IL2R beta / common gamma chain antibody

Antigen binding molecules targeting IL-2Rβ and γc chains mitigate the toxicity of IL-2 therapy by blocking IL-2 binding to lung endothelial cells, addressing the severe side effects of VLS and enabling safer IL-2 treatment.

JP7603738B2Active Publication Date: 2024-12-20AGENCY FOR SCI TECH & RES +1
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Patent Information

Application Number
JP2023069702
Authority / Receiving Office
JP · JP
Patent Type
Patents
Current Assignee / Owner
Priority Date
2018-09-24
Filing Date
2023-04-21
Publication Date
2024-12-20
Estimated Expiration
2038-11-09

AI Technical Summary

Technical Problem

High doses of IL-2 used in medical treatments are highly toxic, leading to severe side effects such as vascular leak syndrome (VLS) due to the binding of IL-2 to lung endothelial cells expressing the high-affinity α-β-γc IL-2R, with no effective cure for VLS other than stopping therapy.

Method used

Development of antigen binding molecules that specifically target the IL-2Rβ (CD122) and/or common γ chain (γc; CD132) to prevent IL-2 binding to lung endothelial cells, thereby reducing the toxicity of IL-2 therapy.

Benefits of technology

The antigen binding molecules effectively reduce the toxicity of IL-2 therapy by preventing VLS, allowing for safer and more effective use of IL-2 in medical treatments.

✦ Generated by Eureka AI based on patent content.

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Patent Text Reader

Abstract

To provide antigen binding molecules capable of binding to CD122 and / or CD132, and compositions comprising the antigen binding molecules.SOLUTION: The invention provides, as one aspect: antigen-binding molecules capable of binding to CD122 and CD132, including (a) an antigen-binding molecule which is capable of binding to CD122 and has HC-CDR1, HC-CDR2, HC-CDR3, LC-CDR1, LC-CDR2 or LC-CDR3, including a specific amino acid sequence or a variant in which one or two or three amino acids in the amino acid sequence are substituted, and (b) an antigen-binding molecule which is capable of binding to CD132 and has HC-CDR1, HC-CDR2, HC-CDR3, LC-CDR1, LC-CDR2 or LC-CDR3, including a specific amino acid sequence or a variant in which one or two or three amino acids in the amino acid sequence are substituted; and compositions comprising the antigen binding molecules.SELECTED DRAWING: None
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Description

[Technical Field]

[0001] This application claims priority from SG 10201709289S, filed November 10, 2017, US 62 / 652501, filed April 4, 2018, and US 62 / 735347, filed September 24, 2018, the contents and elements of which are incorporated herein by reference for all purposes.

[0002] FIELD OF THE INVENTION The present invention relates to the field of molecular biology and to methods of medical treatment and prevention. In particular, the present invention relates to antigen-binding molecules capable of binding to interleukin-2 receptor beta (IL-2Rβ; CD122) and common gamma chain (γc; CD132). [Background technology]

[0003] IL-2 is an essential cytokine that plays a central role in maintaining T cell homeostasis and mediating appropriate immune responses. Its high potency as an immune stimulator has led to its clinical use to treat a range of conditions, including cancer and AIDS; it is also widely used as a vaccination adjuvant because it stimulates the activation and proliferation of a variety of effector cells.

[0004] However, the high doses of IL-2 required for effective treatment of certain diseases are highly toxic. The main side effect of such therapy includes vascular leak syndrome (VLS), which causes intravascular fluid accumulation in organs such as the lungs and liver, followed by pulmonary edema and liver damage. There is no treatment for VLS other than stopping the therapy.

[0005] IL-2 exerts diverse functions by binding to different combinations of receptor components expressed on different cell types: alpha chain (IL-2Rα, also known as CD25), beta chain (IL-2Rβ, or CD122), and common cytokine receptor gamma chain (IL-2Rγ, γc, or CD132).

[0006] The isolated IL-2Rα is referred to as the "low affinity" IL-2 receptor (binding affinity K D ~10 nM) and is not involved in signal transduction. The complex of IL-2Rβ and γc binds with moderate affinity (K D IL-2Rβ binds to IL-2 with a very low affinity (K ~1 nM), whereas IL-2Rβ binds to IL-2 with a very low affinity (K D IL-2Rα, IL-2Rβ, and γc have a high affinity (K ∼100 nM), and γc alone has virtually no detectable binding affinity for IL-2. A complex containing all three subunits, IL-2Rα, IL-2Rβ, and γc, binds IL-2 with high affinity (K D IL-2 binds to IL-2 at concentrations of ∼10 pM.

[0007] Heterodimerization of IL-2Rβ and γc is necessary and sufficient for effective signaling through cytoplasmic domain interaction and subsequent kinase activation of multiple signaling pathways; IL-2Rα plays no role in signaling.

[0008] The high-affinity α-β-γc IL-2R is typically found on CD4+ T regulatory cells (Tregs) and newly activated T cells. The intermediate-affinity β-γc IL-2R is present at low levels on naive CD8+ cells but is prominent on antigen-experienced (memory) and memory phenotype (MP) CD8+ T cells and natural killer (NK) cells. MP CD8+ T cells and NK cells express very high levels of IL-2Rβ and readily respond to IL-2.

[0009] Previous studies have shown that VLS is caused by the release of proinflammatory cytokines from IL-2-activated NK cells. However, recent studies have suggested that IL-2-induced pulmonary edema may result from the direct binding of IL-2 to pulmonary endothelial cells expressing functional high-affinity α-β-γc IL-2R. This was demonstrated by observing that the interaction of IL-2 with pulmonary endothelial cells was abrogated in IL-2Rα-deficient host cells by a blocking anti-IL-2Rα monoclonal antibody (mAb) or by using an IL-2 / anti-IL-2 mAb (IL-2 / mAb) complex, in which the antibody prevented the IL-2 / IL-2Rα interaction and thus VLS. Summary of the Invention

[0010] The present invention relates to antigen-binding molecules that bind to CD122 (i.e., IL-2Rβ) and / or the common gamma chain (γc; CD132). In one aspect, the present invention provides an optionally isolated antigen-binding molecule capable of binding to CD122 and CD132.

[0011] In some embodiments, the antigen binding molecule is: (a) an antigen-binding molecule capable of binding to CD122: The following CDRs: HC-CDR1 having one of the amino acid sequences of SEQ ID NOs: 105, 106, or 108 to 115 HC-CDR2 having one of the amino acid sequences of SEQ ID NOs: 119 to 127 HC-CDR3 having one of the amino acid sequences of SEQ ID NOs: 133 to 144 a heavy chain variable (VH) region incorporating The following CDRs: LC-CDR1 having one of the amino acid sequences of SEQ ID NOs: 151 to 161 LC-CDR2 having one of the amino acid sequences of SEQ ID NO: 164 or 169 to 176 LC-CDR3 having one of the amino acid sequences of SEQ ID NOs: 182 to 194 the light chain variable (VL) region incorporating; or a variant thereof in which one, two or three amino acids are substituted with another amino acid in one or more of HC-CDR1, HC-CDR2, HC-CDR3, LC-CDR1, LC-CDR2 or LC-CDR3. the antigen-binding molecule comprising: (b) an antigen-binding molecule capable of binding to CD132: The following CDRs: HC-CDR1 having one of the amino acid sequences of SEQ ID NOs: 106, 108, 112, or 195 to 201 HC-CDR2 having one of the amino acid sequences of SEQ ID NOs: 119, 120, 124, or 202 to 209 HC-CDR3 having one of the amino acid sequences of SEQ ID NOs: 210 to 225 a VH region incorporating The following CDRs: LC-CDR1 having one of the amino acid sequences of SEQ ID NO: 151 or 226 to 235 LC-CDR2 having one of the amino acid sequences of SEQ ID NO: 174 or 236 to 245 LC-CDR3 having one of the amino acid sequences of SEQ ID NO: 189 or 247 to 258 VL region incorporating; Or HC-CDR1, HC-CDR2, HC-CDR3, LC-CDR1, L a variant thereof in which one, two or three amino acids are replaced by another amino acid in one or more of C-CDR2 or LC-CDR3 The antigen-binding molecule comprising Includes:

[0012] In some embodiments, the antigen binding molecule capable of binding to CD122 is: (P1E7) CDR of: HC-CDR1 having the amino acid sequence of SEQ ID NO: 108 HC-CDR2 having the amino acid sequence of SEQ ID NO: 120 HC-CDR3 having the amino acid sequence of SEQ ID NO: 133 a VH region incorporating The following CDRs: LC-CDR1 having the amino acid sequence of SEQ ID NO: 151 LC-CDR2 having the amino acid sequence of SEQ ID NO: 169 LC-CDR3 having the amino acid sequence of SEQ ID NO: 182 the VL region incorporating; or (P1B10) CDR of: HC-CDR1 having the amino acid sequence of SEQ ID NO: 109 HC-CDR2 having the amino acid sequence of SEQ ID NO: 121 HC-CDR3 having the amino acid sequence of SEQ ID NO: 134 a VH region incorporating The following CDRs: LC-CDR1 having the amino acid sequence of SEQ ID NO: 152 LC-CDR2 having the amino acid sequence of SEQ ID NO: 164 LC-CDR3 having the amino acid sequence of SEQ ID NO: 183 the VL region incorporating; or (P1F3) CDR of: HC-CDR1 having the amino acid sequence of SEQ ID NO: 105 HC-CDR2 having the amino acid sequence of SEQ ID NO: 122 HC-CDR3 having the amino acid sequence of SEQ ID NO: 135 a VH region incorporating The following CDRs: LC-CDR1 having the amino acid sequence of SEQ ID NO: 153 LC-CDR2 having the amino acid sequence of SEQ ID NO: 164 LC-CDR3 having the amino acid sequence of SEQ ID NO: 184 the VL region incorporating; or (P1D10) CDR of: HC-CDR1 having the amino acid sequence of SEQ ID NO: 110 HC-CDR2 having the amino acid sequence of SEQ ID NO: 119 HC-CDR3 having the amino acid sequence of SEQ ID NO: 136 a VH region incorporating The following CDRs: LC-CDR1 having the amino acid sequence of SEQ ID NO: 154 LC-CDR2 having the amino acid sequence of SEQ ID NO: 170 LC-CDR3 having the amino acid sequence of SEQ ID NO: 185 the VL region incorporating; or (P1E1) The following CDRs: HC-CDR1 having the amino acid sequence of SEQ ID NO: 106 HC-CDR2 having the amino acid sequence of SEQ ID NO: 119 HC-CDR3 having the amino acid sequence of SEQ ID NO: 137 a VH region incorporating The following CDRs: LC-CDR1 having the amino acid sequence of SEQ ID NO: 155 LC-CDR2 having the amino acid sequence of SEQ ID NO: 171 LC-CDR3 having the amino acid sequence of SEQ ID NO: 186 the VL region incorporating; or (P2B11) The following CDR: HC-CDR1 having the amino acid sequence of SEQ ID NO: 111 HC-CDR2 having the amino acid sequence of SEQ ID NO: 123 HC-CDR3 having the amino acid sequence of SEQ ID NO: 138 a VH region incorporating The following CDRs: LC-CDR1 having the amino acid sequence of SEQ ID NO: 156 LC-CDR2 having the amino acid sequence of SEQ ID NO: 172 LC-CDR3 having the amino acid sequence of SEQ ID NO: 187 the VL region incorporating; or (P2C9) CDR of: HC-CDR1 having the amino acid sequence of SEQ ID NO: 112 HC-CDR2 having the amino acid sequence of SEQ ID NO: 124 HC-CDR3 having the amino acid sequence of SEQ ID NO: 139 a VH region incorporating The following CDRs: LC-CDR1 having the amino acid sequence of SEQ ID NO: 157 LC-CDR2 having the amino acid sequence of SEQ ID NO: 173 LC-CDR3 having the amino acid sequence of SEQ ID NO: 188 the VL region incorporating; or (P2C10) The following CDRs: HC-CDR1 having the amino acid sequence of SEQ ID NO: 106 HC-CDR2 having the amino acid sequence of SEQ ID NO: 119 HC-CDR3 having the amino acid sequence of SEQ ID NO: 140 a VH region incorporating The following CDRs: LC-CDR1 having the amino acid sequence of SEQ ID NO: 158 LC-CDR2 having the amino acid sequence of SEQ ID NO: 174 LC-CDR3 having the amino acid sequence of SEQ ID NO: 189 the VL region incorporating; or (P2C11) The following CDRs: HC-CDR1 having the amino acid sequence of SEQ ID NO: 113 HC-CDR2 having the amino acid sequence of SEQ ID NO: 125 HC-CDR3 having the amino acid sequence of SEQ ID NO: 141 a VH region incorporating The following CDRs: LC-CDR1 having the amino acid sequence of SEQ ID NO: 159 LC-CDR2 having the amino acid sequence of SEQ ID NO: 175 LC-CDR3 having the amino acid sequence of SEQ ID NO: 190 the VL region incorporating; or (P2E6) CDR of: HC-CDR1 having the amino acid sequence of SEQ ID NO: 114 HC-CDR2 having the amino acid sequence of SEQ ID NO: 126 HC-CDR3 having the amino acid sequence of SEQ ID NO: 142 a VH region incorporating The following CDRs: LC-CDR1 having the amino acid sequence of SEQ ID NO: 160 LC-CDR2 having the amino acid sequence of SEQ ID NO: 176 LC-CDR3 having the amino acid sequence of SEQ ID NO: 191 the VL region incorporating; or (P2E11) CDR of: HC-CDR1 having the amino acid sequence of SEQ ID NO: 109 HC-CDR2 having the amino acid sequence of SEQ ID NO: 121 HC-CDR3 having the amino acid sequence of SEQ ID NO: 134 a VH region incorporating The following CDRs: LC-CDR1 having the amino acid sequence of SEQ ID NO: 159 LC-CDR2 having the amino acid sequence of SEQ ID NO: 164 LC-CDR3 having the amino acid sequence of SEQ ID NO: 192 the VL region incorporating; or (P2F9) CDR of: HC-CDR1 having the amino acid sequence of SEQ ID NO: 115 HC-CDR2 having the amino acid sequence of SEQ ID NO: 127 HC-CDR3 having the amino acid sequence of SEQ ID NO: 143 a VH region incorporating The following CDRs: LC-CDR1 having the amino acid sequence of SEQ ID NO: 151 LC-CDR2 having the amino acid sequence of SEQ ID NO: 174 LC-CDR3 having the amino acid sequence of SEQ ID NO: 193 the VL region incorporating; or (P2F10) CDR of: HC-CDR1 having the amino acid sequence of SEQ ID NO: 115 HC-CDR2 having the amino acid sequence of SEQ ID NO: 127 HC-CDR3 having the amino acid sequence of SEQ ID NO: 144 a VH region incorporating The following CDRs: LC-CDR1 having the amino acid sequence of SEQ ID NO: 161 LC-CDR2 having the amino acid sequence of SEQ ID NO: 164 LC-CDR3 having the amino acid sequence of SEQ ID NO: 194 VL region incorporating Includes:

[0013] In some embodiments, the antigen binding molecule capable of binding to CD122 is: a VH region comprising an amino acid sequence having at least 85% sequence identity to one of SEQ ID NOs: 22-34; and A VL region comprising an amino acid sequence having at least 85% sequence identity to one of SEQ ID NOs: 53 to 65. Includes:

[0014] In some embodiments, the antigen binding molecule capable of binding to CD122 is: (P1E7) a VH region comprising an amino acid sequence having at least 85% sequence identity to SEQ ID NO: 22; and a VL region comprising an amino acid sequence having at least 85% sequence identity to SEQ ID NO: 53; or (P1B10) a VH region comprising an amino acid sequence having at least 85% sequence identity to SEQ ID NO: 23; and a VL region comprising an amino acid sequence having at least 85% sequence identity to SEQ ID NO: 54; or (P1F3) a VH region comprising an amino acid sequence having at least 85% sequence identity to SEQ ID NO: 24; and a VL region comprising an amino acid sequence having at least 85% sequence identity to SEQ ID NO: 55; or (P1D10) a VH region comprising an amino acid sequence having at least 85% sequence identity to SEQ ID NO: 25; and a VL region comprising an amino acid sequence having at least 85% sequence identity to SEQ ID NO: 56; or (P1E1) a VH region comprising an amino acid sequence having at least 85% sequence identity to SEQ ID NO: 26; and a VL region comprising an amino acid sequence having at least 85% sequence identity to SEQ ID NO: 57; or (P2B11) a VH region comprising an amino acid sequence having at least 85% sequence identity to SEQ ID NO: 27; and a VL region comprising an amino acid sequence having at least 85% sequence identity to SEQ ID NO: 58; or (P2C9) a VH region comprising an amino acid sequence having at least 85% sequence identity to SEQ ID NO: 28; and a VL region comprising an amino acid sequence having at least 85% sequence identity to SEQ ID NO: 59; or (P2C10) a VH region comprising an amino acid sequence having at least 85% sequence identity to SEQ ID NO: 29; and a VL region comprising an amino acid sequence having at least 85% sequence identity to SEQ ID NO: 60; or (P2C11) a VH region comprising an amino acid sequence having at least 85% sequence identity to SEQ ID NO: 30; and a VL region comprising an amino acid sequence having at least 85% sequence identity to SEQ ID NO: 61; or (P2E6) a VH region comprising an amino acid sequence having at least 85% sequence identity to SEQ ID NO: 31; and a VL region comprising an amino acid sequence having at least 85% sequence identity to SEQ ID NO: 62; or (P2E11) a VH region comprising an amino acid sequence having at least 85% sequence identity to SEQ ID NO: 32; and a VL region comprising an amino acid sequence having at least 85% sequence identity to SEQ ID NO: 63; or (P2F9) a VH region comprising an amino acid sequence having at least 85% sequence identity to SEQ ID NO: 33; and a VL region comprising an amino acid sequence having at least 85% sequence identity to SEQ ID NO: 64; or (P2F10) a VH region comprising an amino acid sequence having at least 85% sequence identity to SEQ ID NO: 34; and VL region comprising an amino acid sequence having at least 85% sequence identity to SEQ ID NO: 65 Includes:

