CD122-binding agents and methods of use thereof

Abstract

Provided are CD122 binding agents comprising immunoglobulin heavy chain polypeptides and immunoglobulin light chain polypeptides, as well as related compositions and methods of making and using the same.

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to U.S. Provisional Patent Application No. 63 / 423,416, filed November 7, 2022, the entire disclosure of which is incorporated herein by reference.

[0002] Incorporation by Reference of Electronically Submitted Materials The computer readable nucleotide / amino acid sequence listing, submitted concurrently herewith and identified as follows, is incorporated herein by reference in its entirety: One 214,653 byte ASCII (text) file entitled "769570_ST.26.xml", created on November 2, 2023. [Background technology]

[0003] Background of the Invention Interleukin-2 (IL-2) and interleukin-15 (IL-15) are two important cytokines involved in the regulation of the immune system. IL-2 is involved in the development and homeostasis of regulatory T cells (Tregs), whereas IL-15 controls the development of NK cells and NK-T cells and the survival of memory T cells. IL-2 receptor (IL-2R) and IL-15 receptor (IL-15R) each contain three subunits, designated α, β, and γ. IL-2R and IL-15R each have a unique α subunit (CD25 and CD125, respectively), but the two receptors share common β and γ subunits (CD122 and CD132).

[0004] IL-2 and IL-15 signaling are involved in pathogenic immune system responses, therefore there is a need for CD122-binding agents that can modulate such signaling. Summary of the Invention

[0005] Provided herein is a CD122-binding agent comprising an immunoglobulin heavy chain and an immunoglobulin light chain, comprising an immunoglobulin heavy chain variable region comprising SEQ ID NO: 113, or at least the CDR regions thereof, and an immunoglobulin light chain variable region comprising SEQ ID NO: 114, or at least the CDR regions thereof.

[0006] In another aspect, the present 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: 69, or at least the CDR regions thereof, and an immunoglobulin light chain variable region comprises SEQ ID NO: 77, or at least the CDR regions thereof.

[0007] 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 an immunoglobulin light chain variable region comprises SEQ ID NO: 151, or at least the CDR regions thereof.

[0008] In another aspect, the present 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: 24, or at least the CDR regions thereof, and an immunoglobulin light chain variable region comprises SEQ ID NO: 35, or at least the CDR regions thereof.

[0009] The present disclosure further provides methods for inhibiting an immune response and treating an inflammatory or autoimmune disease in a mammal by administering a CD122-binding agent to the mammal. Nucleic acid sequences encoding the aforementioned immunoglobulin polypeptides and binding agents, and related compositions and methods, are also provided. [Brief explanation of the drawings]

[0010] A brief description of some drawings FIG. 1 shows the results of a cell-based receptor binding assay illustrating the binding capacity of anti-CD122 antibodies to CHO-K1 cells expressing human IL-2βγ.

[0011] FIG. 2 shows the results of a cell-based receptor binding assay illustrating the binding capacity of anti-CD122 antibodies to CHO-K1 cells expressing cynomolgus IL-2βγ.

[0012] FIG. 3 shows the results of a cell-based functional assay demonstrating the ability of anti-CD122 antibodies to inhibit IL-2-induced pSTAT5 luciferase activity in HEK cells.

[0013] FIG. 4 shows the results of a CTG (cell titer glo)-based proliferation assay illustrating the ability of a humanized anti-CD122 IgG4 antibody to inhibit IL-2 or IL-15-induced proliferation of PHA-stimulated human primary cell blasts.

[0014] FIG. 5 shows the binding activity of anti-CD122 IgG4 antibodies to CHO-K1 cells expressing human or cynomolgus IL-2βγ.

[0015] FIG. 6 shows the effect of anti-CD122 IgG4 antibody on IL-2 or IL-15-induced proliferation of purified primary human NK cells.

[0016] FIG. 7 shows the effect of a humanized anti-CD122 IgG4 antibody on IL-2 or IL-15-induced proliferation and survival of primary human NK cells gated in PBMC cultures.

[0017] FIG. 8 shows the effect of humanized anti-CD22 IgG4 antibodies on IL-2 or IL-15 binding to HEK cells expressing human IL-2βγ.

[0018] FIG. 9 shows the effect of humanized anti-CD122 IgG4 antibodies on IL-15 or IL-15 / IL-1-5RA-induced proliferation of primary human T cell blasts.

[0019] FIG. 10 shows the effect of humanized anti-CD122 IgG4 antibodies on IL-15 or IL-15 / IL1-5RA-induced proliferation of primary human NK cells.

[0020] FIG. 11 shows the effect of humanized anti-CD122 IgG1 LALA antibody on IL-2 or IL-15-induced proliferation of primary human NK cells.

[0021] FIG. 12 shows the effect of humanized anti-CD122 IgG1 LALA antibody on IL-2 or IL-15 induced proliferation of primary human pan-T cells.

[0022] FIG. 13 shows the effect of humanized anti-CD122 antibodies alone or in combination with CTLA4-Ig in the xenogeneic NSG(huIL-15) / Hu-PBMC GvHD model.

[0023] FIG. 14 shows the effect of humanized anti-CD122 antibodies in a xenogeneic NSG(huIL-15Tg) / HuPBMC graft-versus-host disease (GvHD) model. DETAILED DESCRIPTION OF THE INVENTION

[0024] Detailed Description of the Invention The present invention provides CD122-binding agents. The CD122-binding agents comprise an immunoglobulin heavy chain variable region and an immunoglobulin light chain variable region, each of which comprises three complementarity-determining regions (CDRs), typically referred to as CDR1, CDR2, or CDR3. The CDR regions may also be referred to using "H" or "L" in the nomenclature used to designate 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, USDapartment 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); Abhinandan 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)). .

[0025] Provided herein are CD122 binding agents comprising an immunoglobulin heavy chain variable region and an immunoglobulin light chain variable region, including an immunoglobulin heavy chain variable region comprising SEQ ID NO: 113, or at least the CDR regions thereof, and an immunoglobulin light chain variable region comprising SEQ ID NO: 114, or at least the CDR regions thereof, the CDR regions being determined by Kabat, Chothia, Martin (Enhanced Chothia), IGMT, or AHo.

[0026] Also provided herein are CD122-binding agents comprising an immunoglobulin heavy chain variable region and an immunoglobulin light chain variable region, including an immunoglobulin heavy chain variable region comprising any of SEQ ID NOS: 37-69, or at least the CDRs thereof, and an immunoglobulin light chain variable region comprising the CDRs of any of SEQ ID NOS: 70-77, the CDRs being determined according to various known immunoglobulin numbering schemes (e.g., Kabat, Chothia, Martin (Enhanced Chothia), IGMT, or AHo).

[0027] 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 has 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%, at least 100%, at least 101%, at least 102%, at least 103%, at least 104%, at least 105%, at least 106%, at least 107%, at least 108%, at least 109%, at least 110%, at least 111%, at least 112%, at least 113%, at least 114%, at least 115%, at least 116%, at least 117%, at least 118%, at least 119%, at least 120%, at least 121%, at least 122%, at least 123%, at least 124%, at least 125%, at least 126%, at least 127%, at least 128%, at least 129%, at least 130%, at least 131%, at least 132%, at least 133%, at least 134%, at least 135%, at least 136%, at least 137%, at least 138%, at least 139%, at least 140%, at least 141%, at least 142%, at least 143%, at least 144%, at least 145%, at least 14 and an immunoglobulin light chain variable region comprising an amino acid sequence having 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 CDRs are determined according to Kabat, Chothia, Martin (Enhanced Chothia), IGMT, or AHo; an immunoglobulin heavy chain variable region comprises the CDRs of any of SEQ ID NOs: 37-69 and shares at least 80%, 85%, or 90% sequence identity thereto (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 an immunoglobulin light chain variable region comprising the CDRs of any of SEQ ID NOs: 70 to 77 and having an amino acid sequence having at least 80%, 85%, or 90% sequence identity thereto (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).

[0028] Also provided herein are CD122-binding agents comprising an immunoglobulin heavy chain and an immunoglobulin light chain, wherein the immunoglobulin heavy chain variable region is SEQ ID NO:69; an amino acid sequence having 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 a sequence similar to that described by Kabat, Chothia, and Martin (Enhanced and an immunoglobulin light chain variable region comprising at least the CDRs of SEQ ID NO:69, the CDR regions as determined according to Kabat, Chothia, Martin (Enhanced Chothia), IGMT, or AHo; and an immunoglobulin light chain variable region comprising SEQ ID NO:77; an amino acid sequence having 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, the CDR regions as determined according to 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: 69 and a light chain variable region of SEQ ID NO: 77, or at least the CDRs determined by Kabat. In some embodiments, the antibody comprises a heavy chain variable region of SEQ ID NO: 69 and a light chain variable region of SEQ ID NO: 77, or at least the CDRs determined by Chothia. In some embodiments, the antibody comprises a heavy chain variable region of SEQ ID NO: 69 and a light chain variable region of SEQ ID NO: 77, or at least the CDRs determined by Martin. In some embodiments, the antibody comprises a heavy chain variable region of SEQ ID NO: 69 and a light chain variable region of SEQ ID NO: 77, or at least the CDRs determined by IGMT. In some embodiments, the antibody comprises a heavy chain variable region of SEQ ID NO: 69 and a light chain variable region of SEQ ID NO: 77, or at least the CDRs determined by AHo. As a further example, a 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 amino acid sequences having 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: 115 and 116, respectively, and optionally, which sequences retain the heavy and light chain CDRs of SEQ ID NOs: 115 and 116, respectively, and which CDRs are numbered according to various known immunoglobulin numbering schemes (e.g., Kabat, Chothia, Martin (Enhanced Chothia), IGMT, or AHo).

[0030] Also provided herein are CD122-binding agents comprising an immunoglobulin heavy chain and an immunoglobulin light chain, wherein the immunoglobulin heavy chain variable region is SEQ ID NO:68; an amino acid sequence having 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 a sequence similar to that described by Kabat, Chothia, and Martin (Enhanced and an immunoglobulin light chain variable region comprising at least the CDRs of SEQ ID NO:68, which are the CDR regions as determined according to Kabat, Chothia, Martin (Enhanced Chothia), IGMT, or AHo; and an immunoglobulin light chain variable region comprising SEQ ID NO:77; an amino acid sequence having 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, which are the CDR regions as determined according to 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: 68 and a 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: 68 and a 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 a 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 a 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 a light chain variable region of SEQ ID NO: 77, or at least the CDRs thereof as determined by AHo. As a further example, the CD122-binding agent comprises an immunoglobulin heavy chain comprising SEQ ID NO: 165 and an immunoglobulin light chain comprising SEQ ID NO: 116, or an amino acid sequence having 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: 165 and 116, respectively, optionally in accordance with various known immunoglobulin numbering schemes (e.g., Kabat, Chothia, Martin (Enhanced The present invention also includes sequences that retain the heavy and light chain CDRs of SEQ ID NOs: 165 and 116, respectively, the CDRs being as determined according to either the IL-16A (IL-16A), IL-16B (IL-16B), IL-16C (IL-16C), IL-16D (IL-16D), IL-16E (IL-16F), IL-16H (IL-16H ...

