CD 122 binding agents for inhibiting an immune response in celiac disease or related conditions

Abstract

Provided is a method of inhibiting an immune response in a subject with celiac disease or a subject with HLA-DQ2.5 or HLA-DQ8 haplotype alleles, the method comprising administering a CD122 binding agent to the subject.

Description

Leydig 7739971CD 122 BINDING AGENTS FOR INHIBITING AN IMMUNE RESPONSE IN CELIAC DISEASE OR RELATED CONDITIONSCROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority to U.S. provisional Patent Application No. 63 / 694,534 filed September 13, 2024, the entire disclosure of which is hereby incorporated by reference.INCORPORATION-BY-REFERENCE OF MATERIAL SUBMITTED ELECTRONICALLY

[0002] Incorporated by reference in its entirety herein is a computer-readable nucleotide / amino acid sequence listing submitted concurrently herewith and identified as follows: One 214,5 lOByte ASCII (Text) file named "773997ST.26.xml," created on September 15, 2025.BACKGROUND OF THE INVENTION

[0003] Interleukin-2 (IL-2) and Interleukin- 15 (IL- 15) are two important cytokines involved in immune system regulation. IL-2 is involved in regulatory T-cell (Treg) cell development and homeostasis, whereas IL- 15 regulates NK and NK_T-cell development and memory T-cell survival. The receptors for IL-2 (IL-2R) and IL- 15 (IL-15R) are each comprised of three subunits designated a, P, and y. While IL-2R and IL-15R have unique a subunits (CD25 and CD125, respectively), the two receptors share common P and y subunits (CD122 and CD132).

[0004] IL-2 and IL- 15 signaling is implicated in pathogenic immune system responses, such as those implicated in celiac disease. Thus, there is a need for CD122 binding agents that can modulate such signaling.BRIEF SUMMARY OF THE INVENTION

[0005] Provided herein is a method of inhibiting an immune response in a subject with celiac disease or a subject with HLA-DQ2.5 or HLA-DQ8 haplotype alleles, the method comprising administering a CD122 binding agent to the subject. Also provided is a composition comprising a CD122 binding agent for use in such a method.Leydig 7739972BRIEF DESCRIPTION OF THE SEVERAL VIEWS OF THE DRAWING(S)

[0006] Figs. 1 A-1C show graphs of pSTAT MFI in gated cell populations of NK cells (Fig. 1 A), cytotoxic CD8+ T cells (Fig. IB), or CD4+ Thl / Th2 T cells (Fig. 1C) treated with anti-CD122 antibody or isotype control antibody.

[0007] Figs. 2A-2C show graphs of the Ki67+ proliferating cells on gated cell populations of NK cells (Fig. 2A), cytotoxic CD8+ T cells (Fig. 2B), or CD4+ Thl / Th2 T cells (Fig. 2C) treated with anti-CD122 antibody or isotype control antibody.

[0008] Figs. 3A-3C show graphs of the Ki67+ proliferating cells on gated cell populations of NK cells (Fig. 3A), cytotoxic CD8+ T cells (Fig. 3B), or CD4+ Thl / Th2 T cells (Fig. 3C) treated with anti-CD122 antibody or isotype control antibody.

[0009] Figs. 4A and 4B shows graphs of Interferon gamma (IFNy) (Fig. 4A) and Granzyme B (Fig. 4B) in unstimulated cells and cells treated with anti-CD122 antibody and isotype control antibody.DETAILED DESCRIPTION OF THE INVENTION

[0010] Provided herein is a method of inhibiting an immune response in a subject with celiac disease or a subject with HLA-DQ2.5 or HLA-DQ8 alleles, the method comprising administering a CD 122 binding agent to the subject.

[0011] Human leukemia antigens (HLAs) belonging to Major Histocompatibility Complex (MHC) class II include HLA-DR, HLA-DP and HLA-DQ. HLA-DQ2 and HLA- DQ8 are isoforms of HLA-DQ that predispose subjects to developing a pathological immune response after ingesting gluten. Indeed, a majority (>90%) of the celiac disease patients have an HLA-DQ2.5 haplotype allele, and most of the remaining patients possess an HLA-DQ8 haplotype allele (NPL 6). These isoforms are thought to have stronger affinity towards a gluten peptide. As with other isoforms, the HLA-DQ2.5 and HLA-DQ8 molecules present processed antigens derived from exogenous sources to a T cell receptor (TCR) on T cells. As a result of digestion of gluten-rich food such as bread in celiac disease patients, immunogenic gluten peptides such as gliadin peptides are formed (NPL 2). The peptides are transported through the small intestine epithelium into lamina propria and deamidated by tissue transglutaminase such as transglutaminase 2 (TG2). The deamidated gliadin peptides are processed by antigen-presenting cells (APCs) which load them on the HLA-DQ2.5 / 8 molecules. The loaded peptides are presented to HLA-DQ2.5 / 8-restricted T cells, and activateLeydig 7739973 innate and adaptive immune responses. This causes inflammatory injury of the small intestinal mucosa and symptoms including various types of gastrointestinal disturbance, nutritional deficiencies, and systemic symptoms. Also, celiac disease often involves an autoimmune response against Tissue Transglutaminase (tTg), aslo known as Transglutaminase 2 (TG2). Thus, once an immune response to gliaden proteins or an autoimmune response to tTg begins, subjects with celiac disease will typically have detectable serum antibodies to gliadins (e.g., deamidated gliadins) or tTg, for instance, anti- tTg IgA or IgG, or anti-gliadin IgA or IgG.

[0012] Not all patients with HLA-DQ2.5 and / or HLA-DQ8 alleles have symptoms of celiac disease. Thus, for instance, some subjects with HLA-DQ2.5 and / or HLA-DQ8 alleles will not yet have developed an immune respose to gliadin proteins and / or tTg. Such subjects will be negative to anti-gliadin and / or anti-tTg antiboides. In these patients, the CD122 binding agent can be administered before the onset of an immune response against gliadin or tTg to prevent, reduce the speed of onset, or reduce the severity of onset of an immune response upon ingesting gluten. In other embodiments, the subject will have active celiac disease in which an immune response to gliadin or tTg has already started, which subjects will be positive for anti -gliadin and / or anti-tTg antibodies. The CD122 binding agent can be administered to these subejects to reduce the severity of the immune response. The onset or severity of an immune response to gliaden or tTg can be determined by any suitable method known in the art, such as by measuring the level (titre) of anti-tTg or anti-gliadin antibodies, or serum levels of IL-2.

[0013] In some embodiments, the CD122 binding agent comprises an immunoglobulin heavy chain variable region and an immunoglobulin light chain variable region, each of which comprise three complementarity determining regions (CDRs), usually referred to as CDR1, CDR2, or CDR3. The CDR regions also can be referred to using an “H” or “L” in the nomenclature to denote the heavy or light chain, respectively, i.e., CDRH1, CDRH2, CDRH3, CDRL1, CDRL2, or CDRL3. The CDRs of a given Ig sequence can be determined by any of several conventional numbering schemes, such as Kabat, Chothia, Martin (Enhanced Chothia), IGMT, or AHo (see, e.g., Kabat, et al., Sequences of Proteins of Immunological Interest, U.S. Department of Health and Human Services, NIH (1991); Chothia, et al., Canonical Structures for the Hypervariable Regions of Immunoglobulins, J. Mol. Biol., 196:901-917 (1987); Al-Lazikani et al., Standard Conformations for the Canonical Structures of Immunoglobulins, J. Mol. Biol., 273:927 - 948 (1997); AbhinandanLeydig 7739974 et al., Analysis and Improvements to Kabat and Structurally Correct Numbering of Antibody Variable Domains, Mol. Immunol., 45: 3832 - 3839 (2008); Lefranc et al., The IMGT unique numbering for immunoglobulins, T cell Receptors and Ig-like domains, The Immunologist, 7 : 132-136 (1999); Lefranc et al., IMGT unique numbering for immunoglobulin and T cell receptor variable domains and I superfamily V-like domains, Dev. Comp. Immunol., 27: 55 - 77 (2003); and Honegger et al., Yet another numbering scheme for immunoglobulin variable domains: an automatic modeling and analysis tool, J. Mol. Biol. 309: 657 - 670 (2001).

[0014] Provided herein is a CD 122 binding agent comprising an immunoglobulin heavy chain variable region and an immunoglobulin light chain variable region, wherein the immunoglobulin heavy chain variable region comprises SEQ ID NO: 113, or at least the CDR regions thereof, and the immunoglobulin light chain variable region comprises SEQ ID NO: 114, or at least the CDR regions thereof, wherein the CDR regions are as determined by Kabat, Chothia, Martin (Enhanced Chothia), IGMT, or AHo, .