[0015] In some embodiments, the antigen binding molecule capable of binding to CD132 is: (P1A3) CDR of: HC-CDR1 having the amino acid sequence of SEQ ID NO: 106 HC-CDR2 having the amino acid sequence of SEQ ID NO: 119 HC-CDR3 having the amino acid sequence of SEQ ID NO: 210 a VH region incorporating The following CDRs: LC-CDR1 having the amino acid sequence of SEQ ID NO: 151 LC-CDR2 having the amino acid sequence of SEQ ID NO: 236 LC-CDR3 having the amino acid sequence of SEQ ID NO: 189 the VL region incorporating; or (P2B9) CDR below: HC-CDR1 having the amino acid sequence of SEQ ID NO: 195 HC-CDR2 having the amino acid sequence of SEQ ID NO: 202 HC-CDR3 having the amino acid sequence of SEQ ID NO: 211 a VH region incorporating The following CDRs: LC-CDR1 having the amino acid sequence of SEQ ID NO: 226 LC-CDR2 having the amino acid sequence of SEQ ID NO: 237 LC-CDR3 having the amino acid sequence of SEQ ID NO: 247 the VL region incorporating; or (P1A3_B3) CDR below: HC-CDR1 having the amino acid sequence of SEQ ID NO: 106 HC-CDR2 having the amino acid sequence of SEQ ID NO: 203 HC-CDR3 having the amino acid sequence of SEQ ID NO: 210 a VH region incorporating The following CDRs: LC-CDR1 having the amino acid sequence of SEQ ID NO: 151 LC-CDR2 having the amino acid sequence of SEQ ID NO: 236 LC-CDR3 having the amino acid sequence of SEQ ID NO: 189 the VL region incorporating; or (P1A3_B4) CDR below: HC-CDR1 having the amino acid sequence of SEQ ID NO: 106 HC-CDR2 having the amino acid sequence of SEQ ID NO: 203 HC-CDR3 having the amino acid sequence of SEQ ID NO: 210 a VH region incorporating The following CDRs: LC-CDR1 having the amino acid sequence of SEQ ID NO: 151 LC-CDR2 having the amino acid sequence of SEQ ID NO: 236 LC-CDR3 having the amino acid sequence of SEQ ID NO: 189 the VL region incorporating; or (P1A3_E9) CDR below: HC-CDR1 having the amino acid sequence of SEQ ID NO: 106 HC-CDR2 having the amino acid sequence of SEQ ID NO: 203 HC-CDR3 having the amino acid sequence of SEQ ID NO: 210 a VH region incorporating The following CDRs: LC-CDR1 having the amino acid sequence of SEQ ID NO: 151 LC-CDR2 having the amino acid sequence of SEQ ID NO: 236 LC-CDR3 having the amino acid sequence of SEQ ID NO: 189 the VL region incorporating; or (P1A3_E8) CDR below: HC-CDR1 having the amino acid sequence of SEQ ID NO: 106 HC-CDR2 having the amino acid sequence of SEQ ID NO: 203 HC-CDR3 having the amino acid sequence of SEQ ID NO: 210 a VH region incorporating The following CDRs: LC-CDR1 having the amino acid sequence of SEQ ID NO: 151 LC-CDR2 having the amino acid sequence of SEQ ID NO: 236 LC-CDR3 having the amino acid sequence of SEQ ID NO: 189 the VL region incorporating; or (P1A3_FW2) CDR below: HC-CDR1 having the amino acid sequence of SEQ ID NO: 106 HC-CDR2 having the amino acid sequence of SEQ ID NO: 119 HC-CDR3 having the amino acid sequence of SEQ ID NO: 210 a VH region incorporating The following CDRs: LC-CDR1 having the amino acid sequence of SEQ ID NO: 151 LC-CDR2 having the amino acid sequence of SEQ ID NO: 236 LC-CDR3 having the amino acid sequence of SEQ ID NO: 189 the VL region incorporating; or (P1A10) CDR of: HC-CDR1 having the amino acid sequence of SEQ ID NO: 196 HC-CDR2 having the amino acid sequence of SEQ ID NO: 204 HC-CDR3 having the amino acid sequence of SEQ ID NO: 212 a VH region incorporating The following CDRs: LC-CDR1 having the amino acid sequence of SEQ ID NO: 227 LC-CDR2 having the amino acid sequence of SEQ ID NO: 238 LC-CDR3 having the amino acid sequence of SEQ ID NO: 248 the VL region incorporating; or (P1B6) CDR below: HC-CDR1 having the amino acid sequence of SEQ ID NO: 108 HC-CDR2 having the amino acid sequence of SEQ ID NO: 120 HC-CDR3 having the amino acid sequence of SEQ ID NO: 213 a VH region incorporating The following CDRs: LC-CDR1 having the amino acid sequence of SEQ ID NO: 151 LC-CDR2 having the amino acid sequence of SEQ ID NO: 239 LC-CDR3 having the amino acid sequence of SEQ ID NO: 249 the VL region incorporating; or (P1C10) CDR of: HC-CDR1 having the amino acid sequence of SEQ ID NO: 112 HC-CDR2 having the amino acid sequence of SEQ ID NO: 124 HC-CDR3 having the amino acid sequence of SEQ ID NO: 214 a VH region incorporating The following CDRs: LC-CDR1 having the amino acid sequence of SEQ ID NO: 228 LC-CDR2 having the amino acid sequence of SEQ ID NO: 240 LC-CDR3 having the amino acid sequence of SEQ ID NO: 250 the VL region incorporating; or (P1D7) The following CDRs: HC-CDR1 having the amino acid sequence of SEQ ID NO: 197 HC-CDR2 having the amino acid sequence of SEQ ID NO: 206 HC-CDR3 having the amino acid sequence of SEQ ID NO: 215 a VH region incorporating The following CDRs: LC-CDR1 having the amino acid sequence of SEQ ID NO: 229 LC-CDR2 having the amino acid sequence of SEQ ID NO: 241 LC-CDR3 having the amino acid sequence of SEQ ID NO: 251 the VL region incorporating; or (P1E8) CDR below: HC-CDR1 having the amino acid sequence of SEQ ID NO: 198 HC-CDR2 having the amino acid sequence of SEQ ID NO: 120 HC-CDR3 having the amino acid sequence of SEQ ID NO: 216 a VH region incorporating The following CDRs: LC-CDR1 having the amino acid sequence of SEQ ID NO: 230 LC-CDR2 having the amino acid sequence of SEQ ID NO: 242 LC-CDR3 having the amino acid sequence of SEQ ID NO: 252 the VL region incorporating; or (P2B2) CDR below: HC-CDR1 having the amino acid sequence of SEQ ID NO: 108 HC-CDR2 having the amino acid sequence of SEQ ID NO: 207 HC-CDR3 having the amino acid sequence of SEQ ID NO: 217 a VH region incorporating The following CDRs: LC-CDR1 having the amino acid sequence of SEQ ID NO: 151 LC-CDR2 having the amino acid sequence of SEQ ID NO: 174 LC-CDR3 having the amino acid sequence of SEQ ID NO: 253 the VL region incorporating; or (P2B7) The following CDR: HC-CDR1 having the amino acid sequence of SEQ ID NO: 106 HC-CDR2 having the amino acid sequence of SEQ ID NO: 119 HC-CDR3 having the amino acid sequence of SEQ ID NO: 218 a VH region incorporating The following CDRs: LC-CDR1 having the amino acid sequence of SEQ ID NO: 231 LC-CDR2 having the amino acid sequence of SEQ ID NO: 174 LC-CDR3 having the amino acid sequence of SEQ ID NO: 254 the VL region incorporating; or (P2D11) The following CDRs: HC-CDR1 having the amino acid sequence of SEQ ID NO: 199 HC-CDR2 having the amino acid sequence of SEQ ID NO: 208 HC-CDR3 having the amino acid sequence of SEQ ID NO: 219 a VH region incorporating The following CDRs: LC-CDR1 having the amino acid sequence of SEQ ID NO: 232 LC-CDR2 having the amino acid sequence of SEQ ID NO: 243 LC-CDR3 having the amino acid sequence of SEQ ID NO: 255 the VL region incorporating; or (P2F10) CDR of: HC-CDR1 having the amino acid sequence of SEQ ID NO: 200 HC-CDR2 having the amino acid sequence of SEQ ID NO: 209 HC-CDR3 having the amino acid sequence of SEQ ID NO: 220 a VH region incorporating The following CDRs: LC-CDR1 having the amino acid sequence of SEQ ID NO: 233 LC-CDR2 having the amino acid sequence of SEQ ID NO: 244 LC-CDR3 having the amino acid sequence of SEQ ID NO: 256 the VL region incorporating; or (P2H4) CDR of: HC-CDR1 having the amino acid sequence of SEQ ID NO: 108 HC-CDR2 having the amino acid sequence of SEQ ID NO: 120 HC-CDR3 having the amino acid sequence of SEQ ID NO: 221 a VH region incorporating The following CDRs: LC-CDR1 having the amino acid sequence of SEQ ID NO: 234 LC-CDR2 having the amino acid sequence of SEQ ID NO: 174 LC-CDR3 having the amino acid sequence of SEQ ID NO: 257 the VL region incorporating; or (P2D3) CDR of: HC-CDR1 having the amino acid sequence of SEQ ID NO: 201 HC-CDR2 having the amino acid sequence of SEQ ID NO: 119 HC-CDR3 having the amino acid sequence of SEQ ID NO: 222 a VH region incorporating The following CDRs: LC-CDR1 having the amino acid sequence of SEQ ID NO: 151 LC-CDR2 having the amino acid sequence of SEQ ID NO: 174 LC-CDR3 having the amino acid sequence of SEQ ID NO: 189 the VL region incorporating; or (P1G4) CDR of: HC-CDR1 having the amino acid sequence of SEQ ID NO: 106 HC-CDR2 having the amino acid sequence of SEQ ID NO: 119 HC-CDR3 having the amino acid sequence of SEQ ID NO: 223 a VH region incorporating The following CDRs: LC-CDR1 having the amino acid sequence of SEQ ID NO: 151 LC-CDR2 having the amino acid sequence of SEQ ID NO: 174 LC-CDR3 having the amino acid sequence of SEQ ID NO: 258 the VL region incorporating; or (P1B12) CDR of: HC-CDR1 having the amino acid sequence of SEQ ID NO: 106 HC-CDR2 having the amino acid sequence of SEQ ID NO: 119 HC-CDR3 having the amino acid sequence of SEQ ID NO: 224 a VH region incorporating The following CDRs: LC-CDR1 having the amino acid sequence of SEQ ID NO: 235 LC-CDR2 having the amino acid sequence of SEQ ID NO: 174 LC-CDR3 having the amino acid sequence of SEQ ID NO: 189 the VL region incorporating; or (P1C7) CDR of: HC-CDR1 having the amino acid sequence of SEQ ID NO: 106 HC-CDR2 having the amino acid sequence of SEQ ID NO: 119 HC-CDR3 having the amino acid sequence of SEQ ID NO: 225 a VH region incorporating The following CDRs: LC-CDR1 having the amino acid sequence of SEQ ID NO: 151 LC-CDR2 having the amino acid sequence of SEQ ID NO: 245 LC-CDR3 having the amino acid sequence of SEQ ID NO: 189 VL region incorporating Includes:

[0016] In some embodiments, the antigen binding molecule capable of binding to CD132 is: a VH region comprising an amino acid sequence having at least 85% sequence identity to one of SEQ ID NOs: 66-84; and A VL region comprising an amino acid sequence having at least 85% sequence identity to one of SEQ ID NOs: 85 to 102. Includes:

[0017] In some embodiments, the antigen binding molecule capable of binding to CD132 is: (P1A3) a VH region comprising an amino acid sequence having at least 85% sequence identity to SEQ ID NO: 66; and a VL region comprising an amino acid sequence having at least 85% sequence identity to SEQ ID NO: 85; or (P2B9) a VH region comprising an amino acid sequence having at least 85% sequence identity to SEQ ID NO: 67; and a VL region comprising an amino acid sequence having at least 85% sequence identity to SEQ ID NO: 86; or (P1A3_B3) a VH region comprising an amino acid sequence having at least 85% sequence identity to SEQ ID NO: 68; and a VL region comprising an amino acid sequence having at least 85% sequence identity to SEQ ID NO: 85; or (P1A3_B4) a VH region comprising an amino acid sequence having at least 85% sequence identity to SEQ ID NO: 68; and a VL region comprising an amino acid sequence having at least 85% sequence identity to SEQ ID NO: 87; or (P1A3_E9) a VH region comprising an amino acid sequence having at least 85% sequence identity to SEQ ID NO: 68; and a VL region comprising an amino acid sequence having at least 85% sequence identity to SEQ ID NO: 85; or (P1A3_E8) a VH region comprising an amino acid sequence having at least 85% sequence identity to SEQ ID NO: 69; and a VL region comprising an amino acid sequence having at least 85% sequence identity to SEQ ID NO: 85; or (P1A3_FW2) a VH region comprising an amino acid sequence having at least 85% sequence identity to SEQ ID NO: 70; and a VL region comprising an amino acid sequence having at least 85% sequence identity to SEQ ID NO: 88; or (P1A10) a VH region comprising an amino acid sequence having at least 85% sequence identity to SEQ ID NO: 71; and a VL region comprising an amino acid sequence having at least 85% sequence identity to SEQ ID NO: 89; or (P1B6) a VH region comprising an amino acid sequence having at least 85% sequence identity to SEQ ID NO: 72; and a VL region comprising an amino acid sequence having at least 85% sequence identity to SEQ ID NO: 90; or (P1C10) a VH region comprising an amino acid sequence having at least 85% sequence identity to SEQ ID NO: 73; and a VL region comprising an amino acid sequence having at least 85% sequence identity to SEQ ID NO: 91; or (P1D7) a VH region comprising an amino acid sequence having at least 85% sequence identity to SEQ ID NO: 74; and a VL region comprising an amino acid sequence having at least 85% sequence identity to SEQ ID NO: 92; or (P1E8) a VH region comprising an amino acid sequence having at least 85% sequence identity to SEQ ID NO: 75; and a VL region comprising an amino acid sequence having at least 85% sequence identity to SEQ ID NO: 93; or (P2B2) a VH region comprising an amino acid sequence having at least 85% sequence identity to SEQ ID NO: 76; and a VL region comprising an amino acid sequence having at least 85% sequence identity to SEQ ID NO: 94; or (P2B7) a VH region comprising an amino acid sequence having at least 85% sequence identity to SEQ ID NO: 77; and a VL region comprising an amino acid sequence having at least 85% sequence identity to SEQ ID NO: 95; or (P2D11) a VH region comprising an amino acid sequence having at least 85% sequence identity to SEQ ID NO: 78; and a VL region comprising an amino acid sequence having at least 85% sequence identity to SEQ ID NO: 96; or (P2F10) a VH region comprising an amino acid sequence having at least 85% sequence identity to SEQ ID NO: 79; and a VL region comprising an amino acid sequence having at least 85% sequence identity to SEQ ID NO: 97; or (P2H4) a VH region comprising an amino acid sequence having at least 85% sequence identity to SEQ ID NO: 80; and a VL region comprising an amino acid sequence having at least 85% sequence identity to SEQ ID NO: 98; or (P2D3) a VH region comprising an amino acid sequence having at least 85% sequence identity to SEQ ID NO: 81; and a VL region comprising an amino acid sequence having at least 85% sequence identity to SEQ ID NO: 99; or (P1G4) a VH region comprising an amino acid sequence having at least 85% sequence identity to SEQ ID NO: 82; and a VL region comprising an amino acid sequence having at least 85% sequence identity to SEQ ID NO: 100; or (P1B12) a VH region comprising an amino acid sequence having at least 85% sequence identity to SEQ ID NO: 83; and a VL region comprising an amino acid sequence having at least 85% sequence identity to SEQ ID NO: 101; or (P1C7) a VH region comprising an amino acid sequence having at least 85% sequence identity to SEQ ID NO: 84; and It comprises a VL region comprising an amino acid sequence having at least 85% sequence identity to SEQ ID NO: 102.

[0018] In some embodiments, the antigen binding molecule is: (a) an antigen-binding molecule capable of binding to CD122: The following CDRs: HC-CDR1 having one of the amino acid sequences of SEQ ID NOs: 103 to 115 HC-CDR2 having one of the amino acid sequences of SEQ ID NOs: 116 to 127 HC-CDR3 having one of the amino acid sequences of SEQ ID NOs: 128 to 144 a heavy chain variable (VH) region incorporating The following CDRs: LC-CDR1 having one of the amino acid sequences of SEQ ID NOs: 145 to 161 LC-CDR2 having one of the amino acid sequences of SEQ ID NOs: 162 to 176 LC-CDR3 having one of the amino acid sequences of SEQ ID NOs: 177 to 194 the light chain variable (VL) region incorporating; or a variant thereof in which one, two or three amino acids are substituted with another amino acid in one or more of HC-CDR1, HC-CDR2, HC-CDR3, LC-CDR1, LC-CDR2 or LC-CDR3. The antigen-binding molecule comprising (b) an antigen-binding molecule capable of binding to CD132: The following CDRs: HC-CDR1 having one of the amino acid sequences of SEQ ID NOs: 106, 108, 112, or 196 to 201 HC-CDR2 having one of the amino acid sequences of SEQ ID NOs: 119, 120, 124, or 204 to 209 HC-CDR3 having one of the amino acid sequences of SEQ ID NOs: 212 to 225 a VH region incorporating The following CDRs: LC-CDR1 having one of the amino acid sequences of SEQ ID NO: 151 or 227 to 235 LC-CDR2 having one of the amino acid sequences of SEQ ID NO: 174 or 238 to 245 LC-CDR3 having one of the amino acid sequences of SEQ ID NO: 189 or 248 to 258 VL region incorporating; or a variant thereof in which one, two or three amino acids are substituted with another amino acid in one or more of HC-CDR1, HC-CDR2, HC-CDR3, LC-CDR1, LC-CDR2 or LC-CDR3. The antigen-binding molecule comprising Includes:

[0019] In some embodiments, the antigen binding molecule capable of binding to CD122 is: (P2C4) The following CDRs: HC-CDR1 having the amino acid sequence of SEQ ID NO: 103 HC-CDR2 having the amino acid sequence of SEQ ID NO: 116 HC-CDR3 having the amino acid sequence of SEQ ID NO: 128 a VH region incorporating The following CDRs: LC-CDR1 having the amino acid sequence of SEQ ID NO: 145 LC-CDR2 having the amino acid sequence of SEQ ID NO: 162 LC-CDR3 having the amino acid sequence of SEQ ID NO: 177 the VL region incorporating; or (P2C4_A4) The following CDR: HC-CDR1 having the amino acid sequence of SEQ ID NO: 103 HC-CDR2 having the amino acid sequence of SEQ ID NO: 116 HC-CDR3 having the amino acid sequence of SEQ ID NO: 128 a VH region incorporating The following CDRs: LC-CDR1 having the amino acid sequence of SEQ ID NO: 149 LC-CDR2 having the amino acid sequence of SEQ ID NO: 162 LC-CDR3 having the amino acid sequence of SEQ ID NO: 177 the VL region incorporating; or (P2C4_B1) The following CDR: HC-CDR1 having the amino acid sequence of SEQ ID NO: 103 HC-CDR2 having the amino acid sequence of SEQ ID NO: 116 HC-CDR3 having the amino acid sequence of SEQ ID NO: 128 a VH region incorporating The following CDRs: LC-CDR1 having the amino acid sequence of SEQ ID NO: 145 LC-CDR2 having the amino acid sequence of SEQ ID NO: 166 LC-CDR3 having the amino acid sequence of SEQ ID NO: 177 the VL region incorporating; or (P2C4_B5) The following CDR: HC-CDR1 having the amino acid sequence of SEQ ID NO: 103 HC-CDR2 having the amino acid sequence of SEQ ID NO: 116 HC-CDR3 having the amino acid sequence of SEQ ID NO: 128 a VH region incorporating The following CDRs: LC-CDR1 having the amino acid sequence of SEQ ID NO: 145 LC-CDR2 having the amino acid sequence of SEQ ID NO: 162 LC-CDR3 having the amino acid sequence of SEQ ID NO: 181 the VL region incorporating; or (P2C4_C4) The following CDR: HC-CDR1 having the amino acid sequence of SEQ ID NO: 103 HC-CDR2 having the amino acid sequence of SEQ ID NO: 116 HC-CDR3 having the amino acid sequence of SEQ ID NO: 128 a VH region incorporating The following CDRs: LC-CDR1 having the amino acid sequence of SEQ ID NO: 145 LC-CDR2 having the amino acid sequence of SEQ ID NO: 166 LC-CDR3 having the amino acid sequence of SEQ ID NO: 181 the VL region incorporating; or (P2C4_C7) The following CDR: HC-CDR1 having the amino acid sequence of SEQ ID NO: 103 HC-CDR2 having the amino acid sequence of SEQ ID NO: 116 HC-CDR3 having the amino acid sequence of SEQ ID NO: 128 a VH region incorporating The following CDRs: LC-CDR1 having the amino acid sequence of SEQ ID NO: 145 LC-CDR2 having the amino acid sequence of SEQ ID NO: 162 LC-CDR3 having the amino acid sequence of SEQ ID NO: 181 the VL region incorporating; or (P2C4_D10) The following CDR: HC-CDR1 having the amino acid sequence of SEQ ID NO: 103 HC-CDR2 having the amino acid sequence of SEQ ID NO: 116 HC-CDR3 having the amino acid sequence of SEQ ID NO: 128 a VH region incorporating The following CDRs: LC-CDR1 having the amino acid sequence of SEQ ID NO: 145 LC-CDR2 having the amino acid sequence of SEQ ID NO: 162 LC-CDR3 having the amino acid sequence of SEQ ID NO: 181 the VL region incorporating; or (P2C4_E6) The following CDR: HC-CDR1 having the amino acid sequence of SEQ ID NO: 103 HC-CDR2 having the amino acid sequence of SEQ ID NO: 116 HC-CDR3 having the amino acid sequence of SEQ ID NO: 128 a VH region incorporating The following CDRs: LC-CDR1 having the amino acid sequence of SEQ ID NO: 149 LC-CDR2 having the amino acid sequence of SEQ ID NO: 162 LC-CDR3 having the amino acid sequence of SEQ ID NO: 177 the VL region incorporating; or (P2C4_E7) The following CDR: HC-CDR1 having the amino acid sequence of SEQ ID NO: 103 HC-CDR2 having the amino acid sequence of SEQ ID NO: 116 HC-CDR3 having the amino acid sequence of SEQ ID NO: 128 a VH region incorporating The following CDRs: LC-CDR1 having the amino acid sequence of SEQ ID NO: 145 LC-CDR2 having the amino acid sequence of SEQ ID NO: 162 LC-CDR3 having the amino acid sequence of SEQ ID NO: 181 the VL region incorporating; or (P2C4_F8) The following CDR: HC-CDR1 having the amino acid sequence of SEQ ID NO: 103 HC-CDR2 having the amino acid sequence of SEQ ID NO: 116 HC-CDR3 having the amino acid sequence of SEQ ID NO: 128 a VH region incorporating The following CDRs: LC-CDR1 having the amino acid sequence of SEQ ID NO: 145 LC-CDR2 having the amino acid sequence of SEQ ID NO: 162 LC-CDR3 having the amino acid sequence of SEQ ID NO: 181 the VL region incorporating; or (P2H7) CDR of: HC-CDR1 having the amino acid sequence of SEQ ID NO: 104 HC-CDR2 having the amino acid sequence of SEQ ID NO: 117 HC-CDR3 having the amino acid sequence of SEQ ID NO: 129 a VH region incorporating The following CDRs: LC-CDR1 having the amino acid sequence of SEQ ID NO: 146 LC-CDR2 having the amino acid sequence of SEQ ID NO: 163 LC-CDR3 having the amino acid sequence of SEQ ID NO: 178 the VL region incorporating; or (P2D12) The following CDRs: HC-CDR1 having the amino acid sequence of SEQ ID NO: 105 HC-CDR2 having the amino acid sequence of SEQ ID NO: 118 HC-CDR3 having the amino acid sequence of SEQ ID NO: 130 a VH region incorporating The following CDRs: LC-CDR1 having the amino acid sequence of SEQ ID NO: 147 LC-CDR2 having the amino acid sequence of SEQ ID NO: 164 LC-CDR3 having the amino acid sequence of SEQ ID NO: 179 the VL region incorporating; or (P1G11) CDR of: HC-CDR1 having the amino acid sequence of SEQ ID NO: 106 HC-CDR2 having the amino acid sequence of SEQ ID NO: 119 HC-CDR3 having the amino acid sequence of SEQ ID NO: 131 a VH region incorporating The following CDRs: LC-CDR1 having the amino acid sequence of SEQ ID NO: 148 LC-CDR2 having the amino acid sequence of SEQ ID NO: 165 LC-CDR3 having the amino acid sequence of SEQ ID NO: 180 the VL region incorporating; or (P2C4_A9) CDR below: HC-CDR1 having the amino acid sequence of SEQ ID NO: 103 HC-CDR2 having the amino acid sequence of SEQ ID NO: 116 HC-CDR3 having the amino acid sequence of SEQ ID NO: 132 a VH region incorporating The following CDRs: LC-CDR1 having the amino acid sequence of SEQ ID NO: 145 LC-CDR2 having the amino acid sequence of SEQ ID NO: 162 LC-CDR3 having the amino acid sequence of SEQ ID NO: 177 the VL region incorporating; or (P2C4_B6) The following CDR: HC-CDR1 having the amino acid sequence of SEQ ID NO: 107 HC-CDR2 having the amino acid sequence of SEQ ID NO: 116 HC-CDR3 having the amino acid sequence of SEQ ID NO: 128 a VH region incorporating The following CDRs: LC-CDR1 having the amino acid sequence of SEQ ID NO: 145 LC-CDR2 having the amino acid sequence of SEQ ID NO: 162 LC-CDR3 having the amino acid sequence of SEQ ID NO: 181 the VL region incorporating; or (P2C4_E9) CDR below: HC-CDR1 having the amino acid sequence of SEQ ID NO: 107 HC-CDR2 having the amino acid sequence of SEQ ID NO: 116 HC-CDR3 having the amino acid sequence of SEQ ID NO: 128 a VH region incorporating The following CDRs: LC-CDR1 having the amino acid sequence of SEQ ID NO: 145 LC-CDR2 having the amino acid sequence of SEQ ID NO: 168 LC-CDR3 having the amino acid sequence of SEQ ID NO: 181 the VL region incorporating; or (P2C4_B8) CDR below: HC-CDR1 having the amino acid sequence of SEQ ID NO: 103 HC-CDR2 having the amino acid sequence of SEQ ID NO: 116 HC-CDR3 having the amino acid sequence of SEQ ID NO: 128 a VH region incorporating The following CDRs: LC-CDR1 having the amino acid sequence of SEQ ID NO: 145 LC-CDR2 having the amino acid sequence of SEQ ID NO: 162 LC-CDR3 having the amino acid sequence of SEQ ID NO: 181 the VL region incorporating; or (P2C4_B12) CDR below: HC-CDR1 having the amino acid sequence of SEQ ID NO: 103 HC-CDR2 having the amino acid sequence of SEQ ID NO: 116 HC-CDR3 having the amino acid sequence of SEQ ID NO: 128 a VH region incorporating The following CDRs: LC-CDR1 having the amino acid sequence of SEQ ID NO: 150 LC-CDR2 having the amino acid sequence of SEQ ID NO: 167 LC-CDR3 having the amino acid sequence of SEQ ID NO: 177 the VL region incorporating; or (P2C4_C1) The following CDR: HC-CDR1 having the amino acid sequence of SEQ ID NO: 103 HC-CDR2 having the amino acid sequence of SEQ ID NO: 116 HC-CDR3 having the amino acid sequence of SEQ ID NO: 128 a VH region incorporating The following CDRs: LC-CDR1 having the amino acid sequence of SEQ ID NO: 149 LC-CDR2 having the amino acid sequence of SEQ ID NO: 162 LC-CDR3 having the amino acid sequence of SEQ ID NO: 177 the VL region incorporating; or (P2C4_C12) The following CDR: HC-CDR1 having the amino acid sequence of SEQ ID NO: 103 HC-CDR2 having the amino acid sequence of SEQ ID NO: 116 HC-CDR3 having the amino acid sequence of SEQ ID NO: 128 a VH region incorporating The following CDRs: LC-CDR1 having the amino acid sequence of SEQ ID NO: 145 LC-CDR2 having the amino acid sequence of SEQ ID NO: 162 LC-CDR3 having the amino acid sequence of SEQ ID NO: 181 the VL region incorporating; or (P2C4_E2) The following CDR: HC-CDR1 having the amino acid sequence of SEQ ID NO: 103 HC-CDR2 having the amino acid sequence of SEQ ID NO: 116 HC-CDR3 having the amino acid sequence of SEQ ID NO: 128 a VH region incorporating The following CDRs: LC-CDR1 having the amino acid sequence of SEQ ID NO: 145 LC-CDR2 having the amino acid sequence of SEQ ID NO: 162 LC-CDR3 having the amino acid sequence of SEQ ID NO: 181 the VL region incorporating; or (P2C4_E3) The following CDR: HC-CDR1 having the amino acid sequence of SEQ ID NO: 107 HC-CDR2 having the amino acid sequence of SEQ ID NO: 116 HC-CDR3 having the amino acid sequence of SEQ ID NO: 128 a VH region incorporating The following CDRs: LC-CDR1 having the amino acid sequence of SEQ ID NO: 145 LC-CDR2 having the amino acid sequence of SEQ ID NO: 162 LC-CDR3 having the amino acid sequence of SEQ ID NO: 181 the VL region incorporating; or (P2C4_E8) The following CDR: HC-CDR1 having the amino acid sequence of SEQ ID NO: 103 HC-CDR2 having the amino acid sequence of SEQ ID NO: 116 HC-CDR3 having the amino acid sequence of SEQ ID NO: 128 a VH region incorporating The following CDRs: LC-CDR1 having the amino acid sequence of SEQ ID NO: 145 LC-CDR2 having the amino acid sequence of SEQ ID NO: 162 LC-CDR3 having the amino acid sequence of SEQ ID NO: 181 the VL region incorporating; or (P2C4_F11) CDR below: HC-CDR1 having the amino acid sequence of SEQ ID NO: 103 HC-CDR2 having the amino acid sequence of SEQ ID NO: 116 HC-CDR3 having the amino acid sequence of SEQ ID NO: 128 a VH region incorporating The following CDRs: LC-CDR1 having the amino acid sequence of SEQ ID NO: 145 LC-CDR2 having the amino acid sequence of SEQ ID NO: 162 LC-CDR3 having the amino acid sequence of SEQ ID NO: 181 the VL region incorporating; or (P2C4_G2) The following CDR: HC-CDR1 having the amino acid sequence of SEQ ID NO: 103 HC-CDR2 having the amino acid sequence of SEQ ID NO: 116 HC-CDR3 having the amino acid sequence of SEQ ID NO: 128 a VH region incorporating The following CDRs: LC-CDR1 having the amino acid sequence of SEQ ID NO: 145 LC-CDR2 having the amino acid sequence of SEQ ID NO: 162 LC-CDR3 having the amino acid sequence of SEQ ID NO: 181 the VL region incorporating; or (P2C4_G11) CDR below: HC-CDR1 having the amino acid sequence of SEQ ID NO: 103 HC-CDR2 having the amino acid sequence of SEQ ID NO: 116 HC-CDR3 having the amino acid sequence of SEQ ID NO: 128 a VH region incorporating The following CDRs: LC-CDR1 having the amino acid sequence of SEQ ID NO: 145 LC-CDR2 having the amino acid sequence of SEQ ID NO: 162 LC-CDR3 having the amino acid sequence of SEQ ID NO: 181 the VL region incorporating; or (P2C4_H1) CDR below: HC-CDR1 having the amino acid sequence of SEQ ID NO: 103 HC-CDR2 having the amino acid sequence of SEQ ID NO: 116 HC-CDR3 having the amino acid sequence of SEQ ID NO: 128 a VH region incorporating The following CDRs: LC-CDR1 having the amino acid sequence of SEQ ID NO: 145 LC-CDR2 having the amino acid sequence of SEQ ID NO: 162 LC-CDR3 having the amino acid sequence of SEQ ID NO: 181 the VL region incorporating; or (P2C4_H2) CDR below: HC-CDR1 having the amino acid sequence of SEQ ID NO: 103 HC-CDR2 having the amino acid sequence of SEQ ID NO: 116 HC-CDR3 having the amino acid sequence of SEQ ID NO: 128 a VH region incorporating The following CDRs: LC-CDR1 having the amino acid sequence of SEQ ID NO: 145 LC-CDR2 having the amino acid sequence of SEQ ID NO: 162 LC-CDR3 having the amino acid sequence of SEQ ID NO: 181 the VL region incorporating; or (P2C4_H3) CDR below: HC-CDR1 having the amino acid sequence of SEQ ID NO: 103 HC-CDR2 having the amino acid sequence of SEQ ID NO: 116 HC-CDR3 having the amino acid sequence of SEQ ID NO: 128 a VH region incorporating The following CDRs: LC-CDR1 having the amino acid sequence of SEQ ID NO: 145 LC-CDR2 having the amino acid sequence of SEQ ID NO: 162 LC-CDR3 having the amino acid sequence of SEQ ID NO: 181 the VL region incorporating; or (P2C4_C1D10) The following CDRs: HC-CDR1 having the amino acid sequence of SEQ ID NO: 103 HC-CDR2 having the amino acid sequence of SEQ ID NO: 116 HC-CDR3 having the amino acid sequence of SEQ ID NO: 128 a VH region incorporating The following CDRs: LC-CDR1 having the amino acid sequence of SEQ ID NO: 149 LC-CDR2 having the amino acid sequence of SEQ ID NO: 162 LC-CDR3 having the amino acid sequence of SEQ ID NO: 181 the VL region incorporating; or (P2C4_FW2) CDR below: HC-CDR1 having the amino acid sequence of SEQ ID NO: 103 HC-CDR2 having the amino acid sequence of SEQ ID NO: 116 HC-CDR3 having the amino acid sequence of SEQ ID NO: 128 a VH region incorporating The following CDRs: LC-CDR1 having the amino acid sequence of SEQ ID NO: 145 LC-CDR2 having the amino acid sequence of SEQ ID NO: 162 LC-CDR3 having the amino acid sequence of SEQ ID NO: 177 the VL region incorporating; or (P1E7) CDR of: HC-CDR1 having the amino acid sequence of SEQ ID NO: 108 HC-CDR2 having the amino acid sequence of SEQ ID NO: 120 HC-CDR3 having the amino acid sequence of SEQ ID NO: 133 a VH region incorporating The following CDRs: LC-CDR1 having the amino acid sequence of SEQ ID NO: 151 LC-CDR2 having the amino acid sequence of SEQ ID NO: 169 LC-CDR3 having the amino acid sequence of SEQ ID NO: 182 the VL region incorporating; or (P1B10) CDR of: HC-CDR1 having the amino acid sequence of SEQ ID NO: 109 HC-CDR2 having the amino acid sequence of SEQ ID NO: 121 HC-CDR3 having the amino acid sequence of SEQ ID NO: 134 a VH region incorporating The following CDRs: LC-CDR1 having the amino acid sequence of SEQ ID NO: 152 LC-CDR2 having the amino acid sequence of SEQ ID NO: 164 LC-CDR3 having the amino acid sequence of SEQ ID NO: 183 the VL region incorporating; or (P1F3) CDR of: HC-CDR1 having the amino acid sequence of SEQ ID NO: 105 HC-CDR2 having the amino acid sequence of SEQ ID NO: 122 HC-CDR3 having the amino acid sequence of SEQ ID NO: 135 a VH region incorporating The following CDRs: LC-CDR1 having the amino acid sequence of SEQ ID NO: 153 LC-CDR2 having the amino acid sequence of SEQ ID NO: 164 LC-CDR3 having the amino acid sequence of SEQ ID NO: 184 the VL region incorporating; or (P1D10) CDR of: HC-CDR1 having the amino acid sequence of SEQ ID NO: 110 HC-CDR2 having the amino acid sequence of SEQ ID NO: 119 HC-CDR3 having the amino acid sequence of SEQ ID NO: 136 a VH region incorporating The following CDRs: LC-CDR1 having the amino acid sequence of SEQ ID NO: 154 LC-CDR2 having the amino acid sequence of SEQ ID NO: 170 LC-CDR3 having the amino acid sequence of SEQ ID NO: 185 the VL region incorporating; or (P1E1) The following CDRs: HC-CDR1 having the amino acid sequence of SEQ ID NO: 106 HC-CDR2 having the amino acid sequence of SEQ ID NO: 119 HC-CDR3 having the amino acid sequence of SEQ ID NO: 137 a VH region incorporating The following CDRs: LC-CDR1 having the amino acid sequence of SEQ ID NO: 155 LC-CDR2 having the amino acid sequence of SEQ ID NO: 171 LC-CDR3 having the amino acid sequence of SEQ ID NO: 186 the VL region incorporating; or (P2B11) The following CDR: HC-CDR1 having the amino acid sequence of SEQ ID NO: 111 HC-CDR2 having the amino acid sequence of SEQ ID NO: 123 HC-CDR3 having the amino acid sequence of SEQ ID NO: 138 a VH region incorporating The following CDRs: LC-CDR1 having the amino acid sequence of SEQ ID NO: 156 LC-CDR2 having the amino acid sequence of SEQ ID NO: 172 LC-CDR3 having the amino acid sequence of SEQ ID NO: 187 the VL region incorporating; or (P2C9) CDR of: HC-CDR1 having the amino acid sequence of SEQ ID NO: 112 HC-CDR2 having the amino acid sequence of SEQ ID NO: 124 HC-CDR3 having the amino acid sequence of SEQ ID NO: 139 a VH region incorporating The following CDRs: LC-CDR1 having the amino acid sequence of SEQ ID NO: 157 LC-CDR2 having the amino acid sequence of SEQ ID NO: 173 LC-CDR3 having the amino acid sequence of SEQ ID NO: 188 the VL region incorporating; or (P2C10) The following CDRs: HC-CDR1 having the amino acid sequence of SEQ ID NO: 106 HC-CDR2 having the amino acid sequence of SEQ ID NO: 119 HC-CDR3 having the amino acid sequence of SEQ ID NO: 140 a VH region incorporating The following CDRs: LC-CDR1 having the amino acid sequence of SEQ ID NO: 158 LC-CDR2 having the amino acid sequence of SEQ ID NO: 174 LC-CDR3 having the amino acid sequence of SEQ ID NO: 189 the VL region incorporating; or (P2C11) The following CDRs: HC-CDR1 having the amino acid sequence of SEQ ID NO: 113 HC-CDR2 having the amino acid sequence of SEQ ID NO: 125 HC-CDR3 having the amino acid sequence of SEQ ID NO: 141 a VH region incorporating The following CDRs: LC-CDR1 having the amino acid sequence of SEQ ID NO: 159 LC-CDR2 having the amino acid sequence of SEQ ID NO: 175 LC-CDR3 having the amino acid sequence of SEQ ID NO: 190 the VL region incorporating; or (P2E6) CDR of: HC-CDR1 having the amino acid sequence of SEQ ID NO: 114 HC-CDR2 having the amino acid sequence of SEQ ID NO: 126 HC-CDR3 having the amino acid sequence of SEQ ID NO: 142 a VH region incorporating The following CDRs: LC-CDR1 having the amino acid sequence of SEQ ID NO: 160 LC-CDR2 having the amino acid sequence of SEQ ID NO: 176 LC-CDR3 having the amino acid sequence of SEQ ID NO: 191 the VL region incorporating; or (P2E11) CDR of: HC-CDR1 having the amino acid sequence of SEQ ID NO: 109 HC-CDR2 having the amino acid sequence of SEQ ID NO: 121 HC-CDR3 having the amino acid sequence of SEQ ID NO: 134 a VH region incorporating The following CDRs: LC-CDR1 having the amino acid sequence of SEQ ID NO: 159 LC-CDR2 having the amino acid sequence of SEQ ID NO: 164 LC-CDR3 having the amino acid sequence of SEQ ID NO: 192 the VL region incorporating; or (P2F9) CDR of: HC-CDR1 having the amino acid sequence of SEQ ID NO: 115 HC-CDR2 having the amino acid sequence of SEQ ID NO: 127 HC-CDR3 having the amino acid sequence of SEQ ID NO: 143 a VH region incorporating The following CDRs: LC-CDR1 having the amino acid sequence of SEQ ID NO: 151 LC-CDR2 having the amino acid sequence of SEQ ID NO: 174 LC-CDR3 having the amino acid sequence of SEQ ID NO: 193 the VL region incorporating; or (P2F10) CDR of: HC-CDR1 having the amino acid sequence of SEQ ID NO: 115 HC-CDR2 having the amino acid sequence of SEQ ID NO: 127 HC-CDR3 having the amino acid sequence of SEQ ID NO: 144 a VH region incorporating The following CDRs: LC-CDR1 having the amino acid sequence of SEQ ID NO: 161 LC-CDR2 having the amino acid sequence of SEQ ID NO: 164 LC-CDR3 having the amino acid sequence of SEQ ID NO: 194 the VL region incorporating; or Includes:

[0020] In some embodiments, the antigen binding molecule capable of binding to CD122 is: a VH region comprising an amino acid sequence having at least 85% sequence identity to one of SEQ ID NOs: 1-34; and A VL region comprising an amino acid sequence having at least 85% sequence identity to one of SEQ ID NOs: 35 to 65. Includes:

[0021] In some embodiments, the antigen binding molecule capable of binding to CD122 is: (P2C4) a VH region comprising an amino acid sequence having at least 85% sequence identity to SEQ ID NO: 1; and a VL region comprising an amino acid sequence having at least 85% sequence identity to SEQ ID NO: 35; or (P2C4_A4) a VH region comprising an amino acid sequence having at least 85% sequence identity to SEQ ID NO: 1; and a VL region comprising an amino acid sequence having at least 85% sequence identity to SEQ ID NO: 39; or (P2C4_B1) a VH region comprising an amino acid sequence having at least 85% sequence identity to SEQ ID NO: 1; and a VL region comprising an amino acid sequence having at least 85% sequence identity to SEQ ID NO: 40; or (P2C4_B5) a VH region comprising an amino acid sequence having at least 85% sequence identity to SEQ ID NO: 1; and a VL region comprising an amino acid sequence having at least 85% sequence identity to SEQ ID NO: 41; or (P2C4_C4) a VH region comprising an amino acid sequence having at least 85% sequence identity to SEQ ID NO: 1; and a VL region comprising an amino acid sequence having at least 85% sequence identity to SEQ ID NO: 44; or (P2C4_C7) a VH region comprising an amino acid sequence having at least 85% sequence identity to SEQ ID NO: 1; and a VL region comprising an amino acid sequence having at least 85% sequence identity to SEQ ID NO: 45; or (P2C4_D10) a VH region comprising an amino acid sequence having at least 85% sequence identity to SEQ ID NO: 1; and a VL region comprising an amino acid sequence having at least 85% sequence identity to SEQ ID NO: 42; or (P2C4_E6) a VH region comprising an amino acid sequence having at least 85% sequence identity to SEQ ID NO: 1; and a VL region comprising an amino acid sequence having at least 85% sequence identity to SEQ ID NO: 46; or (P2C4_E7) a VH region comprising an amino acid sequence having at least 85% sequence identity to SEQ ID NO: 1; and a VL region comprising an amino acid sequence having at least 85% sequence identity to SEQ ID NO: 47; or (P2C4_F8) a VH region comprising an amino acid sequence having at least 85% sequence identity to SEQ ID NO: 1; and a VL region comprising an amino acid sequence having at least 85% sequence identity to SEQ ID NO: 49; or (P2H7) a VH region comprising an amino acid sequence having at least 85% sequence identity to SEQ ID NO:2; and a VL region comprising an amino acid sequence having at least 85% sequence identity to SEQ ID NO: 36; or (P2D12) a VH region comprising an amino acid sequence having at least 85% sequence identity to SEQ ID NO: 3; and a VL region comprising an amino acid sequence having at least 85% sequence identity to SEQ ID NO: 37; or (P1G11) a VH region comprising an amino acid sequence having at least 85% sequence identity to SEQ ID NO:4; and a VL region comprising an amino acid sequence having at least 85% sequence identity to SEQ ID NO: 38; or (P2C4_A9) a VH region comprising an amino acid sequence having at least 85% sequence identity to SEQ ID NO: 5; and a VL region comprising an amino acid sequence having at least 85% sequence identity to SEQ ID NO: 35; or (P2C4_B6) a VH region comprising an amino acid sequence having at least 85% sequence identity to SEQ ID NO: 6; and a VL region comprising an amino acid sequence having at least 85% sequence identity to SEQ ID NO: 42; or (P2C4_E9) a VH region comprising an amino acid sequence having at least 85% sequence identity to SEQ ID NO: 6; and a VL region comprising an amino acid sequence having at least 85% sequence identity to SEQ ID NO: 48; or (P2C4_B8) a VH region comprising an amino acid sequence having at least 85% sequence identity to SEQ ID NO: 7; and a VL region comprising an amino acid sequence having at least 85% sequence identity to SEQ ID NO: 42; or (P2C4_B12) a VH region comprising an amino acid sequence having at least 85% sequence identity to SEQ ID NO: 8; and a VL region comprising an amino acid sequence having at least 85% sequence identity to SEQ ID NO: 43; or (P2C4_C1) a VH region comprising an amino acid sequence having at least 85% sequence identity to SEQ ID NO: 9; and a VL region comprising an amino acid sequence having at least 85% sequence identity to SEQ ID NO: 39; or (P2C4_C12) a VH region comprising an amino acid sequence having at least 85% sequence identity to SEQ ID NO: 10; and a VL region comprising an amino acid sequence having at least 85% sequence identity to SEQ ID NO: 42; or (P2C4_E2) a VH region comprising an amino acid sequence having at least 85% sequence identity to SEQ ID NO: 11; and a VL region comprising an amino acid sequence having at least 85% sequence identity to SEQ ID NO: 42; or (P2C4_E3) a VH region comprising an amino acid sequence having at least 85% sequence identity to SEQ ID NO: 12; and a VL region comprising an amino acid sequence having at least 85% sequence identity to SEQ ID NO: 42; or (P2C4_E8) a VH region comprising an amino acid sequence having at least 85% sequence identity to SEQ ID NO: 13; and a VL region comprising an amino acid sequence having at least 85% sequence identity to SEQ ID NO: 42; or (P2C4_F11) a VH region comprising an amino acid sequence having at least 85% sequence identity to SEQ ID NO: 14; and a VL region comprising an amino acid sequence having at least 85% sequence identity to SEQ ID NO: 50; or (P2C4_G2) a VH region comprising an amino acid sequence having at least 85% sequence identity to SEQ ID NO: 15; and a VL region comprising an amino acid sequence having at least 85% sequence identity to SEQ ID NO: 42; or (P2C4_G11) a VH region comprising an amino acid sequence having at least 85% sequence identity to SEQ ID NO: 16; and a VL region comprising an amino acid sequence having at least 85% sequence identity to SEQ ID NO: 42; or (P2C4_H1) a VH region comprising an amino acid sequence having at least 85% sequence identity to SEQ ID NO: 17; and a VL region comprising an amino acid sequence having at least 85% sequence identity to SEQ ID NO: 42; or (P2C4_H2) a VH region comprising an amino acid sequence having at least 85% sequence identity to SEQ ID NO: 18; and a VL region comprising an amino acid sequence having at least 85% sequence identity to SEQ ID NO: 42; or (P2C4_H3) a VH region comprising an amino acid sequence having at least 85% sequence identity to SEQ ID NO: 19; and a VL region comprising an amino acid sequence having at least 85% sequence identity to SEQ ID NO: 42; or (P2C4_C1D10) a VH region comprising an amino acid sequence having at least 85% sequence identity to SEQ ID NO: 20; and a VL region comprising an amino acid sequence having at least 85% sequence identity to SEQ ID NO: 51; or (P2C4_FW2) a VH region comprising an amino acid sequence having at least 85% sequence identity to SEQ ID NO: 21; and a VL region comprising an amino acid sequence having at least 85% sequence identity to SEQ ID NO: 52; or (P1E7) a VH region comprising an amino acid sequence having at least 85% sequence identity to SEQ ID NO: 22; and a VL region comprising an amino acid sequence having at least 85% sequence identity to SEQ ID NO: 53; or (P1B10) a VH region comprising an amino acid sequence having at least 85% sequence identity to SEQ ID NO: 23; and a VL region comprising an amino acid sequence having at least 85% sequence identity to SEQ ID NO: 54; or (P1F3) a VH region comprising an amino acid sequence having at least 85% sequence identity to SEQ ID NO: 24; and a VL region comprising an amino acid sequence having at least 85% sequence identity to SEQ ID NO: 55; or (P1D10) a VH region comprising an amino acid sequence having at least 85% sequence identity to SEQ ID NO: 25; and a VL region comprising an amino acid sequence having at least 85% sequence identity to SEQ ID NO: 56; or (P1E1) a VH region comprising an amino acid sequence having at least 85% sequence identity to SEQ ID NO: 26; and a VL region comprising an amino acid sequence having at least 85% sequence identity to SEQ ID NO: 57; or (P2B11) a VH region comprising an amino acid sequence having at least 85% sequence identity to SEQ ID NO: 27; and a VL region comprising an amino acid sequence having at least 85% sequence identity to SEQ ID NO: 58; or (P2C9) a VH region comprising an amino acid sequence having at least 85% sequence identity to SEQ ID NO: 28; and a VL region comprising an amino acid sequence having at least 85% sequence identity to SEQ ID NO: 59; or (P2C10) a VH region comprising an amino acid sequence having at least 85% sequence identity to SEQ ID NO: 29; and a VL region comprising an amino acid sequence having at least 85% sequence identity to SEQ ID NO: 60; or (P2C11) a VH region comprising an amino acid sequence having at least 85% sequence identity to SEQ ID NO: 30; and a VL region comprising an amino acid sequence having at least 85% sequence identity to SEQ ID NO: 61; or (P2E6) a VH region comprising an amino acid sequence having at least 85% sequence identity to SEQ ID NO: 31; and a VL region comprising an amino acid sequence having at least 85% sequence identity to SEQ ID NO: 62; or (P2E11) a VH region comprising an amino acid sequence having at least 85% sequence identity to SEQ ID NO: 32; and a VL region comprising an amino acid sequence having at least 85% sequence identity to SEQ ID NO: 63; or (P2F9) a VH region comprising an amino acid sequence having at least 85% sequence identity to SEQ ID NO: 33; and a VL region comprising an amino acid sequence having at least 85% sequence identity to SEQ ID NO: 64; or (P2F10) a VH region comprising an amino acid sequence having at least 85% sequence identity to SEQ ID NO: 34; and VL region comprising an amino acid sequence having at least 85% sequence identity to SEQ ID NO: 65 Includes:

