγ and exhibit exceptional biological activity, particularly with respect to blocking cytokine-induced STAT phosphorylation in T cells and blocking graft-versus-host disease in applicable mouse models.

[0027] In accordance with the present invention there may be employed conventional molecular biology, microbiology, and recombinant DNA techniques within the skill of the art. Such techniques are fully explained in the literature, see, e.g., Sambrook, Fritsch & Maniatis, Molecular Cloning: A Laboratory Manual, Second Edition, Edition(1989)Cold Spring Harbor Laborat Books Press, Cold Spring Harbor, NY (hereinafter "Sambrook et al., 1989"); DNA Cloning: A Practical Approach, Volumes I and II (D.N. Glover, ed., 1985); Oligonucleotide Synthesis (M.J. Gait, ed., 1984); Nucleic Acid Hybridization (B.D. Hames & S.J. Higgins, eds., (1985)); Transcription and Translation (B.D. Hames & S.J. Higgins, eds., (1984)); Animal Cell Culture (R.I. Freshney, ed., (1986)); Immobilized Cells and Enzymes (IRL Press, (1986)); B. Perbal, A Practical Guide See To Molecular Cloning (1984); FMA Mausubel et al. (eds.), Current Protocols in Molecular Biology, John Wiley & Sons, Inc. (1994).

[0028] IL-2Rγ Interleukin-2 receptor subunit gamma is also known as CD132; common cytokine receptor gamma chain; IL-2RG; IL-2Rg; IL2R gamma; IL-2Rγ, IMD4; P64:SCIDX; or SCIDX1. IL2Rγ is a subunit common to several interleukin receptors, including IL-2R, IL-4R, IL-7R, IL-9R, IL-15R, and IL21R.

[0029] In an embodiment of the invention, human IL2Rγ is encoded by the nucleotide sequence set forth under Genbank accession number NM_000206. In an embodiment of the invention, human IL2Rγ comprises the amino acid sequence set forth under Genbank accession number NP_000197.

[0030] antigen-binding proteins The present invention provides antigen binding proteins, such as antibodies (e.g., human antibodies, monoclonal antibodies, and recombinant antibodies) and antigen-binding fragments thereof, that specifically bind to the IL2Rγ protein or an antigenic fragment thereof (e.g., the extracellular domain of IL2Rγ). Antigen binding proteins that bind to the same epitope on IL2Rγ as any of the antigen binding proteins described herein, or that compete for binding to IL2Rγ with any of the antigen binding proteins described herein, are also part of the present invention.

[0031] The present invention also relates to the nucleic acids of 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, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 137, 138, 139, 140, 141, 142, 143, 144, 145, 146, 147, 148, 149, 150, 151, 152, 153, 154, 155, 156, 157, 158, 159, 160, 161, 162, 163, 164, 165, 166, 167, 168, 169, 170, 17 23, 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, 191 2, 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, 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 a variant thereof. Optionally, the polypeptide is fused to one or more other polypeptides, such as a human Fc (eg, a human IgG, such as IgG1 or IgG4 (eg, containing an S108P mutation)).

[0032] The term "antibody," as used herein, refers to an immunoglobulin molecule (i.e., a "full antibody molecule") (e.g., IgG) comprising four polypeptide chains, two heavy chains (HC) and two light chains (LC) interconnected by disulfide bonds, such as, 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. In embodiments of the invention, each antibody heavy chain (HC) comprises a heavy chain variable region ("HCVR" or "VVR"). 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 a heavy chain constant region (Domain C H 1. C H 2 and C H 3); each antibody light chain (LC) 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 a light chain constant region (C L ) included. V H and V L The region can be further divided into regions of hypervariability called complementarity-determining regions (CDRs) interspersed with more conserved regions called framework regions (FRs). H and V Lcomprises three CDRs and four FRs arranged from amino-terminus to carboxy-terminus in the following order: FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4. In certain embodiments of the invention, the FRs of the antibody (or antigen-binding fragment thereof) are identical to human germline sequences or are naturally or artificially modified.

[0033] Typically, the variable domains of both heavy and light immunoglobulin chains contain three hypervariable regions, also called complementarity-determining regions (CDRs), located within relatively conserved framework regions (FRs). Generally, from N- to C-terminus, both light and heavy chain variable domains contain FR1, CDR1, FR2, CDR2, FR3, CDR3, and FR4. In an embodiment of the invention, the assignment of amino acids to each domain is shown in Sequences of Proteins of Immunological Interest, Kabat et al; National Institutes of Health, Beth esda, Md.;5th ed.;NIH Publ.No.91~3242(1991);Kabat(1978)Adv.Prot.Chem.32:1~75;Kab at et al. (1977) J. Biol. Chem. 252:6609-6616; Cho Thia et al. (1987) J Mol. Biol. 196:901-917 or Ch According to the definition of Othia et al. (1989) Nature 342:878-883. Therefore, the present invention is H CDR and V L and antibodies and antigen-binding fragments comprising the CDRs of V H and V L includes antibodies and antigen-binding fragments comprising an amino acid sequence as described herein (or a variant thereof) and wherein the CDRs are defined according to Kabat and / or Chothia.

[0034] As used herein, the terms "antigen-binding portion" or "antigen-binding fragment" of an antibody or antigen-binding protein include any naturally occurring, enzymatically obtainable, synthetic, or genetically engineered polypeptide or glycoprotein that specifically binds to an antigen to form a complex. Non-limiting examples of antigen-binding fragments include: (i) Fab fragments; (ii) F(ab')2 fragments; (iii) Fd fragments (heavy chain portions of Fab fragments cleaved with papain); (iv) Fv fragments (V H or V L and (v) single-chain Fv (scFv) molecules, which consist of amino acid residues that mimic the hypervariable regions of an antibody (e.g., isolated complementarity-determining regions (CDRs), such as CDR3 peptides), or constrained FR3-CDR3-FR4 peptides. Other engineered molecules, such as domain-specific antibodies, single-domain antibodies, domain-deleted antibodies, chimeric antibodies, CDR-grafted antibodies, diabodies, triabodies, tetrabodies, minibodies, and small modular immunopharmaceuticals (SMIPs), are also encompassed within the term "antigen-binding fragment" as used herein. In an embodiment of the invention, the antigen-binding fragment comprises H4H12857P; H4H12858P; H4H12859P; H4H12863P; H4H12874P; H4H12871P; H4H12884P; H4H12886P; H4H12889P; H4H12890P; H4H12899P; H4H12900P; H4H12908P; H4H12913P; H4H129 H4H13541P; H4H13544P2; or H4H13545P2.

[0035] In embodiments of the invention, the antigen binding proteins (e.g., antibodies or antigen binding fragments thereof) of the invention are those listed in Table A below: [Table 1] V comprising the heavy chain CDR combinations (CDR-H1, CDR-H2 and CDR-H3) set forth in H and / or a heavy chain immunoglobulin (e.g., HC) comprising: [Table 2] V comprising the light chain CDR combination (CDR-L1, CDR-L2 and CDR-L3) set forth in L and light chain immunoglobulins (e.g., LC) comprising:

[0036] In embodiments of the invention, the antigen binding proteins (e.g., antibodies or antigen binding fragments thereof) of the invention are those listed in Table C below: [Table 3] V comprising the heavy and light chain CDR combinations (CDR-H1, CDR-H2, and CDR-H3; and CDR-L1, CDR-L2, and CDR-L3) set forth in H and V L immunoglobulins include heavy chain (e.g., HC) and light chain (e.g., LC) immunoglobulins, each comprising:

[0037] The present invention provides the following V H and V L and antigen-binding proteins (e.g., antibodies or antigen-binding fragments thereof) comprising a polypeptide pair comprising the amino acid sequences: SEQ ID NO:2 and SEQ ID NO:10; SEQ ID NO:22 and SEQ ID NO:30; SEQ ID NO: 42 and SEQ ID NO: 50; SEQ ID NO: 62 and SEQ ID NO: 70; SEQ ID NO: 81 and SEQ ID NO: 89; SEQ ID NO: 101 and SEQ ID NO: 109; SEQ ID NO: 119 and SEQ ID NO: 127; SEQ ID NO: 138 and SEQ ID NO: 146; SEQ ID NO: 156 and SEQ ID NO: 164; SEQ ID NO: 174 and SEQ ID NO: 182; SEQ ID NO: 190 and SEQ ID NO: 182; SEQ ID NO: 200 and SEQ ID NO: 182; SEQ ID NO: 210 and SEQ ID NO: 182; SEQ ID NO: 218 and SEQ ID NO: 226; SEQ ID NO: 238 and SEQ ID NO: 246; SEQ ID NO: 258 and SEQ ID NO: 266; SEQ ID NO: 276 and SEQ ID NO: 182; SEQ ID NO: 286 and SEQ ID NO: 182; SEQ ID NO: 296 and SEQ ID NO: 304; SEQ ID NO: 315 and SEQ ID NO: 323; SEQ ID NO: 335 and SEQ ID NO: 182; SEQ ID NO: 345 and SEQ ID NO: 353; or SEQ ID NO: 361 and SEQ ID NO: 368.

[0038] The present invention includes antigen-binding proteins (e.g., antibodies or antigen-binding fragments thereof) comprising the following amino acid sequence pairs encoding the HC and LC: SEQ ID NO: 18 and SEQ ID NO: 20; SEQ ID NO: 38 and SEQ ID NO: 40; SEQ ID NO:58 and SEQ ID NO:60; SEQ ID NO: 77 and SEQ ID NO: 79; SEQ ID NO:97 and SEQ ID NO:99; SEQ ID NO: 115 and SEQ ID NO: 117; SEQ ID NO: 134 and SEQ ID NO: 136; SEQ ID NO: 152 and SEQ ID NO: 154; SEQ ID NO: 170 and SEQ ID NO: 172; SEQ ID NO: 186 and SEQ ID NO: 188; SEQ ID NO: 198 and SEQ ID NO: 188; SEQ ID NO: 208 and SEQ ID NO: 188; SEQ ID NO: 216 and SEQ ID NO: 188; SEQ ID NO: 234 and SEQ ID NO: 236; SEQ ID NO: 254 and SEQ ID NO: 256; SEQ ID NO: 272 and SEQ ID NO: 274; SEQ ID NO: 284 and SEQ ID NO: 188; SEQ ID NO: 294 and SEQ ID NO: 188; SEQ ID NO: 311 and SEQ ID NO: 313; SEQ ID NO: 331 and SEQ ID NO: 333; SEQ ID NO: 343 and SEQ ID NO: 188; SEQ ID NO: 357 and SEQ ID NO: 359; or SEQ ID NO: 376 and SEQ ID NO: 378.

[0039] Embodiments of the present invention also include the corresponding V H , V L and immunoglobulin V comprising a variant amino acid sequence comprising an amino acid sequence described herein, wherein the variant amino acid sequence has 70% or more (e.g., 80%, 85%, 90%, 95%, 97% or 99%) overall amino acid sequence identity or similarity to the amino acid sequence of the HC or LC of such immunoglobulin, but the CDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2 and CDR-H3 of such immunoglobulin are not variants. H and V L or antigen binding proteins, e.g., anti-IL2Rγ antibodies and antigen-binding fragments thereof, comprising an HC and an LC. Thus, in such embodiments, the CDRs within the variant antigen binding protein are not themselves variant.

[0040] The present invention includes monoclonal anti-IL2Rγ antigen binding proteins, e.g., antibodies and antigen-binding fragments thereof, as well as monoclonal compositions comprising a plurality of isolated monoclonal antigen binding proteins. The term "monoclonal antibody" or "mAb," as used herein, refers to a member of a population of substantially homogeneous antibodies, i.e., a population The antibody molecules comprising the panel are identical in amino acid sequence except for possible naturally occurring mutations that may be present in minor amounts. A "plurality" of such monoclonal antibodies and fragments in a composition refers to a concentration of identical (i.e., identical in amino acid sequence except for possible naturally occurring mutations that may be present in minor amounts, as discussed above) antibodies and fragments that is greater than would normally occur in nature, e.g., in the blood of a host organism such as a mouse or human.

[0041] In embodiments of the invention, the anti-IL2Rγ antigen-binding protein, e.g., antibody or antigen-binding fragment, comprises a heavy chain constant domain, e.g., a heavy chain constant domain of the IgA (e.g., IgA1 or IgA2), IgD, IgE, IgG (e.g., IgG1, IgG2, IgG3 and IgG4 (e.g., comprising an S228P and / or S108P mutation)) or IgM type. In embodiments of the invention, the antigen-binding protein, e.g., antibody or antigen-binding fragment, comprises a light chain constant domain, e.g., a light chain constant domain of the kappa or lambda type. The present invention provides antigen binding proteins comprising a variable domain as described herein linked to heavy and / or light chain constant domains, e.g., as described above (e.g., H4H12857P; H4H12858P; H4H12859P; H4H12863P; H4H12874P; H4H12871P; H4H12884P; H4H12886P; H4H12887P). 889P; H4H12890P; H4H12899P; H4H12900P; H4H12908P; H4H12913P2; H4H12922P2; H4H12924P2; H4H12926P2; H4H12927P2; H4H12934P2; H4H13538P; H4H13541P; H4H13544P2; or H4H13545P2).

[0042] The term "human" antigen-binding protein, e.g., antibody or antigen-binding fragment, as used herein, includes antibodies and fragments having variable and constant regions derived from human germline immunoglobulin sequences, whether in human cells or grafted into non-human cells, e.g., mouse cells. See, e.g., US8502018, US6596541, or US5789215. In embodiments of the present invention, the human antibodies and antigen-binding fragments of the present invention may contain amino acid residues, e.g., in the CDRs, particularly CDR3, that are not encoded by human germline immunoglobulin sequences (e.g., having mutations introduced by random or site-specific mutagenesis in vitro or by somatic mutation in vivo). However, the term "human antibody," as used herein, is not intended to include mAbs in which CDR sequences derived from the germline of another mammalian species (e.g., mouse) are grafted onto human FR sequences. The term includes antibodies recombinantly produced in or in the cells of non-human mammals. The term is not intended to include antibodies isolated from or generated in a human subject. The present invention provides human antigen binding proteins (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).

[0043] The present invention includes anti-IL2Rγ chimeric antigen-binding proteins, e.g., antibodies and antigen-binding fragments thereof, and methods of use thereof. As used herein, a "chimeric antibody" is an antibody having variable domains from a first antibody and constant domains from a second antibody, wherein the first and second antibodies are from different species. (See, e.g., US 4,816,567; and Morrison et al., (1984) Proc. Natl. Acad. Sci. USA 97:1111-1112). d. Sci. USA 81:6851-6855). The present invention relates to a method for the preparation of a nucleotide sequence encoding ... H4H12913P2; H4H12922P2; H4H12924P2; H4H12926P2; H4H12927P2; H4H12934P2; H4H13538P; H4H13541P; H4H13544P2; or H4H13545P2).

[0044] The term "recombinant" antigen-binding protein, e.g., antibody or antigen-binding fragment thereof, refers to such a molecule that is produced, expressed, isolated, or obtained by techniques or methods known in the art, such as recombinant DNA technology, including, for example, DNA splicing and transgenic expression. The term includes antibodies expressed in non-human mammals (including transgenic non-human mammals, e.g., transgenic mice), or host cells (e.g., Chinese hamster ovary (CHO) cells) or cellular expression systems, or isolated from a recombinant combinatorial human antibody library. The present invention relates to recombinant antigen-binding proteins as described herein (e.g., H4H12857P; H4H12858P; H4H12859P; H4H12863P; H4H12874P; H4H12871P; H4H12884P; H4H12886P; H4H12889P; H4H12890P; H4H12891P; H4H12892P; H4H12893P; H4H12894P; H4H12895P; H4H12896P; H4H12897P; H4H12898P; H4H12899P; H4H12890 ...1P; H4H12892P; H4H12893P; H4 899P; H4H12900P; H4H12908P; H4H12913P2; H4H12922P2; H4H12924P2; H4H12926P2; H4H12927P2; H4H12934P2; H4H13538P; H4H13541P; H4H13544P2; or H4H13545P2).

[0045] Antigen-binding fragments of antibodies, in embodiments of the present invention, comprise at least one variable domain. A variable domain may be of any size or amino acid composition and generally comprises at least one (e.g., three) CDRs adjacent to or in-frame with one or more framework sequences. L V associated with the domain H In an antigen-binding fragment having a domain, V H and V L The domains can be positioned in any suitable arrangement relative to each other. For example, the variable region may be a dimer, with the V H -V H , V H -V L or V L -V L Alternatively, the antigen-binding fragment of an antibody may contain a dimer of non-covalently bound monomeric VH and / or V L It may contain domains.

[0046] In certain embodiments, an antigen-binding fragment of an 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 in an antigen-binding fragment of an antibody of the invention include: (i) a 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 LIn any configuration of variable and constant domains, including any of the exemplary configurations listed above, the variable and constant domains may be directly linked to each other or may be linked by a full or partial hinge or linker region. The hinge region may consist of at least two (e.g., 5, 10, 15, 20, 40, 60, or more) amino acids that result in a flexible or semi-flexible linkage between adjacent variable and / or constant domains in a single polypeptide molecule. Furthermore, antigen-binding fragments of antibodies of the present invention may be composed of one or more monomeric V domains non-covalently associated with each other and / or linked together (e.g., by disulfide bonds). H Or V L Homodimers or heterodimers (or heterodimers) of any of the variable and constant domain configurations listed above with the domain. The present invention may include antigen binding proteins as described herein, e.g., H4H12857P; H4H12858P; H4H12859P; H4H12863P; H4H12874P; H4H12871P; H4H12884P; H4H12886P; H4H12889P; H4H12890P; H4H12899P; H4H12892P; H4H12893P; H4H12894P; H4H12895P; H4H12896P; H4H12897P; H4H12898P; H4H12899P; H4H12899P; H4H12890P; H4H12899P; H4H12891P; H4H12892P; H4H12893P; H4H12894P; H4H12895P; H4H12896P; H4H12897P; H4H12898P; H4H12899P; H4H12899P; H4H12890P; H4H12899P; H4H12890P; H4H12891P; H4H12892P; H4H12893P; H4H12894P; H4H12895P; H4H12896P; H4H12897P; H4H12898P; H4H12899P; H4H12890P; H4H12899P; H4H12890P; H4H12890P; H4H12891P; H4H1 Includes an antigen-binding fragment of H12900P; H4H12908P; H4H12913P2; H4H12922P2; H4H12924P2; H4H12926P2; H4H12927P2; H4H12934P2; H4H13538P; H4H13541P; H4H13544P2; or H4H13545P2.

[0047] Antigen-binding proteins (e.g., antibodies and antigen-binding fragments) may be monospecific or multispecific (e.g., bispecific). Multispecific antigen-binding proteins are further discussed herein. The present invention relates to the antigen-binding proteins specifically described herein (e.g., H4H12857P; H4H12858P; H4H12859P; H4H12863P; H4H12874P; H4H12871P; H4H12884P; H4H12886P; H4H12889P; H4H12890P; H4H12899P; H4H12900P; H4H12908P; H4H1 H4H13538P; H4H13541P; H4H13544P2; or H4H13545P2), as well as multispecific (e.g., bispecific) antigen-binding fragments.

[0048] The terms "specifically binds" or "binds specifically" refer to a specific binding site determined by, for example, real-time label-free biolayer interferometry assays, such as Octet® HTX biosensors, at 25°C or 37°C, or by surface plasmon resonance, such as BI at least about 10 as measured by ACORE™ or by solution affinity ELISA -7 M (e.g., 10 -8 M, 10 -9 M, 10 -10 M, 10 -11 M or 10 -12 M)'s, K DThe present invention includes antigen-binding proteins that specifically bind to IL2Rγ protein. In embodiments of the present invention, the anti-IL2Rγ antigen-binding protein has a K for binding to human and / or mouse and / or cynomolgus monkey and / or rat IL2Rγ or domains thereof, as set forth in any of Tables 3-1 to 3-12. D "Anti-IL2R gamma" refers to an antigen-binding protein (or other molecule), e.g., an antibody or antigen-binding fragment thereof, that specifically binds to IL2R gamma.