[0032] In yet another aspect, the present disclosure provides 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 and light chain variable region of the CD122 binding agent comprise the following CDRs as determined according to Kabat numbering: CDRH1 comprising SEQ ID NO: 108; CDRH2 comprising SEQ ID NO: 109; CDRH3 comprising SEQ ID NO: 98; CDRL1 comprising SEQ ID NO: 110; CDRL2 comprising SEQ ID NO: 111; and CDRL3 comprising SEQ ID NO: 112.

[0033] In some embodiments, the immunoglobulin heavy and light chain variable regions comprise the following CDRs as determined according to 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.

[0034] In another aspect, the disclosure provides a CD122-binding agent comprising an immunoglobulin heavy chain and an immunoglobulin light chain, the immunoglobulin heavy chain variable region comprising SEQ ID NO: 150, or at least the CDR regions thereof, and an immunoglobulin light chain variable region comprising 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.

[0035] Also provided is a CD122 binding agent comprising an immunoglobulin heavy chain variable region and an immunoglobulin light chain variable region, comprising an immunoglobulin heavy chain variable region comprising any one of SEQ ID NOs: 1-24 or at least the CDRs thereof; and an immunoglobulin light chain variable region comprising 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.

[0036] 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 has 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 100%, at least 101%, at least 102%, at least 103%, at least 104%, at least 105%, at least 106%, at least 107%, at least 108%, at least 109%, at least 110%, at least 111%, at least 112%, at least 113%, at least 114%, at least 115%, at least 116%, at least 117%, at least 118%, at least 119%, at least 120%, at least 121%, at least 122%, at least 123%, at least 124%, at least 125%, at least 126%, at least 127%, at least 128%, at least 129%, at least 130%, at least 131%, at least 132%, at least 133%, at least 134%, at least 135%, at least 136%, at least 137%, at least 138%, at least 139%, at least 140%, at least 141%, at least 142%, at least 143%, at least 144%, at least 145%, at least 146%, at least 1 and the immunoglobulin light chain variable region comprises an amino acid sequence having 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 having at least 80%, 85%, or 90% sequence identity to said SEQ ID NO (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); and an immunoglobulin light chain variable The region comprises a CDR of any of SEQ ID NOs: 25-36 and has an amino acid sequence having 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 said SEQ ID NO, wherein said CDR is as determined by Kabat, Chothia, Martin (Enhanced Chothia), IGMT, or AHo.

[0037] 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 having 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 defined by the Kabat, Chothia, and Martin (Enhanced and the immunoglobulin light chain variable region comprises SEQ ID NO:35; an amino acid sequence having 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 of said SEQ ID NO:35, wherein said CDR regions are as determined according to Kabat, Chothia, Martin (Enhanced Chothia), IGMT, or AHo.

[0038] In some embodiments, the CD122-binding agent comprises a heavy chain variable region of SEQ ID NO:24 and a light chain variable region of SEQ ID NO:35, or at least the CDRs of that sequence as determined by Kabat. In some embodiments, the antibody comprises a heavy chain variable region of SEQ ID NO:24 and a light chain variable region of SEQ ID NO:35, or at least the CDRs of that sequence as determined by Chothia. In some embodiments, the antibody comprises a heavy chain variable region of SEQ ID NO:24 and a light chain variable region of SEQ ID NO:35, or at least the CDRs of that sequence as determined by Martin. In some embodiments, the antibody comprises a heavy chain variable region of SEQ ID NO:24 and a light chain variable region of SEQ ID NO:35, or at least the CDRs of that sequence as determined by IGMT. In some embodiments, the antibody comprises a heavy chain variable region of SEQ ID NO:24 and a light chain variable region of SEQ ID NO:35, or at least the CDRs of that sequence as determined by AHo. As a further example, a CD122-binding agent can comprise an immunoglobulin heavy chain comprising SEQ ID NO: 152 and an immunoglobulin light chain comprising SEQ ID NO: 153, or an amino acid sequence having 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, the sequence being numbered according to various known immunoglobulin numbering schemes (e.g., Kabat, Chothia, Martin (Enhanced The sequences may comprise sequences retaining the heavy and light chain CDRs of SEQ ID NOs: 152 and 153 as determined according to either the IgA (IgA), IgM (IgChothia), IgM (IGMT), or IgM (AHo).

[0039] Also provided are CD122-binding agents 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 having 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 selected from the group consisting of those described by Kabat, Chothia, and Martin (Enhanced and the immunoglobulin light chain variable region comprises SEQ ID NO:35; an amino acid sequence having 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 of said SEQ ID NO:35, wherein said CDR regions are as determined by Kabat, Chothia, Martin (Enhanced Chothia), IGMT, or AHo.

[0040] In some embodiments, the CD122-binding agent comprises a heavy chain variable region of SEQ ID NO:23 and a light chain variable region of SEQ ID NO:35, or at least the CDRs of that sequence as determined by Kabat. In some embodiments, the antibody comprises a heavy chain variable region of SEQ ID NO:23 and a light chain variable region of SEQ ID NO:35, or at least the CDRs of that sequence as determined by Chothia. In some embodiments, the antibody comprises a heavy chain variable region of SEQ ID NO:23 and a light chain variable region of SEQ ID NO:35, or at least the CDRs of that sequence as determined by Martin. In some embodiments, the antibody comprises a heavy chain variable region of SEQ ID NO:23 and a light chain variable region of SEQ ID NO:35, or at least the CDRs of that sequence as determined by IGMT. In some embodiments, the antibody comprises a heavy chain variable region of SEQ ID NO:23 and a light chain variable region of SEQ ID NO:35, or at least the CDRs of that sequence as determined by AHo. As a further example, a 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 having 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, and optionally, sequences retaining the heavy and light chain CDRs of SEQ ID NOs: 157 and 153 as determined according to any of a variety of known immunoglobulin numbering schemes (e.g., Kabat, Chothia, Martin (Enhanced Chothia), IGMT, or AHo).

[0041] 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 having 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 selected from the group consisting of the Kabat, Chothia, and Martin (Enhanced and the immunoglobulin light chain variable region comprises SEQ ID NO:28; an amino acid sequence having 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 of said SEQ ID NO:28, wherein said CDR regions are as determined by Kabat, Chothia, Martin (Enhanced Chothia), IGMT, or AHo.

[0042] In some embodiments, the CD122-binding agent comprises a heavy chain variable region of SEQ ID NO: 16 and a light chain variable region of SEQ ID NO: 28, or at least the CDRs of that sequence as determined by Kabat. In some embodiments, the antibody comprises a heavy chain variable region of SEQ ID NO: 16 and a light chain variable region of SEQ ID NO: 28, or at least the CDRs of that sequence as determined by Chothia. In some embodiments, the antibody comprises a heavy chain variable region of SEQ ID NO: 16 and a light chain variable region of SEQ ID NO: 28, or at least the CDRs of that sequence as determined by Martin. In some embodiments, the antibody comprises a heavy chain variable region of SEQ ID NO: 16 and a light chain variable region of SEQ ID NO: 28, or at least the CDRs of that sequence as determined by IGMT. In some embodiments, the antibody comprises a heavy chain variable region of SEQ ID NO: 16 and a light chain variable region of SEQ ID NO: 28, or at least the CDRs of that sequence as determined by AHo. As a further example, a 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 having 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, and optionally can comprise a sequence retaining the heavy and light chain CDRs of SEQ ID NOs: 159 and 161 as determined according to any of a variety of known immunoglobulin numbering schemes (e.g., Kabat, Chothia, Martin (Enhanced Chothia), IGMT, or AHo).

[0043] According to another aspect, the disclosure provides a CD122-binding agent comprising heavy and light chain immunoglobulin variable regions having the following CDRs as determined by Kabat numbering: CDRH1 comprising SEQ ID NO: 146; CDRH2 comprising SEQ ID NO: 147; and CDRH3 comprising SEQ ID NO: 148; CDRL1 comprising SEQ ID NO: 138; CDRL2 comprising SEQ ID NO: 139; and CDRL3 comprising SEQ ID NO: 149. In some embodiments, 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.

[0044] Further provided are CD122-binding agents comprising heavy and light chain variable regions, or at least the CDRs thereof, as set forth in Table 1A or 1B, where the CDRs are as determined according to Kabat, Chothia, Martin (Enhanced Chothia), IGMT, or AHo. Also provided are CD122-binding agents comprising the CDR regions set forth in Table 1C or 1D as determined according to Kabat numbering.

[0045] As described herein, sequence "identity" can be determined by comparing a nucleic acid or amino acid sequence of interest with a reference nucleic acid or amino acid sequence. The percent identity is the number of nucleotides or amino acid residues that are the same (i.e., identical) 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). Many mathematical algorithms for finding optimal alignment and calculating the identity between two or more sequences are known and are incorporated into many available software programs. Examples of such programs include CLUSTAL-W, T-Coffee, and ALIGN (for aligning nucleic acid and amino acid sequences), BLAST programs (e.g., BLAST2.1, BL2SEQ, and later versions), and FASTA programs (e.g., FASTA3x, FASTM, and SSEARCH) (for sequence alignment and sequence similarity searches). Sequence alignment algorithms are also disclosed, for example, in Altschul et al., J. Molecular Biol., 215(3):403-410 (1990); Beigert et al., Proc. Natl. Acad. Sci. USA, 106(10):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(7):951-960 (2005); Altschul et al., Nucleic Acids Res., 25(17):3389-3402 (1997); and Gusfield, Algorithms on Strings, Trees and Sequences, Cambridge University Press, Cambridge UK (1997).

[0046] Variation in sequence identity can be achieved by the addition, substitution, or deletion of one or more amino acid residues. An amino acid "exchange" or "substitution" refers to the replacement of one amino acid at a given position or residue in a polypeptide sequence with another amino acid at the same position or residue. Amino acid exchanges or substitutions can be conservative, semi-conservative, or non-conservative, depending on whether the amino acid is replaced with an amino acid residue with similar properties to the replaced residue. A functional method for defining common properties between individual amino acids is the analysis of normalized frequencies of amino acid changes between corresponding proteins of homologous organisms (Schulz and Schirmer, Principles of Protein Structure, Springer-Verlag, New York (1979)). Based on such an analysis, groups of amino acids can be defined as those that preferentially exchange with each other and thus are most similar to each other in their effect on the overall protein structure (Schulz and Schirmer, supra).