[0022] In some embodiments, the antigen binding molecule capable of binding to CD132 is: (P1A10) CDR of: HC-CDR1 having the amino acid sequence of SEQ ID NO: 196 HC-CDR2 having the amino acid sequence of SEQ ID NO: 204 HC-CDR3 having the amino acid sequence of SEQ ID NO: 212 a VH region incorporating The following CDRs: LC-CDR1 having the amino acid sequence of SEQ ID NO: 227 LC-CDR2 having the amino acid sequence of SEQ ID NO: 238 LC-CDR3 having the amino acid sequence of SEQ ID NO: 248 the VL region incorporating; or (P1B6) CDR below: HC-CDR1 having the amino acid sequence of SEQ ID NO: 108 HC-CDR2 having the amino acid sequence of SEQ ID NO: 120 HC-CDR3 having the amino acid sequence of SEQ ID NO: 213 a VH region incorporating The following CDRs: LC-CDR1 having the amino acid sequence of SEQ ID NO: 151 LC-CDR2 having the amino acid sequence of SEQ ID NO: 239 LC-CDR3 having the amino acid sequence of SEQ ID NO: 249 the VL region incorporating; or (P1C10) CDR of: HC-CDR1 having the amino acid sequence of SEQ ID NO: 112 HC-CDR2 having the amino acid sequence of SEQ ID NO: 124 HC-CDR3 having the amino acid sequence of SEQ ID NO: 214 a VH region incorporating The following CDRs: LC-CDR1 having the amino acid sequence of SEQ ID NO: 228 LC-CDR2 having the amino acid sequence of SEQ ID NO: 240 LC-CDR3 having the amino acid sequence of SEQ ID NO: 250 the VL region incorporating; or (P1D7) The following CDRs: HC-CDR1 having the amino acid sequence of SEQ ID NO: 197 HC-CDR2 having the amino acid sequence of SEQ ID NO: 206 HC-CDR3 having the amino acid sequence of SEQ ID NO: 215 a VH region incorporating The following CDRs: LC-CDR1 having the amino acid sequence of SEQ ID NO: 229 LC-CDR2 having the amino acid sequence of SEQ ID NO: 241 LC-CDR3 having the amino acid sequence of SEQ ID NO: 251 the VL region incorporating; or (P1E8) CDR below: HC-CDR1 having the amino acid sequence of SEQ ID NO: 198 HC-CDR2 having the amino acid sequence of SEQ ID NO: 120 HC-CDR3 having the amino acid sequence of SEQ ID NO: 216 a VH region incorporating The following CDRs: LC-CDR1 having the amino acid sequence of SEQ ID NO: 230 LC-CDR2 having the amino acid sequence of SEQ ID NO: 242 LC-CDR3 having the amino acid sequence of SEQ ID NO: 252 the VL region incorporating; or (P2B2) CDR below: HC-CDR1 having the amino acid sequence of SEQ ID NO: 108 HC-CDR2 having the amino acid sequence of SEQ ID NO: 207 HC-CDR3 having the amino acid sequence of SEQ ID NO: 217 a VH region incorporating The following CDRs: LC-CDR1 having the amino acid sequence of SEQ ID NO: 151 LC-CDR2 having the amino acid sequence of SEQ ID NO: 174 LC-CDR3 having the amino acid sequence of SEQ ID NO: 253 the VL region incorporating; or (P2B7) The following CDR: HC-CDR1 having the amino acid sequence of SEQ ID NO: 106 HC-CDR2 having the amino acid sequence of SEQ ID NO: 119 HC-CDR3 having the amino acid sequence of SEQ ID NO: 218 a VH region incorporating The following CDRs: LC-CDR1 having the amino acid sequence of SEQ ID NO: 231 LC-CDR2 having the amino acid sequence of SEQ ID NO: 174 LC-CDR3 having the amino acid sequence of SEQ ID NO: 254 the VL region incorporating; or (P2D11) The following CDRs: HC-CDR1 having the amino acid sequence of SEQ ID NO: 199 HC-CDR2 having the amino acid sequence of SEQ ID NO: 208 HC-CDR3 having the amino acid sequence of SEQ ID NO: 219 a VH region incorporating The following CDRs: LC-CDR1 having the amino acid sequence of SEQ ID NO: 232 LC-CDR2 having the amino acid sequence of SEQ ID NO: 243 LC-CDR3 having the amino acid sequence of SEQ ID NO: 255 the VL region incorporating; or (P2F10) CDR of: HC-CDR1 having the amino acid sequence of SEQ ID NO: 200 HC-CDR2 having the amino acid sequence of SEQ ID NO: 209 HC-CDR3 having the amino acid sequence of SEQ ID NO: 220 a VH region incorporating The following CDRs: LC-CDR1 having the amino acid sequence of SEQ ID NO: 233 LC-CDR2 having the amino acid sequence of SEQ ID NO: 244 LC-CDR3 having the amino acid sequence of SEQ ID NO: 256 the VL region incorporating; or (P2H4) CDR of: HC-CDR1 having the amino acid sequence of SEQ ID NO: 108 HC-CDR2 having the amino acid sequence of SEQ ID NO: 120 HC-CDR3 having the amino acid sequence of SEQ ID NO: 221 a VH region incorporating The following CDRs: LC-CDR1 having the amino acid sequence of SEQ ID NO: 234 LC-CDR2 having the amino acid sequence of SEQ ID NO: 174 LC-CDR3 having the amino acid sequence of SEQ ID NO: 257 the VL region incorporating; or (P2D3) CDR of: HC-CDR1 having the amino acid sequence of SEQ ID NO: 201 HC-CDR2 having the amino acid sequence of SEQ ID NO: 119 HC-CDR3 having the amino acid sequence of SEQ ID NO: 222 a VH region incorporating The following CDRs: LC-CDR1 having the amino acid sequence of SEQ ID NO: 151 LC-CDR2 having the amino acid sequence of SEQ ID NO: 174 LC-CDR3 having the amino acid sequence of SEQ ID NO: 189 the VL region incorporating; or (P1G4) CDR of: HC-CDR1 having the amino acid sequence of SEQ ID NO: 106 HC-CDR2 having the amino acid sequence of SEQ ID NO: 119 HC-CDR3 having the amino acid sequence of SEQ ID NO: 223 a VH region incorporating The following CDRs: LC-CDR1 having the amino acid sequence of SEQ ID NO: 151 LC-CDR2 having the amino acid sequence of SEQ ID NO: 174 LC-CDR3 having the amino acid sequence of SEQ ID NO: 258 the VL region incorporating; or (P1B12) CDR of: HC-CDR1 having the amino acid sequence of SEQ ID NO: 106 HC-CDR2 having the amino acid sequence of SEQ ID NO: 119 HC-CDR3 having the amino acid sequence of SEQ ID NO: 224 a VH region incorporating The following CDRs: LC-CDR1 having the amino acid sequence of SEQ ID NO: 235 LC-CDR2 having the amino acid sequence of SEQ ID NO: 174 LC-CDR3 having the amino acid sequence of SEQ ID NO: 189 the VL region incorporating; or (P1C7) CDR of: HC-CDR1 having the amino acid sequence of SEQ ID NO: 106 HC-CDR2 having the amino acid sequence of SEQ ID NO: 119 HC-CDR3 having the amino acid sequence of SEQ ID NO: 225 a VH region incorporating The following CDRs: LC-CDR1 having the amino acid sequence of SEQ ID NO: 151 LC-CDR2 having the amino acid sequence of SEQ ID NO: 245 LC-CDR3 having the amino acid sequence of SEQ ID NO: 189 VL region incorporating Includes:

[0023] In some embodiments, the antigen binding molecule capable of binding to CD132 is: a VH region comprising an amino acid sequence having at least 85% sequence identity to one of SEQ ID NOs: 71-84; and A VL region comprising an amino acid sequence having at least 85% sequence identity to one of SEQ ID NOs: 89 to 102. Includes:

[0024] In some embodiments, the antigen binding molecule capable of binding to CD132 is: (P1A10) a VH region comprising an amino acid sequence having at least 85% sequence identity to SEQ ID NO: 71; and a VL region comprising an amino acid sequence having at least 85% sequence identity to SEQ ID NO: 89; or (P1B6) a VH region comprising an amino acid sequence having at least 85% sequence identity to SEQ ID NO: 72; and a VL region comprising an amino acid sequence having at least 85% sequence identity to SEQ ID NO: 90; or (P1C10) a VH region comprising an amino acid sequence having at least 85% sequence identity to SEQ ID NO: 73; and a VL region comprising an amino acid sequence having at least 85% sequence identity to SEQ ID NO: 91; or (P1D7) a VH region comprising an amino acid sequence having at least 85% sequence identity to SEQ ID NO: 74; and a VL region comprising an amino acid sequence having at least 85% sequence identity to SEQ ID NO: 92; or (P1E8) a VH region comprising an amino acid sequence having at least 85% sequence identity to SEQ ID NO: 75; and a VL region comprising an amino acid sequence having at least 85% sequence identity to SEQ ID NO: 93; or (P2B2) a VH region comprising an amino acid sequence having at least 85% sequence identity to SEQ ID NO: 76; and a VL region comprising an amino acid sequence having at least 85% sequence identity to SEQ ID NO: 94; or (P2B7) a VH region comprising an amino acid sequence having at least 85% sequence identity to SEQ ID NO: 77; and a VL region comprising an amino acid sequence having at least 85% sequence identity to SEQ ID NO: 95; or (P2D11) a VH region comprising an amino acid sequence having at least 85% sequence identity to SEQ ID NO: 78; and a VL region comprising an amino acid sequence having at least 85% sequence identity to SEQ ID NO: 96; or (P2F10) a VH region comprising an amino acid sequence having at least 85% sequence identity to SEQ ID NO: 79; and a VL region comprising an amino acid sequence having at least 85% sequence identity to SEQ ID NO: 97; or (P2H4) a VH region comprising an amino acid sequence having at least 85% sequence identity to SEQ ID NO: 80; and a VL region comprising an amino acid sequence having at least 85% sequence identity to SEQ ID NO: 98; or (P2D3) a VH region comprising an amino acid sequence having at least 85% sequence identity to SEQ ID NO: 81; and a VL region comprising an amino acid sequence having at least 85% sequence identity to SEQ ID NO: 99; or (P1G4) a VH region comprising an amino acid sequence having at least 85% sequence identity to SEQ ID NO: 82; and a VL region comprising an amino acid sequence having at least 85% sequence identity to SEQ ID NO: 100; or (P1B12) a VH region comprising an amino acid sequence having at least 85% sequence identity to SEQ ID NO: 83; and a VL region comprising an amino acid sequence having at least 85% sequence identity to SEQ ID NO: 101; or (P1C7) a VH region comprising an amino acid sequence having at least 85% sequence identity to SEQ ID NO: 84; and It comprises a VL region comprising an amino acid sequence having at least 85% sequence identity to SEQ ID NO: 102.

[0025] The present invention also provides an optionally isolated antigen-binding molecule capable of binding to CD122, comprising: The following CDRs: HC-CDR1 having one of the amino acid sequences of SEQ ID NOs: 105, 106, or 108 to 115 HC-CDR2 having one of the amino acid sequences of SEQ ID NOs: 119 to 127 HC-CDR3 having one of the amino acid sequences of SEQ ID NOs: 133 to 144 a heavy chain variable (VH) region incorporating The following CDRs: LC-CDR1 having one of the amino acid sequences of SEQ ID NOs: 151 to 161 LC-CDR2 having one of the amino acid sequences of SEQ ID NO: 164 or 169 to 176 LC-CDR3 having one of the amino acid sequences of SEQ ID NOs: 182 to 194 the light chain variable (VL) region incorporating; or a variant thereof in which one, two or three amino acids are substituted with another amino acid in one or more of HC-CDR1, HC-CDR2, HC-CDR3, LC-CDR1, LC-CDR2 or LC-CDR3. The antigen-binding molecule also comprises:

[0026] In some embodiments, the antigen binding molecule is: (P1E7) CDR of: HC-CDR1 having the amino acid sequence of SEQ ID NO: 108 HC-CDR2 having the amino acid sequence of SEQ ID NO: 120 HC-CDR3 having the amino acid sequence of SEQ ID NO: 133 a VH region incorporating The following CDRs: LC-CDR1 having the amino acid sequence of SEQ ID NO: 151 LC-CDR2 having the amino acid sequence of SEQ ID NO: 169 LC-CDR3 having the amino acid sequence of SEQ ID NO: 182 the VL region incorporating; or (P1B10) CDR of: HC-CDR1 having the amino acid sequence of SEQ ID NO: 109 HC-CDR2 having the amino acid sequence of SEQ ID NO: 121 HC-CDR3 having the amino acid sequence of SEQ ID NO: 134 a VH region incorporating The following CDRs: LC-CDR1 having the amino acid sequence of SEQ ID NO: 152 LC-CDR2 having the amino acid sequence of SEQ ID NO: 164 LC-CDR3 having the amino acid sequence of SEQ ID NO: 183 the VL region incorporating; or (P1F3) CDR of: HC-CDR1 having the amino acid sequence of SEQ ID NO: 105 HC-CDR2 having the amino acid sequence of SEQ ID NO: 122 HC-CDR3 having the amino acid sequence of SEQ ID NO: 135 a VH region incorporating The following CDRs: LC-CDR1 having the amino acid sequence of SEQ ID NO: 153 LC-CDR2 having the amino acid sequence of SEQ ID NO: 164 LC-CDR3 having the amino acid sequence of SEQ ID NO: 184 the VL region incorporating; or (P1D10) CDR of: HC-CDR1 having the amino acid sequence of SEQ ID NO: 110 HC-CDR2 having the amino acid sequence of SEQ ID NO: 119 HC-CDR3 having the amino acid sequence of SEQ ID NO: 136 a VH region incorporating The following CDRs: LC-CDR1 having the amino acid sequence of SEQ ID NO: 154 LC-CDR2 having the amino acid sequence of SEQ ID NO: 170 LC-CDR3 having the amino acid sequence of SEQ ID NO: 185 the VL region incorporating; or (P1E1) The following CDRs: HC-CDR1 having the amino acid sequence of SEQ ID NO: 106 HC-CDR2 having the amino acid sequence of SEQ ID NO: 119 HC-CDR3 having the amino acid sequence of SEQ ID NO: 137 a VH region incorporating The following CDRs: LC-CDR1 having the amino acid sequence of SEQ ID NO: 155 LC-CDR2 having the amino acid sequence of SEQ ID NO: 171 LC-CDR3 having the amino acid sequence of SEQ ID NO: 186 the VL region incorporating; or (P2B11) The following CDR: HC-CDR1 having the amino acid sequence of SEQ ID NO: 111 HC-CDR2 having the amino acid sequence of SEQ ID NO: 123 HC-CDR3 having the amino acid sequence of SEQ ID NO: 138 a VH region incorporating The following CDRs: LC-CDR1 having the amino acid sequence of SEQ ID NO: 156 LC-CDR2 having the amino acid sequence of SEQ ID NO: 172 LC-CDR3 having the amino acid sequence of SEQ ID NO: 187 the VL region incorporating; or (P2C9) CDR of: HC-CDR1 having the amino acid sequence of SEQ ID NO: 112 HC-CDR2 having the amino acid sequence of SEQ ID NO: 124 HC-CDR3 having the amino acid sequence of SEQ ID NO: 139 a VH region incorporating The following CDRs: LC-CDR1 having the amino acid sequence of SEQ ID NO: 157 LC-CDR2 having the amino acid sequence of SEQ ID NO: 173 LC-CDR3 having the amino acid sequence of SEQ ID NO: 188 the VL region incorporating; or (P2C10) The following CDRs: HC-CDR1 having the amino acid sequence of SEQ ID NO: 106 HC-CDR2 having the amino acid sequence of SEQ ID NO: 119 HC-CDR3 having the amino acid sequence of SEQ ID NO: 140 a VH region incorporating The following CDRs: LC-CDR1 having the amino acid sequence of SEQ ID NO: 158 LC-CDR2 having the amino acid sequence of SEQ ID NO: 174 LC-CDR3 having the amino acid sequence of SEQ ID NO: 189 the VL region incorporating; or (P2C11) The following CDRs: HC-CDR1 having the amino acid sequence of SEQ ID NO: 113 HC-CDR2 having the amino acid sequence of SEQ ID NO: 125 HC-CDR3 having the amino acid sequence of SEQ ID NO: 141 a VH region incorporating The following CDRs: LC-CDR1 having the amino acid sequence of SEQ ID NO: 159 LC-CDR2 having the amino acid sequence of SEQ ID NO: 175 LC-CDR3 having the amino acid sequence of SEQ ID NO: 190 the VL region incorporating; or (P2E6) CDR of: HC-CDR1 having the amino acid sequence of SEQ ID NO: 114 HC-CDR2 having the amino acid sequence of SEQ ID NO: 126 HC-CDR3 having the amino acid sequence of SEQ ID NO: 142 a VH region incorporating The following CDRs: LC-CDR1 having the amino acid sequence of SEQ ID NO: 160 LC-CDR2 having the amino acid sequence of SEQ ID NO: 176 LC-CDR3 having the amino acid sequence of SEQ ID NO: 191 the VL region incorporating; or (P2E11) CDR of: HC-CDR1 having the amino acid sequence of SEQ ID NO: 109 HC-CDR2 having the amino acid sequence of SEQ ID NO: 121 HC-CDR3 having the amino acid sequence of SEQ ID NO: 134 a VH region incorporating The following CDRs: LC-CDR1 having the amino acid sequence of SEQ ID NO: 159 LC-CDR2 having the amino acid sequence of SEQ ID NO: 164 LC-CDR3 having the amino acid sequence of SEQ ID NO: 192 the VL region incorporating; or (P2F9) CDR of: HC-CDR1 having the amino acid sequence of SEQ ID NO: 115 HC-CDR2 having the amino acid sequence of SEQ ID NO: 127 HC-CDR3 having the amino acid sequence of SEQ ID NO: 143 a VH region incorporating The following CDRs: LC-CDR1 having the amino acid sequence of SEQ ID NO: 151 LC-CDR2 having the amino acid sequence of SEQ ID NO: 174 LC-CDR3 having the amino acid sequence of SEQ ID NO: 193 the VL region incorporating; or (P2F10) CDR of: HC-CDR1 having the amino acid sequence of SEQ ID NO: 115 HC-CDR2 having the amino acid sequence of SEQ ID NO: 127 HC-CDR3 having the amino acid sequence of SEQ ID NO: 144 a VH region incorporating The following CDRs: LC-CDR1 having the amino acid sequence of SEQ ID NO: 161 LC-CDR2 having the amino acid sequence of SEQ ID NO: 164 LC-CDR3 having the amino acid sequence of SEQ ID NO: 194 VL region incorporating Includes:

[0027] In some embodiments, the antigen binding molecule is: a VH region comprising an amino acid sequence having at least 85% sequence identity to one of SEQ ID NOs: 22-34; and A VL region comprising an amino acid sequence having at least 85% sequence identity to one of SEQ ID NOs: 53 to 65. Includes:

[0028] In some embodiments, the antigen binding molecule is: (P1E7) a VH region comprising an amino acid sequence having at least 85% sequence identity to SEQ ID NO: 22; and a VL region comprising an amino acid sequence having at least 85% sequence identity to SEQ ID NO: 53; or (P1B10) a VH region comprising an amino acid sequence having at least 85% sequence identity to SEQ ID NO: 23; and a VL region comprising an amino acid sequence having at least 85% sequence identity to SEQ ID NO: 54; or (P1F3) a VH region comprising an amino acid sequence having at least 85% sequence identity to SEQ ID NO: 24; and a VL region comprising an amino acid sequence having at least 85% sequence identity to SEQ ID NO: 55; or (P1D10) a VH region comprising an amino acid sequence having at least 85% sequence identity to SEQ ID NO: 25; and a VL region comprising an amino acid sequence having at least 85% sequence identity to SEQ ID NO: 56; or (P1E1) a VH region comprising an amino acid sequence having at least 85% sequence identity to SEQ ID NO: 26; and a VL region comprising an amino acid sequence having at least 85% sequence identity to SEQ ID NO: 57; or (P2B11) a VH region comprising an amino acid sequence having at least 85% sequence identity to SEQ ID NO: 27; and a VL region comprising an amino acid sequence having at least 85% sequence identity to SEQ ID NO: 58; or (P2C9) a VH region comprising an amino acid sequence having at least 85% sequence identity to SEQ ID NO: 28; and a VL region comprising an amino acid sequence having at least 85% sequence identity to SEQ ID NO: 59; or (P2C10) a VH region comprising an amino acid sequence having at least 85% sequence identity to SEQ ID NO: 29; and a VL region comprising an amino acid sequence having at least 85% sequence identity to SEQ ID NO: 60; or (P2C11) a VH region comprising an amino acid sequence having at least 85% sequence identity to SEQ ID NO: 30; and a VL region comprising an amino acid sequence having at least 85% sequence identity to SEQ ID NO: 61; or (P2E6) a VH region comprising an amino acid sequence having at least 85% sequence identity to SEQ ID NO: 31; and a VL region comprising an amino acid sequence having at least 85% sequence identity to SEQ ID NO: 62; or (P2E11) a VH region comprising an amino acid sequence having at least 85% sequence identity to SEQ ID NO: 32; and a VL region comprising an amino acid sequence having at least 85% sequence identity to SEQ ID NO: 63; or (P2F9) a VH region comprising an amino acid sequence having at least 85% sequence identity to SEQ ID NO: 33; and a VL region comprising an amino acid sequence having at least 85% sequence identity to SEQ ID NO: 64; or (P2F10) a VH region comprising an amino acid sequence having at least 85% sequence identity to SEQ ID NO: 34; and VL region comprising an amino acid sequence having at least 85% sequence identity to SEQ ID NO: 65 Includes:

[0029] The present invention also provides an oprionally isolated antigen-binding molecule capable of binding to CD132, comprising: The following CDRs: HC-CDR1 having one of the amino acid sequences of SEQ ID NOs: 106, 108, 112, or 196 to 201 HC-CDR2 having one of the amino acid sequences of SEQ ID NOs: 119, 120, 124, or 204 to 209 HC-CDR3 having one of the amino acid sequences of SEQ ID NOs: 212 to 225 a heavy chain variable (VH) region incorporating The following CDRs: LC-CDR1 having one of the amino acid sequences of SEQ ID NO: 151 or 227 to 235 LC-CDR2 having one of the amino acid sequences of SEQ ID NO: 174 or 238 to 245 LC-CDR3 having one of the amino acid sequences of SEQ ID NO: 189 or 248 to 258 incorporating the light chain variable (LH) region; or a variant thereof in which one, two or three amino acids are substituted with another amino acid in one or more of HC-CDR1, HC-CDR2, HC-CDR3, LC-CDR1, LC-CDR2 or LC-CDR3. Includes:

[0030] In some embodiments, the antigen binding molecule is: (P1A10) CDR of: HC-CDR1 having the amino acid sequence of SEQ ID NO: 196 HC-CDR2 having the amino acid sequence of SEQ ID NO: 204 HC-CDR3 having the amino acid sequence of SEQ ID NO: 212 a VH region incorporating The following CDRs: LC-CDR1 having the amino acid sequence of SEQ ID NO: 227 LC-CDR2 having the amino acid sequence of SEQ ID NO: 238 LC-CDR3 having the amino acid sequence of SEQ ID NO: 248 the VL region incorporating; or (P1B6) CDR below: HC-CDR1 having the amino acid sequence of SEQ ID NO: 108 HC-CDR2 having the amino acid sequence of SEQ ID NO: 120 HC-CDR3 having the amino acid sequence of SEQ ID NO: 213 a VH region incorporating The following CDRs: LC-CDR1 having the amino acid sequence of SEQ ID NO: 151 LC-CDR2 having the amino acid sequence of SEQ ID NO: 239 LC-CDR3 having the amino acid sequence of SEQ ID NO: 249 the VL region incorporating; or (P1C10) CDR of: HC-CDR1 having the amino acid sequence of SEQ ID NO: 112 HC-CDR2 having the amino acid sequence of SEQ ID NO: 124 HC-CDR3 having the amino acid sequence of SEQ ID NO: 214 a VH region incorporating The following CDRs: LC-CDR1 having the amino acid sequence of SEQ ID NO: 228 LC-CDR2 having the amino acid sequence of SEQ ID NO: 240 LC-CDR3 having the amino acid sequence of SEQ ID NO: 250 the VL region incorporating; or (P1D7) The following CDRs: HC-CDR1 having the amino acid sequence of SEQ ID NO: 197 HC-CDR2 having the amino acid sequence of SEQ ID NO: 206 HC-CDR3 having the amino acid sequence of SEQ ID NO: 215 a VH region incorporating The following CDRs: LC-CDR1 having the amino acid sequence of SEQ ID NO: 229 LC-CDR2 having the amino acid sequence of SEQ ID NO: 241 LC-CDR3 having the amino acid sequence of SEQ ID NO: 251 the VL region incorporating; or (P1E8) CDR below: HC-CDR1 having the amino acid sequence of SEQ ID NO: 198 HC-CDR2 having the amino acid sequence of SEQ ID NO: 120 HC-CDR3 having the amino acid sequence of SEQ ID NO: 216 a VH region incorporating The following CDRs: LC-CDR1 having the amino acid sequence of SEQ ID NO: 230 LC-CDR2 having the amino acid sequence of SEQ ID NO: 242 LC-CDR3 having the amino acid sequence of SEQ ID NO: 252 the VL region incorporating; or (P2B2) CDR below: HC-CDR1 having the amino acid sequence of SEQ ID NO: 108 HC-CDR2 having the amino acid sequence of SEQ ID NO: 207 HC-CDR3 having the amino acid sequence of SEQ ID NO: 217 a VH region incorporating The following CDRs: LC-CDR1 having the amino acid sequence of SEQ ID NO: 151 LC-CDR2 having the amino acid sequence of SEQ ID NO: 174 LC-CDR3 having the amino acid sequence of SEQ ID NO: 253 the VL region incorporating; or (P2B7) The following CDR: HC-CDR1 having the amino acid sequence of SEQ ID NO: 106 HC-CDR2 having the amino acid sequence of SEQ ID NO: 119 HC-CDR3 having the amino acid sequence of SEQ ID NO: 218 a VH region incorporating The following CDRs: LC-CDR1 having the amino acid sequence of SEQ ID NO: 231 LC-CDR2 having the amino acid sequence of SEQ ID NO: 174 LC-CDR3 having the amino acid sequence of SEQ ID NO: 254 the VL region incorporating; or (P2D11) The following CDRs: HC-CDR1 having the amino acid sequence of SEQ ID NO: 199 HC-CDR2 having the amino acid sequence of SEQ ID NO: 208 HC-CDR3 having the amino acid sequence of SEQ ID NO: 219 a VH region incorporating The following CDRs: LC-CDR1 having the amino acid sequence of SEQ ID NO: 232 LC-CDR2 having the amino acid sequence of SEQ ID NO: 243 LC-CDR3 having the amino acid sequence of SEQ ID NO: 255 the VL region incorporating; or (P2F10) CDR of: HC-CDR1 having the amino acid sequence of SEQ ID NO: 200 HC-CDR2 having the amino acid sequence of SEQ ID NO: 209 HC-CDR3 having the amino acid sequence of SEQ ID NO: 220 a VH region incorporating The following CDRs: LC-CDR1 having the amino acid sequence of SEQ ID NO: 233 LC-CDR2 having the amino acid sequence of SEQ ID NO: 244 LC-CDR3 having the amino acid sequence of SEQ ID NO: 256 the VL region incorporating; or (P2H4) CDR of: HC-CDR1 having the amino acid sequence of SEQ ID NO: 108 HC-CDR2 having the amino acid sequence of SEQ ID NO: 120 HC-CDR3 having the amino acid sequence of SEQ ID NO: 221 a VH region incorporating The following CDRs: LC-CDR1 having the amino acid sequence of SEQ ID NO: 234 LC-CDR2 having the amino acid sequence of SEQ ID NO: 174 LC-CDR3 having the amino acid sequence of SEQ ID NO: 257 the VL region incorporating; or (P2D3) CDR of: HC-CDR1 having the amino acid sequence of SEQ ID NO: 201 HC-CDR2 having the amino acid sequence of SEQ ID NO: 119 HC-CDR3 having the amino acid sequence of SEQ ID NO: 222 a VH region incorporating The following CDRs: LC-CDR1 having the amino acid sequence of SEQ ID NO: 151 LC-CDR2 having the amino acid sequence of SEQ ID NO: 174 LC-CDR3 having the amino acid sequence of SEQ ID NO: 189 the VL region incorporating; or (P1G4) CDR of: HC-CDR1 having the amino acid sequence of SEQ ID NO: 106 HC-CDR2 having the amino acid sequence of SEQ ID NO: 119 HC-CDR3 having the amino acid sequence of SEQ ID NO: 223 a VH region incorporating The following CDRs: LC-CDR1 having the amino acid sequence of SEQ ID NO: 151 LC-CDR2 having the amino acid sequence of SEQ ID NO: 174 LC-CDR3 having the amino acid sequence of SEQ ID NO: 258 the VL region incorporating; or (P1B12) CDR of: HC-CDR1 having the amino acid sequence of SEQ ID NO: 106 HC-CDR2 having the amino acid sequence of SEQ ID NO: 119 HC-CDR3 having the amino acid sequence of SEQ ID NO: 224 a VH region incorporating The following CDRs: LC-CDR1 having the amino acid sequence of SEQ ID NO: 235 LC-CDR2 having the amino acid sequence of SEQ ID NO: 174 LC-CDR3 having the amino acid sequence of SEQ ID NO: 189 the VL region incorporating; or (P1C7) CDR of: HC-CDR1 having the amino acid sequence of SEQ ID NO: 106 HC-CDR2 having the amino acid sequence of SEQ ID NO: 119 HC-CDR3 having the amino acid sequence of SEQ ID NO: 225 a VH region incorporating The following CDRs: LC-CDR1 having the amino acid sequence of SEQ ID NO: 151 LC-CDR2 having the amino acid sequence of SEQ ID NO: 245 LC-CDR3 having the amino acid sequence of SEQ ID NO: 189 VL region incorporating Includes:

[0031] In some embodiments, the antigen binding molecule is: a VH region comprising an amino acid sequence having at least 85% sequence identity to one of SEQ ID NOs: 71-84; and A VL region comprising an amino acid sequence having at least 85% sequence identity to one of SEQ ID NOs: 89 to 102. Includes:

[0032] In some embodiments, the antigen binding molecule is: (P1A10) a VH region comprising an amino acid sequence having at least 85% sequence identity to SEQ ID NO: 71; and a VL region comprising an amino acid sequence having at least 85% sequence identity to SEQ ID NO: 89; or (P1B6) a VH region comprising an amino acid sequence having at least 85% sequence identity to SEQ ID NO: 72; and a VL region comprising an amino acid sequence having at least 85% sequence identity to SEQ ID NO: 90; or (P1C10) a VH region comprising an amino acid sequence having at least 85% sequence identity to SEQ ID NO: 73; and a VL region comprising an amino acid sequence having at least 85% sequence identity to SEQ ID NO: 91; or (P1D7) a VH region comprising an amino acid sequence having at least 85% sequence identity to SEQ ID NO: 74; and a VL region comprising an amino acid sequence having at least 85% sequence identity to SEQ ID NO: 92; or (P1E8) a VH region comprising an amino acid sequence having at least 85% sequence identity to SEQ ID NO: 75; and a VL region comprising an amino acid sequence having at least 85% sequence identity to SEQ ID NO: 93; or (P2B2) a VH region comprising an amino acid sequence having at least 85% sequence identity to SEQ ID NO: 76; and a VL region comprising an amino acid sequence having at least 85% sequence identity to SEQ ID NO: 94; or (P2B7) a VH region comprising an amino acid sequence having at least 85% sequence identity to SEQ ID NO: 77; and a VL region comprising an amino acid sequence having at least 85% sequence identity to SEQ ID NO: 95; or (P2D11) a VH region comprising an amino acid sequence having at least 85% sequence identity to SEQ ID NO: 78; and a VL region comprising an amino acid sequence having at least 85% sequence identity to SEQ ID NO: 96; or (P2F10) a VH region comprising an amino acid sequence having at least 85% sequence identity to SEQ ID NO: 79; and a VL region comprising an amino acid sequence having at least 85% sequence identity to SEQ ID NO: 97; or (P2H4) a VH region comprising an amino acid sequence having at least 85% sequence identity to SEQ ID NO: 80; and a VL region comprising an amino acid sequence having at least 85% sequence identity to SEQ ID NO: 98; or (P2D3) a VH region comprising an amino acid sequence having at least 85% sequence identity to SEQ ID NO: 81; and a VL region comprising an amino acid sequence having at least 85% sequence identity to SEQ ID NO: 99; or (P1G4) a VH region comprising an amino acid sequence having at least 85% sequence identity to SEQ ID NO: 82; and a VL region comprising an amino acid sequence having at least 85% sequence identity to SEQ ID NO: 100; or (P1B12) a VH region comprising an amino acid sequence having at least 85% sequence identity to SEQ ID NO: 83; and a VL region comprising an amino acid sequence having at least 85% sequence identity to SEQ ID NO: 101; or (P1C7) a VH region comprising an amino acid sequence having at least 85% sequence identity to SEQ ID NO: 84; and It comprises a VL region comprising an amino acid sequence having at least 85% sequence identity to SEQ ID NO: 102.

[0033] The present invention also provides optionally isolated antigen-binding molecules capable of binding to CD122, comprising (i) an antigen-binding molecule according to the present invention, and (ii) an antigen-binding molecule capable of binding to the common gamma chain (CD132).

[0034] The present invention also provides optionally isolated antigen-binding molecules capable of binding to the common gamma chain (CD132), comprising (i) an antigen-binding molecule according to the present invention, and (ii) an antigen-binding molecule capable of binding to CD122.

[0035] The present invention also provides optionally isolated antigen-binding molecules capable of binding to CD122 and the common gamma chain (CD132), comprising (i) an antigen-binding molecule according to the present invention, and (ii) an antigen-binding molecule according to the present invention.

[0036] In some embodiments, the antigen binding molecule further comprises a cell membrane anchor region. In some embodiments, the antigen binding molecule is an IL-2 receptor agonist. In some embodiments, the antigen binding molecule is capable of reducing PD-1 expression by T cells.

[0037] The present invention also provides a chimeric antigen receptor (CAR) comprising an antigen-binding molecule according to the present invention. The present invention also provides in vitro complexes, optionally isolated, comprising an antigen-binding molecule or CAR according to the invention bound to CD122 and / or CD132.

[0038] The present invention also provides nucleic acid molecules, optionally isolated, encoding antigen-binding molecules according to the present invention. The present invention also provides an expression vector comprising a nucleic acid according to the invention.

[0039] The present invention also provides cells comprising the antigen-binding molecules, nucleic acids, or expression vectors according to the present invention. The present invention also provides a method for producing an antigen-binding molecule of the present invention, the method comprising the step of culturing a cell containing a nucleic acid or expression vector of the present invention under conditions suitable for expression of the antigen-binding molecule from the nucleic acid or expression vector.

[0040] The present invention also provides compositions comprising the antigen-binding molecules, nucleic acids, expression vectors, or cells described in the present invention. The present invention also provides an antigen-binding molecule, a nucleic acid, an expression vector, a cell or a composition according to the invention for use in a method of medical treatment or prevention.

[0041] The present invention also provides an antigen-binding molecule, a nucleic acid, an expression vector, a cell or a composition according to the invention for use in a method for treating or preventing a T cell dysfunction disorder, cancer or an infectious disease.

[0042] The present invention also provides the use of an antigen-binding molecule, nucleic acid, expression vector, cell or composition according to the invention in the manufacture of a medicament for use in a method for the treatment or prevention of a T cell dysfunction disorder, cancer or infectious disease.

[0043] The present invention also provides methods for treating or preventing T cell dysfunction disorders, cancer, or infectious diseases, the methods comprising the step of administering to a subject a therapeutically or prophylactically effective amount of an antigen-binding molecule, nucleic acid, expression vector, cell, or composition described in the present invention.

[0044] In some embodiments, the cancer is selected from the group consisting of: colon cancer, colon carcinoma, colorectal cancer, nasopharyngeal cancer, cervical cancer, oropharyngeal cancer, gastric cancer, hepatocellular carcinoma, head and neck cancer, head and neck squamous cell carcinoma (HNSCC), oral cancer, laryngeal cancer, prostate cancer, lung cancer, small cell lung cancer, non-small cell lung cancer, bladder cancer, urothelial carcinoma, melanoma, advanced melanoma, renal cell carcinoma, ovarian cancer, or mesothelioma.

[0045] In some embodiments, the antigen binding molecule is administered in combination with a therapeutically effective amount of an agent capable of inhibiting signal transduction mediated by an immune checkpoint protein. In some embodiments, the immune checkpoint protein is PD-1, CTLA-4, LAG-3, TIM-3, VISTA, TIGIT, or BTLA.

[0046] The present invention also provides a method for generating or expanding an immune cell population, the method comprising contacting an immune cell in vitro, in vivo or ex vivo with an antigen-binding molecule, a nucleic acid, an expression vector, a cell or a composition.

[0047] The present invention also provides a chimeric antigen receptor (CAR) comprising an antigen-binding molecule according to the present invention. The present invention also provides an in vitro complex, optionally isolated, comprising an antigen-binding molecule or CAR according to the present invention bound to CD122 and / or CD132.

[0048] The present invention also provides a nucleic acid, optionally isolated, encoding a CAR according to the present invention. The present invention also provides an expression vector comprising a nucleic acid according to the invention.

[0049] The present invention also provides a cell comprising a CAR, a nucleic acid, or an expression vector according to the present invention. The present invention also provides compositions comprising a CAR, a nucleic acid, an expression vector, or a cell according to the invention.