[0015] Also provided herein is a CD 122 binding agent comprising an immunoglobulin heavy chain variable region and an immunoglobulin light chain variable region, wherein the immunoglobulin heavy chain variable region comprises one of SEQ ID NO: 37-69, or at least the CDRs thereof; and the immunoglobulin light chain variable region comprises the CDRs of any of SEQ ID NOs: 70-77, wherein the CDRs are as determined in accordance with any of the various known immunoglobulin numbering schemes (e.g., Kabat, Chothia, Martin (Enhanced Chothia), IGMT, or AHo).

[0016] Also provided herein is a CD122 binding agent comprising an immunoglobulin heavy chain variable region and an immunoglobulin light chain variable region, wherein the immunoglobulin heavy chain variable region comprises an amino acid sequence with at least 80% , 85%, or 90% sequence identity (e.g., at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity) to any one of SEQ ID NOs: 37- 69; and the immunoglobulin light chain variable region comprises an amino acid sequence with at least 80% , 85%, or 90% sequence identity (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity) to any of SEQ ID NOs: 70-77. In some embodiments, the immunoglobulin heavy chain variable region comprises the CDRs of any of SEQ ID NOs: 37-69 and has an amino acid sequence with at least 80% , 85%, or 90% sequence identityLeydig 7739975(e.g., at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity) thereto; and the immunoglobulin light chain variable region comprises the CDRs of any of SEQ ID NOs: 70-77 and has an amino acid sequence with at least 80% , 85% , or 90% sequence identity (e.g., at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity) thereto; wherein the CDRs are as determined according to Kabat, Chothia, Martin (Enhanced Chothia), IGMT, or AHo.

[0017] Also provided herein is a CD 122 binding agent comprising an immunoglobulin heavy chain and an immunoglobulin light chain, wherein, the immunoglobulin heavy chain variable region comprises SEQ ID NO: 69; an amino acid sequence with at least 80% , 85% , or 90% sequence identity (e.g., at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity) to SEQ ID NO; 69; and / or at least the CDRs of SEQ ID NO: 69, wherein the CDR regions are as determined in accordance with Kabat, Chothia, Martin (Enhanced Chothia), IGMT, or AHo; and the immunoglobulin light chain variable region comprises SEQ ID NO: 77; an amino acid sequence with at least 80%, 85% , or 90% sequence identity (e.g., at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity) to SEQ ID NO: 77; and / or at least the CDR regions of SEQ ID NO: 77, wherein the CDR regions are as determined by Kabat, Chothia, Martin (Enhanced Chothia), IGMT, or AHo.

[0018] In some embodiments, the CD122 binding agent comprises a heavy chain variable region of SEQ ID NO: 69 and light chain variable region of SEQ ID NO: 77, or at least the CDRs thereof as determined by Kabat. In some embodiments, the antibody comprises a heavy chain variable region of SEQ ID NO: 69 and light chain variable region of SEQ ID NO: 77, or at least the CDRs thereof as determined by Chothia. In some embodiments, the antibody comprises a heavy chain variable region of SEQ ID NO: 69 and light chain variable region of SEQ ID NO: 77, or at least the CDRs thereof as determined by Martin. In someLeydig 7739976 embodiments, the antibody comprises a heavy chain variable region of SEQ ID NO: 69 and light chain variable region of SEQ ID NO: 77, or at least the CDRs thereof as determined by IGMT. In some embodiments, the antibody comprises a heavy chain variable region of SEQ ID NO: 69 and light chain variable region of SEQ ID NO: 77, or at least the CDRs thereof as determined by AHo. By way of further example, the CD122 binding agent can comprise an immunoglobulin heavy chain comprising SEQ ID NO: 115 and an immunoglobulin light chain comprising SEQ ID NO: 116, or an amino acid sequence with at least 80% , 85% , or 90% sequence identity (e.g., at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity) to SEQ ID NO: 115 and 116, respectively, optionally wherein the sequence retains the heavy chain and light chain CDRs of SEQ ID NO: 115 and 116, respectively, wherein the CDRs are as determined in accordance with any of the various known immunoglobulin numbering schemes (e.g., Kabat, Chothia, Martin (Enhanced Chothia), IGMT, or AHo).

[0019] Also provided herein is a CD 122 binding agent comprising an immunoglobulin heavy chain and an immunoglobulin light chain, wherein, the immunoglobulin heavy chain variable region comprises SEQ ID NO: 68; an amino acid sequence with at least 80% , 85% , or 90% sequence identity (e.g., at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity) to SEQ ID NO: 68; and / or at least the CDRs of SEQ ID NO: 68, wherein the CDR regions are as determined in accordance with Kabat, Chothia, Martin (Enhanced Chothia), IGMT, or AHo; and the immunoglobulin light chain variable region comprises SEQ ID NO: 77; an amino acid sequence with at least 80% , 85% , or 90% sequence identity (e.g., at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity) to SEQ ID NO: 77; and / or at least the CDR regions of SEQ ID NO: 77, wherein the CDR regions are as determined by Kabat, Chothia, Martin (Enhanced Chothia), IGMT, or AHo.

[0020] In some embodiments, the CD122 binding agent comprises a heavy chain variable region of SEQ ID NO: 68 and light chain variable region of SEQ ID NO: 77, or at least theLeydig 7739977CDRs thereof as determined by Kabat. In some embodiments, the antibody comprises a heavy chain variable region of SEQ ID NO: 68 and light chain variable region of SEQ ID NO: 77, or at least the CDRs thereof as determined by Chothia. In some embodiments, the antibody comprises a heavy chain variable region of SEQ ID NO: 68 and light chain variable region of SEQ ID NO: 77, or at least the CDRs thereof as determined by Martin. In some embodiments, the antibody comprises a heavy chain variable region of SEQ ID NO: 68 and light chain variable region of SEQ ID NO: 77, or at least the CDRs thereof as determined by IGMT. In some embodiments, the antibody comprises a heavy chain variable region of SEQ ID NO: 68 and light chain variable region of SEQ ID NO: 77, or at least the CDRs thereof as determined by AHo. By way of further example, the CD122 binding agent can comprise an immunoglobulin heavy chain comprising SEQ ID NO: 165 and an immunoglobulin light chain comprising SEQ ID NO: 116, or an amino acid sequence with at least 80% , 85% , or 90% sequence identity (e.g., at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity) to SEQ ID NO: 165 and 116, respectively, optionally wherein the sequence retains the heavy chain and light chain CDRs of SEQ ID NO: 165 and 116, respectively, wherein the CDRs are as determined in accordance with any of the various known immunoglobulin numbering schemes (e.g., Kabat, Chothia, Martin (Enhanced Chothia), IGMT, or AHo).

[0021] In yet another aspect, the disclosure provides a CD122 binding agent comprising an immunoglobulin heavy chain variable region and immunoglobulin light chain variable region, wherein the immunoglobulin heavy chain and light chain variable regions of the CD 122 binding agent comprises the following CDRs when determined in accordance with Kabat numbering: a CDRH1 comprising SEQ ID NO: 108; a CDRH2 comprising SEQ ID NO: 109; a CDRH3 comprising SEQ ID NO: 98; a CDRL1 comprising SEQ ID NO: 110; a CDRL2 comprising SEQ ID NO: 111; and a CDRL3 comprising SEQ ID NO: 112.

[0022] In some embodiments, the immunoglobulin heavy and light chain variable regions comprises the following CDRs when determined in accordance with Kabat numbering: CDRH1 comprises any one of SEQ ID NOs: 78-93; CDRH2 comprises any one of SEQ ID NOs: 94-97; CDRH3 comprises SEQ ID NO: 98; CDRL1 comprises any one of SEQ ID NOs: 99-102; CDRL2 comprises SEQ ID NO: 103 or 104; and CDRL3 comprises any one of SEQ ID NOs: 105-107.Leydig 7739978

[0023] In another aspect, the disclosure provides a CD122 binding agent comprising an immunoglobulin heavy chain and an immunoglobulin light chain, wherein, the immunoglobulin heavy chain variable region comprises SEQ ID NO: 150, or at least the CDR regions thereof, and the immunoglobulin light chain variable region comprises SEQ ID NO: 151, or at least the CDR regions thereof, wherein the CDR regions are as determined by Kabat, Chothia, Martin (Enhanced Chothia), IGMT, or AHo.

[0024] Also provided is a CD122 binding agent comprising an immunoglobulin heavy chain variable region and an immunoglobulin light chain variable region, wherein the immunoglobulin heavy chain variable region comprises any one of SEQ ID NOs: 1-24 or at least the CDRs thereof; and the immunoglobulin light chain variable region comprises any one of SEQ ID NOs: 25-36 or at least the CDRs thereof, wherein the CDR regions are as determined by Kabat, Chothia, Martin (Enhanced Chothia), IGMT, or AHo.