[0049] "Isolated" antigen binding proteins (e.g., antibodies or antigen-binding fragments thereof), polypeptides, polynucleotides, and vectors are at least partially free from other biological molecules from the cell or cell culture from which they are produced. Such biological molecules include nucleic acids, proteins, other antibodies or antigen-binding fragments, lipids, carbohydrates, or other materials, such as cell debris and growth medium. Isolated antigen binding proteins may further be at least partially free from expression system components, such as biological molecules from the host cell or its growth medium. In general, the term "isolated" is not intended to refer to the complete absence of such biological molecules (e.g., minor or insignificant amounts of impurities may remain), or the absence of water, buffers, or salts, or components of a pharmaceutical formulation that comprises the antigen binding protein (e.g., antibody or antigen-binding fragment).

[0050] The present invention relates to antigen-binding proteins of the invention (e.g., H4H12857P; H4H12858P; H4H12859P; H4H12863P; H4H12874P; H4H128 H4H12884P; H4H12886P; H4H12889P; H4H12890P; H4H12899P; H4H12900P; H4H12908P; H4H12913P2; H4H12922P2; H4H12924P2; H4H12926P2; H4H12927P2; H4H12934P2; H4H13538P; H4H13541P; H4H13544P2; or H4H13545P2).

[0051] An antigen is, for example, a molecule to which an antibody binds, such as a peptide (e.g., IL2R gamma or a fragment thereof (antigenic fragment)). The unique region on an antigen that an antibody recognizes and binds to is called an epitope. Antigen-binding proteins (e.g., antibodies) of the invention that specifically bind to such antigens are part of the invention.

[0052] The term "epitope" refers to a unique antigen-binding site of an antigen-binding protein, known as a paratope, e.g., an antigenic determinant (e.g., on IL2Rγ) that interacts with the variable region of an antibody molecule. A single antigen may have more than one epitope. Thus, different antibodies may bind to different compartments on the antigen and have different biological effects. The term "epitope" can also refer to the site on an antigen to which B and / or T cells respond and / or the region of the antigen to which an antibody binds. Epitopes can be defined as structural or functional. Functional epitopes are generally a subset of structural epitopes and contain residues that directly contribute to the affinity of the interaction. Epitopes can be linear or conformational, i.e., composed of non-linear amino acids. In certain embodiments, epitopes may include determinants that are chemically active surface groupings of molecules, such as amino acids, sugar side chains, phosphoryl groups, or sulfonyl groups, and, in certain embodiments, may have unique three-dimensional structural characteristics and / or unique charge characteristics. The epitope to which an antigen binding protein of the invention binds may be comprised in a fragment of IL2Rγ, e.g., human IL2Rγ, such as in its ectodomain, domain 1 or domain 2. Antigen binding proteins (e.g., antibodies) of the invention that bind to such epitopes are part of the invention.

[0053] Methods for determining the epitope of an antigen-binding protein, e.g., an antibody or fragment or polypeptide, include alanine scanning mutation analysis, peptide blot analysis (Reineke (2004) Methods Mol. Biol. 248:443-63), These include peptide cleavage analysis, crystallographic studies, and NMR analysis. Additionally, methods such as epitope excision, epitope extraction, and chemical modification of antigens can be used (Tomer (2000) Prot. Sci. 9:487-496). Another method that can be used to identify amino acids within a polypeptide with which an antibody (e.g., an antibody or fragment or polypeptide) interacts is hydrogen / deuterium exchange detected by mass spectrometry. See, e.g., Ehring (1999) Analytical Biochem Histry 267:252-259; Engen and Smith (2001) An See al. Chem. 73:256A-265A.

[0054] The present invention provides antigen-binding proteins of the invention, e.g., H4H12857P; H4H12858P; H4H12859P; H4H12863P; H4H12874P; H4H12871P; H4H12884P; H4H12886P; H4H12889P; H4H12890P; H4H12899P; H4H12900P; H4H12908P; H4H12913P; H4H12914P; or H4H13545P2 for binding to IL2Rγ, e.g., a variant IL2Rγ epitope as discussed herein. The term "compete" as used herein includes antigen binding proteins that compete with H4H12922P2; H4H12924P2; H4H12926P2; H4H12927P2; H4H12934P2; H4H13538P; H4H13541P; H4H13544P2; or H4H13545P2 for binding to IL2Rγ, e.g., a variant IL2Rγ epitope as discussed herein. The term "competition" refers to an antigen-binding protein (e.g., an antibody or antigen-binding fragment thereof) that binds to an antigen (e.g., IL2Rγ) and inhibits or blocks the binding of another antigen-binding protein (e.g., an antibody or antigen-binding fragment thereof) to the antigen. Unless otherwise stated, the term also includes competition between two antigen-binding proteins, e.g., antibodies, in both directions, i.e., a first antibody binds to an antigen and blocks binding by a second antibody, and vice versa. Thus, in embodiments of the invention, competition occurs in one such direction. In certain embodiments, a first antigen-binding protein (e.g., an antibody) and a 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 e.g., overlapping or non-overlapping, epitopes, where the binding of one inhibits or blocks the binding of the second antibody, e.g., via steric hindrance. 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. Binding competition between anti-IL2Rγ antigen-binding proteins (e.g., monoclonal antibodies (mAbs)) can also be determined using real-time label-free biolayer interferometry assays on an Octet RED384 biosensor (Pall ForteBio Corp.).

[0055] Typically, antibodies or antigen-binding fragments of the invention, modified in some way, retain the ability to specifically bind to IL2Rγ, e.g., retain at least 10% of their IL2Rγ binding activity (compared to the parent antibody) when that activity is expressed on a molar basis. Preferably, antibodies or antigen-binding fragments of the invention retain at least 20%, 50%, 70%, 80%, 90%, 95%, or 100% or more of the IL2Rγ binding affinity of the parent antibody. It is also intended that antibodies or antigen-binding fragments of the invention may include conservative or non-conservative amino acid substitutions (referred to as "conservative variants" or "function-conservative variants" of antibodies) that do not substantially alter their biological activity.

[0056] Polypeptides such as immunoglobulin chains (e.g., comprising the amino acid sequences specifically described herein: H4H12857P; H4H12858P; H4H12859P; H4H12863P; H4H12874P; H4H12871P; H4H12884P; H4H12886P; H4H12889P; H4H12890P ;H4H12899P;H4H12900P;H4H12908P;H4H12913P2;H4H12922P2;H4H12924P2;H4H12926P2;H4H12927P2;H4H12934P2;H4H13538P;H4H13541P;H4H13544P2;orH4H13545P2 V H , V L, HC or LC or CDRs thereof) are those that are similar to or are identical to the referenced amino acid sequences described herein (e.g., 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, 76, 77, 78, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 137, 138, 139, 140, 141, 142, 143, 144, 145, 1 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, 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).

[0057] Furthermore, a variant of a polypeptide may be a polypeptide such as an immunoglobulin chain whose amino acid sequence may comprise the amino acid sequence of a reference polypeptide specifically described 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), nonsense mutations, deletions, or insertions (e.g., H4H12857P; H4H12858P; H4H12859P). P;H4H12863P;H4H12874P;H4H12871P;H4H12884P;H4H12886P;H4H12889P;H4H12890P;H4H12899P;H4H12900P;H4H12908P;H4H1 2913P2; H4H12922P2; H4H12924P2; H4H12926P2; H4H12927P2; H4H12934P2; H4H13538P; H4H13541P; V H , V L For example, the present invention provides an immunoglobulin light chain (or VHC or LC, or its CDRs) comprising the amino acid sequence set forth in SEQ ID NO: 10, but with one or more of such mutations.L ) variants and / or immunoglobulin heavy chains (or V) comprising the amino acid sequence set forth in SEQ ID NO:2 but with one or more of such mutations. H In embodiments of the invention, the anti-IL2Rγ antigen binding proteins include immunoglobulin light chain variants comprising one or more (e.g., one, two, or three) of CDR-L1, CDR-L2, and CDR-L3 CDRs with one or more of such mutations (e.g., conservative substitutions) and / or immunoglobulin heavy chain variants comprising one or more (e.g., one, two, or three) of CDR-H1, CDR-H2, and CDR-H3 CDRs with one or more of such mutations (e.g., conservative substitutions).

[0058] The following references relate to the BLAST algorithm, which is often used for sequence analysis: BLAST Algorithm: Altschul et al. (2005) FEBS J.2 72(20):5101-5109; Altschul, SF et al. (1990) J Mol. Biol. 215: 403-410; Gish, W. et al. (1993) Na ture Genet. 3:266-272; Madden, TL et al. (1996) Meth. Enzymol. 266:131-141; Altschul, SF et al. (1997) Nucleic Acids Res. 25:3389-3402; Zhang, J. et al. (1997) Genome Res. 7:649-656; Wo otton, JC et al. (1993) Comput. Chem. 17:149-163 Hancock, JM et al. (1994) Comput. Appl. Biosci .10:67-70; Alignment scoring system: Dayhoff, MO et al., "A model of evolutionary change in proteins." Atlas of Protein Sequence and Structure, (1978) vol.5, suppl.3. MO Dayhoff ( (Eds.), pp. 345-352, Natl. Biomed. Res. Found., Washington, DC; Schwartz, RM et al., "Matrices for detecting distant relationships.", Atlas of Protein Sequence and Structure, (1978) vol.5, suppl.3.” MODayhoff (ed.), pp. 353-358, Natl. Biomed. Res. Found., Washington, DC; Altschul, SF, (1991) J. Mol. Biol. 219: 555-56 Page 5; States, DJ et al. (1991) Methods 3:66-70; H Enikoff, S. et al. (1992) Proc. Natl. Acad. Sci. USA 89:10915-10919; Altschul, S.F. et al. (1993) J. Mol. Evol. 36: pp. 290-300; Alignment statistics: Karlin, S. et al. (1990) Proc. Natl. Acad. Sci. USA 87: 2264-22 68; Karlin, S. et al. (1993) Proc. Natl. Acad. Sci. USA 90:5873-5877; Dembo, A. et al. (1994) Ann. Pr ob. 22: pp. 2022-2039; and Altschul, S.F., "Evaluating the statistical significance of multiple distinct local alignments.", Theoretical and Computational Methods in Genome Research (ed. S. Suhai), (1997), pp. 1-14, Plenum, NY.

[0059] "Conservatively modified variants" or "conservative substitutions," e.g., of immunoglobulin chains described herein, refer to variants in which there are substitutions of one or more amino acids in a polypeptide with other amino acids having similar characteristics (e.g., charge, side chain size, hydrophobicity / hydrophilicity, backbone conformation and rigidity, etc.). Such changes can frequently be made without significantly interfering with the biological activity of the antibody or fragment. Those skilled in the art will recognize that, in general, single amino acid substitutions in non-essential regions of a polypeptide do not substantially alter biological activity (see, e.g., Watson et al., (1987) Molecular Biology of the Gene, The Benjamin / Cummings Pub.Co., 224 pages (4 th (See, e.g., J. Am. Chem. Soc. 1999, 14:131-132, 1999). Additionally, substitutions of structurally or functionally similar amino acids are less likely to significantly interfere with biological activity. The present invention includes anti-IL2Rγ antigen binding proteins comprising such conservatively modified variant immunoglobulin chains.

[0060] Examples of groups of amino acids with side chains that have 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: aspartic acid and glutamic acid; and 7) sulfur-containing side chains: cysteine ​​and methionine. Alternatively, conservative substitutions can be made as described in Gonnet et al. (1992) Science 256:1443. Any change that has a positive value in the PAM250 log-likelihood matrix disclosed on page 45.

[0061] The anti-IL2Rγ antigen binding proteins described herein, including, for example, variant immunoglobulin chains, may exhibit one or more of the following properties: Approximately 2.75 x 10 at 25°C -9 M ~ approx. 3.36×10 -7 K of M D binds to human IL2Rγ (e.g., a fusion thereof, such as a myc-myc-His6 fusion); Approximately 6.42 x 10 at 37°C -9 M ~ approx. 3.53×10 -7 K of M D and binds to human IL2Rγ (and fusions thereof, such as myc-myc-His6 fusions) Or about 3.53 x 10 -7 K lower than M D Combine with); Approximately 3.18 x 10 at 25°C -9 M ~ approx. 2.38×10 -7 K of M D binds to cynomolgus IL-2Rγ (e.g., a fusion thereof, such as a myc-myc-His6 fusion); At 37°C, approximately 8.29 x 10 -9 M ~ approx. 3.20×10 -7 K of M Dto cynomolgus IL-2Rγ (or a fusion thereof, such as a myc-myc-His6 fusion) at 200 ng / mL (or approximately 3.20 × 10 -7 K lower than M D Combine with); Approximately 2.45 x 10 at 25°C -9 M ~ approx. 1.20×10 -8 K of M D (or about 1.20 × 10 -8 K lower than M D to combine with); Approximately 1.86 x 10 at 37°C -11 M ~ approx. 3.00×10 -8 K of M D (or about 3.00 × 10 -8 K lower than M D to combine with); Approximately 1.84 x 10 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 K of M D binding (or lack of binding) to mouse IL2Rγ (e.g., a fusion thereof, such as a myc-myc-His6 fusion); At 37°C, approximately 5.59 x 10 -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 K of M D binding (or lack of binding) to mouse IL2Rγ (e.g., a fusion thereof, such as a myc-myc-His6 fusion); Approximately 3.32 x 10 at 25°C -9 M ~ approx. 1.97×10 -7 K of MD binds (or does not bind) to human IL2Rγ domain 1 (and fusions thereof, such as myc-myc-His6 fusions); At 37°C, approximately 4.13 x 10 -9 M ~ approx. 2.25×10 -7 K of M D binds (or does not bind) to human IL2Rγ domain 1 (and fusions thereof, such as myc-myc-His6 fusions); Approximately 2.91 x 10 at 25°C -7 M ~ approx. 5.35×10 -10 K D binds (or does not bind) to human IL2Rγ domain 2 (e.g., a fusion thereof, such as a myc-myc-His6 fusion); Approximately 1.14 x 10 at 37°C -8 or approximately 1.27 x 10 -8 K D binds (or does not bind) to human IL2Rγ domain 2 (e.g., a fusion thereof, such as a myc-myc-His6 fusion); For example, IC of about 1 nM to about 0.5 nM 50 and T cells (e.g., human CD4 T cells) induced by, for example, IL-2 (e.g., about 10 nM), IL-4 (e.g., about 50 pM), IL-7 (e.g., about 1 pM), IL-15 (e.g., about 0.5 nM), and / or IL-21 (e.g., about 50 pM). + blocking STAT phosphorylation in T cells); For example, about 4 × 10 -10 M IC 50 by blocking STAT phosphorylation in mast cells (e.g., differentiated human mast cells) induced by, for example, IL-9 (e.g., about 2 nM); Mice (e.g., NOD-scid) after injection with human peripheral blood mononuclear cells (PBMCs) reducing 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 IL2rγ null (NSG) mice; Mice (e.g., NOD-scid) after injection with human peripheral blood mononuclear cells (PBMCs) reducing serum human cytokine (e.g., human IFN-γ, human TNFα, human IL-6, human IL-8, and / or human IL-10) and / or mouse cytokine (e.g., mouse TNFα, mouse IL-6, mouse KC / GRO, and / or mouse IL-10) levels in IL2rγ null (NSG) mice; compete with any one or more anti-IL2Rγ antibodies described herein for binding to human IL-2Rγ, e.g., on a cell surface (e.g., tagged with a C-terminal myc-myc-hexahistidine tag); binds to the same epitope on IL2Rγ, e.g., on the cell surface (e.g., tagged with a C-terminal myc-myc-hexahistidine tag), as any one or more anti-IL2Rγ antibodies described herein; does not detectably bind to mouse IL2Rγ or rat IL2Rγ (e.g., as measured by Biacore at 37°C); Protecting mice from GvHD-induced weight loss and / or death in a GvHD mouse model; blocking the binding of a hybrid receptor comprising 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 Inhibiting IL2Rγ intracellular signaling (e.g., in human B lymphocyte cells or human natural killer cells) through the JAK-STAT pathway induced by, e.g., IL2, IL4, IL7, IL9, IL15, and / or IL21, as measured by luciferase expression in cells containing a luciferase gene operably linked to a STAT3 response element.

[0062] "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, unless otherwise stated, H4H12857P; H4H12858P; H4H12859P; H4H12863P; H4H12874P; H4H12871P; H4H12884P; H4H12886P; H4H12889P; H4 H4H12890P; H4H12899P; H4H12900P; H4H12908P; H4H12913P2; H4H12922P2; H4H12924P2; H4H12926P2; H4H12927P2; H4H12934P2; H4H13538P; H4H13541P; H4H13544P2; or H4H13545P2, as specifically described herein (e.g., 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 376) (or a variant thereof) H), and / or H4H12857P;H4H12858P;H4H12859P;H4H12863P;H4H12874P;H4H12871P;H4H12884P;H4H12886P;H4H12889P;H4H12890P;H4H12899P;H4H12900P;H4H12908P;H4H12913P2;H4H12922P2;H4H12924P2;H4H12926P2;H4H12927P2;H4H12934P2;H4H13538P;H4H1354 1P; H4H13544P2; or H4H13545P2; an immunoglobulin light chain or variable region thereof (V) comprising an amino acid sequence specifically described herein (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) (or a variant thereof). L ) respectively; and / or a heavy chain or V containing its CDRs (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 containing its CDRs (CDR-L1 (or a variant thereof), CDR-L2 (or a variant thereof), and CDR-L3 (or a variant thereof)). L In an embodiment of the invention, V refers to an anti-IL2Rγ antigen binding protein, e.g., an antibody and antigen-binding fragments thereof (including multispecific antigen binding proteins), comprising 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 an S228P and / or S108P mutation)), and / or L is linked to a light chain constant domain, e.g., a human light chain constant domain (e.g., a lambda or kappa constant light chain domain). Any such immunoglobulin chain (e.g., V H , V LPolynucleotides encoding one or more of the HC and / or LC form part of the present invention.

[0063] The present invention includes "neutralizing" or "antagonist" anti-IL2Rγ antigen binding proteins (e.g., antibodies or antigen-binding fragments), including molecules that inhibit the activity of IL2Rγ (e.g., binding of a hybrid receptor comprising 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) to any detectable extent.

[0064] Antibodies and antigen-binding fragments of the invention (e.g., H4H12857P; H4H12858P; H4H12859P; H4H12863P; H4H12874P; H4H12871P; H4H12884P; H4H12886P; H4H12889P; H4H12890P; H4H12899P; H4H12900P; H4H12908P; H4H129 13P2; H4H12922P2; H4H12924P2; H4H12926P2; H4H12927P2; H4H12934P2; H4H13538P; H4H13541P; H4H13544P2; or H4H13545P2) include immunoglobulin chains that include the amino acid sequences specifically described herein (and variants thereof), as well as cellular and in vitro post-translational modifications to the antibody or fragment. For example, the present invention includes antibodies and antigen-binding fragments thereof that specifically bind to IL2Rγ comprising the heavy and / or light chain amino acid sequences described herein, as well as 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, the N-terminal glutamine is pyroglutamic acid (pyroE), and / or the C-terminal lysine or other amino acid is deleted.

[0065] The present invention provides anti-IL2Rγ antigen binding proteins of the invention, e.g., H4H12857P; H4H12858P; H4H12859P; H4H12863P; H4H12874P; H4H12871P; H4H12884P; H4H12886P; H4H12889P; H4H12890P; H4H12899P; H4H12900P; H4H12908P; H4H12913P; H4H12914P; Provide a container (e.g., a plastic or glass vial, e.g., with a cap or chromatography column, hollow needle, or syringe cylinder) containing H12922P2; H4H12924P2; H4H12926P2; H4H12927P2; H4H12934P2; H4H13538P; H4H13541P; H4H13544P2; or H4H13545P2.