[0047] Amino acids are broadly classified as "aromatic" and "aliphatic." Aromatic amino acids contain 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). Non-aromatic amino acids are broadly classified as "aliphatic." Examples of "aliphatic" amino acids include glycine (G or Gly), alanine (A or Ala), valine (V or Val), leucine (L or Leu), isoleucine (I or Ile), 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 Gln), lysine (K or Lys), and arginine (R or Arg).

[0048] Aliphatic amino acids can be divided into four subgroups: the "large aliphatic nonpolar subgroup" consisting of valine, leucine, and isoleucine; the "aliphatic slightly polar subgroup" consisting of methionine, serine, threonine, and cysteine; the "aliphatic polar / charged subgroup" consisting of glutamic acid, aspartic acid, asparagine, glutamine, lysine, and arginine; and the "small residue subgroup" consisting of glycine and alanine. The charged / polar amino acid group can be subdivided into three subgroups: the "positively charged subgroup" consisting of lysine and arginine, the "negatively charged subgroup" consisting of glutamic acid and aspartic acid, and the "polar subgroup" consisting of asparagine and glutamine.

[0049] The aromatic amino acids can be subdivided into two subgroups: the "nitrogen-containing ring subgroup" consisting of histidine and tryptophan, and the "phenyl subgroup" consisting of phenylalanine and tyrosine.

[0050] Examples of conservative amino acid substitutions include substitutions of amino acids within the above subgroups, such as substitutions of lysine with arginine and vice versa, so that a positive charge can be maintained, substitutions of glutamic acid with aspartic acid and vice versa, so that a negative charge can be maintained, substitutions of serine with threonine, so that a free -OH can be maintained, and substitutions of glutamine with asparagine, so that a free -NH2 can be maintained. "Semi-conservative mutations" include substitutions of amino acids within the same group listed herein, but do not include substitutions within the same subgroup. For example, substitutions of aspartic acid with asparagine or asparagine with lysine involve amino acids within the same group but in different subgroups. "Non-conservative mutations" include amino acid substitutions between different groups, such as substitutions of lysine with tryptophan or phenylalanine with serine.

[0051] In some embodiments, a CD122-binding agent can comprise, consist essentially of, or consist of immunoglobulin heavy and light chain variable regions or complete heavy and light chain polypeptides provided herein. A CD122-binding agent can be any type of molecule or construct comprising at least the designated immunoglobulin heavy and light chain variable regions. Thus, a CD122-binding agent can be, for example, a whole immunoglobulin or antibody, or an antigen-binding (CD122-binding) immunoglobulin or antibody "fragment," as described herein. The term "fragment," as used with respect to an antibody or immunoglobulin, refers to any molecule or construct that comprises a portion of an immunoglobulin or antibody and binds to a target antigen. Such fragments generally contain at least a portion of the heavy and light chain variable regions, including the CDRs, and may optionally include a portion of the constant region, along with other elements not normally part of an immunoglobulin or antibody (e.g., linkers, etc.). Examples of such "fragments" include: (i) V L , V H , C L (ii) a Fab fragment, which is a monovalent fragment consisting of the CH1 domain; (iii) a F(ab')2 fragment, which is a bivalent fragment containing two Fab fragments linked by a disulfide bridge at the hinge region; and (iv) a V fragment of a single arm of an antibody. L and V H (iv) Fab' fragments, which result from cleavage of the disulfide bridges of the F(ab')2 fragment using mild reducing conditions; (v) bispecific antibodies; (vi) single-chain variable regions (scFv), and (vii) disulfide-stabilized Fv fragments (dsFv).

[0052] 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 (IgA1, IgA2), IgD, IgE, IgG (IgG1, IgG2, IgG3, and IgG4), IgM, including variants. In certain embodiments, the CD122-binding agent comprises an Fc region that binds to an Fc receptor on an antigen-presenting cell (e.g., a dendritic cell, macrophage, Langerhans cell, or B cell). Fc receptors include FcγRI (CD64), FcγRIIA (CD32), FcγRIIB (CD32), FcγR The CD122-binding agent may be an Fcγ receptor (FcγR), such as FcγRIIIA (CD16a), FcγRIIIB (CD16b), or the like. In one embodiment, the CD122-binding agent comprises an Fc region that binds to an FcγR, such as IgG1. Thus, in some embodiments, the CD122-binding agent is a "whole" or "intact" Ig (i.e., antibody). In a further embodiment, the CD122-binding agent is an IgG antibody, particularly an IgG1 antibody. In a further embodiment, the CD122-binding agent is an IgG antibody, particularly an IgG4 antibody.

[0053] 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) Fcγ receptors, and thus reduced immune effector function. The CD122-binding agent may comprise an IgG Fc region (e.g., IgG1 and IgG4) with a mutation that reduces effector function, such as, for example, removal of the Fc N-linked glycosylation site in human IgG1, a substitution of leucine with glutamic acid at position 235 of IgG1 Fc, or other modification of hinge region positions 234-237; a double mutation of Leu234Ala and Leu235Ala (the "LALA" mutation); a P329G substitution in IgG1; or both the P329G and LALA mutations. In some embodiments, the CD122-binding agent comprises an IgG1 Fc with the LALA mutation, alone or together with P329G.

[0054] The isolated CD122-binding agent can also be an antibody conjugate. In this regard, the isolated CD122-binding agent can be a conjugate comprising a CD122-binding agent (e.g., an anti-CD122 antibody or antibody fragment) and another biologically active moiety. For example, the CD122-binding agent can be conjugated with a peptide, a fluorescent molecule, or a chemotherapeutic agent, particularly an agent useful for suppressing immune responses.

[0055] A CD122-binding agent can be or be derived from a human antibody, a non-human antibody, or a chimeric antibody. "Chimeric" refers to an antibody or fragment thereof that contains 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 a rodent (e.g., a mouse or rat). A humanized antibody can contain one, two, or three CDRs obtained or derived from a non-human antibody. In a preferred embodiment of the present invention, the CDRH3 of the CD122-binding agent is obtained or derived from a murine monoclonal antibody, while the remaining variable and constant regions of the CD122-binding agent of the present invention are obtained or derived from a human monoclonal antibody.

[0056] Human antibody, non-human antibody, chimeric antibody or humanized antibody can be obtained by any means, including in vitro sources (for example, hybridoma or cell line that recombinantly produces antibody) and in vivo sources (for example, rodent).The method of producing antibody is known in the art, and is 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): e0152282 (2016)). In certain embodiments, human or chimeric antibodies can be produced using transgenic animals (e.g., mice) in which one or more endogenous immunoglobulin genes have been replaced with one or more human immunoglobulin genes. Examples of transgenic mice in which endogenous antibody genes have been effectively replaced with human antibody genes include, but are not limited to, the Medarex HUMAB-MOUSE™, Kirin TC MOUSE™, and Kyowa Kirin KM-MOUSE™ (see, e.g., Lonberg, Nat. Biotechnol. 23(9):1117-25 (2005), and Lonberg, Handb. Exp. Pharmacol. Pharmacol. 181:69-97 (2008)). Humanized antibodies can be produced 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, for example, grafting 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, humanized antibodies can be produced using the methods described, for example, in US Patent Application Publication No. 2011 / 0287485 (A1).

[0057] 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 (K D The affinity of a binding agent for a ligand, such as the affinity of an antibody for an epitope, can be, for example, from about 1 picomolar (pM) to about 100 micromolar (μM) (e.g., from about 1 picomolar (pM) to about 1 nanomolar (nM), from about 1 nM to about 1 micromolar (μM), or from about 1 μM to about 100 μM). In one embodiment, the CD122-binding agent has a K of 1.5 nM or less (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). D In another embodiment, the CD122-binding agent may bind to CD122 at a K of 200 pM or less (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). DIn some embodiments, the CD122-binding agent is cross-reactive with cynomolgus monkey CD122 with any of the affinity ranges discussed above for 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).

[0058] IL-2Rβ (CD122) is a common β-receptor subunit 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 TRMs has been shown to be a pathogenic driver of tissue-specific immune-mediated inflammation and is often present in the skin of dermatological diseases, where inflammation becomes well-defined and recurrent. TRMs are also observed in other tissue-specific inflammatory diseases, including gastrointestinal and rheumatoid arthritis.

[0059] In some embodiments, the CD122-binding agent binds to CD122 and at least partially (or completely) inhibits IL-15 signaling. Alternatively, or in addition, the CD122-binding agent binds to CD122 and at least partially (or completely) inhibits IL-2 signaling. For example, in some embodiments, the CD122-binding agent at least partially (or completely) inhibits IL-15 signaling and inhibits IL-2 signaling via the low-affinity IL-2 receptor (composed of CD122 and the common gamma subunit, CD132) without eliminating (or inhibiting) IL-2 signaling via the high-affinity IL-2 receptor (composed of CD122, CD132, and the alpha receptor subunit of IL-2, CD25). The CD122-binding agent can bind to CD122 on any CD122-expressing cell type, such as regulatory T cells (Tregs), memory T cells, CD56+ T cells (NKT cells), innate lymphoid cells (ILCs), and gamma delta T cells. Without wishing to be bound by any particular theory or mechanism of action, it is believed that inhibiting IL-15 signaling (in whole or in part) and inhibiting 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, provides an additional anti-inflammatory effect by sparing or potentially enhancing the number of regulatory T cells while simultaneously reducing the number of NK cells and pathogenic T cells.

[0060] Use / Treatment CD122-binding agents are believed to be particularly useful for inhibiting IL-15 signaling and IL-2 signaling, particularly via the low-affinity IL-2 receptor (composed of CD122 and the common gamma subunit CD132). Thus, the binding agents can be used in methods for treating diseases or disorders, or symptoms thereof, caused or promoted by IL-15 signaling or IL-2 signaling, particularly IL-2 signaling via the low-affinity IL-2 receptor. For example, CD122-binding agents can be used to inhibit inflammatory or immune responses or treat diseases or disorders associated therewith, particularly diseases or disorders characterized by pathogenic memory T cells (including tissue-resident memory T cells (TRM cells)) and NK cells. In some embodiments, signaling to regulatory T cells (Tregs) is maintained in whole or in part (i.e., Treg signaling is not completely, significantly, or not at all inhibited in the presence of the CD122-binding agent compared to such signaling in the absence of the CD122-binding agent). As used herein, negative regulation of the immune system is synonymous with immunosuppression. It will be understood that in some cases, a CD122-binding agent can be administered pre-symptomatically (e.g., prior to exposure to an antigen that elicits an immune response) to prevent, suppress, or reduce the severity of an immune response to the introduction of an antigen.