[0025] Also provided herein is a CD 122 binding agent comprising an immunoglobulin heavy chain variable region and an immunoglobulin light chain variable region, wherein the immunoglobulin heavy chain variable region comprises an amino acid sequence with at least; 80% , 85% , or 90% sequence identity (e.g., at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity) to any one of SEQ ID NOs: 1- 24; and the immunoglobulin light chain variable region comprises at least 80% , 85% , or 90% sequence identity (e.g., at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity) to any one of SEQ ID NOs: 25-36. In some embodiments, the immunoglobulin heavy chain variable region comprises the CDRs of any of SEQ ID NOs: 1-24 and has an amino acid sequence with at least 80% , 85% , or 90% sequence identity (e.g., at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity) thereto; and the immunoglobulin light chain variable region comprises the CDRs of any of SEQ ID NOs: 25-36, and has an amino acid sequence with at least 80% , 85% , or 90% sequence identity (e.g., at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at leastLeydig 773997989%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity) thereto; wherein the CDRs are as determined according to Kabat, Chothia, Martin (Enhanced Chothia), IGMT, or AHo.

[0026] Also provided is a CD122 binding agent comprising an immunoglobulin heavy chain and an immunoglobulin light chain, wherein the immunoglobulin heavy chain variable region comprises SEQ ID NO: 24; an amino acid sequence with at least 80% , 85% , or 90% sequence identity (e.g.,at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity) to SEQ ID NO: 24; and / or at least the CDR regions of SEQ ID NO: 24, wherein the CDR regions are as determined in accordance with Kabat, Chothia, Martin (Enhanced Chothia), IGMT, or AHo; and the immunoglobulin light chain variable region comprises SEQ ID NO: 35; an amino acid sequence with at least 80% , 85% , or 90% sequence identity (e.g.,at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity) to SEQ ID NO: 35; and / or at least the CDR regions thereof, wherein the CDR regions are as determined by Kabat, Chothia, Martin (Enhanced Chothia), IGMT, or AHo.

[0027] In some embodiments, the CD122 binding agent comprises a heavy chain variable region of SEQ ID NO: 24 and light chain variable region of SEQ ID NO: 35, or at least the CDRs thereof as determined by Kabat. In some embodiments, the antibody comprises a heavy chain variable region of SEQ ID NO: 24 and light chain variable region of SEQ ID NO: 35, or at least the CDRs thereof as determined by Chothia. In some embodiments, the antibody comprises a heavy chain variable region of SEQ ID NO: 24 and light chain variable region of SEQ ID NO: 35, or at least the CDRs thereof as determined by Martin. In some embodiments, the antibody comprises a heavy chain variable region of SEQ ID NO: 24 and light chain variable region of SEQ ID NO: 35, or at least the CDRs thereof as determined by IGMT. In some embodiments, the antibody comprises a heavy chain variable region of SEQ ID NO: 24 and light chain variable region of SEQ ID NO: 35, or at least the CDRs thereof as determined by AHo. By way of further example, the CD122 binding agent can comprise an immunoglobulin heavy chain comprising SEQ ID NO: 152 and an immunoglobulin lightLeydig 77399710 chain comprising SEQ ID NO: 153, or an amino acid sequence with at least 80% , 85% , or 90% sequence identity (e.g., at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity) to SEQ ID NOs: 152 and 153, optionally wherein the sequence retains the heavy chain and light chain CDRs of SEQ ID NOs: 152 and 153 as determined in accordance with any of the various known immunoglobulin numbering schemes (e.g., Kabat, Chothia, Martin (Enhanced Chothia), IGMT, or AHo).

[0028] Also provided is a CD122 binding agent comprising an immunoglobulin heavy chain and an immunoglobulin light chain, wherein the immunoglobulin heavy chain variable region comprises SEQ ID NO: 23; an amino acid sequence with at least 80% , 85% , or 90% sequence identity (e.g., at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity) to SEQ ID NO: 23; and / or at least the CDR regions of SEQ ID NO: 23, wherein the CDR regions are as determined in accordance with Kabat, Chothia, Martin (Enhanced Chothia), IGMT, or AHo; and the immunoglobulin light chain variable region comprises SEQ ID NO: 35; an amino acid sequence with at least 80% , 85% , or 90% sequence identity (e.g., at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity) to SEQ ID NO: 35; and / or at least the CDR regions thereof, wherein the CDR regions are as determined by Kabat, Chothia, Martin (Enhanced Chothia), IGMT, or AHo.

[0029] In some embodiments, the CD122 binding agent comprises a heavy chain variable region of SEQ ID NO: 23 and light chain variable region of SEQ ID NO: 35, or at least the CDRs thereof as determined by Kabat. In some embodiments, the antibody comprises a heavy chain variable region of SEQ ID NO: 23 and light chain variable region of SEQ ID NO: 35, or at least the CDRs thereof as determined by Chothia. In some embodiments, the antibody comprises a heavy chain variable region of SEQ ID NO: 23 and light chain variable region of SEQ ID NO: 35, or at least the CDRs thereof as determined by Martin. In some embodiments, the antibody comprises a heavy chain variable region of SEQ ID NO: 23 and light chain variable region of SEQ ID NO: 35, or at least the CDRs thereof as determined byLeydig 77399711IGMT. In some embodiments, the antibody comprises a heavy chain variable region of SEQ ID NO: 23 and light chain variable region of SEQ ID NO: 35, or at least the CDRs thereof as determined by AHo. By way of further example, the CD122 binding agent can comprise an immunoglobulin heavy chain comprising SEQ ID NO: 157 and an immunoglobulin light chain comprising SEQ ID NO: 153, or an amino acid sequence with at least 80% , 85% , or 90% sequence identity (e.g., at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity) to SEQ ID NOs: 157 and 153, optionally wherein the sequence retains the heavy chain and light chain CDRs of SEQ ID NOs: 157 and 153 as determined in accordance with any of the various known immunoglobulin numbering schemes (e.g., Kabat, Chothia, Martin (Enhanced Chothia), IGMT, or AHo).

[0030] Also provided is a CD122 binding agent comprising an immunoglobulin heavy chain and an immunoglobulin light chain, wherein the immunoglobulin heavy chain variable region comprises SEQ ID NO: 16; an amino acid sequence with at least 80% , 85% , or 90% sequence identity (e.g., at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity) to SEQ ID NO: 16; and / or at least the CDR regions of SEQ ID NO: 16, wherein the CDR regions are as determined in accordance with Kabat, Chothia, Martin (Enhanced Chothia), IGMT, or AHo; and the immunoglobulin light chain variable region comprises SEQ ID NO: 28; an amino acid sequence with at least 80% , 85% , or 90% sequence identity (e.g., at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity) to SEQ ID NO: 28; and / or at least the CDR regions thereof, wherein the CDR regions are as determined by Kabat, Chothia, Martin (Enhanced Chothia), IGMT, or AHo.

[0031] In some embodiments, the CD122 binding agent comprises a heavy chain variable region of SEQ ID NO: 16 and light chain variable region of SEQ ID NO: 28, or at least the CDRs thereof as determined by Kabat. In some embodiments, the antibody comprises a heavy chain variable region of SEQ ID NO: 16 and light chain variable region of SEQ ID NO: 28, or at least the CDRs thereof as determined by Chothia. In some embodiments, theLeydig 77399712 antibody comprises a heavy chain variable region of SEQ ID NO: 16 and light chain variable region of SEQ ID NO: 28, or at least the CDRs thereof as determined by Martin. In some embodiments, the antibody comprises a heavy chain variable region of SEQ ID NO: 16 and light chain variable region of SEQ ID NO: 28, or at least the CDRs thereof as determined by IGMT. In some embodiments, the antibody comprises a heavy chain variable region of SEQ ID NO: 16 and light chain variable region of SEQ ID NO: 28, or at least the CDRs thereof as determined by AHo. By way of further example, the CD122 binding agent can comprise an immunoglobulin heavy chain comprising SEQ ID NO: 159 and an immunoglobulin light chain comprising SEQ ID NO: 161, or an amino acid sequence with at least 80% , 85% , or 90% sequence identity (e.g., at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity) to SEQ ID NOs: 159 and 161, optionally wherein the sequence retains the heavy chain and light chain CDRs of SEQ ID NOs: 159 and 161 as determined in accordance with any of the various known immunoglobulin numbering schemes (e.g., Kabat, Chothia, Martin (Enhanced Chothia), IGMT, or AHo).