[0066] The present invention also provides one or more antigen binding proteins (e.g., antibodies or antigen-binding fragments) that specifically bind to IL2Rγ, such as H4H12857P; H4H12858P; H4H12859P; H4H12863P; H4H12874P; H4H12871P; H4H12884P; H4H12886P; H4H12889P; H4H12 The present invention provides an injection device comprising: 890P; H4H12899P; H4H12900P; H4H12908P; H4H12913P2; H4H12922P2; H4H12924P2; H4H12926P2; H4H12927P2; H4H12934P2; H4H13538P; H4H13541P; H4H13544P2; or H4H13545P2, or a pharmaceutical formulation thereof. The injection device can be packaged in a kit. The injection device is a device that introduces a substance into a subject's body via a parenteral route, for example, intraocular, intravitreal, intramuscular, subcutaneous or intravenous route. For example, the injection device may be a syringe or autoinjector (e.g., pre-filled with a pharmaceutical formulation) that includes, for example, a cylinder or barrel for holding the fluid to be injected (e.g., containing the antibody or fragment or pharmaceutical formulation thereof), a needle for piercing the skin, blood vessel or other tissue for injection of the fluid; and a plunger for forcing the fluid from the cylinder through the bore of the needle and into the body of the subject.

[0067] The present invention further provides anti-IL2Rγ antigen binding proteins of the invention, e.g., H4H12857P; H4H12858P; H4H12859P; H4H12863P; H4H12874P; H4H12871P; H4H12884P; H4H12886P; H4H12889P; H4H12890P; H4H12899P; H4H12900P; H4H12908P; H4H1291

[0013] The present invention provides a method for administering H4H12922P2; H4H12924P2; H4H12926P2; H4H12927P2; H4H12934P2; H4H13538P; H4H13541P; H4H13544P2; or H4H13545P2 to a subject, the method comprising introducing the antigen-binding protein into the subject's (e.g., human) body, for example, parenterally. For example, the method comprises inserting a syringe needle into the subject's body and injecting the antigen-binding protein into the subject's body, for example, into the subject's vein, artery, eye, muscle tissue, or subcutaneous tissue.

[0068] Polynucleotides and methods of production Polynucleotides include DNA and RNA. The present invention relates to, for example, H4H12857P; H4H12858P; H4H12859P; H4H12863P; H4H12874P; H4H12871P; H4H12884P; H4H12886P; H4H12889P; H4H12890P; H4H12899P; H4H12900P; immunoglobulin V H4H12908P;H4H12913P2;H4H12922P2;H4H12924P2;H4H12926P2;H4H12927P2;H4H12934P2;H4H13538P;H4H13541P;H4H13544P2; or H4H13545P2 H , V L , CDR-H, CDR-L, HC or LC, optionally operably linked to a promoter or other expression control sequence. For example, the present invention includes any polynucleotide of the present invention, including those of 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, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 137, 138, 139, 140, 141, 142, 143, 144, 138, 139, 145, 2, 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, 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 embodiments of the present invention, the polynucleotides of the present invention are fused to a secretory signal sequence. Polypeptides encoded by such polynucleotides are also within the scope of the present invention.

[0069] Generally, a "promoter" or "promoter sequence" is a DNA regulatory region capable of binding RNA polymerase in a cell (e.g., directly or through a protein or substance bound to another promoter) and initiating transcription of a coding sequence. A promoter may be operably linked to other expression control sequences, including enhancer and repressor sequences, and / or to a polynucleotide of the invention. Promoters that can be used to control gene expression include the cytomegalovirus (CMV) promoter (U.S. Pat. Nos. 5,385,839 and 5,168,062), the SV40 early promoter region (Benoist et al., (1981) N Ature 290:304-310), the promoter contained in the 3' long terminal repeat of Rous sarcoma virus (Yamamoto et al. (1980) Cell 22:787-790). 797), herpes thymidine kinase promoter (Wagner et al., (1981) P roc. Natl. Acad. Sci. USA 78:1441-1445), the regulatory sequence of the metallothionein gene (Brinster et al. (1982) Nature 296 : pp. 39-42); prokaryotic expression vectors, e.g., the beta-lactamase promoter (VIIIa-Komaroff et al. (1978) Proc. Natl. Acad. Sci. USA 75:3727-3731), or the tac promoter (DeBoer et al. (1983) Proc. Natl. Acad. Sci. USA 80:21-25); "Useful proteins from recombinant bacteria", Scientific American (1980) 242:74-94. as well as promoter elements from yeast or other fungi, such as, but not limited to, the Gal4 promoter, the ADC (alcohol dehydrogenase) promoter, the PGK (phosphoglycerol kinase) promoter, or the alkaline phosphatase promoter.

[0070] A polynucleotide encoding a polypeptide is "operably linked" to a promoter or other expression control sequence when, in a cell or other expression system, the promoter or other expression control sequence directs RNA polymerase-mediated transcription of the coding sequence into RNA, preferably mRNA, which is then optionally spliced ​​(if it contains introns) and, optionally, translated into the protein encoded by the coding sequence.

[0071] The present invention is H and V L and a polynucleotide comprising the following polynucleotide pair encoding: SEQ ID NO: 1 and SEQ ID NO: 9; SEQ ID NO:21 and SEQ ID NO:29; SEQ ID NO: 41 and SEQ ID NO: 49; SEQ ID NO:61 and SEQ ID NO:69; SEQ ID NO: 80 and SEQ ID NO: 88; SEQ ID NO: 100 and SEQ ID NO: 108; SEQ ID NO: 118 and SEQ ID NO: 126; SEQ ID NO: 137 and SEQ ID NO: 145; SEQ ID NO: 155 and SEQ ID NO: 163; SEQ ID NO: 173 and SEQ ID NO: 181; SEQ ID NO: 189 and SEQ ID NO: 181; SEQ ID NO: 199 and SEQ ID NO: 181; SEQ ID NO: 209 and SEQ ID NO: 181; SEQ ID NO: 217 and SEQ ID NO: 225; SEQ ID NO: 237 and SEQ ID NO: 245; SEQ ID NO: 257 and SEQ ID NO: 265; SEQ ID NO: 275 and SEQ ID NO: 181; SEQ ID NO: 285 and SEQ ID NO: 181; SEQ ID NO: 295 and SEQ ID NO: 303; SEQ ID NO: 314 and SEQ ID NO: 322; SEQ ID NO: 334 and SEQ ID NO: 181; SEQ ID NO: 344 and SEQ ID NO: 352; or SEQ ID NO: 360 and SEQ ID NO: 367.

[0072] The present invention includes polynucleotides comprising the following set of polynucleotides encoding CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2 and CDR-L3: SEQ ID NOs: 3, 5, 7, 11, 13 and 15; SEQ ID NOs: 23, 25, 27, 31, 33 and 35; SEQ ID NOs: 43, 45, 47, 51, 53 and 55; SEQ ID NOs: 63, 65, 67, 71, 73 and 74; SEQ ID NOs: 82, 84, 86, 90, 92 and 94; SEQ ID NOs: 102, 104, 106, 110, 73 and 112; SEQ ID NOs: 120, 122, 124, 128, 130 and 131; SEQ ID NOs: 139, 141, 143, 147, 73 and 149; SEQ ID NOs: 157, 159, 161, 165, 13 and 167; SEQ ID NOs: 175, 177, 179, 71, 73 and 183; SEQ ID NOs: 191, 193, 195, 71, 73 and 183; SEQ ID NOs: 201, 203, 205, 71, 73 and 183; SEQ ID NOs: 175, 211, 213, 71, 73 and 183; SEQ ID NOs: 219, 221, 223, 227, 229 and 231; SEQ ID NOs: 239, 241, 243, 247, 249 and 251; SEQ ID NOs: 259, 261, 263, 267, 73 and 269; SEQ ID NOs: 277, 279, 281, 71, 73 and 183; SEQ ID NOs: 287, 289, 291, 71, 73 and 183; SEQ ID NOs: 297, 299, 301, 305, 307 and 308; SEQ ID NOs: 316, 318, 320, 324, 326 and 328; SEQ ID NOs: 336, 338, 340, 71, 73 and 183; SEQ ID NOs: 346, 348, 350, 71, 73 and 354; or SEQ ID NOs: 362, 364, 365, 369, 371 and 373.

[0073] The present invention includes polynucleotides comprising the following polynucleotide pair encoding HC and LC: SEQ ID NO: 17 and SEQ ID NO: 19; SEQ ID NO: 37 and SEQ ID NO: 39; SEQ ID NO:57 and SEQ ID NO:59; SEQ ID NO: 76 and SEQ ID NO: 78; SEQ ID NO:96 and SEQ ID NO:98; SEQ ID NO: 114 and SEQ ID NO: 116; SEQ ID NO: 133 and SEQ ID NO: 135; SEQ ID NO: 151 and SEQ ID NO: 153; SEQ ID NO: 169 and SEQ ID NO: 171; SEQ ID NO: 185 and SEQ ID NO: 187; SEQ ID NO: 197 and SEQ ID NO: 187; SEQ ID NO: 207 and SEQ ID NO: 187; SEQ ID NO: 215 and SEQ ID NO: 187; SEQ ID NO: 233 and SEQ ID NO: 235; SEQ ID NO: 253 and SEQ ID NO: 255; SEQ ID NO: 271 and SEQ ID NO: 273; SEQ ID NO: 283 and SEQ ID NO: 187; SEQ ID NO: 293 and SEQ ID NO: 187; SEQ ID NO: 310 and SEQ ID NO: 312; SEQ ID NO: 330 and SEQ ID NO: 332; SEQ ID NO: 342 and SEQ ID NO: 187; SEQ ID NO: 356 and SEQ ID NO: 358; or SEQ ID NO: 375 and SEQ ID NO: 377.

[0074] The present invention includes polynucleotides encoding immunoglobulin polypeptide chains whose nucleotide sequences are variants of the polynucleotides specifically described herein. A "variant" of a polynucleotide refers to a polynucleotide that contains a nucleotide sequence that is at least about 70-99.9% identical (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%) to a reference nucleotide sequence described herein when the comparison is performed using the BLAST algorithm and the algorithm parameters are selected to maximize matching between each sequence over the entire length of each reference sequence (e.g., expectation threshold: 10; word size: 28; maximum matches within query range: 0; match / mismatch score: 1, -2; gap cost: linear). In embodiments of the invention, variants of the nucleotide sequences specifically described herein comprise one or more (e.g., 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) of one or more nucleotides. Such mutations may be missense or nonsense mutations in embodiments of the invention. In embodiments of the invention, such variant polynucleotides encode immunoglobulin polypeptide chains that can be incorporated into anti-IL2Rγ antigen binding proteins, i.e., such that the protein retains specific binding to IL2Rγ.

[0075] Eukaryotic and prokaryotic host cells, including mammalian cells, can be used as hosts for expressing anti-IL2Rγ antigen-binding proteins (e.g., antibodies or antigen-binding fragments thereof). Such host cells are well known in the art, and many are available from the American Type Culture Collection (ATCC). These host cells include, among others, Chinese hamster ovary (CHO) cells, NSO, SP2 cells, HeLa cells, baby hamster kidney (BHK) cells, monkey kidney cells (COS), 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, cow, horse, and hamster cells. Other cell lines that can be used are insect cell lines (e.g., Spodoptera frugiperda or Trichoplusia ni), amphibian cells, bacterial cells, plant cells and fungal cells. Fungal cells include yeast and filamentous fungal cells, including, for example, Pisum sativum cells. Pichia, Pichia pastoris, Pichia finlandica, Pichia trehalophila, Pichia koclamae, Pichia membranaefaciens, Pichia minuta (Ogataea minuta, Pichia lindneri), Pichia opuntiae, Pichia thermotolerans, Pichia salictaria, Pichia guercuum, Pichia piduperi pijperi), Pichia stiptis, Pichia methanolica methanolica, Pichia spp., Saccharomyces cerevisiae, Saccharomyces spp., Hansenula polymorpha, Kluyveromyces spp., Kluyveromyces lactis, Candida albicans, Aspergillus nidulans, Aspergillus niger niger, Aspergillus oryzae, Trichoderma reesei, Chrysosporium lucknowense, Fusarium spp., Fusarium gramineum, Fusarium venenatum, Physcomitrella patens, and Neurospora crassa. The present invention relates to antigen-binding proteins, their V 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; H4H12924P P2; H4H12926P2; H4H12927P2; H4H12934P2; H4H13538P; H4H13541P; H4H13544P2; or H4H13545P2; and / or an isolated host cell (e.g., a CHO cell or any type of host cell described above) comprising a polynucleotide encoding one or more immunoglobulin chains thereof (e.g., as discussed herein).

[0076] The present invention also provides antigen-binding proteins (e.g., antibodies or antigen-binding fragments thereof) of the invention, such as H4H12857P; H4H12858P; H4H12859P; H4H12863P; H4H12874P; H4H12871P; H4H12884P; H4H12886P; H4H12889P; H4H12890P; H4H12899P; H4H12900P; H4H12908P; H4H12913P2; The invention includes cells expressing IL2Rγ or an antigenic fragment or fusion thereof (e.g., His6, Fc and / or myc) that is bound by H4H12922P2; H4H12924P2; H4H12926P2; H4H12927P2; H4H12934P2; H4H13538P; H4H13541P; H4H13544P2; or H4H13545P2, e.g., the cells are in the subject's body or in vitro.

[0077] Additionally, the present invention also provides an IL2Rγ polypeptide or antigenic fragment thereof or a fusion thereof and / or an anti-IL2Rγ antibody or fragment thereof conjugated to a secondary antibody or antigen-binding fragment thereof (e.g., a detectably labeled secondary antibody) that specifically binds to the IL2Rγ polypeptide or antigenic fragment thereof or a fusion thereof. In some embodiments, the invention provides a complex comprising an anti-IL2Rγ antigen binding protein, e.g., an antibody or antigen-binding fragment thereof, as discussed in the text. In embodiments of the invention, the complex is in vitro (e.g., immobilized on a solid substrate) or in the body of a subject.

[0078] Recombinant anti-IL2Rγ antigen binding proteins, e.g., antibodies and antigen-binding fragments, disclosed herein can also be produced in an E. coli / T7 expression system. In this embodiment, the anti-IL2Rγ antibody immunoglobulin molecules of the invention (e.g., H4H12857P; H4H12858P; H4H12859P; H4H12863P; H4H12874P; H4H12871P; H4H12884P; H4H12886P; H4H12889P; H4H12890P; H4H128 99P;H4H12900P;H4H12908P;H4H12913P2;H4H12922P2;H4H12924P2;H4H12926P2;H4H12927P2;H4H12934P2;H4H13538P;H4H13541P;H4H13544P2;or H4H13545P2 of HC, LC, V H and / or V Lor its CDRs) can be inserted into a pET-based plasmid and expressed in the E. coli / T7 system. For example, the invention provides a method of expressing an antibody or antigen-binding fragment thereof or an immunoglobulin chain thereof in a host cell (e.g., a bacterial host cell, e.g., E. coli such as BL21 or BL21DE3), comprising expressing an antibody or antigen-binding fragment thereof in a host cell by using a polynucleotide encoding an immunoglobulin chain (e.g., 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, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 1 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, 29 3, 295, 297, 299, 301, 303, 305, 307, 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; or a variant thereof.For example, in an embodiment of the invention, a bacterial host cell such as E. coli contains a polynucleotide encoding a T7 RNA polymerase gene operably linked to a lac promoter, and expression of the polymerase and strands is induced by incubation of the host cells with IPTG (isopropyl-beta-D-thiogalactopyranoside). See US 4,952,496 and US 5,693,489 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.

[0079] There are several methods for producing recombinant antibodies known in the art. One example of a method for recombinant production of antibodies is disclosed in US4816567.

[0080] Transformation can be carried out by any known method for introducing polynucleotides into host cells.Methods for introducing heterologous polynucleotides into mammalian cells are well known in the art, including dextran-mediated transfection, calcium phosphate precipitation, polybrene-mediated transfection, protoplast fusion, electroporation, encapsulation of polynucleotides in liposomes, biolistic injection of DNA into the nucleus, and direct microinjection.In addition, nucleic acid molecules can be introduced into mammalian cells by viral vectors.Methods for transforming cells are well known in the art.See, for example, U.S. Patent Nos. 4,399,216; 4,912,040; 4,740,461 and 4,959,455.As such, the present invention provides a recombinant method for making an anti-IL2Rγ antigen binding protein, e.g., an antibody or antigen-binding fragment thereof of the invention, or an immunoglobulin chain thereof, comprising: (i) an antigen binding protein, e.g., H4H12857P; H4H12858P; H4H12859P; H4H12863P; H4H12874P; H4H12871P; H4H12884P; H4H12886P; H4H12889P; H4H12890P; H4H12899P; H4H12900P; H4H12908P; H4H12913P; H4H12922 H4H13544P2; or H4H13545P2 (e.g., SEQ ID NOs: 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, 152, 153, 154, 155, 156, 157, 160, 161, 162, 163, 164, 165, 166, 167, 168, 169, 170, 171, 172, 173, 174, 175, 176, 177, 178, 179, 180, 181, 182, 183, 184, 185, 186, 187, 188, 189, 190, 191, 192, 193, 194, 195, 196, 197, 198, 199, 200, 201, 202, 203, 204, 205, 206, 207, 208, 209, 210, 211, 212, 213, 214, 215, 216, 217, 218, 220, 221, 222, 223 , 153, 155, 163, 169, 171, 173, 181, 185, 187, 189, 197, 199, 207, 209, 215, 217, 225, 233, 235, 237, 245, 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 variants thereof) in a host (ii) introducing the polynucleotide into a cell, e.g., where the polynucleotide is in a vector; and / or integrated into a host cell chromosome and / or operably linked to a promoter; (ii) culturing the host cell (e.g., CHO or Pichia or Pichia pastoris) under conditions favorable for expression of the polynucleotide; and (iii) optionally isolating the antigen binding protein (e.g., antibody or antigen-binding fragment) or chain from the host cell and / or the medium in which the host cell is grown.When producing antigen-binding proteins (e.g., antibodies or antigen-binding fragments) comprising more than one immunoglobulin chain, e.g., antibodies comprising two immunoglobulin heavy chains and two immunoglobulin light chains, coexpression of the chains in a single host cell leads to association of the chains, e.g., within or on the cell surface, or outside the cell if such chains are secreted, to form the antigen-binding protein (e.g., antibody or antigen-binding fragment). Methods of the invention include methods in which only an immunoglobulin heavy chain, only an immunoglobulin light chain, or both (e.g., any of those discussed herein, including mature fragments and / or variable domains thereof) are expressed in a cell. Such single chains are useful, e.g., as intermediates in the expression of antibodies or antigen-binding fragments comprising such chains. For example, the invention also includes anti-IL2Rγ antigen-binding proteins, e.g., antibodies and antigen-binding fragments thereof, that are the products of the production methods described herein and, optionally, the purification methods described herein.

[0081] In embodiments of the invention, methods of making anti-IL2Rγ antigen binding proteins, e.g., antibodies or antigen-binding fragments thereof, include methods of purifying the antigen binding protein, e.g., by column chromatography, precipitation, and / or filtration. As discussed, the products of such methods also form part of the invention.

[0082] Human antibody production The anti-IL2Rγ antibodies of the present invention can be fully human antibodies. Methods for generating monoclonal antibodies, including fully human monoclonal antibodies, are known in the art. Any such known method can be used in the context of the present invention to generate human antibodies that specifically bind to human IL2Rγ.

[0083] For example, when using VELOCIMMUNE™ technology or any other similar known method for generating fully human monoclonal antibodies, high-affinity chimeric antibodies against IL2Rγ having human variable regions and mouse constant regions are first isolated. As described in the experimental section below, the antibodies are characterized and selected for desired characteristics, including affinity, ligand-blocking activity, selectivity, epitope, etc. If necessary, to generate fully human anti-IL2Rγ antibodies, the mouse constant region is replaced with a desired human constant region, such as a wild-type or engineered IgG1 or IgG4. The constant region selected can vary depending on the specific application, but the characteristics of high-affinity antigen binding and target specificity reside in the variable region. In certain cases, fully human anti-IL2Rγ antibodies are isolated directly from antigen-positive B cells. See, e.g., US 6,596,541, Regeneron Pharmaceuticals, VELOCIMMUNE®.