[0061] In some aspects, CD122-binding agents can be used to treat inflammatory or autoimmune diseases, or to inhibit or suppress immune or inflammatory responses. Examples of inflammatory or autoimmune diseases include, for example, infectious diseases (viral, bacterial, fungal, and parasitic), endotoxic shock associated with infection, arthritis, rheumatoid arthritis including TNF-refractory rheumatoid arthritis, Sjogren's syndrome, asthma, chronic obstructive pulmonary disease (COPD), pelvic inflammatory disease, Behcet's disease, Alzheimer's disease, inflammatory bowel disease including Crohn's disease and ulcerative colitis, Peyronie's disease, celiac disease, gallbladder disease, pilonidal disease, peritonitis, psoriasis, psoriatic arthritis, contact hypersensitivity, allergic diseases, eosinophilia, and the like. Eosinophilic esophagitis, vasculitis, antineutrophil cytoplasmic antibody-associated (ANCA) vasculitis, surgical adhesions, stroke, type 1 diabetes, Lyme disease, arthritis, meningoencephalitis, autoimmune or non-infectious uveitis, immune-mediated inflammatory diseases of the central and peripheral nervous system such as multiple sclerosis, lupus (including systemic lupus erythematosus and chronic discoid lupus erythematosus) and Guillain-Barré syndrome, atopic dermatitis, polymyositis, dermatomyositis, autoimmune hepatitis, fibrosing alveolitis, Graves' disease, IgA nephropathy, idiopathic thrombocytopenic purpura, and Meniere's disease Disease, pemphigus, pemphigoid, primary biliary cholangitis, hepatitis, sarcoidosis, scleroderma (localized scleroderma, systemic sclerosis, and progressive systemic sclerosis), granulomatosis with polyangiitis, other autoimmune diseases, cholangitis, pancreatitis, trauma (surgery), graft-versus-host disease, transplant rejection, ischemic diseases such as myocardial infarction and heart disease including atherosclerosis, periarteritis nodosa (polyarteritis nodosa and microscopic polyangiitis), allergic granulomatous vasculitis, hypersensitivity vasculitis, aortitis syndrome (Takayasu's arteritis), temporal arteritis, intravascular coagulation, bone resorption , osteoporosis, osteoarthritis, periodontitis including chronic periodontitis, and hypochlorhydria, Still's disease, Cogan's syndrome, RS3PE, polymyalgia rheumatica, fibromyalgia syndrome, antiphospholipid antibody syndrome, eosinophilic fasciitis, Guillain-Barré syndrome, myasthenia gravis, chronic atrophic gastritis, Goodpasture's syndrome, rapidly progressive glomerulonephritis, megaloblastic anemia, hemolytic anemia, autoimmune neutropenia, Hashimoto's thyroiditis, autoimmune adrenal insufficiency, primary hypothyroidism, idiopathic Addison's disease (chronic adrenal insufficiency), herpes gestationis, linear IgA bullous dermatosis,These include epidermolysis bullosa acquisita, alopecia areata, vitiligo, Harada's disease, autoimmune optic neuropathy, idiopathic azoospermia, recurrent fetal loss (e.g., recurrent miscarriage or abortion), infertility associated with lack of fetal-maternal tolerance, or respiratory diseases such as asthma and ARDS (acute respiratory distress syndrome).

[0062] In some embodiments, the disease or disorder is psoriasis, psoriatic arthritis, rheumatoid arthritis, contact sensitivity, allergic diseases, eosinophilia, eosinophilic esophagitis, respiratory diseases such as asthma and ARDS (acute respiratory distress syndrome), giant cell arteritis, polymyalgia rheumatica, primary Sjogren's syndrome, TNF-refractory rheumatoid arthritis, alopecia areata, primary biliary cholangitis (PBC), graft-versus-host disease (GvHD), vitiligo, ANCA vasculitis, type 1 diabetes, inflammatory bowel diseases such as Crohn's disease and ulcerative colitis, asthma, chronic periodontitis, recurrent fetal loss, celiac disease, transplant rejection, or non-infectious uveitis.

[0063] An "immune response" can involve, for example, antibody production and / or activation of immune effector cells (e.g., T cells), production of inflammatory cytokines, or any of the indications or disorders described herein or known in the art. As used herein, the terms "treatment," "treating," and the like refer to obtaining a desired pharmacological and / or physiological effect. Preferably, the effect is therapeutic, i.e., the effect partially or completely alleviates adverse symptoms associated with IL-2 signaling or a disease associated therewith. To this end, the methods of the present invention include administering a "therapeutically effective amount" of a CD122-binding agent. A "therapeutically effective amount" refers to an amount effective, at a dosage and for a period of time necessary, to achieve the desired therapeutic result. A therapeutically effective amount may vary depending on factors such as the individual's disease state, age, sex, and weight, as well as the ability of the CD122-binding agent to elicit a desired response in the individual. The pharmacological and / or physiological effect can be preventative, i.e., the effect can completely or partially prevent adverse symptoms or diseases associated with IL-2 signaling.

[0064] 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 and includes a carrier, preferably a pharmaceutically acceptable (e.g., physiologically acceptable) carrier, and an amino acid sequence, antigen-binding agent, or vector of the present invention. Any suitable carrier can be used in the context of the present 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 will be administered and the particular method used to administer the composition. The composition can also include any other excipients used in formulating therapeutic molecules (e.g., proteins or antibodies), particularly parenteral formulations, including, for example, buffers, osmolality adjusting agents, stabilizers, surfactants, etc. The composition can optionally be sterile. The composition can be frozen or lyophilized for storage and reconstituted in a suitable sterile carrier before use. The composition can be produced according to conventional techniques, for example, as described in Remington: The Science and Practice of Pharmacy, 21st Edition, Lippincott Williams & Wilkins, Philadelphia, PA (2001).

[0065] The dosage used will depend on the specific situation in which the binding agent is employed. Typical dosages of CD122-binding agents can range, for example, from 1 pg / kg to 100 mg / kg of animal or human body weight; however, dosages below or above this exemplary range are within the scope of the present invention. Therapeutic or prophylactic effectiveness can be monitored by periodic evaluation of the treated patient. In the case of repeated administration over several days or longer, depending on the condition, treatment can be repeated until the desired suppression of disease symptoms occurs. However, other dosage regimens may be useful and are within the scope of the present invention. The desired dosage can be delivered by a single bolus administration of the composition, multiple bolus administrations of the composition, or continuous infusion administration of the composition.

[0066] The CD122-binding agent can be administered to a mammal using standard administration techniques, including oral administration, intravenous administration, intraperitoneal administration, subcutaneous administration, pulmonary administration, transdermal administration, intramuscular administration, intranasal administration, buccal administration, sublingual administration, or suppository administration. The composition is preferably suitable for parenteral administration. The term "parenteral" as used herein includes intravenous administration, intramuscular administration, subcutaneous administration, rectal administration, intravaginal administration, and intraperitoneal administration. More preferably, the composition is administered to a mammal using peripheral systemic delivery by intravenous, intraperitoneal, or subcutaneous injection.

[0067] Once administered to a mammal (e.g., a human), the biological activity of a CD122-binding agent of the invention can be measured by any suitable method known in the art. For example, biological activity can be assessed by determining the stability of a particular CD122-binding agent. In one embodiment of the present invention, the CD122-binding agent (e.g., an antibody) has an in vivo half-life of 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 of about 2 hours to about 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). In another embodiment, the CD122-binding agent has an in vivo half-life of about 10 days to 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 CD122-binding agents of the invention can be assessed by monitoring receptor occupancy on CD122-expressing cells in tissues such as peripheral blood and skin tissue. In other embodiments, the biological activity of a CD122-binding agent of the invention can be assessed by monitoring the depletion of CD122-expressing immune cells, such as NK cells.

[0068] The CD122-binding agents of the present invention can be administered alone or in combination with other active agents or drugs. For example, the CD122-binding agents can be administered in combination with other drugs for the treatment or prevention of the diseases disclosed herein. In this regard, the CD122-binding agents can be used in combination with at least one other inflammatory or autoimmune disease inhibitor, 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 agents are used in combination (e.g., co-therapy; administered simultaneously or sequentially in any order, or in any dosing regimen) with a CD28 antagonist such as cytotoxic T-lymphocyte-associated protein 4 (CTLA4) (e.g., CTLA4-Ig, belatacept, or abatacept). As described herein, the CD122-binding agents of the present invention can also be used in combination with at least one other immunosuppressant, including, for example, methotrexate, corticosteroids, and other small molecule drugs used to treat autoimmune and inflammatory diseases. When the method of the present invention is used to treat an infectious disease, the CD122-binding agent can be administered in combination with at least one antibacterial agent or at least one antiviral agent. In this regard, the antibacterial agent can be any suitable antibiotic known in the art. The antiviral agent can be any suitable type of vaccine that specifically targets a particular virus (e.g., a live attenuated vaccine, a subunit vaccine, a recombinant vector vaccine, and a small molecule antiviral therapy (e.g., a viral replication inhibitor and a nucleoside analog)). In some embodiments, the CD122-binding agent is used in combination (e.g., co-therapy; administered simultaneously or sequentially in any order, or in any dosage regimen) with a Janus kinase (JAK) inhibitor, such as abrocitinib, baricitinib, delgocitinib, fedratinib, filgotinib, oclacitinib, peficitinib, pacritinib, ruxolitinib, tofacitinib, or upadacitinib.

[0069] In addition to therapeutic applications, the CD122-binding agents described herein can be used for diagnostic or research applications. In this regard, the CD122-binding agents can be used in methods for diagnosing cancer or infectious diseases. Similarly, the CD122-binding agents can be used in assays to monitor CD122 protein levels in subjects being tested for diseases or disorders associated with abnormal CD122 expression. Research applications include, for example, methods that utilize the CD122-binding agents and a label to detect CD122 protein in a sample, such as a human body fluid or a cell or tissue extract. The CD122-binding agents can be used with or without modification, such as covalent or non-covalent labeling with a detectable moiety. For example, the detectable moiety can be a radioisotope (e.g., 3 H, 14 C. 32 P, 35 S, or 125 The detectable moiety may be a fluorophore, a fluorescent or chemiluminescent compound (e.g., fluorescein isothiocyanate, rhodamine, or luciferin), an enzyme (e.g., alkaline phosphatase, β-galactosidase, or horseradish peroxidase), or a prosthetic group. Any method known in the art for separately conjugating an antigen-binding agent (e.g., an antibody) to a detectable moiety can be employed in the context of the present invention (see, e.g., Hunter et al., Nature, 194:495-496 (1962); David et al., Biochemistry, 13:1014-1021 (1974); Pain et al., J. Immunol. Meth., 40:219-230 (1981); and Nygren, J. Histochem. Cytochem., 30:407-412 (1982)).