[0050] The present invention also provides a CAR, a nucleic acid, an expression vector, a cell or a composition according to the invention for use in a method of medical treatment or prevention. Embodiments and experiments illustrating the principles of the present invention will now be discussed with reference to the accompanying figures. [Brief explanation of the drawings]

[0051] [Figure 1]Graphs showing binding of different formats of bispecific anti-IL2Rβ / γc antibodies to (1A) γc-Fc and (1B) IL2Rβ-Fc as determined by ELISA. [Figure 2-1] Graph and bar chart showing binding of bispecific and monospecific IL2Rβ and / or γc-binding antibodies to cells expressing human IL2Rβ, γc, or IL-2Rα on their surface as determined by flow cytometry. (2A) Graph showing analysis of binding of P2C4 / P1A3, P2C4 / P1A10, monospecific anti-γc ("negative / αIL2Rγ"), monospecific anti-IL-2Rβ ("αIL2Rβ / negative") to cells transfected with constructs encoding human IL-2Rβ and γc. Negative unstained, secondary antibody only, and isotype control conditions are shown. [Figure 2-2] (2A) Graph and bar chart showing binding of bispecific and monospecific IL2Rβ and / or γc-binding antibodies to cells expressing human IL2Rβ, γc, or IL-2Rα on their surface as determined by flow cytometry. (2B) Graph showing analysis of binding of P2C4 / P1A3, P2C4 / P1A10, monospecific anti-γc ("negative / αIL2Rγ"), monospecific anti-IL-2Rβ ("αIL2Rβ / negative") to cells transfected with a construct encoding IL-2Rα. Negative unstained, secondary antibody only, and isotype control conditions, and positive αIL2Rα control condition are shown. [Figure 2-3] Graph and bar graph showing binding of bispecific and monospecific IL2Rβ and / or γc-binding antibodies to cells expressing human IL2Rβ, γc, or IL-2Rα on the cell surface as determined by flow cytometry. (2C) Bar graph summarizing the normalized median fluorescence intensity (nMFI) for binding of the indicated antibodies to cells transfected with constructs encoding IL-2Rβ and γc. [Figure 3-1]3A and 3B are bar graphs showing binding of bispecific IL-2Rβ and γc binding antibodies to primary human T cell subsets as determined by flow cytometry. (3A and 3B) Bar graphs summarizing the normalized MFI for binding of the indicated antibodies to the indicated CD4+ (3A) and CD8+ (3B) human T cell subsets. [Figure 3-2] 3A and 3B are bar graphs showing binding of bispecific IL-2Rβ and γc binding antibodies to primary human T cell subsets as determined by flow cytometry. (3A and 3B) Bar graphs summarizing the normalized MFI for binding of the indicated antibodies to the indicated CD4+ (3A) and CD8+ (3B) human T cell subsets. [Figure 4-1] Graph and bar chart showing binding of bispecific and monospecific IL2Rβ and / or γc-binding antibodies to cells expressing rhesus IL2Rβ and γc on their surface as determined by flow cytometry. (4A) Graph showing analysis of binding of P2C4 / P1A3, P2C4 / P1A10, monospecific anti-γc ("negative / αIL2Rγ"), monospecific anti-IL-2Rβ ("αIL2Rβ / negative") to cells transfected with constructs encoding rhesus IL-2Rβ and γc. Negative unstained, secondary antibody only, and isotype control conditions are shown. [Figure 4-2] Graph and bar graph showing binding of bispecific and monospecific IL2Rβ and / or γc-binding antibodies to cells expressing rhesus IL2Rβ and γc on their cell surface as determined by flow cytometry. (4A) Bar graph summarizing the normalized MFI for the indicated binding of the indicated antibodies to cells transfected with constructs encoding rhesus IL-2Rβ and γc. [Figure 5] Bar graph showing binding of bispecific IL-2Rβ and γc binding antibodies to primary cynomolgus macaque T cell subsets as determined by flow cytometry. [Figure 6-1]Graphs showing analysis of NK92 cell proliferation in response to treatment with bispecific IL-2Rβ and γc-binding antibodies or the indicated cytokines. EC50 values ​​for induction of NK92 cell proliferation are shown. 6A and 6B show results from different experiments examining different bispecific IL-2Rβ and γc-binding antibodies. [Figure 6-2] Graphs showing analysis of NK92 cell proliferation in response to treatment with bispecific IL-2Rβ and γc-binding antibodies or the indicated cytokines. EC50 values ​​for induction of NK92 cell proliferation are shown. 6A and 6B show results from different experiments examining different bispecific IL-2Rβ and γc-binding antibodies. [Figure 7-1] Bar graphs and charts showing the analysis of proliferation of pre-activated primary human T cell subsets in response to treatment with bispecific IL-2Rβ and γc binding antibodies or IL-2. Unstimulated cells (media) and anti-CD3 / CD28 bead stimulation controls (beads) are shown. (7A) Absolute numbers of CD4+ T cells. (7B) Absolute numbers of CD8+ T cells. [Figure 7-2] (7C) Absolute numbers of Tregs. (7D) Graph showing the CD4+CD25+FoxP3+ regulatory T cell compartment after stimulation with the indicated agents. [Figure 7-3] Bar graphs and charts showing the analysis of proliferation of pre-activated primary human T cell subsets in response to treatment with bispecific IL-2Rβ and γc-binding antibodies or IL-2. Unstimulated cells (media) and anti-CD3 / CD28 bead stimulation controls (beads) are shown. (7E) Absolute numbers of naive CD8+ T cells. (7F) Absolute numbers of naive CD4+ T cells. [Figure 7-4]Bar graphs and charts showing the analysis of proliferation of pre-activated primary human T cell subsets in response to treatment with bispecific IL-2Rβ and γc-binding antibodies or IL-2. Unstimulated cells (media) and anti-CD3 / CD28 bead stimulation controls (beads) are shown. (7G) Absolute numbers of central memory CD8+ T cells. (7H) Absolute numbers of central memory CD4+ T cells. [Figure 7-5] Bar graphs and charts showing the analysis of proliferation of pre-activated primary human T cell subsets in response to treatment with bispecific IL-2Rβ and γc-binding antibodies or IL-2. Unstimulated cells (media) and anti-CD3 / CD28 bead stimulation controls (beads) are shown. (7I) Absolute number of effector memory CD8+ T cells. (7J) Absolute number of effector memory CD4+ T cells. [Figure 7-6] Bar graphs and charts showing the analysis of proliferation of pre-activated primary human T cell subsets in response to treatment with a bispecific IL-2Rβ and γc-binding antibody or IL-2. Unstimulated cells (media) and anti-CD3 / CD28 bead stimulation control (beads) are shown. (7K) Chart showing dividing effector memory CD8+ T cells as determined by CellTrace Violet staining. [Figure 7-7] Bar graphs and charts showing the analysis of proliferation of pre-activated primary human T cell subsets in response to treatment with bispecific IL-2Rβ and γc-binding antibody or IL-2. Unstimulated cells (media) and anti-CD3 / CD28 bead stimulation control (beads) are shown. (7L) Percentage of dividing CD8+ effector memory cells. [Figure 8-1] Graphs showing analysis of proliferation of pre-activated primary human T cell subsets in response to treatment with different amounts of bispecific IL-2Rβ and γc binding antibody or the indicated cytokines. (8A) Absolute numbers of CD4+ T cells. [Figure 8-2]Graphs showing analysis of proliferation of pre-activated primary human T cell subsets in response to treatment with different amounts of bispecific IL-2Rβ and γc binding antibody or the indicated cytokines. (8B) Absolute numbers of CD8+ T cells. (8C) Absolute numbers of Tregs. [Figure 8-3] Graphs showing analysis of proliferation of pre-activated primary human T cell subsets in response to treatment with different amounts of bispecific IL-2Rβ and γc binding antibody or the indicated cytokines. (8D) Ratio of absolute numbers of CD8+ T cells to absolute numbers of Tregs. (8E) Absolute numbers of effector memory CD4+ T cells. [Figure 8-4] Graphs showing analysis of proliferation of pre-activated primary human T cell subsets in response to treatment with different amounts of bispecific IL-2Rβ and γc-binding antibody or the indicated cytokines. (8F) Absolute number of effector memory CD8+ T cells. (8G) Percentage of dividing CD8+ effector memory cells. Unstimulated cells (media) and anti-CD3 / CD28 bead stimulation control (beads) are shown. [Figure 8-5] Graph showing analysis of proliferation of pre-activated primary human T cell subsets in response to treatment with different amounts of bispecific IL-2Rβ and γc binding antibody or the indicated cytokines. (8H) Absolute numbers of pre-expanded Tregs after treatment with bispecific IL-2Rβ and γc binding antibody or the indicated cytokines. [Figure 9-1] Bar graphs showing the analysis of proliferation of pre-activated T cell subsets in response to treatment of human PBMCs with bispecific IL-2Rβ and γc binding antibodies or IL-2. Unstimulated cells (media) and anti-CD3 / CD28 bead stimulation controls (beads) are shown. (9A) Absolute numbers of CD4+ T cells. [Figure 9-2] Bar graphs showing analysis of proliferation of pre-activated T cell subsets in response to treatment of human PBMCs with bispecific IL-2Rβ and γc binding antibodies or IL-2. Unstimulated cells (media) and anti-CD3 / CD28 bead stimulation controls (beads) are shown. (9B) Absolute numbers of CD8+ T cells. (9C) Absolute numbers of Tregs. [Figure 9-3]Bar graphs showing analysis of proliferation of pre-activated T cell subsets in response to treatment of human PBMCs with bispecific IL-2Rβ and γc-binding antibodies or IL-2. Unstimulated cells (media) and anti-CD3 / CD28 bead stimulation controls (beads) are shown. (9D) Absolute number of naive CD8+ T cells. (9E) Absolute number of naive CD4+ T cells. (9F) Absolute number of central memory CD8+ T cells. [Figure 9-4] Bar graphs showing analysis of proliferation of pre-activated T cell subsets in response to treatment of human PBMCs with bispecific IL-2Rβ and γc-binding antibodies or IL-2. Unstimulated cells (media) and anti-CD3 / CD28 bead stimulation controls (beads) are shown. (9G) Absolute numbers of central memory CD4+ T cells. (9H) Absolute numbers of effector memory CD8+ T cells. (9I) Absolute numbers of effector memory CD4+ T cells. [Figure 10-1] Bar graphs and charts showing analysis of antigen-specific T cell proliferation in response to treatment with bispecific IL-2Rβ and γc-binding antibodies or the indicated cytokines. Unstimulated cells (media) and anti-CD3 / CD28 bead-stimulated controls (beads) are shown. (10A) Absolute numbers of CD4+ EBV-specific T cells. (10B) Absolute numbers of CD8+ EBV-specific T cells. (10C) Absolute numbers of CD56+ EBV-specific T cells. [Figure 10-2] Bar graphs and charts showing analysis of antigen-specific T cell proliferation in response to treatment with bispecific IL-2Rβ and γc-binding antibodies or the indicated cytokines. Unstimulated cells (media) and anti-CD3 / CD28 bead-stimulated controls (beads) are shown. (10D) Absolute numbers of CD4+ EBV-specific T cells. (10E) Absolute numbers of CD8+ EBV-specific T cells. [Figure 10-3] Bar graphs and charts showing analysis of antigen-specific T cell proliferation in response to treatment with bispecific IL-2Rβ and γc-binding antibodies or the indicated cytokines. Unstimulated cells (media) and anti-CD3 / CD28 bead-stimulated controls (beads) are shown. (10F) Percentage of dividing CD8+ EBV-specific T cells. [Figure 10-4](10G) Graph showing dividing CD8+ EBV-specific T cells as determined by CellTrace Violet staining. [Figure 11-1] Bar graphs showing analysis of proliferation of cynomolgus T cell subsets in response to treatment of cynomolgus PBMCs with bispecific IL-2Rβ and γc binding antibodies or IL-2. Unstimulated cells (media) and anti-CD3 / CD28 bead stimulation controls (beads) are shown. (11A) Absolute numbers of CD4+ T cells. (11B) Absolute numbers of CD8+ T cells. (11C) Absolute numbers of Tregs. [Figure 11-2] Bar graphs showing analysis of proliferation of cynomolgus T cell subsets in response to treatment of cynomolgus PBMCs with bispecific IL-2Rβ and γc-binding antibodies or IL-2. Unstimulated cells (media) and anti-CD3 / CD28 bead stimulation controls (beads) are shown. (11D) Absolute numbers of naive CD4+ T cells. (11E) Absolute numbers of effector memory CD4+ T cells. (11F) Absolute numbers of central memory CD4+ T cells. [Figure 11-3] Bar graphs showing analysis of proliferation of cynomolgus T cell subsets in response to treatment of cynomolgus PBMCs with bispecific IL-2Rβ and γc-binding antibodies or IL-2. Unstimulated cells (media) and anti-CD3 / CD28 bead stimulation controls (beads) are shown. (11G) Absolute number of naive CD8+ T cells. (11H) Absolute number of effector memory CD8+ T cells. (11I) Absolute number of central memory CD8+ T cells. [Figure 11-4] Bar graphs showing analysis of proliferation of cynomolgus T cell subsets in response to treatment of cynomolgus PBMCs with bispecific IL-2Rβ and γc-binding antibodies or IL-2. Unstimulated cells (media) and anti-CD3 / CD28 bead-stimulated controls (beads) are shown. (11J) Absolute number of NK cells. (11K) Absolute number of B cells. (11L) Ratio of absolute number of CD8+ T cells to absolute number of CD4+ T cells. [Figure 12-1] Bar graphs showing analysis of proliferation of pre-activated cynomolgus T cell subsets in response to treatment of cynomolgus PBMCs with bispecific IL-2Rβ and γc binding antibodies or IL-2. Unstimulated cells (media) and anti-CD3 / CD28 bead stimulation controls (beads) are shown. (12A) Absolute numbers of CD4+ T cells. (12B) Absolute numbers of CD8+ T cells. (12C) Absolute numbers of Tregs. [Figure 12-2] Bar graphs showing analysis of proliferation of pre-activated cynomolgus T cell subsets in response to treatment of cynomolgus PBMCs with bispecific IL-2Rβ and γc binding antibodies or IL-2. Unstimulated cells (media) and anti-CD3 / CD28 bead stimulation controls (beads) are shown. (12D) Absolute numbers of naive CD4+ T cells. (12E) Absolute numbers of effector memory CD4+ T cells. (12F) Absolute numbers of central memory CD4+ T cells. [Figure 12-3] Bar graph showing analysis of proliferation of pre-activated cynomolgus T cell subsets in response to treatment of cynomolgus PBMCs with bispecific IL-2Rβ and γc-binding antibodies or IL-2. Unstimulated cells (media) and anti-CD3 / CD28 bead stimulation controls (beads) are shown. (12G) Absolute number of naive CD8+ T cells. (12H) Absolute number of effector memory CD8+ T cells. (12I) Absolute number of central memory CD8+ T cells. [Figure 12-4] Bar graph showing analysis of proliferation of pre-activated cynomolgus T cell subsets in response to treatment of cynomolgus PBMCs with bispecific IL-2Rβ and γc-binding antibody or IL-2. Unstimulated cells (media) and anti-CD3 / CD28 bead stimulation control (beads) are shown. (12J) Ratio of absolute number of CD8+ T cells to absolute number of CD4+ T cells. (12K) Percentage of dividing effector memory CD4+ T cells. [Figure 12-5]Bar graph showing analysis of proliferation of pre-activated cynomolgus T cell subsets in response to treatment of cynomolgus PBMCs with bispecific IL-2Rβ and γc-binding antibody or IL-2. Unstimulated cells (media) and anti-CD3 / CD28 bead stimulation control (beads) are shown. (12L) Percentage of dividing central memory CD4+ T cells. (12M) Percentage of dividing effector memory CD8+ T cells. (12N) Percentage of dividing central memory CD8+ T cells. [Figure 13] Graph showing analysis of induction of STAT5 phosphorylation in NK92 cells in response to treatment with a bispecific IL-2Rβ and γc binding antibody or IL-2. EC50 values ​​for induction of STAT5 phosphorylation are shown. [Figure 14-1] Graph showing analysis of induction of STAT5 phosphorylation in human immune cell subsets after treatment of PBMCs with different amounts of bispecific IL-2Rβ and γc-binding antibody or IL-2. EC50 values ​​for induction of STAT5 phosphorylation are shown. (14A) Percentage of pSTAT5-positive naive CD4+ T cells. [Figure 14-2] Graphs showing analysis of induction of STAT5 phosphorylation in human immune cell subsets after treatment of PBMCs with different amounts of bispecific IL-2Rβ and γc-binding antibody or IL-2. EC50 values ​​for induction of STAT5 phosphorylation are shown. (14B) Percentage of pSTAT5-positive memory CD4+ T cells. (14C) Percentage of pSTAT5-positive Tregs. [Figure 14-3] Graphs showing analysis of induction of STAT5 phosphorylation in human immune cell subsets after treatment of PBMCs with different amounts of bispecific IL-2Rβ and γc-binding antibody or IL-2. EC50 values ​​for induction of STAT5 phosphorylation are shown. (14D) Percentage of pSTAT5-positive B cells. (14E) Percentage of pSTAT5-positive naive CD8+ T cells. [Figure 14-4]Graphs showing analysis of induction of STAT5 phosphorylation in human immune cell subsets after treatment of PBMCs with different amounts of bispecific IL-2Rβ and γc-binding antibody or IL-2. EC50 values ​​for induction of STAT5 phosphorylation are shown. (14F) Percentage of pSTAT5-positive memory CD8+ T cells. (14G) Percentage of pSTAT5-positive NK cells. [Figure 14-5] Graph showing analysis of induction of STAT5 phosphorylation in human immune cell subsets after treatment of PBMCs with different amounts of bispecific IL-2Rβ and γc binding antibody or IL-2. EC50 values ​​for induction of STAT5 phosphorylation are shown. (14H) Percentage of pSTAT5-positive monocytes. [Figure 15-1] Graph showing analysis of induction of STAT5 phosphorylation in human immune cell subsets after treatment of pre-activated PBMCs with different amounts of bispecific IL-2Rβ and γc-binding antibody or IL-2. EC50 values ​​for induction of STAT5 phosphorylation are shown. (15A) Percentage of pSTAT5-positive CD4+ T cells. [Figure 15-2] Graphs showing analysis of induction of STAT5 phosphorylation in human immune cell subsets after treatment of pre-activated PBMCs with different amounts of bispecific IL-2Rβ and γc-binding antibody or IL-2. EC50 values ​​for induction of STAT5 phosphorylation are shown. (15B) Percentage of pSTAT5-positive CD8+ T cells. (15C) Percentage of pSTAT5-positive NK cells. [Figure 16] Western blot showing the kinetics of induction of STAT5 phosphorylation in NK92 cells after treatment with a bispecific IL-2Rβ and γc binding antibody or IL-2. Total STAT5 and actin were included as controls. [Figure 17-1] Graphs showing the kinetics of induction of STAT5 phosphorylation in human immune cell subsets after treatment of PBMCs with a bispecific IL-2Rβ and γc binding antibody or IL-2. (17A) Percentage of pSTAT5-positive T cells. (17B) Percentage of pSTAT5-positive CD8+ T cells. [Figure 17-2]Graphs showing the kinetics of induction of STAT5 phosphorylation in human immune cell subsets after treatment of PBMCs with a bispecific IL-2Rβ and γc binding antibody or IL-2. (17C) Percentage of pSTAT5-positive CD4+ T cells. (17D) Percentage of pSTAT5-positive monocytes. [Figure 17-3] Graph showing the kinetics of induction of STAT5 phosphorylation in human immune cell subsets after treatment of PBMCs with a bispecific IL-2Rβ and γc binding antibody or IL-2. (17E) Percentage of pSTAT5-positive B cells. [Figure 18-1] Graphs showing the kinetics of induction of STAT5 phosphorylation in antigen-specific T cells after treatment with a bispecific IL-2Rβ and γc binding antibody or IL-2. (18A) Percentage of pSTAT5-positive EBV-specific T cells. (18B) Percentage of pSTAT5-positive CD8+ EBV-specific T cells. [Figure 18-2] Graph showing the kinetics of induction of STAT5 phosphorylation in antigen-specific T cells after treatment with bispecific IL-2Rβ and γc binding antibody or IL-2. (18C) Percentage of pSTAT5-positive CD4+ EBV-specific T cells. [Figure 19] Western blot showing induction of STAT6 phosphorylation by IL-4 in THP-1 cells after treatment with a bispecific IL-2Rβ and γc-binding antibody, an isotype control antibody, or IL-2. Total STAT6 and actin were included as controls. [Figure 20-1] Bar graphs showing analysis of immune cell subset proliferation in response to treatment of freshly obtained, non-activated human PBMCs with bispecific IL-2Rβ and γc-binding antibodies or IL-2. Unstimulated cells (media) and anti-CD3 / CD28 bead-stimulated controls (beads) are shown. (20A) Absolute numbers of CD4+ T cells. (20B) Absolute numbers of CD8+ T cells. [Figure 20-2]Bar graphs showing analysis of immune cell subset proliferation in response to treatment of freshly obtained, non-activated human PBMCs with bispecific IL-2Rβ and γc-binding antibodies or IL-2. Unstimulated cells (media) and anti-CD3 / CD28 bead-stimulated controls (beads) are shown. (20C) Absolute numbers of Tregs. (20D) Absolute numbers of NK cells. [Figure 20-3] Bar graphs showing analysis of immune cell subset proliferation in response to treatment of freshly obtained, non-activated human PBMCs with bispecific IL-2Rβ and γc-binding antibodies or IL-2. Unstimulated cells (media) and anti-CD3 / CD28 bead-stimulated controls (beads) are shown. (20E) Absolute numbers of B cells. (20F) Absolute numbers of naive CD4+ T cells. [Figure 20-4] Bar graphs showing the analysis of immune cell subset proliferation in response to treatment of freshly obtained, non-activated human PBMCs with bispecific IL-2Rβ and γc-binding antibodies or IL-2. Unstimulated cells (media) and anti-CD3 / CD28 bead stimulation controls (beads) are shown. (20G) Absolute numbers of naive CD8+ T cells. (20H) Absolute numbers of central memory CD4+ T cells. [Figure 20-5] Bar graphs showing analysis of immune cell subset proliferation in response to treatment of freshly obtained, non-activated human PBMCs with bispecific IL-2Rβ and γc-binding antibodies or IL-2. Unstimulated cells (media) and anti-CD3 / CD28 bead stimulation controls (beads) are shown. (20I) Absolute numbers of central memory CD8+ T cells. (20J) Absolute numbers of effector memory CD4+ T cells. [Figure 20-6] Bar graph showing analysis of immune cell subset proliferation in response to treatment of freshly obtained non-activated human PBMCs with bispecific IL-2Rβ and γc-binding antibodies or IL-2. Unstimulated cells (media) and anti-CD3 / CD28 bead stimulation control (beads) are shown. (20K) Absolute numbers of effector memory CD8+ T cells. [Figure 21-1]Bar graph showing analysis of immune cell subset proliferation in response to treatment of non-activated human T cells with bispecific IL-2Rβ and γc-binding antibody or IL-2. Unstimulated cells (media) and anti-CD3 / CD28 bead stimulation control (beads) are shown. (21A) Absolute numbers of CD4+ T cells. [Figure 21-2] Bar graphs showing analysis of immune cell subset proliferation in response to treatment of non-activated human T cells with bispecific IL-2Rβ and γc-binding antibodies or IL-2. Unstimulated cells (media) and anti-CD3 / CD28 bead stimulation controls (beads) are shown. (21B) Absolute numbers of CD8+ T cells. (21C) Absolute numbers of Tregs. [Figure 22] Graph showing levels of bispecific IL-2Rβ / γc antibody (P2C4:P1A3) in cynomolgus monkey serum at the indicated time points after administration of the indicated amounts of antibody, as determined by ELISA. [Figure 23] Graphs showing expression of (23A) IL-2Rβ and (23B) γc on human immune cell subsets with or without activation with anti-CD3 / CD28. The graphs show normalized median fluorescence intensity (nMFI) of antibody staining for IL-2Rβ and γc as determined by flow cytometry. [Figure 24] Graphs showing expression of (24A) IL-2Rβ and (24B) γc on EBV-specific immune cell subsets. The graphs show the normalized median fluorescence intensity (nMFI) of antibody staining for IL-2Rβ and γc as determined by flow cytometry. [Figure 25] Schedule of administration of VST with or without a bispecific IL-2Rβ and γc binding antibody (BiAb), an isotype control antibody, or IL-2 to a murine EBV-LCL tumor model. [Figure 26-1]Graphs showing analysis of T cell subset proliferation and PD-1 expression in an in vivo murine EBV-LCL tumor model after treatment with VST and a bispecific IL-2Rβ and γc-binding antibody, an isotype control antibody, or IL-2. (26A) Absolute numbers of CD3+ T cells 8 days after VST treatment. (26B) Absolute numbers of CD3+CD4+ T cells 8 days after VST treatment. [Figure 26-2] Graph showing analysis of T cell subset proliferation and PD-1 expression in an in vivo murine EBV-LCL tumor model after treatment with VST and a bispecific IL-2Rβ and γc-binding antibody, an isotype control antibody, or IL-2. (26C) Absolute numbers of CD3+CD8+ T cells 8 days after VST treatment. [Figure 26-3] Graph showing analysis of T cell subset proliferation and PD-1 expression in an in vivo murine EBV-LCL tumor model after treatment with VST and a bispecific IL-2Rβ and γc-binding antibody, an isotype control antibody, or IL-2. (26D) Absolute numbers of CD3+, CD3+CD4+, and CD3+CD8+ T cells from blood 22 days after VST treatment, and CD3 T cell PD-1 expression analyzed by MFI. [Figure 26-4] Graph showing analysis of T cell subset proliferation and PD-1 expression in an in vivo murine EBV-LCL tumor model after treatment with VST and a bispecific IL-2Rβ and γc-binding antibody, an isotype control antibody, or IL-2. (26E) Absolute numbers of CD3+, CD3+CD4+, and CD3+CD8+ T cells from the spleen 22 days after VST treatment, and CD3 T cell PD-1 expression analyzed by MFI. [Figure 26-5] Graph showing analysis of T cell subset proliferation and PD-1 expression in an in vivo murine EBV-LCL tumor model after treatment with VST and a bispecific IL-2Rβ and γc-binding antibody, an isotype control antibody, or IL-2. (26F) Absolute numbers of CD3+, CD3+CD4+, and CD3+CD8+ T cells from the liver 22 days after VST treatment, and CD3 T cell PD-1 expression analyzed by MFI. [Figure 26-6] Graph showing analysis of T cell subset proliferation and PD-1 expression in an in vivo murine EBV-LCL tumor model after treatment with VST and a bispecific IL-2Rβ and γc-binding antibody, an isotype control antibody, or IL-2. (26G) Absolute numbers of CD3+, CD3+CD4+, and CD3+CD8+ T cells from tumor-draining lymph nodes 22 days after VST treatment, and CD3 T cell PD-1 expression analyzed by MFI. [Figure 26-7] Graph showing analysis of T cell subset proliferation and PD-1 expression in an in vivo murine EBV-LCL tumor model after treatment with VST and a bispecific IL-2Rβ and γc-binding antibody, an isotype control antibody, or IL-2. (26H) Absolute numbers of CD3+, CD3+CD4+, and CD3+CD8+ T cells from tumors 22 days after VST treatment, and CD3 T cell PD-1 expression analyzed by MFI. [Figure 26-8] Graph showing analysis of T cell subset proliferation and PD-1 expression in an in vivo murine EBV-LCL tumor model after treatment with VST and a bispecific IL-2Rβ and γc-binding antibody, an isotype control antibody, or IL-2. (26I) Total organ tumor burden as indicated by the absolute total number of CD19+ cells in the spleen, liver, tumor-draining lymph nodes, and tumor. [Figure 27-1] Graphs showing analysis of proliferation of pre-activated human NK cells after treatment with different amounts of bispecific IL-2Rβ and γc-binding antibodies or the indicated cytokines. Isotype antibodies were used as controls. (27A) Absolute numbers of CD16+CD56+ NK cells. EC50 values ​​are shown. (27B) Absolute numbers of CD16-CD56+ NK cells. [Figure 27-2]Graphs showing analysis of proliferation of pre-activated human NK cells after treatment with different amounts of bispecific IL-2Rβ and γc-binding antibodies or the indicated cytokines. Isotype antibodies were used as controls. (27C) Percentage of dividing cells that are CD16+CD56+ as determined by CellTrace™ Violet (CTV). EC50 values ​​are shown. (27D) Percentage of dividing cells that are CD16-CD56+ as determined by CTV. EC50 values ​​are shown. [Figure 28-1] Graphs showing analysis of CAR-T cell proliferation after treatment with different amounts of bispecific IL-2Rβ and γc-binding antibody or IL-2. Isotype antibody was used as a control. EC50 is shown for 28A-D. (28A) Absolute number of CD4+ CAR-T cells. (28B) Absolute number of CD4+ CAR-T cells. [Figure 28-2] Graphs showing analysis of CAR-T cell proliferation after treatment with different amounts of bispecific IL-2Rβ and γc-binding antibody or IL-2. Isotype antibody was used as a control. EC50 is shown for 28A-D. (28C) Percentage of dividing CAR-T cells that are CD4+, as determined by CellTrace™ Violet (CTV). (28D) Percentage of dividing CAR-T cells that are CD8+, as determined by CTV. [Figure 29] Schedule of administration of VST and Tregs with or without bispecific IL-2Rβ and γc binding antibody (BiAb), isotype control antibody (Iso), or IL-2 against a murine EBV-BLCL tumor model. [Figure 30-1] Graphs showing analysis of T cell subset proliferation in an in vivo murine EBV-BLCL tumor model following treatment with a bispecific IL-2Rβ and γc binding antibody, an isotype control antibody (Iso), or IL-2, in addition to VSTs and Tregs. (30A) Absolute numbers of CD3+ T cells at 7, 14, and 21 days after treatment. [Figure 30-2]Graph showing analysis of T cell subset proliferation in an in vivo murine EBV-BLCL tumor model following treatment with a bispecific IL-2Rβ and γc binding antibody, an isotype control antibody (Iso), or IL-2, in addition to VSTs and Tregs. (30B) Absolute numbers of CD3+, CD3+CD4+, and CD3+CD8+ T cells from the spleen 22 days after treatment. [Figure 30-3] Graph showing analysis of T cell subset proliferation in an in vivo murine EBV-BLCL tumor model after treatment with a bispecific IL-2Rβ and γc binding antibody, an isotype control antibody (Iso), or IL-2, in addition to VSTs and Tregs. (30C) Absolute numbers of CD3+, CD3+CD4+, and CD3+CD8+ T cells from the liver after 22 days of treatment. [Figure 30-4] Graph showing analysis of T cell subset proliferation in an in vivo murine EBV-BLCL tumor model after treatment with a bispecific IL-2Rβ and γc binding antibody, an isotype control antibody (Iso), or IL-2, in addition to VSTs and Tregs. (30D) Absolute numbers of CD3+, CD3+CD4+, and CD3+CD8+ T cells from tumor-draining lymph nodes 22 days after treatment. [Figure 30-5] Graph showing analysis of T cell subset proliferation in an in vivo murine EBV-BLCL tumor model following treatment with a bispecific IL-2Rβ and γc binding antibody, an isotype control antibody (Iso), or IL-2, in addition to VSTs and Tregs. (30E) Absolute numbers of CD3+, CD3+CD4+, and CD3+CD8+ T cells from the injection site 22 days after treatment. [Figure 30-6] Graph showing analysis of T cell subset proliferation in an in vivo murine EBV-BLCL tumor model after treatment with a bispecific IL-2Rβ and γc binding antibody, an isotype control antibody (Iso), or IL-2, in addition to VSTs and Tregs. (30F) Ratio of absolute numbers of CD8+ T cells to absolute numbers of Tregs in the spleen, liver, and tumor-draining lymph nodes 22 days after treatment. [Figure 30-7]Graph showing analysis of T cell subset proliferation in an in vivo murine EBV-BLCL tumor model after treatment with a bispecific IL-2Rβ and γc binding antibody, an isotype control antibody (Iso), or IL-2, in addition to VSTs and Tregs. (30G) Total numbers of CD3+, CD3+CD4+, and CD3+CD8+ T cells pooled from spleen, liver, tumor-draining lymph nodes, and injection site. [Figure 30-8] Graph showing analysis of T cell subset proliferation in an in vivo murine EBV-BLCL tumor model after treatment with a bispecific IL-2Rβ and γc-binding antibody, an isotype control antibody (Iso), or IL-2, in addition to VSTs and Tregs. (30H) Ratio of total CD8+ T cells to total Tregs pooled from spleen, liver, tumor-draining lymph nodes, and injection site 22 days after treatment. [Figure 30-9] Graph showing analysis of T cell subset proliferation in an in vivo murine EBV-BLCL tumor model following treatment with a bispecific IL-2Rβ and γc binding antibody, an isotype control antibody (Iso), or IL-2, in addition to VSTs and Tregs. (30I) Absolute numbers of EBV-BLCL tumor cells from the spleen, liver, and lymph node(s) 22 days after treatment. [Figure 30-10] Graph showing analysis of T cell subset proliferation in an in vivo murine EBV-BLCL tumor model following treatment with a bispecific IL-2Rβ and γc binding antibody, an isotype control antibody (Iso), or IL-2, in addition to VSTs and Tregs. (30J) Total organ tumor burden as indicated by the absolute total number of CD19+ tumor cells in the spleen, liver, and tumor-draining lymph nodes. [Figure 30-11]Graph showing analysis of T cell subset proliferation in an in vivo murine EBV-BLCL tumor model after treatment with a bispecific IL-2Rβ and γc binding antibody, an isotype control antibody (Iso), or IL-2, in addition to VSTs and Tregs. (30K) Total numbers of CD107a+, IFN-γ+, and perforin+ CD8 T cells pooled from spleen, liver, tumor-draining lymph nodes, and injection site 22 days after treatment. DETAILED DESCRIPTION OF THE INVENTION