[0084] Anti-IL2Rγ antibodies containing Fc variants According to certain embodiments of the present invention, there are provided anti-IL2Rγ antibodies comprising an Fc domain containing one or more mutations that enhance or decrease antibody binding to the FcRn receptor, e.g., at acidic pH compared to neutral pH. For example, the present invention provides an anti-IL2Rγ antibody comprising an Fc domain containing one or more mutations that enhance or decrease antibody binding to the FcRn receptor at acidic pH compared to neutral pH. H 2 or C H Anti-IL2Rγ antibodies containing mutations in the 3 region that increase the affinity of the Fc domain for FcRn in acidic environments (e.g., in endosomes where the pH is between about 5.5 and about 6.0). Such mutations can result in an increase in the serum half-life of the antibody when administered to an animal.

[0085] Non-limiting examples of such Fc modifications include, for example, modifications to the positions: 250 (for example, E or Q); 250 and 428 (e.g., L or F); 252 (e.g., L / Y / F / W or T), 254 (e.g., S or T), and / or 256 (e.g., S / R / Q / E / D or T) Modifications in; and / or location: 428 and / or 433 (e.g., H / L / R / S / P / Q or K), and / or 434 (e.g., H / F or Y) Modifications in; and / or location: 250 and / or 428 Modifications in; and / or location: 307 or 308 (e.g., 308F, V308F), and / or 434 Changes in Examples include:

[0086] In an embodiment of the invention, the modification is: · 428L (e.g., M428L) and 434S (e.g., N434S) modifications; · 428L, 259I (e.g., V259I), and 308F (e.g., V308F) modifications; · 433K (e.g., H433K) and 434 (e.g., 434Y) modifications; · Modifications of 252, 254, and 256 (e.g., 252Y, 254T, and 256E); Modifications of 250Q and 428L (e.g., T250Q and M428L); and / or Modifications of 307 and / or 308 (e.g., 308F or 308P) Includes:

[0087] For example, the present invention: 250Q and 248L (e.g., T250Q and M248L); 252Y, 254T and 256E (for example, M252Y, S254T and T256E); 428L and 434S (e.g., M428L and N434S); and 433K and 434F (e.g., H433K and N434F) and (iii) an anti-IL2Rγ antibody comprising an Fc domain comprising one or more pairs or groups of mutations selected from the group consisting of:

[0088] In an embodiment of the invention, the heavy chain constant domain is γ4 containing an S228P and / or S108P mutation. of chimeric mouse / human (IgG4)antibody” , Mol Immunol. 1993 Jan;30(1):105-108.

[0089] All possible combinations of the above Fc domain mutations, and other mutations in the antibody variable domains disclosed herein, are contemplated within the scope of the present invention.

[0090] Anti-IL2Rγ antibodies of the invention may comprise an altered Fc domain with reduced effector function. As used herein, an "altered Fc domain with reduced effector function" refers to any Fc portion of an immunoglobulin that has been altered, mutated, truncated, etc., relative to a wild-type, naturally occurring Fc domain such that the molecule comprising the altered Fc exhibits a reduction in the severity or extent of at least one effect selected from the group consisting of cell killing (e.g., ADCC and / or CDC), complement activation, phagocytosis, and opsonization, relative to a comparison molecule comprising a wild-type, naturally occurring version of the Fc portion. In certain embodiments, an "altered Fc domain with reduced effector function" is an Fc domain with reduced or attenuated binding to an Fc receptor (e.g., FcγR).

[0091] In certain embodiments of the present invention, the modified Fc domain is a variant IgG1 Fc or variant IgG4 Fc comprising a substitution in the hinge region. For example, a modified Fc for use in the context of the present invention may comprise a variant IgG1 Fc in which at least one amino acid in the IgG1 Fc hinge region is replaced with the corresponding amino acid from an IgG2 Fc hinge region. Alternatively, a modified Fc for use in the context of the present invention may comprise a variant IgG4 Fc in which at least one amino acid in the IgG4 Fc hinge region is replaced with the corresponding amino acid from an IgG2 Fc hinge region. Non-limiting exemplary modified Fc regions that can be used in the context of the present invention include those described in U.S. Patent Application Publication No. 2014 / 0243504, the disclosure of which is incorporated herein by reference in its entirety, as well as the modified Fc regions described therein. and any functionally equivalent variant of the Fc region.

[0092] Other modified Fc domains and Fc modifications that can be used in the context of the present invention include any modifications as described in US2014 / 0171623; US8697396; US2014 / 0134162; WO2014 / 043361, the disclosures of which are incorporated herein by reference in their entireties. Methods for constructing antibodies or other antigen-binding fusion proteins comprising modified Fc domains as described herein are known in the art.

[0093] Multispecific antigen-binding proteins The present invention includes anti-IL2Rγ antigen binding proteins, e.g., antibodies and antigen-binding fragments thereof, as well as methods of their use and methods of making such antigen binding proteins. The term "anti-IL2Rγ" or "anti-IL2R gamma" antigen binding protein, e.g., antibody or antigen-binding fragment, refers to a protein that specifically binds to IL2Rγ and contains at least one first antigen-binding domain (e.g., H4H12857P; H4H12858P; H4H12859P; H4H12863P; H4H12874P; H4H12871P; H4H12884P; H4H12886P; H4H12889P; H4H12890P; H4H12899P; H4H12900P; H4H12908P; and multispecific (e.g., bispecific or biparatopic) molecules comprising an antigen-binding domain from one of: H4H12913P2; H4H12922P2; H4H12924P2; H4H12926P2; H4H12927P2; H4H12934P2; H4H13538P; H4H13541P; H4H13544P2; or H4H13545P2) and at least one second antigen-binding domain that binds to a different antigen or a different epitope in IL2Rγ than 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.

[0094] Multispecific binding refers to binding to two or more different epitopes, which may be on the same or different antigens. Multispecificity includes bispecific, trispecific, and tetraspecific.

[0095] "H4H12857P"; "H4H12858P"; "H4H12859P"; "H4H12863P"; "H4H12874P"; "H4H12871P"; "H 4H12884P”; “H4H12886P”; “H4H12889P”; “H4H12890P”; “H4H12899P”; “H4H12900P”; “H4H 12908P";"H4H12913P2";"H4H12922P2";"H4H12924P2";"H4H12926P2";"H4H12927P2";"H4H12934P2";"H4H13538P";"H4H13541P";"H4H13544P2";or"H4H13545P2" are respectively "H4H 12857P"; "H4H12858P"; "H4H12859P"; "H4H12863P"; "H4H12874P"; "H4H12871P"; "H4H12 884P";"H4H12886P";"H4H12889P";"H4H12890P";"H4H12899P";"H4H12900P";"H4H1290 8P";"H4H12913P2";"H4H12922P2";"H4H12924P2";"H4H12926P2";"H4H12927P2";"H4H12934P2";"H4H13538P";"H4H13541P";"H4H13544P2";or"H4H13545P2" HCDR and LCDR, V H and V L or a multispecific molecule, such as an antibody or antigen-binding fragment, comprising an HC and an LC, and one or more antigen-binding domains that bind to different epitopes.

[0096] In an embodiment of the invention, an antigen-binding domain that specifically binds to IL2Rγ that can be comprised in a multispecific molecule is: (1) (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 a variant thereof); H) array, and (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 a variant thereof); L )array; or (2) (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 a variant thereof); H ); and (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 a variant thereof); L ); and One or more antigen-binding domains that bind to different epitopes Includes:

[0097] In one embodiment of the invention, the bispecific antigen-binding fragment comprises a first scFv (e.g., H4H12857P; H4H12858P; H4H12859P; H4H12863P; H4H12874P; H4H12871P; H4H12884P; H4H12886P; H4H12887P) that has binding specificity for a first epitope (e.g., IL2Rγ). 889P;H4H12890P;H4H12899P;H4H12900P;H4H12908P;H4H12913P2;H4H12922P2;H4H12924P2;H4H12926P2;H4H12927P2;H4H12934P2;H4H13538P;H4H13541P;H4H13544P2;or H4H13545P2 V H and V Land a second scFv having binding specificity for a second, different epitope. For example, in embodiments of the invention, the first and second scFvs may be linked via a linker, e.g., a peptide linker (e.g., a GS linker, e.g., (GGGGS) n (SEQ ID NO: 386) (where n is, for example, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10).

[0098] Other bispecific antigen-binding fragments include H4H12857P; H4H12858P; H4H12859P; H4H12863P; H4H12874P; H4H12871P; H4H12884P; H4H12886P; H4H12889P; H4H12890P; H4H12899P; H4H12900P; H4H12908P; H4H12913P2 or H4H13545P2 and a F(ab)2 of a bispecific IgG antibody comprising the heavy and light chain CDRs of another antibody that binds to a different epitope.

[0099] Immunoconjugates The present invention encompasses anti-IL2Rγ antigen binding proteins, e.g., antibodies or antigen-binding fragments, conjugated to another moiety, e.g., a therapeutic moiety (an "immunoconjugate"). In embodiments of the invention, the anti-IL2Rγ antigen binding protein, e.g., antibody or antigen-binding fragment, is As used herein, the term "immunoconjugate" refers to an antigen-binding protein, e.g., an antibody or antigen-binding fragment, chemically or biologically linked to another antigen-binding protein, a drug, a radioactive agent, a reporter moiety, an enzyme, a peptide, a protein, or a therapeutic agent.

[0100] Administration and Treatment The present invention provides a method of treating or preventing an IL2Rγ-mediated disease or condition in a subject, comprising administering a therapeutically effective dose of an anti-IL2Rg antigen binding protein (H4H12857P; H4H12858P; H4H12859P; H4H12863P; H4H12874P; H4H12871P; H4H12884P; H4H12886P; H4H12889P; H4H12890 P; H4H12899P; H4H12900P; H4H12908P; H4H12913P2; H4H12922P2; H4H12924P2; H4H12926P2; H4H12927P2; H4H12934P2; H4H13538P; H4H13541P; H4H13544P2; or H4H13545P2) to a subject.

[0101] An "IL2Rγ-mediated disease or condition" is any disease state whose symptoms are mediated by the activity of one or more of the cytokines IL-2, IL-4, IL-7, IL-9, IL-15, and IL-21 and / or the receptors that bind such cytokines; for example, autoimmunity and / or inflammation mediated by such cytokines and / or receptors. For example, IL2Rγ-mediated diseases or conditions include graft-versus-host disease (GvHD), organ transplant rejection (e.g., skin grafts (skin grafts), b-pancreatic islet cell grafts, heart transplants, lung transplants, kidney transplants, and / or liver transplants), shotgun chorioretinopathy, multiple sclerosis, uveitis, autoimmune diseases (e.g., type 1 diabetes, 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)).

[0102] The present invention also provides antigen binding proteins (e.g., antibodies or antigen-binding fragments thereof) that specifically bind to IL2Rγ, such as H4H12857P; H4H12858P; H4H12859P; H4H12863P; H4H12874P; H4H12871P; H4H12884P; H4H12886P; H4H12889P; H4H12890P; H4H12899P; H4H12900P; H4H12908P; H4H H4H12913P2; H4H12922P2; H4H12924P2; H4H12926P2; H4H12927P2; H4H12934P2; H4H13538P; H4H13541P; H4H13544P2; or H4H13545P2 to a subject, e.g., having an IL2Rγ-mediated disease or condition, comprising introducing the antigen binding protein into the subject's body, e.g., by injection.

[0103] GvHD is a condition that can occur after allogeneic transplantation. For example, in GvHD, donated bone marrow or peripheral blood stem cells may view the recipient's body as foreign, and the donated cells / bone marrow attack the body. GvHD can occur, for example, after hematopoietic cell transplantation (HCT; e.g., in subjects with acute myeloid leukemia (AML) or acute lymphocytic leukemia (ALL) and / or myelodysplastic syndrome or myeloproliferative neoplasm), blood transfusion, thymus transplant, 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 or both forms of aGvHD or cGvHD, or neither. The present invention provides a method for treating or preventing GvHD (of any type) in a subject. and a method for treating IL2Rγ comprising administering to a subject a therapeutically effective dose of an anti-IL2Rγ antigen binding protein.

[0104] Symptoms of aGvHD may include skin rash or reddened areas on the skin (signs of cutaneous aGvHD); yellowing of the skin and / or eyes and abnormal blood test results (signs of liver aGvHD); nausea, vomiting, diarrhea, or abdominal cramps (signs of gastrointestinal, or "gut," aGvHD); and / or increased dryness / irritation of the eyes (signs of ocular GvHD).

[0105] Symptoms of cGvHD may include rash, raised, or discolored areas, thickened or hardened skin (signs of skin cGvHD); abdominal swelling, yellowing of the skin and / or eyes, and abnormal blood test results (signs of liver cGvHD); dry eyes or visual changes (signs of eye cGvHD); dry mouth, white patches in the mouth, pain or sensitivity to spicy foods (signs of mouth, oral cGvHD); shortness of breath or changes seen on a chest x-ray (signs of lung, dry cough, pulmonary cGvHD); difficulty swallowing, pain with swallowing, or weight loss (signs of gastrointestinal or "gut" cGvHD); fatigue, muscle weakness, or pain (signs of nerve and muscle, neuromuscular cGvHD); and / or increased need to urinate (urination frequency), burning or bleeding with urination, vaginal dryness / hardness, or penile dysfunction (signs of genitourinary system, bladder, or reproductive organ cGvHD).

[0106] Organ transplant rejection is the rejection of a transplanted organ by the recipient's immune system. Hyperacute rejection occurs within minutes of transplantation, acute rejection occurs within one week to three months after transplantation, and chronic rejection occurs over many years. Transplanted organs include, for example, solid organs such as skin, pancreas, kidney, liver, heart, and lung. The present invention includes a method for treating or preventing organ transplant rejection (of any type) in a subject, comprising administering to the subject a therapeutically effective dose of an anti-IL2Rγ antigen-binding protein.

[0107] Shotgun chorioretinopathy is a rare form of posterior uveitis, i.e., inflammation of the uvea, the part of the eye that provides the retina with most of its blood supply. Shotgun chorioretinopathy can be caused by autoimmunity. Symptoms of shotgun chorioretinopathy can include night blindness, problems with color vision, sensitivity to bright light, seeing flashing lights, distortions in vision, pain in the eye, and loss of depth perception and / or peripheral vision. The present invention includes methods for treating or preventing shotgun chorioretinopathy or uveitis in a subject, comprising administering to the subject a therapeutically effective dose of an anti-IL2Rγ antigen-binding protein, for example, by intraocular administration, e.g., intravitreal injection.

[0108] The present invention also provides a method for treating or preventing any autoimmune disease or condition by inhibiting IL2Rγ. Blocking the signaling of one or more cytokines in the γc family can be beneficial in patients suffering from autoimmunity due to the inhibitory effect 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 the myelin sheath of nerve fibers, causing communication problems between the brain and other parts of the body. Ultimately, the disease can cause deterioration or permanent damage to the nerves themselves. Rheumatoid arthritis (RA) is an autoimmune disease in which the body's immune system attacks joints. This causes thickening of the tissue lining the joints (synovium), generating inflammation that results in swelling and pain in and around the joints. Psoriasis is an autoimmune disease with primary symptoms affecting the skin. Inflammation can also affect the joints, vasculature, and eyes of people with psoriasis. Type 1 diabetes is an autoimmune disease in which the immune system attacks and destroys insulin-producing beta cells in the pancreas. The pancreas then produces little or no insulin. Systemic lupus erythematosus (SLE) is a condition in which the body's immune system attacks its own tissues and organs. Lupus is a systemic autoimmune disease that occurs when inflammation occurs in the nervous system. Inflammation caused by lupus can affect many different body systems, including joints, skin, kidneys, blood cells, brain, heart, and lungs. Myasthenia gravis is an autoimmune disease in which antibodies block acetylcholine receptors at the neuromuscular junction, preventing muscle contraction. In most individuals with myasthenia gravis, it is caused by antibodies against the acetylcholine receptor itself. However, antibodies against other proteins, such as MuSK (muscle-specific kinase) protein, can also lead to impaired transmission at the neuromuscular junction. The present invention includes methods for treating or preventing an autoimmune disorder or condition in a subject (e.g., multiple sclerosis or any other central nervous system inflammation, rheumatoid arthritis, psoriasis, type 1 diabetes, systemic lupus erythematosus, and / or myasthenia gravis), comprising administering to the subject a therapeutically effective dose of an anti-IL2Rγ antigen-binding protein.

[0109] An effective or therapeutically effective dose of an anti-IL2Rg antigen-binding protein, e.g., an antibody or antigen-binding fragment, for treating or preventing an IL2Rγ-mediated disease or condition refers to the amount of antigen-binding protein sufficient to alleviate one or more signs and / or symptoms of the disease or condition in the treated subject, whether by inducing regression or elimination of such signs and / or symptoms or by inhibiting the progression of such signs and / or symptoms. In an embodiment of the invention, an effective or therapeutically effective dose of anti-IL2Rg antigen-binding protein is approximately 0.05-50 mg per kg of body weight. The dose may vary depending on the age and size of the subject, the target disease or condition, the route of administration, and the like. In certain embodiments, the initial dose can be followed by administration of a second or multiple subsequent doses of the antigen binding protein in an amount that can be about the same as, less than, or more than the initial dose, with the subsequent doses being at least 1 day to 3 days apart; 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 apart.

[0110] As used herein, the term "subject" refers to a mammal (e.g., rat, mouse, cat, dog, cow, sheep, horse, goat, rabbit), preferably a human, in need of prevention and / or treatment of, for example, an IL2Rγ-mediated disease. The subject may have an IL2Rγ-mediated disease or may be predisposed to developing such a disease.

[0111] "Preventing" an IL2Rγ-mediated disease or condition, in relation to the use of anti-IL2Rγ antigen binding proteins of the invention, refers to administration to a subject prior to the appearance of the disease or condition in the subject's body so as to prevent such appearance.

[0112] Combinations and Pharmaceutical Formulations The present invention provides compositions comprising anti-IL2Rγ antigen binding proteins together with one or more other ingredients, as well as methods of using and making such compositions. Pharmaceutical formulations comprising anti-IL2Rγ antigen binding proteins and a pharmaceutically acceptable carrier or excipient are part of the invention.

[0113] Anti-IL2Rγ antigen binding proteins, e.g., antibodies and antigen-binding fragments thereof (e.g., H4H12857P; H4H12858P; H4H12859P; H4H12863P; H4H12874P; H4H12871P; H4H12884P; H4H12886P; H4H12889P; H4H12890P; H4H12899P; H4H12900P; H

[0049] To prepare a pharmaceutical formulation of the antigen binding protein of the present invention, the antigen binding protein may be administered in a pharmaceutically acceptable carrier or excipient. and mixed with an excipient. See, e.g., Remington's Pharmaceutical Sciences and US Pharmacopeia: National Formulary, Mack Publishing Company, Easton, Pa. (1984); Hardman et al. (2001) Goodman and Gil man's The Pharmacological Basis of Therapeutics, McGraw-Hill, New York, NY; Gennaro (2000) Remington: The Science and Practic e of Pharmacy, Lippincott, Williams, and Wilkins, New York, NY; Avis et al. (eds.) (1993) Pharma Ceutical Dosage Forms: Parenteral Medications, Marcel Dekker, NY; Lieberman et al. (eds.) (1990) Pharmaceutical Dosage Forms: Tablets, Mar cel Dekker, NY; Lieberman et al. (eds.) (1990) Pharmac eutical Dosage Forms: Disperse Systems, Marcel Dekker, NY; Weiner and Kotkoskie (2000) See Excipient Toxicity and Safety, Marcel Dekker, Inc., New York, NY. In an embodiment of the invention, the pharmaceutical formulation is sterile. Such compositions are part of the present invention.

[0114] Pharmaceutical formulations of the invention comprise an anti-IL2Rγ antigen binding protein and a pharmaceutically acceptable carrier comprising, for example, water, a buffering agent, a preservative and / or a surfactant.

[0115] The scope of the present invention includes 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;H4H13544P2;or H4H13545P2), or a pharmaceutical formulation thereof comprising a pharmaceutically acceptable carrier but substantially devoid of water.

[0116] In further embodiments of the invention, the presently disclosed 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; H4H13544P2; or H4H13545P2) may be administered to a subject in accordance with the Physicians' Desk Reference 2003 (Thomson Healthcare;57 th The test is administered to the subject according to the following standard:

[0117] The mode of administration of an anti-IL2Rγ antigen binding protein or composition thereof can be varied, including parenteral, non-parenteral, oral, rectal, transmucosal, intestinal, intramuscular, subcutaneous, intradermal, intramedullary, intrathecal, direct intraventricular, intravenous, intraperitoneal, intranasal, intraocular, inhalation, insufflation, topical, dermal, intraocular, intravitreal, transdermal, or intra-arterial.