[0070] The level of CD122 protein can be measured using the CD122-binding agents of the present invention by any suitable method known in the art. Such methods include, for example, radioimmunoassay (RIA) and FACS. A normal or standard expression value of CD122 protein can be established using any suitable technique, for example, by combining a CD122-specific antibody with a sample containing or suspected of containing a CD122 polypeptide under conditions suitable for forming an antigen-antibody complex. The antibody is directly or indirectly labeled with a detectable substance to facilitate detection of bound or unbound antibody. Suitable detectable substances include various enzymes, prosthetic groups, fluorescent substances, luminescent substances, and radioactive substances (see, e.g., Zola, Monoclonal Antibodies: A Manual of Techniques, CRC Press, Inc. (1987)). The amount of PD-1 polypeptide expressed in the sample is then compared with the standard value.

[0071] The CD122-binding agent can be provided as a kit, i.e., a packaged combination of predetermined amounts of reagents along with instructions for performing the diagnostic assay. When the CD122-binding agent is labeled with an enzyme, the kit desirably includes substrates and cofactors required by the enzyme (e.g., substrate precursors that provide a detectable chromophore or fluorophore). Additionally, other additives, such as stabilizers, buffers (e.g., blocking buffers or lysis buffers), and the like, may be included in the kit. The relative amounts of the various reagents can be varied to provide concentrations in solution of the reagents that substantially optimize the sensitivity of the assay. The reagents can be provided as dry powders (typically lyophilized) containing excipients that, upon dissolution, provide a reagent solution having the appropriate concentration.

[0072] Nucleic acids, cells, production methods The present invention also provides one or more isolated or purified nucleic acid sequences encoding a CD122-binding agent or its individual heavy or light chain immunoglobulin polypeptides. Thus, in one embodiment, the nucleic acid encodes an immunoglobulin light chain variable region or a complete immunoglobulin light chain as provided herein. In another embodiment, the nucleic acid encodes an immunoglobulin heavy chain variable region or a complete immunoglobulin heavy chain as provided herein. In yet another embodiment, the nucleic acid encodes both an immunoglobulin light chain variable region or a complete immunoglobulin light chain and an immunoglobulin heavy chain variable region or a complete immunoglobulin heavy chain as provided herein.

[0073] The terms "nucleic acid" and "nucleic acid sequence" are intended to encompass polymers of DNA or RNA, i.e., polynucleotides, which may be single- or double-stranded and may contain non-natural or altered nucleotides. As used herein, the terms "nucleic acid" and "polynucleotide" refer to polymeric forms of nucleotides of any length, either ribonucleotides (RNA) or deoxyribonucleotides (DNA). These terms refer to the primary structure of the molecule, and thus include double- and single-stranded DNA, as well as double- and single-stranded RNA. The terms include, as equivalents, analogs of either RNA or DNA made from nucleotide analogs, and modified polynucleotides, such as, but not limited to, methylated polynucleotides and / or capped polynucleotides. Nucleic acids are typically linked via phosphate linkages to form nucleic acid sequences or polynucleotides, although many other linkages are known in the art (e.g., phosphorothioate, boranophosphate, etc.).

[0074] Nucleic acid can be part of a vector.Vector can be, for example, a plasmid, an episome, a cosmid, a virus vector (for example, retrovirus or adenovirus), or a phage.Suitable vectors and vector preparation methods are well known in the art (see, for example, Sambrook et al., Molecular Cloning, a Laboratory Manual, 3rd edition, Cold Spring Harbor Press, Cold Spring Harbor, NY (2001) and Ausubel et al., Current Protocols in Molecular Biology, Greene Publishing Associates and John Wiley & Sons, New York, NY (1994)).

[0075] In addition to the nucleic acid sequences encoding immunoglobulin heavy and / or light chains, the vectors can include expression control sequences, such as promoters, enhancers, polyadenylation signals, transcription terminators, internal ribosome entry sites (IRES), etc., that provide for expression of the coding sequences in host cells. Exemplary expression control sequences are known in the art and are described, for example, in Goeddel, Gene Expression Technology: Methods in Enzymology, Vol. 185, Academic Press, San Diego, Calif. (1990).

[0076] Numerous promoters, including constitutive, inducible, and repressible promoters from a variety of different sources, are well known in the art. Representative promoter sources include, for example, viruses, mammals, insects, plants, yeast, and bacteria, and suitable promoters from these sources are readily available or can be synthetically produced based on publicly available sequences, for example, from depositories such as ATCC or other commercial or individual sources. Promoters can be unidirectional (i.e., initiate transcription in one direction) or bidirectional (i.e., initiate transcription in either the 3' or 5' direction). Non-limiting examples of promoters include, for example, the T7 bacterial expression system, the pBAD (araA) bacterial expression system, the cytomegalovirus (CMV) promoter, the SV40 promoter, and the RSV promoter. Inducible promoters include, for example, the Tet system (U.S. Pat. Nos. 5,464,758 and 5,814,618), the Ecdysone-inducible system (No et al., Proc. Natl. Acad. Sci., 93:3346-3351 (1996)), the T-REX™ system (Invitrogen, Carlsbad, CA), the LACSWITCH™ system (Stratagene, San Diego, CA), and the Cre-ERT tamoxifen-inducible recombinase system (Indra et al., Nuc. Acid. Res., 27:4324-4327 (1999); Nuc. Acid. Res., 28:e99 (2000); U.S. Pat. No. 7,112,715; and Kramer & Fussenegger, Methods Mol. Biol., 308:123-144(2005)).

[0077] The term "enhancer," as used herein, refers to a DNA sequence that increases transcription of, for example, a nucleic acid sequence to which it is operably linked. Enhancers can be located many kilobases away from the coding region of a nucleic acid sequence and can mediate the binding of regulatory factors, DNA methylation patterns, or changes in DNA structure. Numerous enhancers from a variety of different sources are well known in the art and are available as or within cloned polynucleotides (e.g., from depositories such as the ATCC or other commercial or individual sources). Some polynucleotides containing promoters (such as the commonly used CMV promoter) also contain enhancer sequences. Enhancers can be located upstream of, within, or downstream of a coding sequence.

[0078] The vector may also contain a selectable marker gene. The term "selectable marker gene" as used herein refers to a nucleic acid sequence that allows cells expressing the nucleic acid sequence to be specifically selected or not selected in the presence of a corresponding selection agent. Suitable selectable marker genes are known in the art, and are described, for example, in International Patent Applications WO1992 / 008796 and WO1994 / 028143; Wigler et al., Proc. Natl. Acad. Sci. USA, 77:3567-3570 (1980); O'Hare et al., Proc. Natl. Acad. Sci. USA, 78:1527-1531 (1981); Mulligan & Berg, Proc. Natl. Acad. Sci. USA, 78:2072-2076 (1981); Colberre-Garapin et al., J.M. ol. Biol., 150:1-14 (1981); Santerre et al., Gene, 30:147-156 (1984); Kent et al., Science, 237:901-903 (1987); Wigler et al., Cell, 11:223-232 (1977); Szybalska & Szybalski, Proc. Natl. Acad. Sci. USA, 48:2026-2034 (1962); Lowy et al., Cell, 22:817-823 (1980); and U.S. Patent Nos. 5,122,464 and 5,770,359.

[0079] In some embodiments, the vector is an "episomal expression vector" or "episome," capable of replicating within a host cell and persisting as an extrachromosomal segment of DNA within the host cell under appropriate selection pressure (see, e.g., Conese et al., Gene Therapy, 11:1735-1742 (2004)). Representative commercially available episomal expression vectors include, but are not limited to, episomal plasmids that utilize the Epstein-Barr nuclear antigen 1 (EBNA1) and Epstein-Barr virus (EBV) origin of replication (oriP). The vectors pREP4, pCEP4, pREP7, and pcDNA3.1 from Invitrogen (Carlsbad, CA) and pBK-CMV from Stratagene (La Jolla, CA) are non-limiting representative examples of episomal vectors that use T antigen and the SV40 origin of replication in place of EBNA1 and oriP.

[0080] Other suitable vectors include integrative expression vectors, which can be randomly integrated into the DNA of a host cell or contain recombination sites that allow specific recombination between the expression vector and the host cell chromosome. Such integrative expression vectors can utilize endogenous expression control sequences in the host cell chromosome to express the desired protein. Examples of vectors that integrate in a site-specific manner include, for example, components of the flp-in system (e.g., pcDNA™5 / FRT) from Invitrogen (Carlsbad, CA) or the cre-lox system found in the pExchange-6 core vector from Stratagene (La Jolla, CA). Examples of vectors that randomly integrate into the host cell chromosome include, for example, pcDNA3.3 (when introduced in the absence of T-antigen) from ThermoFisher (Carlsbad, CA), UCOE from Millipore (Billerica, MA), and pCI or pFN10A(ACT)FLEXI™ from Promega (Madison, WI).

[0081] Viral vectors can also be used. Exemplary commercially available viral expression vectors include, but are not limited to, the adenovirus-based Per.C6 system available from Crucell (Leiden, The Netherlands), the lentivirus-based pLP1 available from ThermoFisher (Carlsbad, CA), and the retroviral vectors pFB-ERV plus pCFB-EGSH available from Agilent (Stratagene, La Jolla, CA).

[0082] Nucleic acid sequences encoding the amino acid sequences of the present invention may be provided to cells on the same vector (i.e., in cis). A unidirectional promoter may be used to control the expression of each nucleic acid sequence. In another embodiment, a combination of bidirectional and unidirectional promoters may be used to control the expression of multiple nucleic acid sequences. Nucleic acid sequences encoding the amino acid sequences of the present invention may be provided to a population of cells on separate vectors (i.e., in trans). Each nucleic acid sequence on the separate vectors may contain the same or different expression control sequences. The separate vectors may be provided to cells simultaneously.

[0083] Vectors containing nucleic acids encoding the amino acid sequences of the invention can be introduced into host cells capable of expressing the polypeptides encoded by the vectors, including any suitable prokaryotic or eukaryotic cells. Thus, the invention provides in vitro cells or cell lines containing the vectors of the invention. The invention also provides in vitro cells or cell lines that express immunoglobulin heavy and / or light chain polypeptides or that express PD-1-binding agents. Preferred host cells are those that can be grown easily and reliably, have a reasonably fast growth rate, have a well-characterized expression system, and can be easily and efficiently transformed or transfected.

[0084] Examples of suitable prokaryotic cells include, but are not limited to, cells of the genera Bacillus (such as Bacillus subtilis and Bacillus brevis), Escherichia (such as E. coli), Pseudomonas, Streptomyces, Salmonella, and Erwinia. Particularly useful prokaryotic cells include various strains of E. coli (e.g., K12, HB101 (ATCC No. 33694), DH5α, DH10, MC1061 (ATCC No. 53338), and CC102).