[0032] According to another aspect, the disclosure provides a CD122 binding agent comprises heavy and light chain immunoglobulin variable regions with the following CDRs when determined by Kabat numbering: a CDRH1 comprising SEQ ID NO: 146; a CDRH2 comprising SEQ ID NO: 147; and a CDRH3 comprising SEQ ID NO: 148; a CDRL1 comprising SEQ ID NO: 138; a CDRL2 comprising SEQ ID NO: 139; and a CDRL3 comprising SEQ ID NO: 149. In some embodiments, the CDRH1 comprises any of SEQ ID NOs: 117-126; CDRH2 comprises any one of SEQ ID NOs: 127-135; CDRH3 comprises SEQ ID NO: 136 or 137; CDRL1 comprises SEQ ID NO: 138, CDRL2 comprises SEQ ID NO: 139; and CDRL3 comprises any of SEQ ID NOs: 140-145.

[0033] Further provided is a CD 122 binding agent comprising the heavy and light chain variable regions set forth in Table 1 A or IB or at least the CDRs thereof as determined Kabat, Chothia, Martin (Enhanced Chothia), IGMT, or AHo. Also provided is a CD122 binding agent comprising the CDR regions set forth in Table 1C or ID when determined according to Kabat numbering.

[0034] Sequence “identity,” as described herein, can be determined by comparing a nucleic acid or amino acid sequence of interest to a reference nucleic acid or amino acid sequence. The percent identity is the number of nucleotides or amino acid residues that areLeydig 77399713 the same (i.e., that are identical) as between the sequence of interest and the reference sequence divided by the length of the longest sequence (i.e., the length of either the sequence of interest or the reference sequence, whichever is longer). A number of mathematical algorithms for obtaining the optimal alignment and calculating identity between two or more sequences are known and incorporated into a number of available software programs. Examples of such programs include CLUSTAL-W, T-Coffee, and ALIGN (for alignment of nucleic acid and amino acid sequences), BLAST programs (e.g., BLAST 2.1, BL2SEQ, and later versions thereof) and FASTA programs (e.g., FASTA3x, FASTM, and SSEARCH) (for sequence alignment and sequence similarity searches). Sequence alignment algorithms also are disclosed in, for example, Altschul et al., J. Molecular Biol., 215(3): 403-410 (1990), Beigert et al., Proc. Natl. Acad. Sci. USA, 106( Q): 3770-3775 (2009), Durbin et al., eds., Biological Sequence Analysis: Probalistic Models of Proteins and Nucleic Acids, Cambridge University Press, Cambridge, UK (2009), Soding, Bioinformatics, 21(1) 951-960 (2005), Altschul et al., Nucleic Acids Res., 25(Y1): 3389-3402 (1997), and Gusfield, Algorithms on Strings, Trees and Sequences, Cambridge University Press, Cambridge UK (1997)).

[0035] Variation in sequence identity can be accomplished through addition, substitution, or deletion of one or more amino acid residues. An amino acid “replacement” or “substitution” refers to the replacement of one amino acid at a given position or residue by another amino acid at the same position or residue within a polypeptide sequence. The amino acid replacement or substitution can be conservative, semi-conservative, or non-conservative depending upon whether the substitution is by an amino acid residue that has similar properties to the residue being replaced. A functional way to define common properties between individual amino acids is to analyze the normalized frequencies of amino acid changes between corresponding proteins of homologous organisms (Schulz and Schirmer, Principles of Protein Structure, Springer-Verlag, New York (1979)). According to such analyses, groups of amino acids may be defined where amino acids within a group exchange preferentially with each other, and therefore resemble each other most in their impact on the overall protein structure (Schulz and Schirmer, supra).

[0036] Amino acids can be broadly grouped as “aromatic” or “aliphatic.” An aromatic amino acid includes an aromatic ring. Examples of “aromatic” amino acids include histidine (H or His), phenylalanine (F or Phe), tyrosine (Y or Tyr), and tryptophan (W or Trp). Nonaromatic amino acids are broadly grouped as “aliphatic.” Examples of “aliphatic” amino acids include glycine (G or Gly), alanine (A or Ala), valine (V or Vai), leucine (L or Leu),Leydig 77399714 isoleucine (I or He), methionine (M or Met), serine (S or Ser), threonine (T or Thr), cysteine (C or Cys), proline (P or Pro), glutamic acid (E or Glu), aspartic acid (A or Asp), asparagine (N or Asn), glutamine (Q or Gin), lysine (K or Lys), and arginine (R or Arg).

[0037] Aliphatic amino acids may be sub-divided into four sub-groups. The “large aliphatic non-polar sub-group” consists of valine, leucine, and isoleucine. The “aliphatic slightly-polar sub-group” consists of methionine, serine, threonine, and cysteine. The “aliphatic polar / charged sub-group” consists of glutamic acid, aspartic acid, asparagine, glutamine, lysine, and arginine. The “small-residue sub-group” consists of glycine and alanine. The group of charged / polar amino acids may be sub-divided into three sub-groups: the “positively-charged sub-group” consisting of lysine and arginine, the “negatively-charged sub-group” consisting of glutamic acid and aspartic acid, and the “polar sub-group” consisting of asparagine and glutamine.

[0038] Aromatic amino acids may be sub-divided into two sub-groups: the “nitrogen ring sub-group” consisting of histidine and tryptophan and the “phenyl sub-group” consisting of phenylalanine and tyrosine.

[0039] Examples of conservative amino acid substitutions include substitutions of amino acids within the sub-groups described above, for example, lysine for arginine and vice versa such that a positive charge may be maintained, glutamic acid for aspartic acid and vice versa such that a negative charge may be maintained, serine for threonine such that a free -OH can be maintained, and glutamine for asparagine such that a free -NH2 can be maintained. “Semiconservative mutations” include amino acid substitutions of amino acids within the same groups listed herein, but not within the same sub-group. For example, the substitution of aspartic acid for asparagine, or asparagine for lysine, involves amino acids within the same group, but different sub-groups. “Non-conservative mutations” involve amino acid substitutions between different groups, for example, lysine for tryptophan, or phenylalanine for serine, etc.

[0040] In some embodiments, the CD122 binding agent can comprise, consist essentially of, or consist of the immunoglobulin heavy and light chain variable region or full heavy and light chain polypeptides provided herein. The CD 122 binding agent can be any type of molecule or construct comprising at least the specified immunoglobulin heavy and light chain variable regions. Thus, the CD 122 binding agent can be, for instance, a whole immunoglobulin or antibody, as described herein, or an antigen -binding (CD 122 binding) immunoglobulin or antibody “fragment.” The term “fragment” used with respect to anLeydig 77399715 antibody or immunoglobulin means any molecule or construct that comprises some part of an immunoglobulin or antibody and binds the target antigen. Such a fragment will generally comprise at least the parts of the heavy and light chain variable regions including the CDRs, and may also include parts of the constant regions, optionally along with other elements that are not normally part of an immunoglobulin or antibody (e.g., linkers, etc.). Examples of such “fragments” include, but are not limited to, (i) a Fab fragment, which is a monovalent fragment consisting of the VL, VH, CL, and CHi domains, (ii) a F(ab’)2 fragment, which is a bivalent fragment comprising two Fab fragments linked by a disulfide bridge at the hinge region, (iii) a Fv fragment consisting of the VL and VH domains of a single arm of an antibody, (iv) a Fab’ fragment, which results from breaking the disulfide bridge of an F(ab’)2 fragment using mild reducing conditions; (v) a diabody; (vi) a single-chain variable region (scFv), and (vii) a disulfide-stabilized Fv fragment (dsFv).

[0041] In some embodiments, the CD122 binding agent comprises an immunoglobulin heavy chain constant region, such as a fragment crystallizable (Fc) region or portion thereof. The Fc region can be of any Ig class / subclass (IgA (IgAl, IgA2), IgD, IgE, IgG (IgGl, IgG2, IgG3 and IgG4),IgM , including variants thereof. In a particular embodiment, the CD 122 binding agent comprises an Fc region that binds an Fc receptor of an antigen-presenting cell (e.g., dendritic cell, macrophage, Langerhans cell, or B cell). The Fc receptor can be an Fey receptor (FcyR), such as FcyRI (CD64), FcyRIIA (CD32), FcyRIIB (CD32), FcyRIIIA (CD16a), FcyRIIIB (CD16b). In one embodiment, the CD122 binding agent comprises an Fc region that binds FcyR, such as IgGl. Thus, in some embodiments, the CD122 binding agent is a “whole” or “complete” Ig (i.e., an antibody). In additional embodiments, the CD122 binding agent is an IgG antibody, particularly an IgGl antibody. In additional embodiments, the CD122 agent is an IgG antibody, particularly an IgG4 antibody.