[0052] Treatment with IL-2 is an approved immunotherapy for cancer treatment and works by promoting the proliferation and activity of effector immune cells such as T cells and NK cells (see, e.g., Skorombolas and Frelinger, Expert Rev Clin Immunol. 2014; 10(2): 207-217).

[0053] However, there are several drawbacks associated with IL-2 therapy. IL-2 has a very short serum half-life, and therefore requires very high doses and regular administration to achieve stimulation of T cell and NK cell proliferation / activity. High doses of IL-2 cause increased levels of pro-inflammatory cytokines, sometimes referred to as a "cytokine storm," which is thought to be the result of widespread stimulation of immune cells. Cytokine storm, in turn, is thought to be responsible for many of the undesirable side effects of IL-2 treatment, including vascular leak syndrome (VLS). Furthermore, IL-2 can act on Tregs (expressing the high-affinity IL-2Rα / β / γc receptor), and thus, treatment with IL-2 induces the expansion of this suppressor T cell subset, which can downregulate effector immune cell activity.

[0054] The present inventors have designed and produced an agonistic antibody that selectively binds to and activates the intermediate affinity IL-2Rβ / γc antibody receptor. The antibody has been demonstrated to mimic the effects of IL-2 on cells expressing CD122 and CD132, leading to the expansion of effector immune cells. Unlike IL-2, the bispecific antibody of the present invention selectively binds to and activates regulatory T cells (high levels of the high affinity IL-2Rα / β / γc receptor). The bispecific antibody preferentially stimulates the proliferation of effector immune cells (expressing the intermediate affinity IL-2Rβ / γc receptor) over effector immune cells (expressing the intermediate affinity IL-2Rβ / γc receptor). Furthermore, the bispecific antibody has an increased serum half-life compared to IL-2 and therefore can be administered less frequently and / or at lower doses.

[0055] IL-2Rβ (CD122) and common gamma chain (γc; CD132) Human IL-2Rβ (also known as CD122, IL15RB, and P70-75) is a protein identified by UniProt P14784-1, v1 (SEQ ID NO:434). The N-terminal 26 amino acids of SEQ ID NO:434 constitute a signal peptide, and thus the mature form of the human CD122 protein (i.e., after processing to remove the signal peptide) has the amino acid sequence set forth in SEQ ID NO:435. Amino acids 27-240 of SEQ ID NO:434 constitute the extracellular domain of CD122, set forth in SEQ ID NO:436.

[0056] As used herein, "IL-2Rβ" or "CD122" refers to CD122 from any species, and includes isoforms, fragments, variants, or homologs of CD122 from any species.

[0057] As used herein, a "fragment," "variant," or "homologue" of a protein may be characterized as having at least 60%, preferably 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% amino acid sequence identity to the amino acid sequence of the reference protein, as desired. Fragments, variants, isoforms, and homologues of a reference protein may also be characterized by their ability to perform a function performed by the reference protein.

[0058] A "fragment" generally refers to a portion of a reference protein. A "variant" generally refers to a protein having an amino acid sequence that contains one or more amino acid substitutions, insertions, deletions, or other modifications compared to the amino acid sequence of the reference protein, but retains a significant degree of sequence identity (e.g., at least 60%) to the amino acid sequence of the reference protein. An "isoform" generally refers to a variant of a reference protein that is expressed by the same species as the reference protein. A "homologue" generally refers to a variant of a reference protein that is produced by a different species compared to the species of the reference protein. For example, human CD122 (P14784-1, v1; SEQ ID NO: 434) and cynomolgus monkey CD122 (UniProt: Q38J85-1, v1) are homologs of each other.

[0059] A "fragment" of a reference protein may be of any length (in terms of number of amino acids), but may optionally be at least 25% of the length of the reference protein (i.e., the protein from which the fragment is derived), and may have a maximum length of one of 50%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% of the length of the reference protein.

[0060] A fragment of CD122 may have a minimum length of one of 10, 20, 30, 40, 50, 100, 150, 200, 250 or 300 amino acids and a maximum length of one of 20, 30, 40, 50, 100, 150, 200, 250, 300, 350, 400, 450 or 500 amino acids.

[0061] In some embodiments, the CD122 is mammalian CD122 (e.g., cynomolgus monkey, human, and / or rodent (e.g., rat and / or murine) CD122). CD122 isoforms, fragments, variants, or homologs optionally contain at least 7 amino acid residues in the amino acid sequence of immature or mature CD122 from a given species, e.g., human CD122. 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% amino acid sequence identity with a reference CD122. Isoforms, fragments, variants, or homologs of CD122 may optionally be functional isoforms, fragments, variants, or homologs that have a functional property / activity of a reference CD122 (e.g., full-length human CD122) as determined, for example, by analysis with a suitable assay for the functional property / activity. For example, an isoform, fragment, variant, or homolog of CD122 may exhibit one or more of: association with one or more of CD132, IL-2Rα (CD25), or IL-15Rα (CD215), or binding to IL-2 or IL-15.

[0062] In some embodiments, CD122 has at least 70%, preferably 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% amino acid sequence identity to one of SEQ ID NOs: 434-436.

[0063] Human common gamma chain (γc; also known as CD132, IL-2RG, and CIDX) is a protein identified by UniProt P31785-1, v1 (SEQ ID NO: 437). The N-terminal 23 amino acids of SEQ ID NO: 437 constitute the signal peptide, and thus the mature form of the human CD132 protein (i.e., after processing to remove the signal peptide) has the amino acid sequence set forth in SEQ ID NO: 438. Amino acids 23-262 of SEQ ID NO: 437 constitute the extracellular domain of CD132, set forth in SEQ ID NO: 439.

[0064] As used herein, "γc" or "CD132" refers to CD132 from any species, and includes isoforms, fragments, variants, or homologs of CD132 from any species.

[0065] In some embodiments, the CD132 is mammalian CD132 (e.g., cynomolgus monkey, human, and / or rodent (e.g., rat and / or murine) CD132). CD132 isoforms, fragments, variants, or homologs may optionally be characterized as having at least 70%, preferably 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% amino acid sequence identity to the amino acid sequence of immature or mature CD132 from a given species, e.g., human CD132. CD132 isoforms, fragments, variants, or homologs may optionally be functional isoforms, fragments, variants, or homologs that have a functional property / activity of a reference CD132 (e.g., full-length human CD132), e.g., as determined by analysis with an appropriate assay for functional property / activity. For example, an isoform, fragment, variant or homologue of CD132 may exhibit one or more of: association with one or more of CD122, IL-2Rα, IL-15Rα, IL-4R (CD124), IL-9R (CD129), IL-21R (CD360) or IL7R (CD127), or binding to one or more of IL-2, IL-15, IL-4, IL-9, IL-21 or IL-7.

[0066] A fragment of CD132 may have a minimum length of one of 10, 20, 30, 40, 50, 100, 150, 200, 250 or 300 amino acids and a maximum length of one of 20, 30, 40, 50, 100, 150, 200, 250, 300, 350 amino acids.

[0067] In some embodiments, CD132 is at least 70%, preferably 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 100%, 101%, 102%, 103%, 104%, 105%, 106%, 107%, 108%, 109%, 110%, 111%, 112%, 113%, 114%, 115%, 116%, 117%, 118%, 119%, 120%, 121%, 122%, 123%, 124%, 125%, 126%, 127%, 128%, 129%, 130%, 131%, 132%, 133%, 134%, 135%, 136%, 137%, %, 96%, 97%, 98%, 99% or 100% amino acid sequence identity with one of the sequences.

[0068] The IL-2 receptor and its biology are described, for example, in Skrombolas and Frelinger, Expert Rev Clin Immunol. (2014) 10(2): 207-217, which is incorporated herein in its entirety.

[0069] CD122 and CD132 are involved in forming the receptor for IL-2. CD122 and CD132 associate with IL-2Rα (CD25) to form a trimeric high-affinity IL-2 receptor (sometimes referred to as "IL-2Rα / β / γc" or "CD25 / CD122 / CD132"), which binds IL-2 with a Kd of ∼10 pM. CD122 and CD132 can also associate to form a functional intermediate-affinity IL-2 receptor (sometimes referred to as "IL-2Rβ / γc" or "CD122 / CD132"), which binds IL-2 with a Kd of ∼1 nM.

[0070] The composition, number, and potential signaling capabilities of receptors can vary depending on the cell type and activation stage. IL-2 receptors are expressed at relatively low levels on resting naive T cells. However, activated CD4 and CD8 T cells begin to express high levels of CD25, allowing the cells to efficiently bind IL-2. CD25 is expressed in higher amounts (8-10 times) than CD122 and CD132. It is believed that CD25 first binds to IL-2, effectively increasing its concentration on the cell surface and inducing a conformational change in IL-2, which then subsequently binds to CD122 and CD132 (Liao et al., Immunity (2013) 38(1):13-25). NK cells and memory phenotype CD8 cells express high levels of CD122 and CD132 compared to naive cells, and some NK cells can also express CD25 after stimulation with IL-2.

[0071] Importantly, CD4 regulatory T cells (Tregs) constitutively express high levels of CD25. Tregs act in multiple ways to downregulate many immune responses, including anti-tumor responses (e.g., Shevach, Immunity (2009) 30(5):636-45).

[0072] antigen binding molecule The present invention provides antigen-binding molecules. In aspects of the present invention, the antigen-binding molecules are capable of binding to CD122. In aspects of the present invention, the antigen-binding molecules are capable of binding to CD132. In aspects of the present invention, the antigen-binding molecules are capable of binding to CD122 and CD132. In aspects of the present invention, the antigen-binding molecules are capable of binding to CD122 and CD132, and include antigen-binding molecules capable of binding to CD122 and antigen-binding molecules capable of binding to CD132.

[0073] An "antigen-binding molecule," as used herein, refers to a polypeptide or polypeptide complex capable of binding to one or more target antigens, and includes monoclonal antibodies, polyclonal antibodies, monospecific and multispecific antibodies (e.g., bispecific antibodies), as well as antibody fragments, so long as they bind to the appropriate target antigen(s).

[0074] The antigen-binding molecules of the present invention comprise one or more portions capable of binding to a target antigen(s). The portion capable of binding to a target antigen comprises an antibody heavy chain variable region (VH) and an antibody light chain variable region (VL) of an antibody capable of specifically binding to the target antigen. In some embodiments, the portion capable of binding to a target antigen comprises an antibody capable of binding to the target antigen. The aptamer may comprise or consist of an aptamer, such as a nucleic acid aptamer (reviewed, for example, in Zhou and Rossi Nat Rev Drug Discov. 2017 16(3):181-202). In some embodiments, the moiety capable of binding to a target antigen comprises or consists of an antigen-binding peptide / polypeptide, such as a peptide aptamer, thioredoxin, monobody, anticalin, Kunitz domain, avimer, knottin, fynomer, atrimer, DARPin, affibody, nanobody (i.e., single domain antibody (sdAb)), affilin, armadillo repeat protein (ArmRP), OBody, or fibronectin, e.g., as reviewed in Reverdatto et al., Curr Top Med Chem. 2015; 15(12): 1082-1101, which is incorporated herein by reference in its entirety (see also, e.g., Boersma et al., J Biol Chem (2011) 286:41273-85 and Emanuel et al., Mabs (2011) 3:38-48).