[0085] In some embodiments, the vector is introduced into a eukaryotic cell. Suitable eukaryotic cells are known in the art and include, for example, yeast cells, insect cells, and mammalian cells. Examples of suitable yeast cells include those of the genera Kluyveromyces, Pichia, Rhino-sporidium, Saccharomyces, and Schizosaccharomyces. Preferred yeast cells include, for example, Saccharomyces cerivisae and Pichia pastoris.

[0086] Suitable insect cells are described, for example, in Kitts et al., Biotechniques, 14:810-817 (1993); Lucklow, Curr. Opin. Biotechnol., 4:564-572 (1993); and Lucklow et al., J. Virol., 67:4566-4579 (1993). Preferred insect cells include Sf-9 and HI5 (Invitrogen, Carlsbad, CA).

[0087] In some embodiments, mammalian cells are utilized in the present invention. A number of suitable mammalian host cells are known in the art, and many are available from the American Type Culture Collection (ATCC, Manassas, VA). Examples of suitable mammalian cells include Chinese hamster ovary cells (CHO) (e.g., CHO-K1 ATCC No. CCL61), CHO DHFR- cells (e.g., Urlaub et al., Proc. Natl. Acad. Sci. USA, 97:4216-4220 (1980)), human embryonic kidney (HEK) 293 or 293T cells (e.g., ATCC No. CRL1573), and 3T3 cells (e.g., ATCC No. CCL92). Other suitable mammalian cell lines are the monkey COS-1 (e.g., ATCC No. CRL1650) and COS-7 cell lines (e.g., ATCC No. CRL1651), as well as the CV-1 cell line (e.g., ATCC No. CCL70). Further exemplary mammalian host cells include primate cell lines, rodent cell lines, including the mouse cell line NS0 derived from the mouse myeloma line MOPC21 (e.g., Tysabri), and transformed cell lines. Normal diploid cells, cell lines derived from in vitro culture of primary tissue, and primary explants are also suitable. Other suitable mammalian cell lines include, but are not limited to, mouse neuroblastoma N2A cells, HeLa, mouse L-929 cells, and BHK or HaK hamster cell lines, all of which are available from the ATCC. Methods for selecting appropriate mammalian host cells and for transforming, culturing, amplifying, screening, and purifying the cells are known in the art.

[0088] In some embodiments, mammalian cells are human cells.For example, mammalian cells can be human lymphocytes or lymphocyte-derived cell lines, such as pre-B lymphocyte-derived cell lines.Examples of human lymphocyte cell lines include, but are not limited to, RAMOS (e.g., CRL-1596), Daudi (e.g., CCL-213), EB-3 (e.g., CCL-85), Raji cells (e.g., CCL-86), and their derivatives.

[0089] Nucleic acid sequences encoding the amino acid sequences of the present invention can be introduced into cells by any suitable technique, such as "transfection," "transformation," or "transduction." "Transfection," "transformation," or "transduction," as used herein, refers to the introduction of one or more exogenous polynucleotides into host cells using physical or chemical methods. Many transfection techniques are known in the art, including calcium phosphate DNA coprecipitation (see, for example, Murray EJ (ed.), Methods in Molecular Biology, Vol. 7, Gene Transfer and Expression Protocols, Humana Press (1991)); DEAE-dextran; electroporation; cationic liposome-mediated transfection; tungsten particle-promoted biolistics (Johnston, Nature, 346:776-777 (1990)); and strontium phosphate DNA coprecipitation (Brash et al., Mol. Cell Biol., 7:2031-2034 (1987)). Phage or viral vectors can be introduced into host cells after propagation of the infectious particles in suitable packaging cells, many of which are commercially available.

[0090] The nucleic acids and cells can be used for any purpose, including producing the CD122-binding agents described herein. In this regard, the present method provides a method for preparing a CD122-binding agent, comprising culturing cells containing nucleic acids encoding heavy and / or light immunoglobulin polypeptides of the CD122-binding agent. Stated differently, the method comprises expressing nucleic acids encoding the immunoglobulin heavy and / or light chains of the CD122-binding agent in the cells. It will be understood that the immunoglobulin heavy and light chains can be expressed from a single nucleic acid in a given cell, or the immunoglobulin heavy and light chains can be expressed from separate nucleic acids in the same cell. The method may further comprise harvesting and / or purifying the CD122-binding agent from the cells or cell culture medium using known techniques.

[0091] The following examples further illustrate the invention but, of course, should not be construed as in any way limiting its scope. [Example]

[0092] The following examples describe specific CD122-binding agent heavy and light chain polypeptide sequences according to embodiments of the invention. The antibodies used in these examples are as follows:

[0093] Antibodies were transiently expressed in ExpiCHO-S mammalian cells and purified by Protein A affinity chromatography. The antibody sequences of the M10-1275 and M6-p1625 series are summarized in Tables 1A and 1B, respectively, where "H" and "L" refer to the heavy and light chains. The CDRs of these antibodies, determined according to Kabat numbering, are listed in Tables 1C and 1D. The amino acid and nucleic acid sequences of the complete heavy and light chains of specific antibodies are summarized in Table 1E. M10-1275 and M6-p1625 represent two classes of antibodies, members of which were developed from parental heavy and light chains by mutagenesis and screening.

[0094] [Table 1A]

[0095] [Table 1B]

[0096] [Table 1C]

[0097] [Table 1D]

[0098] [Table 1E]

[0099] Example 1 This example demonstrates the binding kinetics (affinity) of the antibodies disclosed herein.

[0100] Surface plasmon resonance (SPR) was used to measure binding affinity. M6-1625 and M10-1275 antibodies were captured on a Cytiva Protein A Chip at 0.5 μg / mL for 60 seconds. The antibodies were exposed to recombinant human IL-2Rβ or cynomolgus IL-2Rβ (corresponding to residues Ala1-Thr215 of the extracellular domain, excluding the signal peptide) at typical concentrations ranging from 0.4 nM to 11 nM for a typical association time of 300 seconds and dissociation time of 1200 seconds using a Biacore S200 instrument. Sensorgrams were globally fitted using a 1:1 binding model in the Biacore T200 Evaluation Software to measure on-rates, off-rates, and K D The K values ​​were calculated for the CD122-binding agents disclosed herein by SPR. D A summary of the measurements is shown in Tables 2A and 2B.

[0101] [Table 2A]

[0102] [Table 2B]

[0103] Example 2 This example demonstrates that the anti-CD122 chimeric antibodies of the present invention bind to human or cynomolgus IL-2Rβγ expressed on CHO-K1 cells in a dose-dependent manner.

[0104] CHO-K1 cells stably expressing full-length human or cynomolgus monkey IL-2Rβ and IL-2Rγ cultured in logarithmic growth phase were harvested with Accutase solution, resuspended in FACS buffer, and plated at 100,000 cells / well in a 96-well plate. Antibodies at the concentrations indicated in Figures 1 and 2, starting at 100 nM and diluted 1:3, were incubated with the cells for 45 minutes on a plate shaker at 4°C. After washing, the cells were incubated with goat anti-human κDyL650 secondary antibody for 20 minutes on a plate shaker at 4°C. The cells were washed again and analyzed using a FACSArray flow cytometer. Data were analyzed using Novoexpress and GraphPad Prism software. The results are shown in Figures 1 and 2. Table 3 shows the binding characteristics of anti-CD122 chimeric antibodies: affinity (K) for human and cynomolgus monkey CD122 proteins. D , measured by SPR assay), ability to block IL-2 (SPR assay), and binding EC50 to cell-expressed human and cynomolgus CD122 / CD132 (cell-based receptor binding assay).

[0105] [Table 3]

[0106] Example 3 This example demonstrates that anti-CD122 antibodies of the invention can inhibit IL-2- or IL-15-induced pSTAT5 luciferase activity in HEK cells expressing human IL-2βγ.

[0107] HEK293 cells stably transfected with IL-2Rβ, IL-2Rγ, and a STAT5-luciferase reporter were plated at 50,000 cells per well in a 96-well plate. Chimeric antibodies or JAK inhibitors were titrated from 100 nM at the concentrations shown in Figure 3 and added to the cells for 30 minutes. Recombinant IL-2 or IL-15 was then added to the cells for an additional 3.5 hours. SteadyGlo substrate was added for 10 minutes, and the plate was read on a GloMax instrument. Data were analyzed using GraphPad Prism software. The results are shown in Figure 3.

[0108] Example 4 This example demonstrates that anti-CD122 IgG4 antibodies can inhibit IL-2 or IL-15-induced proliferation of PHA-stimulated primary human T cell blasts.

[0109] Primary human PBMCs were isolated from whole blood donors and cultured in T75 flasks with 5 μg / mL PHA for 3 days. Cells were washed, counted, and plated at 100,000 cells / well in 96-well plates. Antibodies were titrated at the concentrations indicated in Figure 4, starting at 100 nM and diluted 1:3, and added to the cells. Recombinant IL-2 (15 pM) or IL-15 (150 pM) was added to the cells. Cells were cultured for an additional 3 days. SteadyGlo substrate was added for 10 minutes, and the plates were read on a GloMax instrument. Data were analyzed using Graphpad Prism software.

[0110] The results are shown in Figure 4. Both M10-1275 and M6-1625 were superior to upadacitinib in blocking IL-2 and IL-15.

[0111] Example 5 This example demonstrates that anti-CD122 IgG4 antibodies bind to human IL-2Rβγ expressed on CHO-K1 cells in a dose-dependent manner. CHO-K1 cells stably expressing either full-length human or cynomolgus monkey IL-2Rβ and IL-2Rγ, cultured in logarithmic growth phase, were harvested with Accutase solution, resuspended in FACS buffer, and plated at 100,000 cells / well in a 96-well plate. Antibodies at the concentrations indicated in Figure 5, starting at 100 nM and diluted 1:3, were incubated with the cells for 45 minutes on a plate shaker at 4°C. After washing, the cells were incubated with goat anti-human κDyL650 secondary antibody for 20 minutes on a plate shaker at 4°C. The cells were washed again and analyzed on a FACSArray flow cytometer. Data were analyzed using Novoexpress and GraphPad Prism software.

[0112] The results are shown in Figure 5. All antibodies show human and cynomolgus binding with EC50 in the range of 0.3-0.1 nM.

[0113] Example 6 This example demonstrates that a humanized anti-CD122 IgG4 antibody inhibits IL-2 or IL-15-induced proliferation of purified primary human NK cells.

[0114] Primary human PBMCs were isolated from whole blood donors, and naive NK cells were isolated using a Miltenyi bead kit. One hundred thousand cells were plated in a 96-well plate. Antibodies were titrated at the indicated concentrations, starting at 100 nM in a 1:10 dilution, and added to the cells. Recombinant IL-2 (50 pM) or recombinant IL-15 (60 pM) was added to the cells. The cells were cultured for 5 days. Finally, SteadyGlo substrate was added for 10 minutes, and the plate was read on a GloMax instrument. Data were analyzed using Graphpad Prism software. The results are shown in Figure 6.