[0042] In some embodiments, the CD122 binding agent comprises an Fc region that has reduced (including substantially or completely abolished) binding to one or more (or all) Fey receptors and, thus, reduced immune effector function. The CD 122 binding agent can comprise, for example, an IgG Fc region (e.g., an IgGl or IgG4) with mutations that reduce effector functions, for instance removal of the Fc N-linked glycosylation site in human IgGl, leucine to glutamic acid substitution at position 235 of IgGl Fc, or other modifications of the hinge region positions 234-237; double mutation Leu234Ala and Leu235Ala (“LALA” mutation); substitution P329G in IgGl; or both P329G and LALA mutations. In someLeydig 77399716 embodiments, the CD 122 binding agent comprises an IgGl Fc with the LALA mutation, alone or together with P329G.

[0043] The isolated CD122-binding agent also can be an antibody conjugate. In this respect, the isolated CD122-binding agent can be a conjugate comprising the CD122-binding agent (e.g., anti-CD122 antibody or antibody fragment) and another biologically active moiety. For example, the CD122 binding agent can be conjugated to a peptide, a fluorescent molecule, or a chemotherapeutic agent, particularly an agent useful in suppressing an immune response.

[0044] The CD 122 binding agent can be, or can be obtained from, a human antibody, a non-human antibody, or a chimeric antibody. By “chimeric” is meant an antibody or fragment thereof comprising both human and non-human regions. Preferably, the isolated CD122 binding agent is a humanized antibody. A “humanized” antibody is a monoclonal antibody comprising a human antibody scaffold and at least one CDR obtained or derived from a non-human antibody. Non-human antibodies include antibodies isolated from any non-human animal, such as, for example, a rodent (e.g., a mouse or rat). A humanized antibody can comprise, one, two, or three CDRs obtained or derived from a non-human antibody. In a preferred embodiment of the invention, CDRH3 of the CD122 binding agent is obtained or derived from a mouse monoclonal antibody, while the remaining variable regions and constant region of the inventive CD 122 binding agent are obtained or derived from a human monoclonal antibody.

[0045] A human antibody, a non-human antibody, a chimeric antibody, or a humanized antibody can be obtained by any means, including via in vitro sources (e.g., a hybridoma or a cell line producing an antibody recombinantly) and in vivo sources (e.g., rodents). Methods for generating antibodies are known in the art and are described in, for example, Kohler and Milstein, Eur. J. Immunol., 5: 511-519 (1976); Harlow and Lane (eds.), Antibodies: A Laboratory Manual, CSH Press (1988); and Janeway et al. (eds.), Immunobiology, 5th Ed., Garland Publishing, New York, NY (2001); Starkie et al., PLoS One, 11(3). eOl 52282 (2016)). In certain embodiments, a human antibody or a chimeric antibody can be generated using a transgenic animal (e.g., a mouse) wherein one or more endogenous immunoglobulin genes are replaced with one or more human immunoglobulin genes. Examples of transgenic mice wherein endogenous antibody genes are effectively replaced with human antibody genes include, but are not limited to, the Medarex HUMAB-MOUSE™, the Kirin TC MOUSE™, and the Kyowa Kirin KM-MOUSE™ (see, e.g., Lonberg, Nat. Biotechnol.,Leydig 7739971723(9): 1117-25 (2005), and Lonberg, Handb. Exp. Pharmacol., 181: 69-97 (2008)). A humanized antibody can be generated using any suitable method known in the art (see, e.g., An, Z. (ed.), Therapeutic Monoclonal Antibodies: From Bench to Clinic, John Wiley & Sons, Inc., Hoboken, New Jersey (2009)), including, e.g., grafting of non-human CDRs onto a human antibody scaffold (see, e.g., Kashmiri et al., Methods, 36(1): 25-34 (2005); and Hou et al., J. Biochem., 144(1): 115-120 (2008)). In one embodiment, a humanized antibody can be produced using the methods described in, e.g., U.S. Patent Application Publication 2011 / 0287485 Al.

[0046] The CD122 binding agent can have any suitable affinity for human CD122. The term “affinity” refers to the equilibrium constant for the reversible binding of two agents and is expressed as the dissociation constant (KD). Affinity of a binding agent to a ligand, such as affinity of an antibody for an epitope, can be, for example, from about 1 picomolar (pM) to about 100 micromolar (pM) (e.g., from about 1 picomolar (pM) to about 1 nanomolar (nM), from about 1 nM to about 1 micromolar (pM), or from about 1 pM to about 100 pM). In one embodiment, the CD 122 binding agent can bind to a CD 122 protein with a KD less than or equal to 1.5 nM (e.g., 1.4 nM, 1.3 nM, 1.2 nM, 1.0 nM, 0.9 nM, 0.8 nM, 0.7 nM, 0.6 nM, 0.5 nM, 0.4 nM, 0.3 nM, 0.2 nM, 0.1 nM, 0.05 nM, 0.025 nM, 0.01 nM, 0.001 nM, or a range defined by any two of the foregoing values). In another embodiment, the CD 122 binding agent can bind to CD122 with a KD less than or equal to 200 pM (e.g., 190 pM, 175 pM, 150 pM, 125 pM, 110 pM, 100 pM, 90 pM, 80 pM, 75 pM, 60 pM, 50 pM, 40 pM, 30 pM, 25 pM, 20 pM, 15 pM, 10 pM, 5 pM, 1 pM, or a range defined by any two of the foregoing values). In some embodiments, the CD122 binding agent is cross-reactive with cynomolgus CD122 with an affinity in any of the foregoing ranges discussed with respect to human CD122. Immunoglobulin affinity for an antigen or epitope of interest can be measured using any art-recognized assay. Such methods include, for example, fluorescence activated cell sorting (FACS), separable beads (e.g., magnetic beads), surface plasmon resonance (SPR), solution phase competition (KinExA®), antigen panning, and / or ELISA (see, e.g., Janeway et al. (eds.), Immunobiology, 5th ed., Garland Publishing, New York, NY, 2001).

[0047] IL-2RP (CD122) is the common beta receptor subunit shared for IL-15 and IL-2. IL- 15 and IL-2 signaling mediate the survival and maintenance of tissue resident memory T cells (TRM) and NK cell subsets. The presence of long-lived and persistent TRM have been shown to be pathogenic drivers of tissue-specific immune-mediated inflammation, present in the skin of dermatologic diseases, where defined borders of inflammation often recur. TRMLeydig 77399718 are also observed in other tissue-specific inflammatory disorders including gastroenterology and rheumatology.

[0048] In some embodiments, the CD 122 binding agent binds CD 122 and at least partially (or completely) inhibits IL- 15 signaling. Alternatively or in addition, the CD 122 binding agent binds CD 122 and at least partially (or completely) inhibits IL-2 signaling. For instance, in some embodiments, the CD 122 binding agent inhibits IL- 15 signaling at least partially (or completely) and inhibits IL-2 signaling through the low affinity IL-2 receptor (comprised of CD 122 and the common gamma subunit, CD 132), without eliminating (or without inhibiting) IL-2 signaling through the high affinity IL-2 receptor (comprised of CD122, CD132 and the alpha receptor subunit for IL-2, CD25). The CD122 binding agent can bind CD122 on any CD122-expressing cell type, such as regulatory T-cells (Tregs), memory T-cells, CD56+T cells (NKT cells), innate lymphocytes (ILCs), and gamma delta T cells. Without wishing to be bound by any particular theory or mechanism of action, it is believed that the inhibition of IL- 15 signaling (in whole or in part) and inhibition of IL-2 signaling (in whole or in part) through the low affinity IL-2 receptor expressed on NK cells and T cells, without eliminating IL-2 signaling through the high affinity IL-2 receptor expressed on regulatory T cells, is believed to provide additional anti-inflammatory benefit by reducing NK cell and pathogenic T cell numbers while sparing or potentially enhancing regulatory T cell numbers.

[0049] The CD122 binding agent can be part of a composition suitable for administration to a mammal. Preferably, the composition is a pharmaceutically acceptable (e.g., physiologically acceptable) composition, which comprises a carrier, preferably a pharmaceutically acceptable (e.g., physiologically acceptable) carrier, and the inventive amino acid sequences, antigen-binding agent, or vector. Any suitable carrier can be used within the context of the invention, and such carriers are well known in the art. The choice of carrier will be determined, in part, by the particular site to which the composition may be administered and the particular method used to administer the composition. The composition also can comprise any other excipient used in the formulation of therapeutic molecules (e.g., proteins or antibodies), particularly parenteral formulations, including, for instance, buffers, tonicity modifiers, stabilizers, surfactants and the like. The composition optionally can be sterile. The composition can be frozen or lyophilized for storage and reconstituted in a suitable sterile carrier prior to use. The compositions can be generated in accordance withLeydig 77399719 conventional techniques described in, e.g., Remington: The Science and Practice of Pharmacy, 21st Edition, Lippincott Williams & Wilkins, Philadelphia, PA (2001).