[0118] The present invention provides anti-IL2Rγ antigen binding proteins, e.g., antibodies or antigen-binding fragments thereof (e.g., For example, H4H12857P;H4H12858P;H4H12859P;H4H12863P;H4H12874P;H4H12871P;H4H12884P;H4H12886P;H4H12889P;H4H12890P;H4H12899P;H4H12900P;H4H12908P;H4H12913P;H4H1 2922P2; H4H12924P2; H4H12926P2; H4H12927P2; H4H12934P2; H4H13538P; H4H13541P; H4H13544P2; or H4H13545P2) to a subject, comprising introducing the protein or pharmaceutical formulation thereof into the subject's body. For example, in embodiments of the invention, the method comprises inserting, e.g., a needle from a syringe, into the subject's body and injecting the antigen-binding protein or pharmaceutical formulation thereof into the subject's body, e.g., into the subject's eye, vein, artery, muscle tissue, or subcutaneous tissue.

[0119] The present invention provides 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;H4H13544P2;orH4H13545P2), or a pharmaceutical formulation thereof comprising a pharmaceutically acceptable carrier, is provided.

[0120] The present invention provides a method for treating IL2Rγ disease by administering to a patient an anti-IL2Rγ antigen binding protein of the invention, e.g., an antibody or antigen-binding fragment thereof (e.g., H4H12857P; H4H12858P; H4H12859P; H4H12863P; H4H12874P; H4H12871P; H4H12884P; H4H12886P; H4H12889P; H4H12890P), in combination with one or more additional therapeutic agents. H4H12890P; H4H12899P; H4H12900P; H4H12908P; H4H12913P2; H4H12922P2; H4H12924P2; H4H12926P2; H4H12927P2; H4H12934P2; H4H13538P; H4H13541P; H4H13544P2; or H4H13545P2). The anti-IL2Rγ antigen binding protein and the additional therapeutic agent can be in a single composition or in separate compositions. For example, in embodiments of the invention, the additional therapeutic agent is an immunosuppressant. In embodiments of the invention, the additional therapeutic agent is an anti-TNFα antibody or binding protein (e.g., infliximab, adalimumab, etanercept, or golimumab), tacrolimus, cyclosporine, corticoids, prednisolone, methylprednisolone, antithymocyte globulin, alemtuzumab, daclizumab, extracorporeal photopheresis, mycophenolate mofetil, sirolimus, pentostatin, mesenchymal stem cells, inolimomab, denileukin, a multispecific (e.g., bispecific) antibody or antigen-binding fragment thereof that binds to BCMA (B-cell maturation antigen) and CD3, and / or basiliximab.

[0121] Anti-IL2Rγ antigen binding proteins together with an additional therapeutic agent, e.g., H4H12857P; H4H12858P; H4H12859P; H4H12863P; H4H12874P; H4H12871P; H4H12884P; H4H12886P; H4H12889P; H4H12890P; H4H12899P; H4H12900P; H4H12908P or H4H13545P2 to treat or prevent an IL2Rγ-mediated disease in a subject in need thereof by administering;H4H12913P2;H4H12922P2;H4H12924P2;H4H12926P2;H4H12927P2;H4H12934P2;H4H13538P;H4H13541P;H4H13544P2; or H4H13545P2. Methods for treating or preventing sexual disorders are part of the present invention.

[0122] The term "together with" indicates that a component of the invention, an anti-IL2Rγ antigen-binding protein, e.g., an antibody or antigen-binding fragment thereof, along with another agent, such as methotrexate, can be formulated in a single composition, e.g., for simultaneous delivery, or can be formulated separately in two or more compositions (e.g., a kit comprising each component). Components administered together with each other can be administered to a subject at a time different from the time at which the other component is administered; for example, each administration can be given non-concurrently (e.g., separately or sequentially), spaced over a given period of time. Separate components administered together with each other can also be administered sequentially but essentially simultaneously during the same administration session. Furthermore, separate components administered together with each other can be administered to a subject by the same or different routes. [Example]

[0123] The following examples are put forth so as to provide those of ordinary skill in the art with a complete disclosure and description of how to make and use the methods and compositions of the present invention, and are not intended to limit the scope of what the inventors regard as their invention.

[0124] Example 1 : Identification and isolation of anti-IL2Rγ antibodies Anti-IL2Rγ antibodies were obtained by immunizing VELOCIMMUNE® mice (i.e., engineered mice containing DNA encoding human immunoglobulin heavy chain and kappa light chain variable regions) with an IL2Rγ protein immunogen containing the extracellular sequence (ectodomain) of IL2Rγ.

[0125] In particular, the immunogen, human IL2Rg ecto-mmh, has the amino acid sequence: [ka] Including, Amino acids (1-240): human IL2Rg ecto (L23-A262 of NP_000197.1), and Amino acids (241-268): Myc-Myc-hexahistidine tag (underlined) It included:

[0126] Antibody immune responses were monitored by an IL2Rγ-specific immunoassay. Fully human anti-IL2Rγ antibodies were isolated and purified.

[0127] [Table 4]

[0128] [Table 5]

[0129] The amino acid sequences of the anti-IL2Rγ antibody immunoglobulin heavy and light chains are set forth below (CDRs are underlined; variable regions are in bold font):

[0130] H4H12857P Heavy chain (SEQ ID NO: 311) [ka]

[0131] Light chain (SEQ ID NO: 313)

change

[0132] H4H12858P Heavy chain (SEQ ID NO: 331)

change

[0133] Light chain (SEQ ID NO: 333)

change

[0134] H4H12859P Heavy chain (SEQ ID NO: 18)

change

[0135] Light chain (SEQ ID NO: 20)

change

[0136] H4H12863P Heavy chain (SEQ ID NO: 38)

change

[0137] Light chain (SEQ ID NO: 40)

change

[0138] H4H12874P Heavy chain (SEQ ID NO: 58)

change

[0139] Light chain (SEQ ID NO: 60)

change

[0140] H4H12871P Heavy chain (SEQ ID NO: 376)

change

[0141] Light chain (SEQ ID NO: 378)

change

[0142] H4H12884P Heavy chain (SEQ ID NO: 77)

change

[0143] Light chain (SEQ ID NO: 79)

change

[0144] H4H12886P Heavy chain (SEQ ID NO: 97)

change

[0145] Light chain (SEQ ID NO: 99)

change

[0146] H4H12889P Heavy chain (SEQ ID NO: 357)

change

[0147] Light chain (SEQ ID NO: 359)

change

[0148] H4H12890P Heavy chain (SEQ ID NO: 115)

change

[0149] Light chain (SEQ ID NO: 117)

change

[0150] H4H12899P Heavy chain (SEQ ID NO: 134)

change

[0151] Light chain (SEQ ID NO: 136)

change

[0152] H4H12900P Heavy chain (SEQ ID NO: 152)

change

[0153] Light chain (SEQ ID NO: 154)

change

[0154] H4H12908P Heavy chain (SEQ ID NO: 170)

change

[0155] Light chain (SEQ ID NO: 172)

change

[0156] H4H12913P2 Heavy chain (SEQ ID NO: 186)

change

[0157] Light chain (SEQ ID NO: 188)

change

[0158] H4H12922P2 Heavy chain (SEQ ID NO: 343)

change

[0159] Light chain (SEQ ID NO: 188)

change

[0160] H4H12924P2 Heavy chain (SEQ ID NO: 198)

change

[0161] Light chain (SEQ ID NO: 188)

change

[0162] H4H12926P2 Heavy chain (SEQ ID NO: 208)

change

[0163] Light chain (SEQ ID NO: 188)

change

[0164] H4H12927P2 Heavy chain (SEQ ID NO: 216)

change

[0165] Light chain (SEQ ID NO: 188)

change

[0166] H4H12934P2 Heavy chain (SEQ ID NO: 234)

change

[0167] Light chain (SEQ ID NO: 236)

change

[0168] H4H13538P Heavy chain (SEQ ID NO: 254)

change

[0169] Light chain (SEQ ID NO: 256) [ka]

[0170] H4H13541P Heavy chain (SEQ ID NO: 272) [ka]

[0171] Light chain (SEQ ID NO: 274) [ka]

[0172] H4H13544P2 Heavy chain (SEQ ID NO: 284) [ka]

[0173] Light chain (SEQ ID NO: 188) [ka]

[0174] H4H13545P2 Heavy chain (SEQ ID NO: 294) [ka]

[0175] Light chain (SEQ ID NO: 188) [ka] *The antibodies referred to in these examples are those having immunoglobulin chains with amino acid sequences as specifically set out in Example 1.

[0176] Example 2 : Surface plasmon resonance binding assay The dissociation rate constant (k) for the binding of IL-2Rγ reagents to purified anti-IL2Rγ monoclonal antibodies was determined using a real-time surface plasmon resonance-based Biacore 4000 biosensor platform. d ) was determined. All binding studies were performed at 25°C and 37°C using two running 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). A CM5 Biacore sensor surface derivatized by amine coupling with a monoclonal mouse anti-human Fc antibody (GE, catalog #BR-1008-39) was used to capture anti-IL2Rγ monoclonal antibodies expressed with human IgG4 Fc. All IL2Rγ reagents contain a C-terminal myc-myc-hexyl group. The IL-2Rg-MMH extracellular domain was expressed with a C-terminal myc-myc-hexahistidine tag (hereafter referred to with the suffix -MMH). Different concentrations of human IL-2Rg-MMH extracellular domain (hIL-2Rg-MMH; SEQ ID NO: 379) or cynomolgus monkey IL-2Rg-MMH extracellular domain (mfIL-2Rg-MMH; SEQ ID NO: 380) expressed with a C-terminal myc-myc-hexahistidine tag were prepared in PBS-T pH 7.4 running buffer (100 nM to 11.11 nM; 3-fold serial dilutions) and injected for 4 min at a flow rate of 30 μL / min. Dissociation of bound IL-2Rg-MMH was performed for 6 min in PBS-T pH 7.4 or PBS-T pH 6.0 running buffer.

[0177] The dissociation rate constants (k) in the two running buffers were determined by fitting the real-time binding sensorgrams to a 1:1 binding model using Scrubber 2.0c curve-fitting software. d The dissociation rate values ​​for the binding of anti-hemojuvelin mAb to hIL-2RG-MMH and mfIL-2RG-MMH in PBS-T-pH 7.4 and PBS-T-pH 6.0 at 25°C and 37°C are shown in Tables 2-1 to 2-8.

[0178] [Table 6]

[0179] [Table 7]

[0180] [Table 8]

[0181] [Table 9]

[0182] [Table 10]

[0183] [Table 11]

[0184] [Table 12]

[0185] [Table 13]

[0186] Example 3 :Binding kinetics A Biacore 4000 instrument equipped with a real-time surface plasmon resonance biosensor was used to determine the equilibrium dissociation constant (K) for the binding of IL-2Rγ to purified anti-IL2Rγ monoclonal antibodies. D The binding activity (p < 0.05) was determined. All binding studies were performed at 25°C and 37°C in a running buffer of 10 mM HEPES, 150 mM NaCl, 3 mM EDTA, and 0.05% v / v Surfactant Tween-20, pH 7.4 (HBS-ET). The Biacore sensor surface was first derivatized by amine coupling with a monoclonal mouse anti-human Fc antibody (GE, #BR-1008-39) to capture the anti-IL2Rγ monoclonal antibody.

[0187] Binding studies were performed against the following IL-2Rγ reagents:

[0188] Amino acid sequence: [ka] Including, Amino acids (1-240): Human IL2Rg ecto (L23-A262 of NP_000197.1) Amino acids (241-268): Myc-Myc-hexahistidine tag (underlined) Human IL2Rγ extracellular domain expressed with a C-terminal myc-myc-hexahistidine tag (hIL-2Rg-MMH; SEQ ID NO: 379)

[0189] Amino acid sequence: [ka] Including, Amino acids (1-240): Cynomolgus monkey IL2Rg ecto (L23-A262 of XP_005593949.1) Amino acids (241-268): Myc-Myc-hexahistidine tag (underlined) Cynomolgus monkey IL2Rγ extracellular domain expressed with a C-terminal myc-myc-hexahistidine tag (mfIL-2Rg-MMH; SEQ ID NO: 380)

[0190] Amino acid sequence: [ka] Including, Amino acids (1-240): Human IL2Rg ecto (L23-A262 of NP_000197.1) Amino acids (241-473): Mouse IgG2a Fc tag (underlined) Human IL2Rγ extracellular domain expressed with a C-terminal mouse IgG2a Fc tag containing In (hIL-2Rg-mFc; SEQ ID NO: 381)

[0191] Amino acid sequence: [ka] Including, Amino acids (1-131): Human IL2Rg domain 1 (L23-I153 of NP_000197.1) Amino acids (132-159): Myc-Myc-hexahistidine tag (underlined) the D1 domain of the human IL-2R gamma extracellular domain expressed with a C-terminal myc-myc-hexahistidine tag (hIL-2Rg_D1-MMH; SEQ ID NO: 382),

[0192] Amino acid sequence: [ka] Including, Amino acids (1-88): Human IL2Rg domain 2 (P154-S241 of NP_000197.1) Amino acids (89-116): Myc-Myc-hexahistidine tag (underlined) the D2 domain of the human IL2Rγ extracellular domain expressed with a C-terminal myc-myc-hexahistidine tag (hIL-2Rg_D2-MMH; SEQ ID NO: 383),

[0193] Amino acid sequence: [ka] Including, Amino acids (1-241): Mouse IL2Rg ecto (W23-A263 of NP_038591.1) Amino acids (242-269): Myc-Myc-hexahistidine tag (underlined) Mouse IL2Rγ extracellular domain expressed with a C-terminal myc-myc-hexahistidine tag (mIL-2Rg-MMH; SEQ ID NO: 384)

[0194] Amino acid sequence: [ka] Including, Amino acids (1-240): Rat IL2Rg ecto (W23-A262 of NP_543165.1) Amino acids (241-268): Myc-Myc-hexahistidine tag (underlined) Rat IL2Rγ extracellular domain expressed with a C-terminal myc-myc-hexahistidine tag (rIL-2Rg-MMH; SEQ ID NO: 385)

[0195] Different concentrations of IL2Rγ reagent were prepared in HBS-ET running buffer (100 nM to 6.25 nM; 4-fold serial dilutions or 50 nM to 3.125 nM; 4-fold serial dilutions for hIL-2Rg-mFc) and injected over the anti-human Fc-captured anti-IL2Rγ monoclonal antibody surface at a flow rate of 30 μL / min for 4 min. Dissociation of the monoclonal antibody-bound IL2Rγ reagent was monitored for 8–10 min in HBS-ET running buffer. Kinetic association (k) was calculated by fitting the real-time sensorgram to a 1:1 binding model using Scrubber 2.0c curve-fitting software. a ) and dissociation (k d The binding-dissociation equilibrium constant (K D ) and dissociation half-life (t1 / 2)

number

[0196] 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.

[0197] [Table 14]

[0198] [Table 15]

[0199] [Table 16]

[0200] [Table 17]

[0201] [Table 18]

[0202] [Table 19]

[0203] [Table 20]

[0204] [Table 21]

[0205] [Table 22]

[0206] [Table 23]

[0207] [Table 24]

[0208] [Table 25]

[0209] [Table 26]

[0210] [Table 27]

[0211] Example 4 Octet cross-competition between different anti-IL-2Rγ monoclonal antibodies A real-time label-free biolayer interferometry assay was used on an Octet HTX biosensor platform (Pall ForteBio Corp.) to determine binding competition between a series of anti-IL2Rγ monoclonal antibodies. 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 shaker speed of 1000 rpm. The two antibodies bound their respective IL2Rγ extracellular domains (hIL-2Rg-MMH; SEQ ID NO: 379) expressed with a C-terminal myc-myc-hexahistidine tag. To assess whether the antibodies compete with each other for binding to the epitope, an anti-pentaHis antibody-coated Octet biosensor chip (Fortebio Inc, #18-5122) was used to capture approximately 0.27 nM of hIL-2Rg-MMH by immersing the biosensor chip in a well containing 10 μg / mL hIL-2Rg-MMH for 3 minutes. The biosensor chip with the captured antigen was then saturated with a first anti-IL2Rγ monoclonal antibody (hereafter referred to as mAb-1) by immersing it in a well containing 50 μg / mL mAb-1 for 300 seconds. The biosensor chip was then immersed in a well containing 50 μg / mL of a second anti-IL2Rγ monoclonal antibody (hereafter referred to as mAb-2) for 240 seconds. Between each step of the experiment, the biosensor chip was washed in HBS-ETB buffer. Real-time binding responses were monitored throughout the course of the experiment, and binding responses were recorded at the end of each step. The binding response of mAb-2 to hIL-2Rg-MMH pre-complexed with mAb-1 was compared to determine the competitive / non-competitive behavior of different anti-IL2Rγ monoclonal antibodies, as shown in Table 4-1.

[0212] [Table 28] [Table 29] [Table 30]

[0213] Example 5 : Flow cytometric analysis of STAT phosphorylation in human CD4+ T cells (human PBMCs) To evaluate the in vitro characteristics of the IL2Rγ antibodies of the present invention, CD4 T cells induced by IL-2, IL-4, IL-7, IL-15, and IL-21 were assayed. + Their ability to block T cell activation was assessed by flow cytometry (BD™ Phosflow assay). BD™ Phosflow is a phosphoprotein assay that measures the amount of phosphorylated proteins in cells. This technique allows for simultaneous analysis of cellular signaling in distinct subpopulations of cells, including human CD4+ cells, upon stimulation with cytokines from the gamma c family. + STAT phosphorylation in T cells was analyzed.

[0214] Human peripheral blood mononuclear cells (PBMCs) were isolated from fresh whole blood (Bioreclammation IVT) by density gradient centrifugation. K2 EDTA whole blood was purified by X-VIVO™ The cells were diluted 1:1 in 15 medium (Lonza) and added to a SepMate tube (StemCell) containing FicollPaque PLUS (Healthcare) and centrifuged to separate the PBMCs. The upper layer containing the PBMCs was transferred to a new tube and washed twice with DPBS (Life Technologies). The PBMCs were then collected at approximately 5.0 × 10 6 Resuspend cells in X-VIVO™ 15 medium at a concentration of 100 cells / mL and plate in a 96-well plate. Plates were plated (50 uL cells / well; approximately 250,000 cells / well) and incubated at 37° C. for 2 hours before addition of cytokines and antibodies.

[0215] Serial dilutions (1:5) of antibodies were prepared in pre-warmed X-VIVO™ 15 medium and added to the cells (50 uL), with final antibody concentrations starting at 400 nM. Fixed cytokine concentrations were prepared in pre-warmed X-VIVO™ 15 medium and added to cells (100 uL) in a final volume of 200 uL per well, with final concentrations of 1 pM for IL-4 (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).

[0216] For cytokine dose responses, serial dilutions (1:5) of each cytokine were also diluted in pre-warmed X-VIVO™ 1 ml solution, with final cytokine concentrations starting at 5 nM for IL-4, IL-7, and IL-21, or 50 nM for IL-2 and IL-15. First, 50 uL of X-VIVO™ 15 medium was added to the cells, followed by 100 uL of serial cytokine dilutions, for a total volume of 200 uL per well. The liquid was added.

[0217] After adding cytokines and antibodies to the cells, they were incubated at 37°C for 15 minutes to activate the PBMCs (STAT phosphorylation). Stimulation was then stopped by adding 200uL of warm 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 kept overnight at 4°C. The next day, the cells were centrifuged and permeabilized by slowly adding 100uL of cold Perm Buffer III (BD) to the pellet. The cells were incubated at 4°C for 30 minutes and then washed twice with staining buffer. CD4 IgG was used to measure STAT phosphorylation. +To allow for the analysis of T cell populations, 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 the relevant anti-phospho-STAT-AlexaFluor647 (BD) were prepared in staining buffer: - anti-phospho-STAT3 (1 / 10): for cells stimulated with IL-21, - anti-phospho-STAT5 (1 / 20): for cells stimulated with IL-2, IL-7 and IL-15, - Anti-phospho-STAT6 (1 / 10): for cells stimulated with IL-4 The cells were stained with a mix of

[0218] Samples were kept in the dark for 1 hour. Cells were then centrifuged and washed twice with staining buffer. Sample data were acquired on an LSR Fortessa X-20 cell analyzer using an HTS attachment (BD). Data analysis was performed using FlowJo X software (Tree Star, OR). CD4 + T cells, intact cells, singlets, CD33 - , CD3 + , CD4 + STAT phosphorylation was analyzed within this cell population (MFI = mean fluorescence intensity).