[0115] Example 7 This example demonstrates that a humanized anti-CD122 IgG4 antibody inhibits IL-2 or IL-15-induced proliferation and survival of primary human NK cells gated within PBMC cultures.

[0116] Primary human PBMCs were isolated from whole blood donors, labeled with CFSE, and plated at 250,000 cells / well in 96-well plates. Antibodies were titrated at the concentrations indicated in Figure 7, starting at 100 nM and diluted 1:3, and added to the cells. Recombinant IL-2 (250 pM) or recombinant IL-15 (200 pM) was added to the cells. Cells were cultured for 5 days. Cells were stained with CD56 and CD3 to gate the NK cell population and with Annexin V as an indicator of apoptotic cells. Cells were analyzed using a flow cytometer, and data were analyzed using Novoexpress and GraphPad Prism software. As shown in Figure 7, proliferation was expressed as the percentage of cells with a dilute CFSE peak (over the unstimulated fraction), and apoptosis was indicated by Annexin V staining. All tested antibodies effectively inhibited IL-2- or IL-15-induced proliferation as measured by CFSE.

[0117] Example 8 This example demonstrates that a humanized anti-CD122 IgG4 antibody inhibits the binding of IL-2 or IL-15 to HEK cells expressing human IL-2βγ.

[0118] HEK293 cells stably transfected with human IL-2Rβ and IL-2Rγ were plated at 100,000 cells / well in a 96-well plate. Antibodies were titrated at the concentrations indicated in Figure 8, starting at 100 nM and diluted 1:3, and added to the cells. Recombinant IL-2 (5 nM) or recombinant IL-15 (2 nM) was also added to the cells. Cells were incubated at 4°C on a plate shaker for 30 minutes. Cells were washed and then analyzed on a flow cytometer, and data were analyzed using Novoexpress and GraphPad Prism software. The results are shown in Figure 8.

[0119] Example 9 This example demonstrates that a humanized anti-CD122 IgG4 antibody inhibits IL-15 or IL-15 / IL1-5RA-induced proliferation of primary human T cell blasts.

[0120] Primary human PBMCs were isolated from whole blood donors and cultured in T75 flasks with 5 μg / mL PHA for 3 days. Cells were washed, counted, and plated at 100,000 cells / well in a 96-well plate. Antibodies were titrated at the concentrations shown in Figure 9, starting at 100 nM in a 1:3 dilution, and added to the cells. Recombinant IL-15 alone (1 nM) or recombinant IL-15 + IL-15Ra (1 nM each) was added to the cells. Cells were cultured for an additional 3 days. Finally, SteadyGlo substrate was added for 10 minutes, and the plates were read on a GloMax instrument. Data were analyzed using Graphpad Prism software. The results are shown in Figure 9.

[0121] Example 10 This example demonstrates that humanized anti-CD122 IgG4 antibodies inhibit IL-15 or IL-15 / IL1-5RA-induced proliferation of primary human NK cells.

[0122] Primary human PBMCs were isolated from whole blood donors, and naive NK cells were isolated using a Miltenyi bead kit. One hundred thousand cells were plated in a 96-well plate. Antibodies were titrated at the concentrations shown in Figure 10, starting at 100 nM in a 1:10 dilution, and added to the cells. Recombinant IL-15 (60 pM) or recombinant IL-15:IL15RA (60 pM each) was added to the cells. The cells were cultured for 5 days. Finally, SteadyGlo substrate was added for 10 minutes, and the plates were read on a GloMax instrument. Data were analyzed using Graphpad Prism software. The results are shown in Figure 10.

[0123] Example 11 This example demonstrates that a humanized anti-CD122 IgG1 antibody inhibits IL-2 or IL-15-induced proliferation of primary human NK cells.

[0124] Primary human PBMCs were isolated from whole blood donors, and naive NK cells were isolated using a Miltenyi bead kit. One hundred thousand cells were plated in a 96-well plate. Antibodies were titrated at the concentrations shown in Figure 11, starting at 100 nM at a 1:10 dilution, and added to the cells. Recombinant IL-2 (50 pM) or recombinant IL-15 (60 pM) was added to the cells. The cells were cultured for 5 days. Finally, SteadyGlo substrate was added for 10 minutes, and the plate was read on a GloMax instrument. Data were analyzed using Graphpad Prism software. The results are shown in Figure 11.

[0125] Example 12 This example demonstrates that a humanized anti-CD122 IgG1 antibody inhibits IL-2 or IL-15-induced proliferation of primary human pan-T cells.

[0126] Primary human PBMCs were isolated from whole blood donors, and naive pan-T cells were isolated using a Miltenyi bead kit. One hundred thousand cells were plated in a 96-well plate. Antibodies were titrated at the concentrations shown in Figure 12, starting at 100 nM in a 1:3 dilution, and added to the cells. Recombinant IL-2 (1 nM) or recombinant IL-15 was added to the cells. The cells were cultured for 7 days. Finally, SteadyGlo substrate was added for 10 minutes, and the plates were read on a GloMax instrument. Data were analyzed using Graphpad Prism software. The results are shown in Figure 12.

[0127] Example 13 This example demonstrates that a humanized anti-CD122 antibody exhibits in vivo efficacy in a xenogeneic NSG-Tg(huIL-15) / Hu-PBMC graft-versus-host disease (GvHD) model.

[0128] A xenogeneic NSG-Tg(huIL-15) / Hu-PBMC GvHD model was performed. NOD-scid IL2rγ null(NSG) human IL-15 transgenic mice were irradiated with 1 Gy and then intravenously injected with human PBMCs. Antibodies (APE15170-IgG4P, APE15295-IgG4P, CTLA4-Ig (positive control), and APE15170-IgG4 combined with CTLA4-Ig) were administered intraperitoneally. APE15170-IgG4P, APE15295-IgG4P, and APE15170-IgG4P were administered at 10 mg / kg twice weekly for 4 weeks, and CTLA4-Ig was administered at 75 μg three times weekly, both starting the day after PBMC injection. A control IgG4 isotype was also administered twice weekly.

[0129] The anti-CD122 antagonist antibodies disclosed herein show significant improvement in mortality prevention compared to isotype control and CTLA4-Ig alone. APE15170-IgG4P in combination with CTLA4-Ig showed even better improvement than APE15170-IgG4P or APE15295-IgG4P alone. The results are shown in Figure 13.

[0130] Example 14 This example demonstrates that a humanized anti-CD122 antibody exhibits in vivo efficacy in a xenogeneic NSG(huIL-15Tg) / Hu-PBMC graft-versus-host disease (GvHD) model.

[0131] The Jackson laboratory JAX® In Vivo Pharmacology Services (Sacramento, CA) conducted a xenogeneic NSG (huIL-15Tg) / Hu-PBMC GvHD model to test the efficacy of the anti-CD122 antibodies disclosed herein. null(NSG) human IL-15 transgenic mice were irradiated with 1 Gy and then intravenously injected with human PBMCs. APE15428 (IgG1-LALA) was administered intraperitoneally at 10 mg / kg, 3 mg / kg, or 1 mg / kg twice weekly for 4 weeks, starting the day after PBMC injection. Disease was monitored three times weekly for weight loss, mortality, and GvHD scores: weight loss, activity, coat condition, paleness, and posture. Animals with more than 10% weight loss were observed daily, and animals with more than 20% weight loss from their starting weight were euthanized.

[0132] The anti-CD122 antagonist antibodies disclosed herein demonstrated statistically significant efficacy in median survival compared to the isotype control. The percentage of starting body weight for individual animals administered doses of the isotype control, anti-CD122 antibody APE15428 (IgG1 LALA), and CTLA-4-Ig (positive control) is shown. The results are shown in Figure 14.

[0133] All references, including publications, patent applications, and patents, cited in this specification are herein incorporated by reference to the same extent as if each reference was individually and specifically indicated to be incorporated by reference and was set forth in its entirety herein.

[0134] Use of the terms "a," "an," "the," "at least one," and similar reference words in the context of describing the invention (particularly in the context of the claims below) shall be construed to include both the singular and the plural unless stated herein or otherwise clearly contradicted by context. The use of the term "at least one" followed by a list of one or more items (e.g., "at least one of A and B") shall 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" shall be construed as open-ended terms (i.e., meaning "including, but not limited to") unless otherwise noted. The recitation of ranges of values ​​herein, unless otherwise indicated herein, is intended to serve merely as a shorthand method for individually referring to each separate value falling within the range, and each separate value is incorporated herein as if it were individually referred to herein. All methods described herein can be performed in any suitable order unless otherwise indicated herein or clearly contradicted by context. Any examples provided herein, or the use of exemplary language (e.g., "such as"), are intended merely to better clarify the invention and do not limit the scope of the invention unless otherwise asserted. No language in the specification should be construed as indicating any non-claimed element as essential to the practice of the invention.

[0135] 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 will become apparent to one of ordinary skill in the art upon reading the foregoing description. The inventors expect that skilled artisans will adopt such variations as they see fit, and the inventors intend 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, this invention encompasses any combination of the above-described elements in all possible variations thereof, whether as described herein or unless otherwise clearly contradicted by context.

Claims

1. 1. A CD122-binding agent comprising an immunoglobulin heavy chain variable region and an immunoglobulin light chain variable region, (a) As determined according to Kabat numbering: the immunoglobulin heavy chain variable region comprising: CDR1 comprising SEQ ID NO: 108; CDR2 comprising SEQ ID NO: 109; and comprising a CDR3 comprising SEQ ID NO: 98; and the immunoglobulin light chain variable region CDR1 comprising SEQ ID NO: 110; CDR2 comprising SEQ ID NO: 111; and comprising a CDR3 comprising SEQ ID NO: 112; Optionally: As determined according to Kabat numbering; the immunoglobulin heavy chain variable region CDR1 comprising SEQ ID NO: 78; CDR2 comprising SEQ ID NO:94; and comprising a CDR3 comprising SEQ ID NO: 98; and the immunoglobulin light chain variable region CDR1 comprising SEQ ID NO:99; CDR2 comprising SEQ ID NO: 103; and comprising a CDR3 comprising SEQ ID NO: 105; (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 NOs: 70-77, and / or comprises at least the CDR regions of any one of SEQ ID NOs: 70-77; Optionally, said 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 said 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) As determined according to Kabat numbering; the immunoglobulin heavy chain variable region comprising: CDR1 comprising SEQ ID NO: 146; CDR2 comprising SEQ ID NO: 147; and comprising a CDR3 comprising SEQ ID NO: 148; and the immunoglobulin light chain variable region CDR1 comprising SEQ ID NO: 138; CDR2 comprising SEQ ID NO: 139; and comprising a CDR3 comprising SEQ ID NO: 140; Optionally: As determined according to Kabat numbering; the immunoglobulin heavy chain variable region CDR1 comprising SEQ ID NO: 117 or 124; CDR2 comprising SEQ ID NO: 127; and comprising a CDR3 comprising SEQ ID NO: 136; and the immunoglobulin light chain variable region CDR1 comprising SEQ ID NO: 138; CDR2 comprising SEQ ID NO: 139; and comprising a CDR3 comprising SEQ ID NO: 144 or 145; (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 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; Optionally, said 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 said 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. CD122 binding agents.