[0050] The dosage used will depend on the particular circumstances in which the binding agent is employed. A typical dose of the CD 122 binding agent can be, for example, in the range of 1 pg / kg to 100 mg / kg of animal or human body weight; however, doses below or above this exemplary range are within the scope of the invention. Therapeutic or prophylactic efficacy can be monitored by periodic assessment of treated patients. For repeated administrations over several days or longer, depending on the condition, the treatment can be repeated until a desired suppression of disease symptoms occurs. However, other dosage regimens may be useful and are within the scope of the invention. The desired dosage can be delivered by a single bolus administration of the composition, by multiple bolus administrations of the composition, or by continuous infusion administration of the composition.

[0051] The CD 122 binding agent can be administered to a mammal using standard administration techniques, including oral, intravenous, intraperitoneal, subcutaneous, pulmonary, transdermal, intramuscular, intranasal, buccal, sublingual, or suppository administration. The composition preferably is suitable for parenteral administration. The term “parenteral,” as used herein, includes intravenous, intramuscular, subcutaneous, rectal, vaginal, and intraperitoneal administration. More preferably, the composition is administered to a mammal using peripheral systemic delivery by intravenous, intraperitoneal, or subcutaneous injection.

[0052] Once administered to a mammal (e.g., a human), the biological activity of the inventive CD 122 binding agent can be measured by any suitable method known in the art. For example, the biological activity can be assessed by determining the stability of a particular CD 122 binding agent. In one embodiment of the invention, the CD 122 binding agent (e.g., an antibody) has an in vivo half-life between about 30 minutes and 45 days (e.g., about 30 minutes, about 45 minutes, about 1 hour, about 2 hours, about 4 hours, about 6 hours, about 10 hours, about 12 hours, about 1 day, about 5 days, about 10 days, about 15 days, about 25 days, about 35 days, about 40 days, about 45 days, or a range defined by any two of the foregoing values). In another embodiment, the CD122 binding agent has an in vivo half-life between about 2 hours and 20 days (e.g., about 5 hours, about 10 hours, about 15 hours, about 20 hours, about 2 days, about 3 days, about 7 days, about 12 days, about 14 days, about 17 days, about 19 days, or a range defined by any two of the foregoing values).Leydig 77399720In another embodiment, the CD122 binding agent has an in vivo half-life between about 10 days and about 40 days (e.g., about 10 days, about 13 days, about 16 days, about 18 days, about 20 days, about 23 days, about 26 days, about 29 days, about 30 days, about 33 days, about 37 days, about 38 days, about 39 days, about 40 days, or a range defined by any two of the foregoing values). In other embodiments, the biological activity of the inventive CD122 binding agent can be assessed by monitoring receptor occupancy on CD122-expressing cells in peripheral blood and tissues, such as skin tissues. In other embodiments, the biological activity of the inventive CD122-binding agent can be assessed by monitoring reduction of immune cells that express CD122, such as NK cells.

[0053] The CD122-binding agent of the invention may be administered alone or in combination with other active agents or drugs. In this respect, the CD122-binding agent can be used in combination with at least one other inflammatory or autoimmune disorderinhibiting agent including, for example, other monoclonal antibodies, disease-killing viruses, gene therapy, cytokine therapy and adoptive T-cell transfer, and / or surgery. In some embodiments, the CD122-binding agent is used in combination with (e.g., co-therapy; administered simultaneously or sequentially in any order, or in any dosing regimen) with a CD28 antagonist, such as a cytotoxic T-lymphocyte-associated protein 4 (CTLA4) (e.g., CTLA4-Ig, belatacept, or abatacept). The inventive CD122-binding agent described herein can also be used in combination with at least one other immunosuppressive agent, including, for example, methotrexate, corticosteroids, and other small molecule agents used to treat autoimmune and inflammatory disease. When the inventive method treats an infectious disease, the CD122-binding agent can be administered in combination with at least one antibacterial agent or at least one anti-viral agent. In this respect, the anti-bacterial agent can be any suitable antibiotic known in the art. The anti-viral agent can be any vaccine of any suitable type that specifically targets a particular virus (e.g., live-attenuated vaccines, subunit vaccines, recombinant vector vaccines, and small molecule anti-viral therapies (e.g., viral replication inhibitors and nucleoside analogs). In some embodiments, the CD122-binding agent is used in combination with (e.g., co-therapy; administered simultaneously or sequentially in any order, or in any dosing regimen) with a Janus kinase (JAK) inhibitor, for instance, abrocitinib, baricitinib, delgocitinib, fedratinib, filgotinib, oclacitinib, peficitinib, pacritinib, ruxolitinib, tofacitinib, or upadacitinib.

[0054] The following examples further illustrate the invention but, of course, should not be construed as in any way limiting its scope.Leydig 77399721EXAMPLES

[0055] The following examples describe particular CD 122 binding agent heavy chain polypeptide and light chain polypeptide sequences, according to embodiments of the invention. The antibodies used in these examples are as set forth below.

[0056] The antibodies were produced in transient expression in ExpiCHO-S mammalian cells and purified by Protein A affinity chromatography. The antibody sequences for the MIO-1275 and M6-pl625 series antibodies are summarized in Tables 1 A and IB, respectively, wherein “H” and “L” chains refer to heavy and light chains. The CDRs of these antibodies as determined according to Kabat numbering are presented in Tables 1C and ID. The amino acid and nucleic acid sequences for the full heavy and light chains for certain antibodies are summarized in Table IE. The MIO-1275 and M6-pl625 represent two classes of antibodies, the members of which were developed through mutagenesis and screening from parental heavy and light chains.Table 1ALeydig 77399722Table IBLeydig 77399723Table 1CLeydig 77399724Table IDLeydig 77399725Table IE

[0057] Binding affinities of the antibodies are set forth in Tables 2A and 2B. Surface plasmon resonance (SPR) was used to determine the binding affinities. The M6-1625 and MIO-1275 antibodies were captured onto a Cytiva Protein A Chip for 60 seconds at 0.5 pg / mL for 60 seconds. The antibodies were exposed to recombinant human IL-2RP or cynomolgus IL-2RP (corresponding to residues Alal-Thr215 of the extracellular domains excluding the signal peptide) at typical concentrations ranging from 0.4 nM to 11 nM with typical 300 second associations and 1200 second dissociations using a BiacoreS200 instrument. Sensorgrams were fit globally using a 1 : 1 binding model in the Biacore T200 Evaluation Software to calculate on- and off-rates and KD values.Leydig 77399726Table 2 A: M6-pl625 Binding Affinity DataLeydig 77399727Table 2B MIO-1275 Binding Affinity DataLeydig 77399728EXAMPLE 2

[0058] This Example demonstrates that humanized anti-CD122 IgGl LALA antibodies (APE15428) inhibit IL-2- and IL-15-induced receptor signaling in primary human immune cells.

[0059] Primary human PBMCs were isolated from whole blood of healthy donors. Each well of a 96 well plate was seeded with 1 x 106cells. Antibodies (APE15428 or isotype control) were titrated at the concentrations indicated in Figs. 1 A-C, starting at 1000 nM with 1 :7 dilutions, and added to the cells. Recombinant IL-2 and recombinant IL-15 were added to the cells and stimulated for 30 minutes. Cells were harvested and fixed with PFA followed by ice-cold methanol. Cells were then stained with antibodies for phenotypic markers and with anti-phospho STAT5 antibody. Finally, cells were analyzed on an Agilent Penteon flow cytometer using NovoExpress software. Data were analyzed using Graphpad Prism software. The MFI of pSTAT5 antibody on each gated cell population was graphed as a percentage of MFI for cells treated with equivalent concentration of isotype control. Results are shown in Figs. 1 A-C.EXAMPLE 2

[0060] This Example demonstrates that humanized anti-CD122 IgGl LALA antibodies (APE15428) inhibit IL-2- and IL-15-induced receptor signaling in primary human immune cells.

[0061] Primary human PBMCs were isolated from whole blood of healthy donors. Each well of a 96 well plate was seeded with 1 x 106cells. Antibodies (APE15428 or isotype control) were titrated at the concentrations indicated in Figs. 2A-C, starting at 1000 nM with 1 :6 dilutions, and added to the cells. Recombinant IL-2 and recombinant IL-15 were added to the cells. Cells were cultured for 7 days. Cells were harvested and surface-stained with antibodies for phenotypic markers then fixed, permeabilized and stained with anti-Ki67 antibody. Finally, cells were analyzed on an Agilent Penteon flow cytometer using NovoExpress software. Data were analyzed using Graphpad Prism software. Ki67+ proliferating cells in each gated population were graphed as a percentage of cells proliferating when treated with equivalent concentration of isotype control. Results are shown in Figs. 2A-C.Leydig 77399729EXAMPLE 3

[0062] This Example demonstrates that humanized anti-CD122 IgGl LALA antibodies (APE15428) inhibit IL-2- and IL-15-induced proliferation of primary human immune cells.