[0219] Both H4H12889P and H4H12922P2 similarly efficiently blocked STAT phosphorylation induced by all cytokines tested in this assay (IL-2, IL-4, IL-7, IL-15, and IL-21), whereas H4H12874P, H4H12886P, H4H12857P, as well as the comparative antibody COMP1499 (anti-IL2Rγ antibody CP.B8, see US2002 / 0028202), only partially or did not block cytokine-induced STAT phosphorylation.

[0220] [Table 31]

[0221] See also Figure 1 (A-E), in which the level of STAT phosphorylation was determined at each concentration of antibody tested.

[0222] Example 6 Flow cytometric analysis of STAT3 phosphorylation in in vitro differentiated human mast cells To assess the in vitro characteristics of the anti-IL2Rγ antibodies of the invention, their ability to block IL-9-induced human mast cell activation was measured by flow cytometry (BD™ Phosflow assay). We used this technique to examine STAT3 phosphorylation in differentiated human mast cells in vitro.

[0223] Briefly, bone marrow CD133 cells were cultured for 6 weeks in StemSpan serum-free medium supplemented with human SCF, IL-6, and IL-3. + Human mast cells were generated in vitro from precursor cells.

[0224] Approximately 4.0 × 10 human mast cells 6 in X-VIVO™ 15 medium at a concentration of 100 cells / mL Cells were resuspended and plated in 96-well plates (50 uL cells / well; approximately 200,000 cells / well) and incubated at 37° C. for 2 hours before addition of cytokines and antibodies.

[0225] Serial dilutions (1:5) of the antibody were prepared in pre-warmed X-VIVO™ 15 medium and added to the cells (50 uL), with a final antibody concentration starting at 400 nM. A fixed IL-9 (R&D) concentration was prepared in pre-warmed X-VIVO™ 15 medium in a final volume of 200 uL / well and added to the cells (100 uL).

[0226] For cytokine dose response, serial dilutions (1:5) of IL-9 were also prepared in pre-warmed X-VIVO™ 15 medium, with final cytokine concentrations starting at 100 nM. First, 50 μL of X-VIVO ( ™ 15 medium was added to the cells, followed by 100 uL of serial dilutions of cytokines.

[0227] After adding cytokines and antibodies to the cells, they were incubated at 37°C for 15 minutes to activate the mast cells (measured by STAT3 phosphorylation). Stimulation was then stopped by adding 200 μL of warm 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 kept overnight at 4°C. The next day, the cells were centrifuged and permeabilized by slowly adding 100 μL of cold Perm 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 mix 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.

[0228] Samples were kept in the dark for 1 hour. Cells were then centrifuged and washed twice with staining buffer. Sample data were acquired on an LSR Fortessa X-20 cell analyzer using an HTS attachment (BD). Data analysis was performed using FlowJo X software (Tree Star, OR). Mast cells were classified as intact cells, singlets, or c-Kit. + STAT3 phosphorylation was analyzed within this cell population (MFI = mean fluorescence intensity).

[0229] Both H4H12889P and H4H12922P2 blocked IL-9-induced STAT3 phosphorylation equally efficiently.

[0230] [Table 32]

[0231] See also Figure 2, where the level of IL-9-induced STAT phosphorylation was determined at each concentration of antibody tested.

[0232] Example 7 : Testing monoclonal antibodies in an in vivo model; a xenogeneic acute graft-versus-host disease model to evaluate blocking activity of IL-2R gamma antibodies as a therapeutic treatment To determine the effects of our anti-IL2Rγ antibodies, H4H12889P and H4H12922P2, along with the comparative IL-2Rγ antibody COMP1499 in the context of an in vivo model, a xenogeneic acute graft-versus-host disease (GvHD) study was performed. Briefly, to induce GvHD in mice, human peripheral blood mononuclear cells (huPBMCs) were transfected with NOD-scid IL2Rγ antibodies. null (NSG) mice (Jackson Lab). Once implanted, the human immune cells recognize the mouse host as foreign and mount a vigorous immune response against its tissues.

[0233] In this experiment, NSG mice (Jackson Lab) were injected retro-orbitally with DPBS. Ten million resuspended huPBMCs (ReachBio) were injected (10 million cells / 100 μL; five groups of 10 mice each). Briefly, on the day of injection, human PBMCs were thawed in IMDM medium (Irvine Scientific) supplemented with 10% FBS (Seradigm) and incubated in this supplemented medium for 2 hours at 37°C. Cells were then washed in DPBS (Life Technologies) and resuspended at 10 million cells / 100 μL for injection. A control group (10 mice) was injected retro-orbitally with 100 μL of PBS. Four groups of huPBMC-transplanted NSG mice were injected subcutaneously with 25 mg / kg of either H4H12889P, H4H12922P2, COMP1499, or an isotype control antibody (REGN1945; human anti-domestic cat (Felis domesticus) Fel d1 antibody (IgG4(S108P) / kappa)) twice per week for 6 weeks, starting 3 weeks after huPBMC injection. The experiment was terminated 161 days after huPBMC transplantation by sacrificing the remaining mice. The experimental dosing and treatment protocol for the groups of mice is shown in Table 7-1.

[0234] [Table 33]

[0235] Mice were monitored twice weekly for weight loss and death (to assess the effect of therapeutic antibodies on survival) throughout the experiment. Serum mouse and human cytokine levels, as well as human cell engraftment in the blood, were assessed at different time points, as shown in Table 7-2.

[0236] [Table 34]

[0237] During the entire experiment, mice were monitored twice weekly for weight loss (Figure 3(A-F); % of initial body weight on the day of huPBMC transplantation) and death (Figure 4; to assess the effect of therapeutic antibodies on survival). Animals that showed a weight loss of 20% of their initial body weight were euthanized.

[0238] Blood samples from mice were collected into Microtainer tubes (BD, Cat# 3659740) at different time points after huPBMC injection, and human cell engraftment was assessed by flow cytometry to determine the absolute human cell count in the blood. 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. Cells were then washed in DPBS, stained with LIVE / DEAD fixable dead stain (Invitrogen), washed in MACS buffer (Miltenyi Biotec), and immunoblotted for human CD45. + cell, T cell, CD4 + T cells and CD8 + The antibodies used to identify T cells were labeled with a mix of antibodies (anti-human CD45, anti-human CD3, anti-human CD4, and anti-human CD8 [BD] diluted 1 / 50 in brilliant staining buffer [BD], along with human and mouse Fc inhibitor antibodies [eBioscience and BD, respectively]). Finally, samples were washed in MACS buffer, fixed in BD CytoFix (BD), and then resuspended in MACS buffer containing CountBright beads (Life Technologies) to calculate absolute cell numbers in each sample. Sample data were acquired on an LSR Fortessa X-20 cell analyzer using an HTS attachment (BD). Data analysis was performed using FlowJo X software (Tree Star, OR). Human CD45 + Live T cells, singlets, CD45 + Within this population, CD4 + T cells and CD8 + T cells are CD3 + , CD4 + and CD3 + , CD8+ was further defined as

[0239] [Table 35]

[0240] As an example, absolute human cell counts in the blood at day 35 after huPBMC injection are shown in Figure 5 (A-D). Human CD45+ cells, T cells, CD4+ T cells, and CD8+ T cells were counted over time. The blood counts of T cells are shown in Figure 6 (A to D).

[0241] Serum was collected from mice on different days after huPBMC injection to assess serum levels of mouse and human cytokines. Briefly, whole blood was collected into Microtainer tubes (BD, Cat# 365967) and allowed to clot by standing at room temperature for at least 30 minutes. The clotted blood and cells were pelleted by centrifugation at 15,000 × g for 10 minutes at 4°C. The resulting supernatant, designated serum, was transferred to a clean plate, and cytokine concentrations in the serum were measured using two Proinflammatory (mouse and human) multiplex immunoassay kits (Meso Scale Discovery) according to the manufacturer's instructions. The plate was washed with PBS containing 0.05% (w / v) Tween-20 (Life Technologies). Electrochemiluminescence was immediately read on an MSD Spector instrument. Data analysis was performed using FlowJo X software (Tree Star, OR).

[0242] [Table 36]

[0243] [Table 37]

[0244] Also, as an example, serum human and mouse cytokine levels at day 42 after huPBMC injection are shown in Figure 7 (A-I). Serum levels of human IFN-γ, human TNFα, mouse TNFα, and mouse IL-6 over time are shown in Figure 8 (A-D).

[0245] This in vivo study demonstrated the efficacy of anti-IL2Rγ antibodies, H4H12889P and H4H12922P2, when administered therapeutically in a model of graft-versus-host disease. Both H4H12889P and H4H12922P2, but not COMP1499, efficiently blocked the development of GvHD in mice. Mice therapeutically treated with either of these two antibodies were protected from weight loss and death, which was accompanied by a dramatic reduction in both mouse and human serum cytokine levels and human T cell numbers in the blood. See Tables 7-3, 7-4, and 7-5.

[0246] Example 8 Bioassay using NK92 / hIL7R / STAT3-Luc and Ramos.2G6.4C10 / STAT3-Luc cells The IL2Rγ family of cytokines, IL-2, IL-4, IL-7, IL-9, IL-15, and IL-21, signal through the JAK-STAT (Janus kinase-signal transducer and activator of transcription) pathway (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 bioassay 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 expresses IL2Rγ as well as ligand-selective receptors that mediate signaling for IL-2, IL-9, IL-15, and IL-21. To also evaluate modulation of IL-7 signaling, NK-92 cells were transduced with a lentivirus containing human IL-7R, and stable expressing cells were selected and maintained in G418. The resulting cell line is hereafter referred to as NK-92 / hIL7R / STAT3-Luc. To test the regulation of IL-4-mediated signaling, Ramos.2G6.4C10 (human B lymphocytic cell line, ATCC) cells, which endogenously express IL2Rγ and IL-4R receptors, were transduced with the STAT3-luc reporter, and the resulting cell line is designated Ramos.2G6.4C10 / STAT3-Luc.

[0247] Anti-IL2γ antibodies of the invention were 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 plating 20,000 NK-92 / hIL7R / STAT3-Luc cells / well in growth medium (prepared according to ATCC instructions, but without IL-2) in 96-well plates and incubating overnight at 37°C in 5% CO. The next day, anti-IL2Rγ antibodies or isotype controls were serially diluted from 500 to 0.008 nM in assay buffer (plus samples containing buffer alone without the test molecule), added to the cells, and incubated for 30 minutes. After incubation, ligands were added to 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 activation was determined using serial dilutions of ligand from 10 nM to 0.2 pM added to cells (plus samples containing buffer alone without ligand). After 5 hours of incubation at 37°C in 5% CO2, cells were read using OneGlo™ reagent (Promega, #E6031) and a Victor™ X multilabel plate reader (Perkin Elmer). Luciferase activity was measured using the r).

[0248] To test anti-IL2γ antibodies of the present invention in inhibiting human IL-4 (hIL-4) signaling, Ramos.2G6.4C10 / STAT3-Luc cells were plated in growth medium (prepared according to ATCC instructions) at a density of 100,000 cells / well in 96-well plates. Anti-IL2Rγ antibodies or isotype controls were serially diluted from 500 to 0.008 nM in assay buffer (plus samples containing buffer 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 from 10 nM to 0.2 pM (plus samples containing buffer alone without the ligand) added to the cells. After overnight incubation at 37°C in 5% CO2, the plates were read using OneGlo™ reagent (Promega, #E6031) and a Victor™ X multilabel plate reader (Perkin E Luciferase activity was measured using a 100% ELISA kit (Imer).

[0249] Nonlinear regression (four parameters) was performed using Prism 5 software (GraphPad). -Logistics) and analyze the results to 50 and IC 50 The value was obtained using the following equation:

number

[0250] In this equation, "RLU ベースライン ” is the luminescence value from cells treated with a fixed amount of ligand without antibody, and “RLU” 阻害 ” is the minimum luminescence value from cells treated with a dose response of a particular antibody at a particular ligand concentration, and “RLU” バックグラウンド " is the luminescence value from cells treated without any ligand or antibody.

[0251] [Table 38]

[0252] [Table 39]

[0253] Twenty-three anti-IL2γ antibodies of the present invention were tested for their ability to inhibit signaling by cytokines of the IL2Rγ family using bioassays. As shown in Table 8-1, 19 of the 23 anti-IL2γ antibodies inhibited IL2Rγ activation to different degrees, and as shown in Table 8-2, 4 of the 23 anti-IL2γ antibodies showed no inhibition of ligand-induced IL2Rγ activation.

[0254] Example 9 Flow cytometric cell binding analysis using NK-92, Jurkat, NIH / 3T3, MC / 9, and HEK293 cells To assess the binding of anti-IL2Rγ antibodies to human and mouse IL-2Rγ expressed on cells, flow cytometry analysis was performed using cell lines that endogenously express IL-2Rγ: NK-92 (human natural killer cell line), Jurkat (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.

[0255] For flow cytometry analysis, cells were preincubated with 100 μg / ml mouse IgG for 15 min at room temperature (RT) to block antibody binding to Fc receptors. 0.5–1 × 10 cells were cultured in PBS (calcium- and magnesium-free) containing 1% FBS for Jurkat, NIH / 3T3, and HEK293 cells or in growth medium (prepared according to the ATCC instructions) for NK-92 and MC / 9. 6Anti-IL2Rγ antibodies of the present invention and isotype control antibodies were used at 10 μg / ml for 30-45 minutes at room temperature using each cell type per well. Cells were washed and incubated with anti-human antibody conjugated to allophycocyanin (APC) (Jackson ImmunoResearch, #109-136-170) for 30 minutes on ice. Cells were washed, fixed using BD CytoFix™ (BD biosciences, #554655), and then cultured using IQue® (Intellicyt®) Flow Cell Imaging. Cell lines were analyzed on a Flow cytometer or Accuri Flow cytometer (BD). Unstained and secondary antibody-only controls were also included for all cell lines. Results were analyzed using IntelliCyt® (IntelliCyt®) software to determine the geometric mean fluorescence (MFI) for viable cells. Binding ratios were calculated by normalizing the MFI of test samples by the MFI of unstained samples.

[0256] As shown in Table 9-1, 19 of 23 anti-IL2Rγ antibodies of the invention tested at 10 μg / ml demonstrated binding to Jurkat and NK-92 cells at binding ratios of 1-19 and 1-94, respectively. Anti-IL2Rγ antibodies demonstrated binding to NIH / 3T3 and MC / 9 cells at binding ratios of 1-13 and 1. The human isotype control antibody, REGN1945, and secondary alone control condition exhibited binding ratios of 1-13 to all cell lines tested.

[0257] As shown in Table 9-2, four of the 23 anti-IL2Rγ antibodies of the invention tested at 10 μg / ml demonstrated binding to NK-92 cells at a binding ratio of 1 to 37 and to HEK293 cells at a binding ratio of 1 to 3. The human isotype control antibody, REGN1945, and the secondary alone control condition exhibited binding ratios of 1 to 2 to NK-92 and HEK293 cells.

[0258] [Table 40]

[0259] [Table 41]

[0260] Example 10 : In vivo immunosuppression experiments to evaluate the effects of anti-IL2Rγ antibody H4H12889P on immune cell populations in the blood Experimental Procedure: Velocigene® (VG) background mice (C57BL / 6NTac (75%) / 129S6SvEvTac (25%)) from the Regeneron Velocigene® breeding colony, genetically modified to replace the endogenous IL2RG ectodomain with the corresponding human sequence, were administered subcutaneously at doses of 10 mg / kg or 25 mg / kg twice per week for 3 weeks (6 doses total) with or without isotype control (REGN1945) or H4H12889P.

[0261] [Table 42]

[0262] Analysis of immune cell populations in blood over time by flow cytometry. Total immune cell, B cell, T cell, NK cell, and neutrophil counts in peripheral blood were analyzed via flow cytometry at various time points (weekly) to assess the effect of H4H12889P on the absolute numbers of these cell types. Briefly, at each time point, blood samples from mice were collected into Microtainer tubes containing K2EDTA [BD #365974], and 30-75 μL of each blood sample was incubated in red blood cell lysis buffer [Sigma #R7757] at room temperature for 5 minutes to lyse red blood cells. A second round of lysis was performed if necessary. Cells were then washed in DPBS [Gibco #14190-144] and lysed with LIVE / DEAD™ Fixable N™ diluted 1:500 in DPBS. The cells were stained with ear-IR Dead Cell Stain [Invitrogen #L34962] for 20 minutes, washed again in DPBS, and then resuspended in MACS buffer [autoMACS Running Buffer; Miltenyi Biotec, #130 Cells were then blocked with purified anti-mouse CD16 / CD32 (Fc Shield) [Tonbo Biosciences, #70-0161-M001] diluted 1:50 in [BD Biosciences, #70-0161-M001]. Cells were then stained for cell surface markers and analyzed by BD Biosciences. CD45 was detected by adding a mix of fluorescently labeled antibodies (listed in Table 2) diluted in horizon brilliant staining buffer [BD #566349]. + CD45, T cells, B cells, NK cells, and neutrophils were identified. Finally, samples were washed in MACS buffer and fixed in BD CytoFix (BD #554655) diluted 1:4 in DPBS, followed by washing and resuspension in MACS buffer before acquisition. Sample data were acquired on a FACSymphony A5 analyzer using an HTS attachment (BD). A fixed volume of each sample was run. Data analysis was performed using FlowJo v10 software (Tree Star, OR). + Immune cells, singlets, live cells, CD45 + Within this population, T cells are defined as CD3 + As a result, B cells are CD3 - CD19 + As a result, NK cells - CD19 - NKp46 + As a result, neutrophils were classified as F4 / 80 - Ly6G + The absolute number of each cell type run through the analyzer, the sample volume run, and the volume of blood originally stained were used to calculate the number of cells per μL of blood for each sample.

[0263] [Table 43]

[0264] Analysis of serum therapeutic antibody levels over time by antigen capture ELISA. Serum levels of IL2Rγ antibody or isotype control antibody were measured weekly using a Human total IgG Platinum ELISA kit. Serial dilutions of each antibody in a 0.5% solution of BSA in PBS were made to generate standard curves from 1.56 to 100 ng / mL of H4H12889P and REGN1945. Absorbance at 450 nm was measured on a SpectraMax M5 plate reader (Molecular Devices). Data analysis was performed using Prism 8.1.2 (GraphPad).

[0265] Summary of Results and Conclusions. Treatment with H4H12889P (10 mg / kg and 25 mg / kg) significantly increased the total CD45 + This resulted in a significant reduction in the numbers of immune cells (Figure 9(A)), NK cells (Figure 9(B)), T cells (Figure 9(C)), and B cells (Figure 9(D)), but no effect on neutrophil counts (Figure 9(E)). After the end of the 3-week dosing period, serum concentrations of H4H12889P decreased over time. This decrease in H4H12889P concentrations was due to the presence of total CD45 + This was accompanied by a continuous increase in the number of immune cells (Figure 9(A)), NK cells (Figure 9(B)), T cells (Figure 9(C)) and B cells (Figure 9(D)). By the end of the study, all these populations had recovered to levels similar to those observed before treatment and in mice untreated or treated with REGN1945 (isotype control).

[0266] Example 11 An in vivo skin graft rejection model to evaluate the blocking activity of the IL2Rγ antibody H4H12889P 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 the Regeneron Velocigene® breeding colony, which had been 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 donor mice. The skin was peeled off using forceps and punched using a 10 mm diameter biopsy punch.