2. The CD122-binding agent of claim 1, 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.

3. The CD122-binding agent of claim 1, 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.

4. When determined according to Kabat numbering: the immunoglobulin heavy chain variable region comprising: CDR1 comprising SEQ ID NO: 108; CDR2 comprising SEQ ID NO: 109; comprising a CDR3 comprising SEQ ID NO: 98; and the immunoglobulin light chain variable region CDR1 comprising SEQ ID NO: 110, CDR2 comprising SEQ ID NO: 111, comprising a CDR3 comprising SEQ ID NO: 112; A CD122 binding agent according to any one of claims 1 to 3.

5. The CD122-binding agent of claim 4, wherein the immunoglobulin heavy chain variable region CDR1 comprises any one of SEQ ID NOs: 78 to 93.

6. The CD122-binding agent of claim 4 or 5, wherein the immunoglobulin heavy chain variable region CDR2 comprises any one of SEQ ID NOs: 94 to 97.

7. The CD122-binding agent of any one of claims 4 to 6, wherein the immunoglobulin light chain variable region CDR1 comprises SEQ ID NO: 99 to 102.

8. The CD122-binding agent of any one of claims 4 to 7, wherein the immunoglobulin light chain variable region CDR2 comprises SEQ ID NO: 103 or 104.

9. The CD122-binding agent of any one of claims 4 to 8, wherein the immunoglobulin light chain variable region CDR3 comprises SEQ ID NOs: 105 to 107.

10. The CD122-binding agent of any one of claims 4 to 9, comprising the immunoglobulin heavy chain variable region of any one of SEQ ID NOs: 37 to 69.

11. The CD122-binding agent of any one of claims 4 to 10, comprising the immunoglobulin light chain variable region of any one of SEQ ID NOs: 70 to 77.

12. When determined according to Kabat numbering: the immunoglobulin heavy chain variable region comprising: CDR1 comprising SEQ ID NO: 78; CDR2 comprising SEQ ID NO:94; and comprising a CDR3 comprising SEQ ID NO: 98; and the immunoglobulin light chain variable region CDR1 comprising SEQ ID NO:99; CDR2 comprising SEQ ID NO: 103; and comprising a CDR3 comprising SEQ ID NO: 105; The CD122 binding agent of claim 4.

13. The CD122-binding agent of claim 1, 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.

14. The CD122-binding agent of claim 13, wherein the immunoglobulin heavy chain variable region comprises SEQ ID NO: 69 and the immunoglobulin light chain variable region comprises SEQ ID NO:

77.

15. The CD122-binding agent of claim 1, 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.

16. The CD122-binding agent of claim 15, wherein the immunoglobulin heavy chain variable region comprises SEQ ID NO: 68 and the immunoglobulin light chain variable region comprises SEQ ID NO:

77.

17. The CD122-binding agent of claim 1, wherein the immunoglobulin heavy chain variable region comprises at least 90% sequence identity with 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.

18. The CD122-binding agent of claim 1, wherein the immunoglobulin light chain variable region comprises at least 90% sequence identity with 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.

19. When determined according to Kabat numbering: the immunoglobulin heavy chain variable region comprising: CDR1 comprising SEQ ID NO: 146; CDR2 comprising SEQ ID NO: 147; and comprising a CDR3 comprising SEQ ID NO: 148; and the immunoglobulin light chain variable region CDR1 comprising SEQ ID NO: 138; CDR2 comprising SEQ ID NO: 139; and comprising a CDR3 comprising SEQ ID NO: 149; 19. A CD122-binding agent according to any one of claims 1, 17 or 18.

20. The CD122-binding agent of claim 19, wherein the immunoglobulin heavy chain variable region CDR1 comprises any one of SEQ ID NOs: 117-126.

21. The CD122-binding agent of claim 19 or 20, wherein the immunoglobulin heavy chain variable region CDR2 comprises any one of SEQ ID NOs: 127 to 135.

22. The CD122-binding agent of any one of claims 19 to 21, wherein the immunoglobulin heavy chain variable region CDR3 comprises SEQ ID NO: 136 or 137.

23. The CD122-binding agent of any one of claims 19 to 22, wherein the immunoglobulin light chain variable region CDR3 comprises any one of SEQ ID NOs: 140 to 145.

24. The CD122-binding agent of any one of claims 19 to 23, comprising the immunoglobulin heavy chain variable region of any one of SEQ ID NOs: 1 to 24.

25. The CD122-binding agent of any one of claims 19 to 24, comprising the immunoglobulin light chain variable region of any one of SEQ ID NOs: 25 to 36.

26. When determined according to Kabat numbering: the immunoglobulin heavy chain variable region comprising: CDR1 comprising SEQ ID NO: 117; CDR2 comprising SEQ ID NO: 127; and comprising a CDR3 comprising SEQ ID NO: 136; and the immunoglobulin light chain variable region CDR1 comprising SEQ ID NO: 138; CDR2 comprising SEQ ID NO: 139; and comprising a CDR3 comprising SEQ ID NO: 144; The CD122 binding agent of claim 12.

27. When determined according to Kabat numbering: the immunoglobulin heavy chain variable region comprising: CDR1 comprising SEQ ID NO: 124; CDR2 comprising SEQ ID NO: 127; and comprising a CDR3 comprising SEQ ID NO: 136; and the immunoglobulin light chain variable region CDR1 comprising SEQ ID NO: 138; CDR2 comprising SEQ ID NO: 139; and comprising a CDR3 comprising SEQ ID NO: 145; The CD122 binding agent of claim 12.

28. The CD122-binding agent of claim 1, 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.

29. The CD122-binding agent of claim 28, wherein the immunoglobulin heavy chain variable region comprises SEQ ID NO: 24 and the immunoglobulin light chain variable region comprises SEQ ID NO:

35.

30. The CD122-binding agent of claim 1, wherein the immunoglobulin heavy chain variable region comprises at least 90% sequence identity with 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 with SEQ ID NO: 35 or comprises at least the CDRs of SEQ ID NO:

35.

31. The CD122-binding agent of claim 30, wherein the immunoglobulin heavy chain variable region comprises SEQ ID NO: 23 and the immunoglobulin light chain variable region comprises SEQ ID NO:

35.

32. The CD122-binding agent of claim 1, 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.

33. The CD122-binding agent of claim 32, wherein the immunoglobulin heavy chain variable region comprises SEQ ID NO: 16 and the immunoglobulin light chain variable region comprises SEQ ID NO:

28.

34. The CD122-binding agent of any one of claims 1 to 33, wherein the CD122-binding agent is an antibody, an antigen-binding antibody fragment, or a conjugate thereof.

35. The CD122-binding agent is F(ab') ２ , Fab', Fab, Fv, scFv, dsFv, or single-chain binding polypeptide.

36. 36. The CD122-binding agent of any one of claims 1 to 35, wherein the CD122-binding agent comprises an IgG Fc region that binds to an Fc receptor on an antigen-presenting cell, optionally an IgG1 Fc region.

37. A pharmaceutical composition comprising: (a) the CD122-binding agent of any one of claims 1 to 36; and (b) a pharmaceutically acceptable carrier.

38. A method for inhibiting an immune response in a mammal, comprising administering to the mammal a CD122-binding agent of any of claims 1 to 36 or a pharmaceutical composition of claim 37.

39. A method for treating an inflammatory or autoimmune disease in a mammal, comprising administering to the mammal a CD122-binding agent described in any one of claims 1 to 36 or a pharmaceutical composition described in claim 37.

40. 40. The method of claim 39, wherein the inflammatory disease or autoimmune disease is psoriasis, psoriatic arthritis, rheumatoid arthritis, contact hypersensitivity, allergic diseases, eosinophilia, eosinophilic esophagitis, respiratory diseases such as asthma and ARDS (acute respiratory distress syndrome), giant cell arteritis, polymyalgia rheumatica, primary Sjogren's syndrome, TNF-refractory rheumatoid arthritis, alopecia areata, primary biliary cholangitis (PBC), graft-versus-host disease (GvHD), vitiligo, ANCA vasculitis, type 1 diabetes, inflammatory bowel diseases including Crohn's disease and ulcerative colitis, asthma, chronic periodontitis, recurrent fetal loss, celiac disease, transplant rejection, or non-infectious uveitis.

41. The method of any of claims 38 to 40, further comprising administering to the mammal a CD28 antagonist or a JAK kinase inhibitor.

42. A nucleic acid encoding the immunoglobulin heavy chain and / or immunoglobulin light chain of the CD122-binding agent of any one of claims 1 to 36, optionally contained in a vector.

43. A cell expressing the CD122-binding agent of any one of claims 1 to 36.

44. A method for preparing a CD122-binding agent described in any one of claims 1 to 36, comprising expressing in a cell a nucleic acid sequence encoding the immunoglobulin heavy chain and a nucleic acid sequence encoding the immunoglobulin light chain of the CD122-binding agent described in any one of claims 1 to 36.

45. A CD122-binding agent according to any one of claims 1 to 36 or a pharmaceutical composition according to claim 37 for inhibiting an immune response in a mammal.

46. A CD122-binding agent according to any one of claims 1 to 36 or a pharmaceutical composition according to claim 37 for treating an inflammatory or autoimmune disease in a mammal.

47. 47. The CD122-binding agent or pharmaceutical composition of claim 46, wherein the inflammatory disease or autoimmune disease is psoriasis, psoriatic arthritis, rheumatoid arthritis, contact hypersensitivity, allergic diseases, eosinophilia, eosinophilic esophagitis, respiratory diseases such as asthma and ARDS (acute respiratory distress syndrome), giant cell arteritis, polymyalgia rheumatica, primary Sjogren's syndrome, TNF-refractory rheumatoid arthritis, alopecia areata, primary biliary cholangitis (PBC), graft-versus-host disease (GvHD), vitiligo, ANCA vasculitis, type 1 diabetes, inflammatory bowel diseases including Crohn's disease and ulcerative colitis, asthma, chronic periodontitis, recurrent fetal loss, celiac disease, transplant rejection, or non-infectious uveitis.

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