[0063] Primary human PBMCs were isolated from whole blood of donors diagnosed with celiac disease. Each well of a 96 well plate was seeded with 500,000 cells. Antibodies (APE15428 or isotype control) were titrated at the concentrations indicated in Figs. 2A-C, starting at 1000 nM with 1 :6 dilutions, and added to the cells. Recombinant IL-2 and recombinant IL-15 were added to the cells. Cells were cultured for 7 days. Cells were harvested and surface-stained with antibodies for phenotypic markers then fixed, permeabilized and stained with anti-Ki67 antibody. Finally, cells were analyzed on an Agilent Penteon flow cytometer using NovoExpress software. Data were analyzed using Graphpad Prism software. Ki67+ proliferating cells in each gated population were graphed as a percentage of cells proliferating when treated with equivalent concentration of isotype control. Results are shown in Figs. 3A-3C.EXAMPLE 4

[0064] This Example demonstrates that humanized anti-CD122 IgGl LALA antibodies (APE15428) inhibit pro-inflammatory cytokines and mediators of cytotoxicity from activated T cells.

[0065] Primary human PBMCs were isolated from whole blood of donors diagnosed with celiac disease. Each well of a 96 well plate was seeded with 200,000 cells. Antibodies (APE15428 or isotype control) were added at a concentration of 100 nM. Anti-CD3 and anti- CD28 antibodies were then added to the cells. Cells were cultured for 3 days. Following 3 day culture, supernatant was harvested and analyzed for Interferon gamma and Granzyme B by MSD assay and read on an MSD instrument according to manufacturer’s instructions. Data were analyzed using Graphpad Prism software and graphed as a percentage of untreated stimulated cells. Significance testing was performed using a t test (p < 0.01). Results are shown in Figs. 4A and 4B.

[0066] All references, including publications, patent applications, and patents, cited herein are hereby incorporated by reference to the same extent as if each reference wereLeydig 77399730 individually and specifically indicated to be incorporated by reference and were set forth in its entirety herein.

[0067] The use of the terms “a” and “an” and “the” and “at least one” and similar referents in the context of describing the invention (especially in the context of the following claims) are to be construed to cover both the singular and the plural, unless otherwise indicated herein or clearly contradicted by context. The use of the term “at least one” followed by a list of one or more items (for example, “at least one of A and B”) is to be construed to mean one item selected from the listed items (A or B) or any combination of two or more of the listed items (A and B), unless otherwise indicated herein or clearly contradicted by context. The terms “comprising,” “having,” “including,” and “containing” are to be construed as open-ended terms (i.e., meaning “including, but not limited to,”) unless otherwise noted. Recitation of ranges of values herein are merely intended to serve as a shorthand method of referring individually to each separate value falling within the range, unless otherwise indicated herein, and each separate value is incorporated into the specification as if it were individually recited herein. All methods described herein can be performed in any suitable order unless otherwise indicated herein or otherwise clearly contradicted by context. The use of any and all examples, or exemplary language (e.g., “such as”) provided herein, is intended merely to better illuminate the invention and does not pose a limitation on the scope of the invention unless otherwise claimed. No language in the specification should be construed as indicating any non-claimed element as essential to the practice of the invention.

[0068] Preferred embodiments of this invention are described herein, including the best mode known to the inventors for carrying out the invention. Variations of those preferred embodiments may become apparent to those of ordinary skill in the art upon reading the foregoing description. The inventors expect skilled artisans to employ such variations as appropriate, and the inventors intend for the invention to be practiced otherwise than as specifically described herein. Accordingly, this invention includes all modifications and equivalents of the subject matter recited in the claims appended hereto as permitted by applicable law. Moreover, any combination of the above-described elements in all possible variations thereof is encompassed by the invention unless otherwise indicated herein or otherwise clearly contradicted by context.

Claims

Leydig 77399731CLAIM(S):

1. A method of inhibiting an immune response in a subject with celiac disease or a subject with HLA-DQ2.5 or HLA-DQ8 haplotype alleles, the method comprising administering a CD 122 binding agent to the subject.

2. The method of claim 1, wherein the subject is asymptomatic for celiac disease.

3. The method of claim 1, wherein the subject is negative for antibodies against tissue transgutaminase (tTg).

4. The method of any of claims 1-3, wherein the CD122 binding agent is administered to the subject before the onset of an immune response against a gliadin protein or tTg, and the method prevents an immune response against a gliadin protein or tTg, or reduces the speed or severity of the onset of an immune response immune response against a gliadin protein or tTg.

5. The method of any of claim 1, wherein the subject has a symptom of celiac disease.

6. The method of claim 5, wherein the subject is positive for anti -tTg antibodies.

7. The method of claim 5 or 6, wherein the CD 122 binding agent is administered to the subject after the onset of an immune response against a gliadin protein or tTg, and the method reduces the severity of the immune response.

8. The method of any of claims 1-7, wherein the CD122 binding agent comprises an immunoglobulin heavy chain variable region and an immunoglobulin light chain variable region, wherein(a) the immunoglobulin heavy chain variable region comprises: a CDR1 comprising SEQ ID NO: 108; a CDR2 comprising SEQ ID NO: 109; and a CDR3 comprising SEQ ID NO: 98; and the immunoglobulin light chain variable region comprises a CDR1 comprising SEQ ID NO: 110; a CDR2 comprising SEQ ID NO: 111; andLeydig 77399732 a CDR3 comprising SEQ ID NO: 112; when determined according to Kabat numbering, optionally wherein: the immunoglobulin heavy chain variable region comprises a CDR1 comprising SEQ ID NO: 78; a CDR2 comprising SEQ ID NO: 94; and a CDR3 comprising SEQ ID NO: 98; and the immunoglobulin light chain variable region comprises a CDR1 comprising SEQ ID NO: 99; a CDR2 comprising SEQ ID NO: 103; and a CDR3 comprising SEQ ID NO: 105, when determined according to Kabat numbering;(b) the immunoglobulin heavy chain variable region comprises SEQ ID NO: 113 and the immunoglobulin light chain variable region comprises SEQ ID NO: 114;(c) the immunoglobulin heavy chain variable region comprises at least 80% sequence identity to any one of SEQ ID NOs: 37-69, and / or comprises at least the CDR regions of any one of SEQ ID NOs: 37-69, and the immunoglobulin light chain variable region comprises at least 80% sequence identity to any one of SEQ ID NO: 70-77, and / or comprises at least the CDR regions of any one of SEQ ID NO: 70-77; optionally wherein the immunoglobulin heavy chain variable region comprises at least 80% sequence identity to any one of SEQ ID NOs: 68 or 69, and / or comprises at least the CDR regions of any one of SEQ ID NOs: 68 or 69, and the immunoglobulin light chain variable region comprises at least 80% sequence identity to SEQ ID NO: 77, and / or comprises at least the CDR regions of SEQ ID NO: 77;(e) the immunoglobulin heavy chain variable region comprises: a CDR1 comprising SEQ ID NO: 146; a CDR2 comprising SEQ ID NO: 147; and a CDR3 comprising SEQ ID NO: 148; and the immunoglobulin light chain variable region comprises a CDR1 comprising SEQ ID NO: 138;Leydig 77399733 a CDR2 comprising SEQ ID NO: 139; and a CDR3 comprising SEQ ID NO: 140; when determined according to Kabat numbering; optionally wherein: the immunoglobulin heavy chain variable region comprises: a CDR1 comprising SEQ ID NO: 117 or 124; a CDR2 comprising SEQ ID NO: 127; and a CDR3 comprising SEQ ID NO: 136; and the immunoglobulin light chain variable region comprises a CDR1 comprising SEQ ID NO: 138; a CDR2 comprising SEQ ID NO: 139; and a CDR3 comprising SEQ ID NO: 144 or 145; when determined according to Kabat numbering;(d) the immunoglobulin heavy chain variable region comprises SEQ ID NO: 150 and the immunoglobulin light chain variable region comprises SEQ ID NO: 151; or(f) the immunoglobulin heavy chain variable region comprises at least 80% sequence identity to any one of SEQ ID NOs: 1-24, and / or comprises at least the CDR regions of any one of SEQ ID NOs: 1-24, and the immunoglobulin light chain variable region comprises at least 80% sequence identity to SEQ ID NOs: 25-36, and / or comprises at least the CDR regions of any one of SEQ ID NOs: 25-36; optionally wherein the immunoglobulin heavy chain variable region comprises at least 80% sequence identity to any one of SEQ ID NOs: 16, 23, or 24, and / or comprises at least the CDR regions of any one of SEQ ID NOs: 16, 23, or 24, and the immunoglobulin light chain variable region comprises at least 80% sequence identity to SEQ ID NO: 28 or 35, and / or comprises at least the CDR regions of SEQ ID NO: 28 or 35.