[0267] VG mice (humanized for IL2Rγ) used as graft recipients were subcutaneously administered with or without an isotype control (REGN1945) or H4H12889P at a dose of 25 mg / kg twice weekly starting 3 weeks before transplantation and continuing until rejection. The surgical site was shaved, and the recipient was anesthetized with isoflurane via the nose cone and administered an analgesic (buprenorphine-sustained release) (ZooPharm). Povidone-iodine and alcohol were applied to the shaved dorsal section. A graft bed was created midway down the flank between the dorsal and ventral sides of the mouse by pinching the skin with forceps and then excising it using a sterile 10 mm diameter biopsy skin punch. The graft was then placed on the graft bed and covered with an adhesive bandage, which was secured to the skin using two sterile surgical staples. Aseptic technique was observed throughout the entire procedure. After 5 days, the bandages and staples were removed and subsequent monitoring was performed.

[0268] [Table 44]

[0269] The experimental design is described in FIG.

[0270] Monitoring of Skin Graft Rejection. Skin graft monitoring included the following criteria: (1) Skin grafts that were not adequately vascularized were considered technical failures and excluded from analysis. These grafts exhibited scabbing and shrinkage within hours of dressing removal. (2) Scabbing and shrinkage of the graft at later time points were used as indicators of graft rejection. The time of complete rejection was recorded as the first day on which 100% of the graft tissue was necrotic (Figure 12). Rejection onset was recorded as the first day on which there were signs of rejection (i.e., flushing) (Figure 11). Significance was determined by the log-rank (Mantel-Cox) test with Bonferroni correction (corrected p-value 0.005, K = 9).

[0271] Detection of donor-specific antibodies by flow cytometry. Blood was sampled 56 days after transplantation. The formation of donor-specific antibodies was assessed by pooling (Figure 13).

[0272] CT26.WT (ATCC® CRL-2638™) cells were cultured at 80% confluence. Cells were cultured in tissue culture flasks until confluent. Cells were washed with 1x DPBS and dissociated by incubating with TrypLE Express reagent (Gibco) at room temperature for 5 minutes and rinsing the flask with complete RPMI 1640 medium. Cells were then centrifuged (500g, 10 minutes) and resuspended at 5 million cells / ml in a 1:50 dilution of 4µg / ml Fc block (Tonbo) in 1x DPBS for 15 minutes at room temperature. The suspension was plated at 250,000 cells / well (50µL) into 384-well V-bottom plates.

[0273] 50 μl of serially diluted sample serum from transplanted and non-transplanted wild-type VG mice (C57BL / 6NTac (75%) / 129S6SvEvTac (25%)) and wild-type BALB / cJ mice obtained from The Jackson Laboratory was added to each well and incubated for 45 minutes at 37° C. After two washes with MACS buffer (500 g, 4 minutes), 50 μl of LIVE / DEAD™ Fixable Blue diluted 1:500 in 1×DPBS in a total volume of 50 μl per well was added. Cells were resuspended in Dead Cell Stain Kit (Invitrogen) and incubated for 15 minutes at room temperature. After centrifugation at 500g for 4 minutes, the supernatant was discarded and the cells were resuspended in 25ul of Fc Block (Tonbo) and incubated at 4°C for 15 minutes. Next, 25ul of 2x antibody cocktail (Table 11-2) was added and incubated at 4°C for 25 minutes. After centrifugation (500g, 4 minutes), cells were washed in MACS buffer by adding 100ul of MACS™ buffer to each well. 100ul of Cytofix™ Fixation Buffer diluted 1:4 in 1x DPBS was added. Cells were fixed by resuspending them in fer (BD) and incubated at 4°C for 15 minutes. After centrifugation and discarding the fixative, the samples were resuspended in MACS buffer. Cells were acquired using a BD Fortessa X-20. Acquired events were analyzed using FlowJo (BD). MFI was derived from doublet discrimination (FSC-H, FSC-A) and Live / Dead dye-negative cells. Results plotted were the median fluorescence intensity values ​​at a 1 / 512 dilution of the sample serum.

[0274] [Table 45]

[0275] Summary of results and conclusions. In a skin transplant model (BALB / cJ to VG mice), H4H12889P (anti-IL2Rγ Ab) treatment delayed the onset of skin graft rejection and improved overall skin graft survival. H4H12889P treatment also prevented the generation of donor-specific antibodies in this transplantation model.

Claims

1. 1. An isolated antigen binding protein that specifically binds to IL2Rγ or an antigenic fragment thereof, comprising: Approximately 2.75 x 10 at 25°C －９ M ~ approx. 3.36 x 10 －７ M, approx. 2.45 x 10 －９ M ~ approx. 1.20 x 10 －８ M; or approximately 1.20 x 10 －８ K is lower than M Ｄ binding to the human IL2Rγ extracellular domain at Approximately 6.42 x 10 at 37°C －９ M ~ approx. 3.53 x 10 －７ M; approx. 1.86 x 10 －１１ M ~ approx. 3.00 x 10 －８ M; approx. 3.00 x 10 －８ Lower than M, or about 3.53 x 10 －７ K is lower than M Ｄ binding to the human IL2Rγ extracellular domain at Approximately 3.18 x 10 at 25°C －９ M ~ approx. 2.38 x 10 －７ K of M Ｄ binds to the cynomolgus monkey IL-2Rγ extracellular domain; Approximately 8.29 x 10 at 37°C －９ M ~ approx. 3.20 x 10 －７ K of M Ｄ or about 3.20 x 10 －７ K is lower than M Ｄ To combine with; Approximately 1.84 x 10 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 K of M Ｄ binds to the mouse IL2Rγ extracellular domain at 200 ng / mL; or does not detectably bind; Approximately 5.59 x 10 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 K of M Ｄ binds to the mouse IL2Rγ extracellular domain at 200 ng / mL; or does not detectably bind; Approximately 3.32 x 10 at 25°C －９ M ~ approx. 1.97 x 10 －７ K of M Ｄ binds to human IL2Rγ domain 1 at 200 ng / mL; or does not detectably bind; Approximately 4.13 x 10 at 37°C －９ M ~ approx. 2.25 x 10 －７ K of M Ｄ binds to human IL2Rγ domain 1 at 200 ng / mL; or does not detectably bind; Approximately 2.91 x 10 at 25°C －７ M ~ approx. 5.35 x 10 －１０ K Ｄ binds to human IL2Rγ domain 2 at 200 ng / mL; or does not detectably bind; Approximately 1.14 x 10 at 37°C －８ Or about 1.27 x 10 －８ K Ｄ binds to human IL2Rγ domain 2 at 200 ng / mL; or does not detectably bind; - does not detectably bind to mouse or rat IL2Rγ; - blocking STAT phosphorylation in T cells induced by IL-2, IL-4, IL-7, IL-15 and / or IL-21; Blocking IL-9-induced STAT phosphorylation in mast cells; - reducing the number of human peripheral blood mononuclear cells (PBMCs) and / or human cytokines in the blood or serum of immunodeficient mice injected with such cells; - Protecting mice from weight loss and / or death due to GvHD in a GvHD mouse model; blocking the binding of hybrid receptors comprising IL2Rγ complexed with cytokine-specific receptor subunits to IL-2, IL-4, IL-7, IL-9, IL-15 and / or IL-21; - inhibiting IL2Rγ intracellular signaling through the JAK-STAT pathway induced by IL2, IL4, IL7, IL9, IL15 and / or IL21; - specifically binds to the same epitope on IL2Rγ as a reference antibody or antigen-binding fragment thereof, and the reference antibody or antigen-binding fragment thereof is H4H12857P; H4H12858P; H4H12859P; H4H12863P; H4H12874P; H4H12871P; H4H12884P; H4H12886P; H4H12889P; H4H12890P; H4H12899P; H4H12900P; H4H12908P; H4H12913P2; H4H12922P2; H4H12924P2; H4H12926P2; H4H1292 7P2; H4H12934P2; H4H13538P; H4H13541P; H4H13544P2; or H4H13545P2; - competes with a reference antibody or antigen-binding fragment thereof for binding to an IL2Rγ polypeptide or an antigenic fragment thereof, and the reference antibody or antigen-binding fragment thereof is H4H12857P; H4H12858P; H4H12859P; H4H12863P; H4H12874P; H4H12871P; H4H12884P; H4H12886P; H4H12889P; H4 H12890P; H4H12899P; H4H12900P; H4H12908P; H4H12913P2; H4H12922P2; H4H12924P2; H4H12926P2; H4H12927P2; H4H12934P2; H4H13538P; H4H13541P; H4H13544P2; or H4H13545P2; and / or - reducing CD45+ cells, B cells, T cells and / or NK cells in the blood or serum The antigen-binding protein is characterized by one or more of the following:

2. The antigen-binding protein that specifically binds to IL2Rγ or an antigenic fragment thereof according to claim 1, which is an antibody or an antigen-binding fragment thereof.

3. The antigen-binding protein of claim 2 which is an antibody and specifically binds to IL2Rγ or an antigenic fragment thereof.

4. 1. An isolated antigen-binding protein that specifically binds to IL2Rγ or an antigenic fragment thereof, comprising: (a) a heavy chain immunoglobulin or its variable region comprising CDR-H1, CDR-H2, and CDR-H3, comprising the amino acid sequence set forth 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; or a variant thereof a light chain immunoglobulin or a variable region thereof comprising CDR-L1, CDR-L2, and CDR-L3 of a heavy chain immunoglobulin or a variable region thereof; and / or (b) an amino acid sequence set forth 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; or a variant thereof The antigen-binding protein comprising:

5. (a) a heavy chain immunoglobulin or variable region thereof comprising an amino acid sequence having at least 90% amino acid sequence identity to the amino acid sequence set forth 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; 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 to the amino acid sequence set forth 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; 5. An antigen-binding protein that specifically binds to IL2Rγ or an antigenic fragment thereof according to any one of claims 1 to 4, comprising:

6. (a) an amino acid sequence set forth 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; or a heavy chain immunoglobulin or variable region thereof comprising CDR-H1, CDR-H2 and CDR-H3 of a heavy chain immunoglobulin or variable region thereof comprising an amino acid sequence having at least 90% amino acid sequence identity to the amino acid sequence set forth in 38, 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; and / or (b) the amino acid sequence set forth 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; or 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. A light chain immunoglobulin or a variable region thereof comprising CDR-L1, CDR-L2, and CDR-L3 of the variable region thereof.

6. An antigen-binding protein that specifically binds to IL2Rγ or an antigenic fragment thereof according to any one of claims 1 to 5, comprising:

7. (i) CDR-H1 comprising the amino acid sequence set forth in SEQ ID NO:4; CDR-H2 comprising the amino acid sequence set forth in SEQ ID NO:6; and CDR-H3 comprising the amino acid sequence set forth in SEQ ID NO:8; and / or CDR-H1 comprising the amino acid sequence set forth in SEQ ID NO:24; CDR-H2 comprising the amino acid sequence set forth in SEQ ID NO:26; and CDR-H3 comprising the amino acid sequence set forth in SEQ ID NO:28; and / or CDR-H1 comprising the amino acid sequence set forth in SEQ ID NO: 44; CDR-H2 comprising the amino acid sequence set forth in SEQ ID NO: 46; and CDR-H3 comprising the amino acid sequence set forth in SEQ ID NO: 48; and / or CDR-H1 comprising the amino acid sequence set forth in SEQ ID NO: 64; CDR-H2 comprising the amino acid sequence set forth in SEQ ID NO: 66; and CDR-H3 comprising the amino acid sequence set forth in SEQ ID NO: 68; and / or CDR-H1 comprising the amino acid sequence set forth in SEQ ID NO: 83; CDR-H2 comprising the amino acid sequence set forth in SEQ ID NO: 85; and CDR-H3 comprising the amino acid sequence set forth in SEQ ID NO: 87; and / or CDR-H1 comprising the amino acid sequence set forth in SEQ ID NO: 103; CDR-H2 comprising the amino acid sequence set forth in SEQ ID NO: 105; and CDR-H3 comprising the amino acid sequence set forth in SEQ ID NO: 107; and / or CDR-H1 comprising the amino acid sequence set forth in SEQ ID NO: 121; CDR-H2 comprising the amino acid sequence set forth in SEQ ID NO: 123; and CDR-H3 comprising the amino acid sequence set forth in SEQ ID NO: 125; and / or CDR-H1 comprising the amino acid sequence set forth in SEQ ID NO: 140; CDR-H2 comprising the amino acid sequence set forth in SEQ ID NO: 142; and CDR-H3 comprising the amino acid sequence set forth in SEQ ID NO: 144; and / or CDR-H1 comprising the amino acid sequence set forth in SEQ ID NO: 158; CDR-H2 comprising the amino acid sequence set forth in SEQ ID NO: 160; and CDR-H3 comprising the amino acid sequence set forth in SEQ ID NO: 162; and / or CDR-H1 comprising the amino acid sequence set forth in SEQ ID NO: 176; CDR-H2 comprising the amino acid sequence set forth in SEQ ID NO: 178; and CDR-H3 comprising the amino acid sequence set forth in SEQ ID NO: 180; and / or CDR-H1 comprising the amino acid sequence set forth in SEQ ID NO: 192; CDR-H2 comprising the amino acid sequence set forth in SEQ ID NO: 194; and CDR-H3 comprising the amino acid sequence set forth in SEQ ID NO: 196; and / or CDR-H1 comprising the amino acid sequence set forth in SEQ ID NO: 202; CDR-H2 comprising the amino acid sequence set forth in SEQ ID NO: 204; and CDR-H3 comprising the amino acid sequence set forth in SEQ ID NO: 206; and / or CDR-H1 comprising the amino acid sequence set forth in SEQ ID NO: 176; CDR-H2 comprising the amino acid sequence set forth in SEQ ID NO: 212; and CDR-H3 comprising the amino acid sequence set forth in SEQ ID NO: 214; and / or CDR-H1 comprising the amino acid sequence set forth in SEQ ID NO: 220; CDR-H2 comprising the amino acid sequence set forth in SEQ ID NO: 222; and CDR-H3 comprising the amino acid sequence set forth in SEQ ID NO: 224; and / or CDR-H1 comprising the amino acid sequence set forth in SEQ ID NO: 240; CDR-H2 comprising the amino acid sequence set forth in SEQ ID NO: 242; and CDR-H3 comprising the amino acid sequence set forth in SEQ ID NO: 244; and / or CDR-H1 comprising the amino acid sequence set forth in SEQ ID NO: 260; CDR-H2 comprising the amino acid sequence set forth in SEQ ID NO: 262; and CDR-H3 comprising the amino acid sequence set forth in SEQ ID NO: 264; and / or CDR-H1 comprising the amino acid sequence set forth in SEQ ID NO: 278; CDR-H2 comprising the amino acid sequence set forth in SEQ ID NO: 280; and CDR-H3 comprising the amino acid sequence set forth in SEQ ID NO: 282; and / or CDR-H1 comprising the amino acid sequence set forth in SEQ ID NO: 288; CDR-H2 comprising the amino acid sequence set forth in SEQ ID NO: 290; and CDR-H3 comprising the amino acid sequence set forth in SEQ ID NO:292; and / or CDR-H1 comprising the amino acid sequence set forth in SEQ ID NO:298; CDR-H2 comprising the amino acid sequence set forth in SEQ ID NO: 300; and CDR-H3 comprising the amino acid sequence set forth in SEQ ID NO: 302; and / or CDR-H1 comprising the amino acid sequence set forth in SEQ ID NO: 317; CDR-H2 comprising the amino acid sequence set forth in SEQ ID NO: 319; and CDR-H3 comprising the amino acid sequence set forth in SEQ ID NO: 321; and / or CDR-H1 comprising the amino acid sequence set forth in SEQ ID NO: 337; CDR-H2 comprising the amino acid sequence set forth in SEQ ID NO: 339; and CDR-H3 comprising the amino acid sequence set forth in SEQ ID NO: 341; and / or CDR-H1 comprising the amino acid sequence set forth in SEQ ID NO: 347; CDR-H2 comprising the amino acid sequence set forth in SEQ ID NO: 349; and CDR-H3 comprising the amino acid sequence set forth in SEQ ID NO: 351; and / or CDR-H1 comprising the amino acid sequence set forth in SEQ ID NO: 363; CDR-H2 comprising the amino acid sequence set forth in SEQ ID NO: 66; and CDR-H3 comprising the amino acid sequence set forth in SEQ ID NO: 366; and / or (ii) CDR-L1 comprising the amino acid sequence set forth in SEQ ID NO: 12; CDR-L2 comprising the amino acid sequence set forth in SEQ ID NO: 14; and CDR-L3 comprising the amino acid sequence set forth in SEQ ID NO: 16; and / or CDR-L1 comprising the amino acid sequence set forth in SEQ ID NO: 32; CDR-L2 comprising the amino acid sequence set forth in SEQ ID NO: 34; and CDR-L3 comprising the amino acid sequence set forth in SEQ ID NO: 36; and / or CDR-L1 comprising the amino acid sequence set forth in SEQ ID NO:52; CDR-L2 comprising the amino acid sequence set forth in SEQ ID NO:54; and CDR-L3 comprising the amino acid sequence set forth in SEQ ID NO:56; and / or CDR-L1 comprising the amino acid sequence set forth in SEQ ID NO: 72; CDR-L2 comprising the amino acid sequence set forth in SEQ ID NO:54; and CDR-L3 comprising the amino acid sequence set forth in SEQ ID NO: 75; and / or CDR-L1 comprising the amino acid sequence set forth in SEQ ID NO:91; CDR-L2 comprising the amino acid sequence set forth in SEQ ID NO:93; and CDR-L3 comprising the amino acid sequence set forth in SEQ ID NO:95; and / or CDR-L1 comprising the amino acid sequence set forth in SEQ ID NO: 111; CDR-L2 comprising the amino acid sequence set forth in SEQ ID NO:54; and CDR-L3 comprising the amino acid sequence set forth in SEQ ID NO: 113; and / or CDR-L1 comprising the amino acid sequence set forth in SEQ ID NO: 129; CDR-L2 comprising the amino acid sequence set forth in SEQ ID NO:54; and CDR-L3 comprising the amino acid sequence set forth in SEQ ID NO: 132; and / or CDR-L1 comprising the amino acid sequence set forth in SEQ ID NO: 148; CDR-L2 comprising the amino acid sequence set forth in SEQ ID NO:54; and CDR-L3 comprising the amino acid sequence set forth in SEQ ID NO: 150; and / or CDR-L1 comprising the amino acid sequence set forth in SEQ ID NO: 166; CDR-L2 comprising the amino acid sequence set forth in SEQ ID NO: 14; and CDR-L3 comprising the amino acid sequence set forth in SEQ ID NO: 168; and / or CDR-L1 comprising the amino acid sequence set forth in SEQ ID NO: 72; CDR-L2 comprising the amino acid sequence set forth in SEQ ID NO:54; and CDR-L3 comprising the amino acid sequence set forth in SEQ ID NO: 184; and / or CDR-L1 comprising the amino acid sequence set forth in SEQ ID NO: 228; CDR-L2 comprising the amino acid sequence set forth in SEQ ID NO: 230; and CDR-L3 comprising the amino acid sequence set forth in SEQ ID NO: 232; and / or CDR-L1 comprising the amino acid sequence set forth in SEQ ID NO:248; CDR-L2 comprising the amino acid sequence set forth in SEQ ID NO: 250; and CDR-L3 comprising the amino acid sequence set forth in SEQ ID NO: 252; and / or CDR-L1 comprising the amino acid sequence set forth in SEQ ID NO: 268; CDR-L2 comprising the amino acid sequence set forth in SEQ ID NO:54; and CDR-L3 comprising the amino acid sequence set forth in SEQ ID NO: 270; and / or CDR-L1 comprising the amino acid sequence set forth in SEQ ID NO: 306; CDR-L2 comprising the amino acid sequence set forth in SEQ ID NO: 230; and CDR-L3 comprising the amino acid sequence set forth in SEQ ID NO: 309; and / or CDR-L1 comprising the amino acid sequence set forth in SEQ ID NO: 325; CDR-L2 comprising the amino acid sequence set forth in SEQ ID NO: 327; and CDR-L3 comprising the amino acid sequence set forth in SEQ ID NO: 329; and / or CDR-L1 comprising the amino acid sequence set forth in SEQ ID NO: 72; CDR-L2 comprising the amino acid sequence set forth in SEQ ID NO:54; and CDR-L3 comprising the amino acid sequence set forth in SEQ ID NO: 355; and / or CDR-L1 comprising the amino acid sequence set forth in SEQ ID NO: 370; CDR-L2 comprising the amino acid sequence set forth in SEQ ID NO: 372; and CDR-L3 comprising the amino acid sequence set forth in SEQ ID NO: 374 7. An antigen-binding protein that specifically binds to IL2Rγ or an antigenic fragment thereof according to any one of claims 1 to 6, comprising:

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

8. An antigen-binding protein that specifically binds to IL2Rγ or an antigenic fragment thereof according to any one of claims 1 to 7, comprising one or more members selected from the group consisting of:

9. 1. An antigen-binding protein that is an antibody or antigen-binding fragment that specifically binds to IL2Rγ or an antigenic fragment thereof, a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO:2; and a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO:10; a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 22; and a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 30; a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO:42; and a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO:50; a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 62; and a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 70; a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 81; and a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 89; a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 101; and a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 109; a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 119; and a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 127; a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 138; and a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 146; a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 156; and a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 164; a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 174; and a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 182; a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 190; and a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 182; a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 200; and a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 182; a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 210; and a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 182; a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 218; and a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 226; a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 238; and a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 246; a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 258; and a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 266; a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 276; and a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 182; a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 286; and a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 182; a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 296; and a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 304; a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 315; and a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 323; a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 335; and a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 182; a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 345; and a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 353; and / or a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 361; and a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO:

368. The antigen-binding protein comprising:

10. 1. An antigen-binding protein that is an antibody or antigen-binding fragment that specifically binds to IL2Rγ or an antigenic fragment thereof, Amino acid sequence: QVQLVQSGAEVKKPGASVRVSCKASGYTFTDYDIHWVRQAPGHGLEWMGWINPNSGGTNYAQKFQGRVTMTRDTSISTVYMDLSRLRSDDTAVYYCARADYSSSYYYYGMDV WGQGTTVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKY GPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEK TISKAKGQPREPQVYTLPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK (SEQ ID NO: 18); and Amino acid sequence: DIVMTQSPDSLAVSLGERATINCKSSQSVLYSSKNKNYLSWYQQKPGQPPKLLIYWASTREFGVPDRFSGRGSGTDFTLTISSLQAEDVAVYYCQQYYTTPYTFGQGTKL EIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 20); Amino acid sequence: QVQLVESGGGVVQPGRSLRLSCTASGFTFRSYDMYWVRQAPGKGLEWVSVITYDGNNKYYADSVKGRFTISRDNSKNTLFLQMSSLRPEDTAVYYCAKRGLIWVGESFDYWG QGTLVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYG PPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKT ISKAKGQPREPQVYTLPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK (SEQ ID NO: 38); and Amino acid sequence: DIQMTQSPSTLSASVGDRVTITCRASQSINSWLAWYQQKPGKAPNLLIYKASSLESGVPSRFSGSGSGTEFTLTISSLQPDDFATYYCQQYKSYSWTFGQGTKVEIK RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 40); Amino acid sequence: QVQLVESGGGVVQPGRSLRLSCAASGFNFRNFGMHWVRQAPGKGLEWVAGILYDGSSKYYADSVKDRFTISRDNSKNTLFLQMNSLRAEDTAMYYCAKEEDTAMVPFDSWG PGTLVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYG PPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKT ISKAKGQPREPQVYTLPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK (SEQ ID NO: 58); and Amino acid sequence: DIQLTQSPSFLSASVGDRVTITCWASQGISSYLAWYQQKPGKAPTLLIYAASTLQSGVPSRFSGSGSGTEFTLTISSLQPEDFASYYCQQLKSYPLTFGGGTKVEIK RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 60); Amino acid sequence: QVQLQESGPGLVKPSQTLSLTCTVSGGSISSGGYYWSWIRQHPGKGLEWIGFIYYSGKTYYNPSLKSRLTISVDTSKSQFSLKLRSVTAADTAVYYCARLGYTNSAGWFDPWGQGTLVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVT VSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKE YKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK (SEQ ID NO: 77); and Amino acid sequence: DIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPNLLIYAASSLQSGVPSRFSGSGSGTDFTLTISSLQPEDLATYYCQQSYTTPFTFGPGTKVDIK RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 79); Amino acid sequence: EVQLVESGGGLVKPGGSLRLSCAASGFTFSTAWMSWVRQSPGRGLEWVGRMKSKTDGGTTFYAAPVKGRFTISRDDSKNTLYLQMNSLKTEDTAVYYCTTGLVPAFYKYYGVD VWGQGTTVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESK YGPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEK TISKAKGQPREPQVYTLPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK (SEQ ID NO: 97); and Amino acid sequence: DIQMTQSPSSLSASVGDRITITCQASQDITNYLNWYQQKPGKAPNLLIYDASNLVTGVPSRFSGSGSGTDFTFTILSLQPEDIATYYCQQYDSLLTFGPGTKVDIK RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 99); Amino acid sequence: EVQLVESGGGLVQPGGSLRLSCAASGFTFNNYAMHWVRQAPGKGLEYVSSISSSGGSTYYEDSVKGRFTISRDNSKNTLYLQMGSLRAEDMAVYYCARSFYGSGTYYDTFDM WGQGTMVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKY GPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEK TISKAKGQPREPQVYTLPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK (SEQ ID NO: 115); and Amino acid sequence: DIQMTQSPSSLSASIGDRVTITCRASQSISRYLNWYQQKPGKAPKLLIYAASSLQSGVPSRFSASGSGTDFTLTISSLQPEDFATYYCQQSYSTPFTFGQGTKLEIK RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 117); Amino acid sequence: QVQLVESGGDLVKPGGSLRLSCATSGFTFSDFYMTWIRQAPGKGLEWISYISNSGSIVKYADSVKGRFTISRDNAKNSLYLQMNSLRAEDTAIYYCARFYGDRWGQGTLV TVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPC PPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTI SKAKGQPREPQVYTLPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK (SEQ ID NO: 134); and Amino acid sequence: DIQLTQSPSFLSASVGDRVTITCWASQGISTFLAWYQQKPGKAPKLLIYAASTLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYHCQQLNNYPWTFGQGTKVEIK RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 136); Amino acid sequence: QVQLVESGGGLVKPGGSLRLSCEASGFTFNDFYMTWIRQAPGKGLEWIAYISKSGDKMRYADSVKGRFSTSRDNAKNSLSLQMNSLRAEDTAVYYCARFYGDIWGQGTLVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGAL TSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVL TVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK (SEQ ID NO: 152); and Amino acid sequence: DIQLTQSPSFLSASVGDRVTITCWASQDISSFLVWYQQKPGKAPNLLIYAASALQSGVPSRFSGSGSGTEFTLTISSLQPEDFASYYCEQLNNYPWTFGQGTKVEIK RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 154); Amino acid sequence: EVQLVESGGRLVQPGGSLRLSCEASGFTFSNYGMTWVRQAPGKGLEWVSVISGSDNRKYYAESVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAKLGYSRSSKDFYYGMD VWGQGTTVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESK YGPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEK TISKAKGQPREPQVYTLPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK (SEQ ID NO: 170); and Amino acid sequence: DIVMTQSPDSLAVSLGERATINCKSSQSVLYNSNNRNYLVWYQQKPGQSPKLLIYWASTRESGVPDRFSGSGSGTDFTLTISSLQAEDVAVYYCQQYYNVPYTFGQGTKL EIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 172); Amino acid sequence: EVQLVESGGGVVRPGGSLRLSCAASGFTFDDYGMSWVRQAPGKGLEWISSINRNGGSADYADSVKGRFTISRDNAKNSLFLQMSSLRAEDTALYHCASGEFRDYWGQGT LVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPP CPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTI SKAKGQPREPQVYTLPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK (SEQ ID NO: 186); and Amino acid sequence: DIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAASSLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQSYSTPPITFGQGTRLEI KRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 188); Amino acid sequence: EVQLVESGGGLVQPGRSLRLSCAASGFTLEDYAMHWVRQAPGKGLEWVSGISWNRGSTGYADSVKGRFTISRDNAKNSLYLQMTSLRAEDTALYYCAKGFYSMDVWGQGT TVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPP CPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTI SKAKGQPREPQVYTLPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK (SEQ ID NO: 198); and Amino acid sequence: DIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAASSLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQSYSTPPITFGQGTRLEI KRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 188); Amino acid sequence: QVQLQQSGPGLVKPSQTLSLTCAISGDSVSSNIAAWNWIRLSPSRGLEWLGRTFFRSTWFYDYSLSVKGRITINPDTSKNQFSLHLNSVTPEDAAVYYCARTGRRWSLDYWG QGTLVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYG PPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKT ISKAKGQPREPQVYTLPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK (SEQ ID NO: 208); and Amino acid sequence: DIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAASSLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQSYSTPPITFGQGTRLEI KRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 188); Amino acid sequence: EVQLVESGGGVVRPGGSLRLSCATSGFTFDDYGMSWVRQVPGKGLEWVSSVNRNGGTTDYADSVKGRFTISRDNAKRSLFLQMNSLRAEDTALYHCATGELFFDYWGQGT LVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPP CPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTI SKAKGQPREPQVYTLPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK (SEQ ID NO: 216); and Amino acid sequence: DIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAASSLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQSYSTPPITFGQGTRLEI KRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 188); Amino acid sequence: QVQLVQSGAEVKKPGASVKVSCKASGYTFTGHYMHWVRQAPGQGLEWMGWIYPHSGHTNYAKRFQGRVTMTRDTSITTAYMELIRLRSDDTAVYYCARRSGRSWYFDLWGR GTLVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGP PCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKT ISKAKGQPREPQVYTLPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK (SEQ ID NO: 234); and Amino acid sequence: EIVLTQSPGTLSLSPGERATLSCRASQSVSSSYLAWYQQKPGQAPRLLIYGASSRATGIPDRFSGSGSGTDFTLTISRLEPEDFAVYYCQQYGSSPWTFGQGTKVEI KRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 236); Amino acid sequence: EVQLVESGGGLVQPGGSLGLSCAASGFTFSNYAMSWVRQAPGKGLEWVSAVSGGGGGTYYADSVKGRFTISRDNSKNTVLLQMNSLRAEDTAVYYCARGRTGGLDYWGPGT LVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPP CPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTI SKAKGQPREPQVYTLPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK (SEQ ID NO: 254); and Amino acid sequence: DVVMTQSPLSLPVIFGQPASISCRSSQSLVDSDGNTYLNWLQQRPGQSPRRLIYEVSNRDSGVPDRFSGSGSGTDFTLTISRVEAEDVGIYYCMQGTRWPPTFGGGTKV EIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 256); Amino acid sequence: EVQLVESGGGVVRPGGSLRLSCAASGFIFDDYDMSWVRQPPGRGLEWVSGIDWFGGTRGYADSMKGRFTISRDNAKNSLYLQMNSLRVEDTAFYYCARGGAIVGAVTPFDYW GQGTLVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKY GPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEK TISKAKGQPREPQVYTLPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK (SEQ ID NO: 272); and Amino acid sequence: DIQMTQSPSSLSASVGNRVTLSCRASQSINTYLSWYQQRPGKAPKLLIYAASSLQSGVPSRFSGSGAGTDFTLTISSLQPEDFATYYCQQSYSAPLTFGGGTKVEIK RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 274); Amino acid sequence: QLQLQESGPGLVKPSETLSLTCTVSGGSISIKNYYWGWIRQPPGKGLEWIGSIYYSGTTYYNPSLKSRVTISVDTSKNQFSLKLSSVTAADTAVYHCARHGYSYGHGWFDPW GQGTLVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKY GPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEK TISKAKGQPREPQVYTLPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK (SEQ ID NO: 284); and Amino acid sequence: DIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAASSLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQSYSTPPITFGQGTRLEI KRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 188); Amino acid sequence: QVQLQQSGPGLVKPSQTLSLTCDISGDSVSSNIATWNWIRQSPSRGLEWLGRTYYRSKWYKDYAVSVKSRITINPDTSKNQFSLQVNSVTPEDTAVYYCARMTGPRYYFEYW GQGTLVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKY GPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEK TISKAKGQPREPQVYTLPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK (SEQ ID NO: 294); and Amino acid sequence: DIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAASSLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQSYSTPPITFGQGTRLEI KRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 188); Amino acid sequence: EVQLVESGGGVVRPGGSLRLSCAASGFTFDDFDMSWVRQGPGKGLEWVSGINWHGSSTGYADSVKGRFTISRDNAKNSLYLQMSSLRAEDTALYHCVRGGTIVGATTPLDYW GQGTLVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKY GPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEK TISKAKGQPREPQVYTLPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK (SEQ ID NO: 311); and Amino acid sequence: DIQMTQSPSSLSASVGDRVTMTCRASRTISSYLSWYQQKSGKVPNLLIFGASSLQSGVPSRFSASGSGTDFTLIISSLQP EDFATYYCQQSYSSPLTFGGGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 313); Amino acid sequence: EVQLVESGGDLVQPGGSLRLSCTASGFIFRNYAMNWVRQAPGKGLEWLSGILGSNDNTYYVDSVKGRFTISRDNSRNTLYLQMNSLRAEDSAVYYCAKGDAGGFDYWGQGT LVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPP CPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTI SKAKGQPREPQVYTLPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK (SEQ ID NO: 331); and Amino acid sequence: DVVMTQSPLSLPVILGQPASISCRSSQSLVSSDGNTYLNWFQQRPGQSPRRLIYKVSNRDSGVPDRFSGSGSGTDFTLKISRVEAEDVGAYYCMQGSYWPPTFGQGTKL EIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 333); Amino acid sequence: QVQLVESGGGVVKPGGSLRLSCAASGFTFSNSGIHWVRQAPGKGLEWVALISYAGSNKYYADSVKGRFTISRDNSKNTLSLQMNSLRAEDTAVYYCAKEVWTGTYDSFDMWG RGTMVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYG PPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKT ISKAKGQPREPQVYTLPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK (SEQ ID NO: 343); and Amino acid sequence: DIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAASSLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQSYSTPPITFGQGTRLEI KRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 188); Amino acid sequence: EVQLVESGGGLVQPGGSLRLSCAASGFIFSSYEMHWVRQAPGKGLEWISYISSSGTTIYYADSVKGRFTISRDNAKNSLYLHMNSLRAEDTAVYYCTRARITGTFDVFDIWG QGTMVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYG PPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKT ISKAKGQPREPQVYTLPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK (SEQ ID NO: 357); and Amino acid sequence: DIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIFAASNLQSGVPSRFSGSRSGTDFTLTISSLQPEDFATYYCQQNYNIPYTFGQGTKLEIK RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 359); and / or Amino acid sequence: QVQLQESGPGLVKPSQTLSLTCTVSGGSITSGGYYWSWIRQYPGQGLEWIGYIYYSGKTYYNPSFTSRITISVDTSKKQFSLKMSSVTAADTAVYYCARAGFTSSNGWFDPW GQGTLVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKY GPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEK TISKAKGQPREPQVYTLPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK (SEQ ID NO: 376); and Amino acid sequence: DIQMTQSPSSLSASVGDRVTITCRASQNIRSYLNWYQQKPGKAPKLLIYSASSLQSGVPSRFSGSGSGTDFTLTISSLQPEDFPTYYCQQTYSSPWTFGPGTKVEIK RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 378) The antigen-binding protein comprising:

11. 11. The antigen-binding protein of any one of claims 1 to 10, which is multispecific.

12. A complex comprising an antigen-binding protein according to any one of claims 1 to 11 bound to an IL2Rγ polypeptide or an antigenic fragment thereof.

13. 12. A method for producing an antigen-binding protein or an immunoglobulin chain thereof according to any one of claims 1 to 11, comprising the steps of: (a) introducing into a host cell one or more polynucleotides encoding the immunoglobulin chains of said antigen binding protein; (b) culturing host cells under conditions favorable for expression of the polynucleotide; and (c) optionally isolating the antigen binding protein or immunoglobulin chain from the host cell and / or the medium in which the host cell was grown. The method comprising:

14. 14. The method of claim 13, wherein the host cell is a Chinese hamster ovary cell.

15. An antigen binding protein or immunoglobulin chain that is the product of the method of any one of claims 13-14.

16. A polypeptide comprising: (a) CDR-H1, CDR-H2, and CDR-H3 of a heavy chain immunoglobulin or variable region thereof comprising the amino acid sequence set forth 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, or a variant thereof; and / or (b) CDR-L1, CDR-L2, and CDR-L3 of a light chain immunoglobulin or variable region thereof comprising an amino acid sequence set forth 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, and / or 378, or a variant thereof; or (c) an amino acid sequence set forth in a member selected from the group consisting of SEQ ID NOs: 1 to 385, or a variant thereof. The polypeptide comprising:

17. 17. A polynucleotide encoding one or more of the polypeptides of claim 16.

18. A vector comprising the polynucleotide of claim 17.

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 15 to 18.

20. 16. A composition or kit comprising one or more of the antigen binding proteins of any one of claims 1 to 11 and 15, optionally together with a further therapeutic agent.

21. 16. A pharmaceutical formulation comprising the antigen-binding protein of any one of claims 1 to 11 and 15, and a pharmaceutically acceptable carrier or excipient and, optionally, a further therapeutic agent.

22. 22. The composition or kit or formulation of claim 20 or 21, which also comprises a further therapeutic agent that is an anti-inflammatory agent.

23. 22. The composition, kit, or formulation of claim 20 or 21, further comprising an additional therapeutic agent which is one or more members selected from the group consisting of anti-TNFα antibodies or binding proteins, infliximab, adalimumab, etanercept, golimumab, corticoids, prednisolone, methylprednisolone, antithymocyte globulin, alemtuzumab, daclizumab, tacrolimus, cyclosporine, extracorporeal photopheresis, mycophenolate mofetil, sirolimus, pentostatin, mesenchymal stem cells, inolimomab, denileukin, and basiliximab.

24. 24. A container or injection device comprising an antigen-binding protein or composition or formulation according to any one of claims 1 to 11, 15, 20, 21, 22 or 23.

25. 24. A method of administering the antigen binding protein, composition or formulation of any one of claims 1 to 11, 15, 20, 21, 22 or 23 to a subject, said method comprising injecting the antigen binding protein, composition or formulation into the body of the subject.

26. 26. A method of treating or preventing an IL2Rγ mediated disease or condition in a subject in need thereof, said method comprising administering an effective amount of an antigen binding protein or composition or formulation of any one of claims 1 to 11, 15, 20, 21, 22 or 23.

27. 27. The method of claim 26, wherein the IL2Rγ mediated disease or condition is graft versus host disease, organ transplant rejection, b-pancreatic islet cell transplant rejection, skin graft rejection, heart transplant rejection, lung transplant rejection, kidney transplant rejection, liver transplant rejection, shattered chorioretinopathy, multiple sclerosis, uveitis, autoimmune disease, type I diabetes, 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).

28. 28. The method of any one of claims 25 to 27, wherein the antigen binding protein is administered subcutaneously, intravenously or intramuscularly into the subject's body by injection.

29. In the subject, - to block cytokine-induced STAT phosphorylation in peripheral blood mononuclear cells; - to block cytokine-induced STAT phosphorylation in mast cells; - to reduce serum levels of interferon-gamma, tumor necrosis factor-alpha, IL-6, IL-8, IL-10 and / or mKC / GRO; - to block JAK-STAT-mediated intracellular signaling induced by cytokines of the ILRγ family; and / or - to reduce serum levels of CD45+ immune cells, NK cells, T cells and / or B cells 26. A method according to claim 1, comprising administering to a subject an effective amount of an antigen binding protein or composition or formulation according to any one of claims 1 to 11, 15, 20, 21, 22 or 23.

30. 30. The method of claim 29, wherein the subject is suffering from an IL2Rγ-mediated disease or condition.

31. 31. The method of claim 30, wherein the IL2Rγ mediated disease or condition is graft versus host disease, organ transplant rejection, b-pancreatic islet cell transplant rejection, skin graft rejection, heart transplant rejection, lung transplant rejection, kidney transplant rejection, liver transplant rejection, shattered chorioretinopathy, multiple sclerosis, uveitis, autoimmune disease, type I diabetes, 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).

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