9. The method of claim 8, wherein the immunoglobulin heavy chain variable region comprises at least 90% sequence identity to any one of SEQ ID NOs: 37-69, and / or comprises at least the CDR regions of any one of SEQ ID NOs: 37-69.Leydig 7739973410. The method of claim 8, wherein the immunoglobulin light chain variable region comprises at least 90% sequence identity to any one of SEQ ID NOs: 70-77, and / or comprises at least the CDR regions of any one of SEQ ID NOs: 70-77.

11. The method of claim 8, wherein the immunoglobulin heavy chain variable region comprises: a CDR1 comprising SEQ ID NO: 108; a CDR2 comprising SEQ ID NO: 109; a CDR3 comprising SEQ ID NO: 98; and the immunoglobulin light chain variable region comprises a CDR1 comprising SEQ ID NO: 110, a CDR2 comprising SEQ ID NO: 111, a CDR3 comprising SEQ ID NO: 112; when determined according to Kabat numbering.

12. The method of claim 8, wherein the immunoglobulin heavy chain variable region CDR1 comprises any one of SEQ ID NOs: 78-93.

13. The method of claim 8, wherein the immunoglobulin heavy chain variable region CDR2 comprises any one of SEQ ID NOs: 94-97.

14. The method of claim 8, wherein the immunoglobulin light chain variable region CDR1 comprises SEQ ID NOs: 99-102.

15. The method of claim 8, wherein the immunoglobulin light chain variable region CDR2 comprises SEQ ID NOs: 103 or 104.

16. The method of claim 8, wherein the immunoglobulin light chain variable region CDR3 comprises SEQ ID NOs: 105-107.

17. The method of claim 8, comprising the immunoglobulin heavy chain variable region of any one of SEQ ID NOs: 37-69.

18. The method of claim 8, comprising the immunoglobulin light chain variable region of any one of SEQ ID NOs: 70-77.Leydig 7739973519. The method of claim 8, wherein the immunoglobulin heavy chain variable region comprises: a CDR1 comprising SEQ ID NO: 78; a CDR2 comprising SEQ ID NO: 94; and a CDR3 comprising SEQ ID NO: 98; and the immunoglobulin light chain variable region comprises a CDR1 comprising SEQ ID NO: 99; a CDR2 comprising SEQ ID NO: 103; and a CDR3 comprising SEQ ID NO: 105; when determined according to Kabat numbering.

20. The method of claim 8, wherein the immunoglobulin heavy chain variable region comprises at least 90% sequence identity to SEQ ID NO: 69, or comprises at least the CDRs of SEQ ID NO: 69, and the immunoglobulin light chain variable region comprises at least 90% sequence identity to SEQ ID NO: 77, or comprises at least the CDRs of SEQ ID NO: 77.

21. The method of claim 8, wherein the immunoglobulin heavy chain variable region comprises SEQ ID NO: 69, and the immunoglobulin light chain variable region comprises SEQ ID NO: 77.

22. The method of claim 8, wherein the immunoglobulin heavy chain variable region comprises at least 90% sequence identity to SEQ ID NO: 68, or comprises at least the CDRs of SEQ ID NO: 68, and the immunoglobulin light chain variable region comprises at least 90% sequence identity to SEQ ID NO: 77, or comprises at least the CDRs of SEQ ID NO: 77.

23. The method of claim 8, wherein the immunoglobulin heavy chain variable region comprises SEQ ID NO: 68, and the immunoglobulin light chain variable region comprises SEQ ID NO: 77.

24. The method of claim 8, wherein the immunoglobulin heavy chain variable region comprises at least 90% sequence identity to any one of SEQ ID NOs: 1-24, and / or comprises at least the CDR regions of any one of SEQ ID NOs: 1-24.Leydig 7739973625. The method of claim 8, wherein the immunoglobulin light chain variable region comprises at least 90% sequence identity to any one of SEQ ID NOs: 25-36, and / or comprises at least the CDR regions of any one of SEQ ID NOs: 25-36.

26. The method of claim 8, wherein the immunoglobulin heavy chain variable region comprises: a CDR1 comprising SEQ ID NO: 146; a CDR2 comprising SEQ ID NO: 147; and a CDR3 comprising SEQ ID NO: 148; and the immunoglobulin light chain variable region comprises a CDR1 comprising SEQ ID NO: 138; a CDR2 comprising SEQ ID NO: 139; and a CDR3 comprising SEQ ID NO: 149; when determined according to Kabat numbering.

27. The method of claim 8, wherein the immunoglobulin heavy chain variable region CDR1 comprises any one of SEQ ID NOs: 117-126.

28. The method of claim 8, wherein the immunoglobulin heavy chain variable region CDR2 comprises any one of SEQ ID NOs: 127-135.

29. The method of claim 8, wherein the immunoglobulin heavy chain variable region CDR3 comprises SEQ ID NO: 136 or 137.

30. The method of claim 8, wherein the immunoglobulin light chain variable region CDR3 comprises any one of SEQ ID NOs: 140-145.

31. The method of claim 8, comprising the immunoglobulin heavy chain variable region of any one of SEQ ID NOs: 1-24.

32. The method of claim 8, comprising the immunoglobulin light chain variable region of any one of SEQ ID NOs: 25-36.

33. The method of claim 8, wherein the immunoglobulin heavy chain variable region comprises: a CDR1 comprising SEQ ID NO: 117;Leydig 77399737 a CDR2 comprising SEQ ID NO: 127; and a CDR3 comprising SEQ ID NO: 136; and the immunoglobulin light chain variable region comprises a CDR1 comprising SEQ ID NO: 138; a CDR2 comprising SEQ ID NO: 139; and a CDR3 comprising SEQ ID NO: 144; when determined according to Kabat numbering.

34. The method of claim 8, wherein the immunoglobulin heavy chain variable region comprises: a CDR1 comprising SEQ ID NO: 124; a CDR2 comprising SEQ ID NO: 127; and a CDR3 comprising SEQ ID NO: 136; and the immunoglobulin light chain variable region comprises a CDR1 comprising SEQ ID NO: 138; a CDR2 comprising SEQ ID NO: 139; and a CDR3 comprising SEQ ID NO: 145; when determined according to Kabat numbering.

35. The method of claim 8, wherein the immunoglobulin heavy chain variable region comprises at least 90% sequence identity to SEQ ID NO: 24, or comprises at least the CDRs of SEQ ID NO: 24, and the immunoglobulin light chain variable region comprises at least 90% sequence identity to SEQ ID NO: 35, or comprises at least the CDRs of SEQ ID NO: 35.

36. The method of claim 8, wherein the immunoglobulin heavy chain variable region comprises SEQ ID NO: 24, and the immunoglobulin light chain variable region comprises SEQ ID NO: 35.

37. The method of claim 8, wherein the immunoglobulin heavy chain variable region comprises at least 90% sequence identity to SEQ ID NO: 23, or comprises at least the CDRs of SEQ ID NO: 23, and the immunoglobulin light chain variable region comprises at least 90% sequence identity to SEQ ID NO: 35, or comprises at least the CDRs of SEQ ID NO: 35.Leydig 7739973838. The method of claim 8, wherein the immunoglobulin heavy chain variable region comprises SEQ ID NO: 23, and the immunoglobulin light chain variable region comprises SEQ ID NO: 35.

39. The method of claim 8, wherein the immunoglobulin heavy chain variable region comprises at least 90% sequence identity to SEQ ID NO: 16, or comprises at least the CDRs of SEQ ID NO: 16, and the immunoglobulin light chain variable region comprises at least 90% sequence identity to SEQ ID NO: 28, or comprises at least the CDRs of SEQ ID NO: 28.

40. The method of claim 8, wherein the immunoglobulin heavy chain variable region comprises SEQ ID NO: 16, and the immunoglobulin light chain variable region comprises SEQ ID NO: 28.

41. The method of any of claims 8-40, wherein the CD122 binding agent is an antibody, an antigen-binding antibody fragment, or a conjugate thereof.

42. The method of any of claims 8-40, wherein the CD122 binding agent is a F(ab’)2, Fab’, Fab, Fv, scFv, dsFv, or a single chain binding polypeptide.

43. The method of any of claims 8-40, wherein the CD 122 binding agent comprises an IgG Fc region that binds an Fc receptor on an antigen presenting cell, optionally an Fc region of IgGl.

44. A composition for inhibiting an immune response in a subject with celiac disease or a subject with a subject with HLA-DQ2.5 or HLA-DQ8 haplotype alleles, the composition comprising a CD122 binding agent and a pharmaceutically acceptable carrier.

45. The composition of claim 44, for use according to any of claims 1-43.

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