[0075] The antigen-binding molecules of the present invention generally comprise an antigen-binding portion comprising the VH and VL of an antibody capable of specifically binding to a target antigen. The antigen-binding portion formed by the VH and VL may also be referred to herein as an Fv region.

[0076] An antigen-binding molecule may be or may comprise an antigen-binding polypeptide or an antigen-binding polypeptide complex. An antigen-binding molecule may comprise more than one polypeptide that together form an antigen-binding domain. The polypeptides may be covalently or non-covalently associated. In some embodiments, a polypeptide forms part of a larger polypeptide that comprises the polypeptide (e.g., in the case of an scFv comprising a VH and a VL, or in the case of an scFab comprising a VH-CH1 and a VL-CL).

[0077] An antigen-binding molecule may comprise or consist of one or more polypeptides. In some embodiments, an antigen-binding molecule comprises one, two, three, four, five, six, seven, eight, nine, ten, eleven, or twelve polypeptides. In some embodiments, an antigen-binding molecule is a covalent or non-covalent complex of more than one polypeptide (e.g., two, three, four, six, eight, ten, or more polypeptides). For example, in some embodiments, an antigen-binding molecule comprises two heavy chain polypeptides and two light chain polypeptides.

[0078] The antigen-binding molecules described herein preferably exhibit specific binding to an appropriate target (e.g., CD122 and / or CD132). As used herein, "specific binding" refers to binding that is selective for an antigen and distinguishable from non-specific binding to non-target antigens. An antigen-binding molecule that specifically binds to a target molecule preferably binds to the target with higher affinity and / or for a longer period than it binds to other non-target molecules.

[0079] The antigen-binding molecules described herein may be capable of binding to CD122 as described herein. The antigen-binding molecules described herein may be capable of binding to CD132 as described herein. The antigen-binding molecules described herein may be capable of binding to CD122 as described herein and CD132 as described herein.

[0080] The ability of a given polypeptide to specifically bind to a given molecule can be assayed according to methods known in the art, for example, by ELISA, surface plasmon resonance (SPR; see, e.g., Hearty et al., Methods Mol Biol (2012) 907:411-442), Bio-Layer Interferometry (see, e.g., Lad et al. (2015) J Biomol Screen 20(4):498-507), The binding may be determined by flow cytometry or by radiolabeled antigen binding assay (RIA) enzyme-linked immunosorbent assay. Through such analysis, binding to a predetermined molecule may be measured and quantified. In some embodiments, binding may be a reaction detected in a predetermined assay.

[0081] In some embodiments, the degree of binding of the antigen-binding molecule to the non-target molecule is less than about 10% of the binding of the antibody to the target molecule, as measured, for example, by ELISA, SPR, Bio-Layer interferometry, or RIA. Alternatively, the binding specificity is at least 0.1 orders of magnitude (i.e., 0.1 x 10) lower than the dissociation constant (KD) of the antigen-binding molecule toward the non-target molecule. n , where n is an integer corresponding to the order of magnitude), which can be reflected in binding affinity, binding with a large KD, which can optionally be at least one of 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.5, or 2.0.

[0082] In certain embodiments, the antigen-binding molecule binds to the target molecule with a KD of ≦10 μM, ≦1 μM, ≦100 nM, ≦10 nM, ≦1 nM, ≦0.1 nM, ≦0.01 nM, or ≦0.001 nM, as determined by analysis according to SPR, Bio-Layer interferometry, or by RIA.

[0083] In some embodiments, the antigen-binding molecule binds to the same or overlapping epitope of the target molecule as a reference antigen-binding molecule capable of binding to the target molecule (i.e., CD122 or CD132). In some embodiments, the antigen-binding molecule exhibits competitive binding with the reference antigen-binding molecule capable of binding to the target molecule. Whether a given antigen-binding molecule exhibits such competitive binding may be determined by a variety of methods known to those skilled in the art, including competitive ELISA.

[0084] In some embodiments, the antigen-binding molecule comprises a complementarity-determining region (CDR) of the antigen-binding molecule capable of binding to a target molecule (i.e., CD122 or CD132). Antibodies generally comprise six CDRs: three in the light chain variable region (VL): LC-CDR1, LC-CDR2, and LC-CDR3, and three in the heavy chain variable region (VH): HC-CDR1, HC-CDR2, and HC-CDR3. The six CDRs together define the paratope of the antibody, which is the portion of the antibody that binds to the target molecule. There are several different conventions for defining antibody CDRs, see, for example, Kabat et al., Sequences of Proteins of Immunological Interest, 5th ed., Public Health Service, National Institutes of Health, Bethesda, MD (1991), Chothia et al., J. Mol. Biol. 196:901-917 (1987), and VBASE2 as described in Retter et al., Nucl. Acids Res. (2005) 33 (suppl 1): D671-D674. Unless otherwise specified, the CDRs of the antigen-binding molecules described herein are defined according to Kabat et al., Sequences of Proteins of Immunological Interest, 5th ed., Public Health Service, National Institutes of Health, Bethesda, MD (1991).

[0085] The sequences of the monoclonal antibodies (mAbs) capable of binding to CD122 and mAbs capable of binding to CD132 described herein may be used to design and prepare antigen-binding molecules. Antigen-binding regions of antibodies, such as single-chain variable fragments (scFv), Fab and Fab2 fragments, may also be used / provided. An "antigen-binding region" is any fragment of an antibody that is capable of binding to a target for which a given antibody is specific.

[0086] In some embodiments, the antigen-binding molecule of the present invention is a CD122-binding molecule. In some embodiments, the antigen-binding molecule comprises or consists of a CD122-binding molecule. In some embodiments, the antigen-binding molecule comprises a heavy chain variable (VH) region comprising HC-CDR1, HC-CDR2, and HC-CDR3 of a CD122-binding antibody clone described herein, or a variant thereof in which one, two, or three amino acids in one or more of HC-CDR1, HC-CDR2, and HC-CDR3 are substituted with other amino acids. In some embodiments, the antigen-binding molecule comprises a light chain variable (VL) region comprising LC-CDR1, LC-CDR2, and LC-CDR3 of a CD122-binding antibody clone described herein, or a variant thereof in which one, two, or three amino acids in one or more of LC-CDR1, LC-CDR2, and LC-CDR3 are substituted with other amino acids. In some embodiments, the antigen binding molecule comprises a VH region comprising HC-CDR1, HC-CDR2 and HC-CDR3, and a VL region comprising LC-CDR1, LC-CDR2 and LC-CDR3 of a CD122-binding antibody clone described herein, or a variant thereof in which one, two or three amino acids in one or more of HC-CDR1, HC-CDR2, HC-CDR3, LC-CDR1, LC-CDR2 or LC-CDR3 are substituted with another amino acid.

[0087] In some embodiments, the antigen binding molecule comprises a VH region comprising or consisting of an amino acid sequence having at least 70%, more preferably at least 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the VH region of a CD122-binding antibody clone described herein. In some embodiments, the antigen-binding molecule comprises a VL region comprising or consisting of an amino acid sequence having at least 70%, more preferably at least 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the VL region of a CD122-binding antibody clone described herein. In some embodiments, the antigen-binding molecule comprises a VH region comprising or consisting of an amino acid sequence having at least 70%, more preferably at least 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the VH region of a CD122-binding antibody clone described herein, and a VL region comprising or consisting of an amino acid sequence having at least 70%, more preferably at least 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the VL region of a CD122-binding antibody clone described herein.

[0088] In some embodiments, the CD122 binding antibody clones are: P2C4, P2C4_A4, P2C4_B1, P2C4_B5, P2C4_C1, P2C4_C4, P2C4_C7, P2C4_D10, P2C4_E6, P2C4_E7, P2C4_F8, P2C4_C1D10, P2C4_FW2, P2H7, P2D12, P1G11, P2C4_A9, P2C4_B6, P2C4_E9, P2C 4_B8, P2C4_B12, P2C4_C12, P2C4_E2, P2C4_E3, P2C4_E8, P2C4_F11, P2C4_G2, P2C4_G11, P2C4_H1, P2C4_H2, P2C4_H3, P1E7, P1B10, P1F3, P1D10, P1E1, P2B11, P2C9, P2C10, P2C11, P2E6, P2E11, P2F9 and P2F10. In some embodiments, the CD122 binding antibody clone is selected from: P1E7, P1B10, P1F3, P1D10, P1E1, P2B11, P2C9, P2C10, P2C11, P2E6, P2E11, P2F9 and P2F10. In some embodiments, the CD122-binding antibody clone is P2C4 or P2C4_FW2.

[0089] In some embodiments, the antigen-binding molecule of the present invention is a CD132-binding molecule. In some embodiments, the antigen-binding molecule comprises or consists of a CD132-binding molecule. In some embodiments, the antigen-binding molecule comprises a heavy chain variable (VH) region comprising HC-CDR1, HC-CDR2, and HC-CDR3 of a CD132-binding antibody clone described herein, or a variant thereof in which one, two, or three amino acids in one or more of HC-CDR1, HC-CDR2, and HC-CDR3 are substituted with other amino acids. In some embodiments, the antigen-binding molecule comprises a light chain variable (VL) region comprising LC-CDR1, LC-CDR2, and LC-CDR3 of a CD132-binding antibody clone described herein, or a variant thereof in which one, two, or three amino acids in one or more of LC-CDR1, LC-CDR2, and LC-CDR3 are substituted with other amino acids. In some embodiments, the antigen binding molecule comprises a VH region comprising HC-CDR1, HC-CDR2 and HC-CDR3, and a VL region comprising LC-CDR1, LC-CDR2 and LC-CDR3 of a CD132-binding antibody clone described herein, or a variant thereof in which one, two or three amino acids in one or more of HC-CDR1, HC-CDR2, HC-CDR3, LC-CDR1, LC-CDR2 or LC-CDR3 are substituted with another amino acid.

[0090] In some embodiments, the antigen binding molecule comprises a VH region comprising or consisting of an amino acid sequence having at least 70%, more preferably at least 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the VH region of a CD132-binding antibody clone described herein. In some embodiments, the antigen binding molecule comprises a VL region comprising or consisting of an amino acid sequence having at least 70%, more preferably at least 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the VL region of a CD132-binding antibody clone described herein. In some embodiments, the antigen-binding molecule comprises a VH region comprising or consisting of an amino acid sequence having at least 70%, more preferably at least 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the VH region of a CD132-binding antibody clone described herein, and a VL region comprising or consisting of an amino acid sequence having at least 70%, more preferably at least 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the VL region of a CD132-binding antibody clone described herein.

[0091] In some embodiments, the CD132 binding antibody clone is selected from: P1A3, P1A3_B3, P1A3_E8, P1A3_E9, P2B9, P1A3_B4, P1A3_FW2, P1A10, P1B6, P1C10, P1D7, P1E8, P2B2, P2B7, P2D11, P2F10, P2H4, P2D3, P1G4, P1B12 and P1C7. In some embodiments, the CD132 binding antibody clone is selected from: P1A10, P1B6, P1C10, P1D7, P1E8, P2B2, P2B7, P2D11, P2F10, P2H4, P2D3, P1G4, P1B12 and P1C7. In some embodiments, the CD132-binding antibody clone is P1A10. In some embodiments, the CD132-binding antibody clone is P1A3 or P1A3_FW2.

[0092] In some embodiments, the antigen binding molecule of the present invention comprises: a VH region comprising HC-CDR1, HC-CDR2 and HC-CDR3, and a VL region comprising LC-CDR1, LC-CDR2 and LC-CDR3 of a CD122-binding antibody clone, or a variant thereof in which one or two or three amino acids in one or more of HC-CDR1, HC-CDR2, HC-CDR3, LC-CDR1, LC-CDR2 or LC-CDR3 are substituted with another amino acid; and A VH region comprising HC-CDR1, HC-CDR2 and HC-CDR3, and a VL region comprising LC-CDR1, LC-CDR2 and LC-CDR3 of a CD132-binding antibody clone, or a variant thereof in which one, two or three amino acids in one or more of HC-CDR1, HC-CDR2, HC-CDR3, LC-CDR1, LC-CDR2 or LC-CDR3 are replaced with another amino acid. Includes; where: the CD122-binding antibody clone is P2C4 and the CD132-binding antibody clone is P1A10; or the CD122-binding antibody clone is P2C4 and the CD132-binding antibody clone is P1A3; or the CD122-binding antibody clone is P2C4_FW2 and the CD132-binding antibody clone is P1A3; or the CD122-binding antibody clone is P2E6 and the CD132-binding antibody clone is P1A10; or the CD122-binding antibody clone is P1D10 and the CD132-binding antibody clone is P1A10; or the CD122-binding antibody clone is P1E7 and the CD132-binding antibody clone is P1A10; or The CD122-binding antibody clone is P1G11, and the CD132-binding antibody clone is P1A10.

[0093] In some embodiments, the antigen binding molecule of the present invention comprises: a VH region having at least 70% sequence identity to the VH region of a CD122-binding antibody clone, and a VL region having at least 70% sequence identity to the VL region of a CD122-binding antibody clone; and a VH region having at least 70% sequence identity to the VH region of a CD132-binding antibody clone, and a VL region having at least 70% sequence identity to the VL region of a CD132-binding antibody clone Includes; where: the CD122-binding antibody clone is P2C4 and the CD132-binding antibody clone is P1A10; or the CD122-binding antibody clone is P2C4 and the CD132-binding antibody clone is P1A3; or the CD122-binding antibody clone is P2C4_FW2 and the CD132-binding antibody clone is P1A3; or the CD122-binding antibody clone is P2E6 and the CD132-binding antibody clone is P1A10; or the CD122-binding antibody clone is P1D10 and the CD132-binding antibody clone is P1A10; or the CD122-binding antibody clone is P1E7 and the CD132-binding antibody clone is P1A10; or The CD122-binding antibody clone is P1G11, and the CD132-binding antibody clone is P1A10.

[0094] In some embodiments, the antigen binding molecule of the present invention comprises: (i) (P2C4) The following CDRs: HC-CDR1 having the amino acid sequence of SEQ ID NO: 103 HC-CDR2 having the amino acid sequence of SEQ ID NO: 116 HC-CDR3 having the amino acid sequence of SEQ ID NO: 128 a VH region incorporating The following CDRs: LC-CDR1 having the amino acid sequence of SEQ ID NO: 145 LC-CDR2 having the amino acid sequence of SEQ ID NO: 162 LC-CDR3 having the amino acid sequence of SEQ ID NO: 177 VL region incorporating a CD122-binding antigen-binding molecule comprising: (ii) (P1A10) CDR of: HC-CDR1 having the amino acid sequence of SEQ ID NO: 196 HC-CDR2 having the amino acid sequence of SEQ ID NO: 204 HC-CDR3 having the amino acid sequence of SEQ ID NO: 212 a VH region incorporating The following CDRs: LC-CDR1 having the amino acid sequence of SEQ ID NO: 227 LC-CDR2 having the amino acid sequence of SEQ ID NO: 238 LC-CDR3 having the amino acid sequence of SEQ ID NO: 248 VL region incorporating a CD132-binding antigen-binding molecule comprising Includes:

[0095] In some embodiments, the antigen binding molecule is: (i) (P2C4) a VH region comprising an amino acid sequence having at least 85% sequence identity to SEQ ID NO: 1; and VL region comprising an amino acid sequence having at least 85% sequence identity to SEQ ID NO: 35 a CD122-binding antigen-binding molecule comprising: (ii) (P1A10) a VH region comprising an amino acid sequence having at least 85% sequence identity to SEQ ID NO: 71; and A VL region comprising an amino acid sequence having at least 85% sequence identity to SEQ ID NO: 89. a CD132-binding antigen-binding molecule comprising Includes:

[0096] In some embodiments, the antigen-binding molecule may comprise a variant of a reference VL / VH region, e.g., a variant comprising one, two, three, four, five, six, seven, eight, nine, or ten substitutions with respect to the amino acid sequence of the reference VL / VH region(s). In some embodiments, the substitution(s) are not in the CDRs. In some embodiments, the substitution(s) are in the framework region(s), i.e., the amino acid sequence of the VL / VH region(s) other than the CDRs.

[0097] In some embodiments, substitutions are conservative substitutions, for example, according to the following table: In some embodiments, amino acids in the same block in the middle column are substituted. In some embodiments, amino acids in the same line in the rightmost column are substituted:

[0098] [Table 1]

[0099] In some embodiments, the antigen binding molecules of the present invention do not comprise a CDR or VL / VH domain combination disclosed in WO 2017 / 021540 A1 (incorporated herein in its entirety).

[0100] In some embodiments, the CD122-binding antigen binding molecule of the present invention comprises or consists of an amino acid sequence having at least 70%, more preferably at least 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to one of SEQ ID NOs: 265-308. In some embodiments, the CD122-binding antigen binding molecule of the present invention comprises or consists of an amino acid sequence having at least 70%, more preferably at least 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to one of SEQ ID NOs: 296-308.

[0101] In some embodiments, the CD132-binding antigen binding molecule of the present invention comprises or consists of an amino acid sequence having at least 70%, more preferably at least 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to one of SEQ ID NOs: 309-329. In some embodiments, the CD132-binding antigen binding molecule of the present invention comprises or consists of an amino acid sequence having at least 70%, more preferably at least 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to one of SEQ ID NOs: 316-329.

[0102] In some embodiments, the CD122-binding antigen binding molecule according to the present invention is selected from the group consisting of the following clones: P2C4, P2C4_A4, P2C4_B1, P2C4_B5, P2C4_C1, P2C4_C4, P2C4_C7, P2C4_D10, P2C4_E6, P2C4_E7, P2C4_F8, P2C4_C1D10, P2C4_FW2, P2H7, P2D12, P1G11, P2C4_A9, P2C4_B In some embodiments, the CD122-binding antigen binding molecule of the present invention lacks the HC-CDR1, HC-CDR2, HC-CDR3, LC-CDR1, LC-CDR2, and LC-CDR3 of one or more of the clones P2C4_6, P2C4_E9, P2C4_B8, P2C4_B12, P2C4_C12, P2C4_E2, P2C4_E3, P2C4_E8, P2C4_F11, P2C4_G2, P2C4_G11, P2C4_H1, P2C4_H2, and P2C4_H3. In some embodiments, the CD122-binding antigen binding molecule of the present invention lacks the VL domain sequence and / or VH domain sequence of one or more of the clones. In some embodiments, the CD122-binding antigen binding molecule of the present invention lacks the VL domain sequence and / or VH domain sequence of one or more of the clones. lacks more VL and / or VH domain sequences.

[0103] In some embodiments, the CD132-binding antigen binding molecules of the invention lack the HC-CDR1, HC-CDR2, HC-CDR3, LC-CDR1, LC-CDR2, and LC-CDR3 of one or more of the following clones: P1A3, P1A3_B3, P1A3_E8, P1A3_E9, P1A3_B4, P1A3_FW2, and P2B9. In some embodiments, the CD132-binding antigen binding molecules of the invention lack the VL domain sequence and / or VH domain sequence of one or more of the clones.

[0104] Antigen-binding molecules can also be produced by the process of affinity maturation, which generates modified antibodies with improved affinity for antigen compared to unmodified parent antibodies. Affinity-matured antigen-binding molecules can be produced by methods known in the art, such as those described in Marks et al., Rio / Technology 10:779-783 (1992); Barbas et al., Proc Nat. Acad. Sci. USA 91:3809-3813 (1994); Schier et al., Gene 169:147-155 (1995); Yelton et al., J. Immunol. 155:1994-2004 (1995); Jackson et al., J. Immunol. 154(7):331 0-15 9 (1995); and Hawkins et al., J. Mol. Biol. 226:889-896 (1992).

[0105] The VL and VH regions of the antigen-binding region of an antibody together constitute the Fv region. In some embodiments, the antigen-binding molecule according to the present invention comprises or consists of an Fv region that binds to CD122. In some embodiments, the antigen-binding molecule comprises or consists of an Fv region that binds to CD132.

[0106] The VL and light chain constant (CL) regions, and the VH region and heavy chain constant 1 (CH1) region of the antigen-binding region of an antibody together constitute a Fab region. In some embodiments, the antigen-binding molecule of the antigen-binding molecule described herein comprises or consists of a Fab region that binds to CD122. In some embodiments, the antigen-binding molecule comprises or consists of a Fab region that binds to CD132.

[0107] In some embodiments, the antigen-binding molecules described herein comprise or consist of a whole antibody that binds to CD122. In some embodiments, the antigen-binding molecules described herein comprise or consist of a whole antibody that binds to CD132. As used herein, "whole antibody" refers to an antibody having a structure substantially similar to that of an immunoglobulin (Ig). Different types of immunoglobulins and their structures are described, for example, in Schroeder and Cavacini J Allergy Clin Immunol. (2010) 125(202): S41-S52, the entire contents of which are incorporated herein by reference.

[0108] G-type immunoglobulins (i.e., IgG) are ∼150 kDa glycoproteins comprising two heavy chains and two light chains. From the N- to C-terminus, the heavy chain comprises a VH followed by a heavy chain constant region comprising three constant domains (CH1, CH2, and CH3), and similarly, the light chain comprises a VL followed by a CL. Depending on the heavy chain, immunoglobulins can be classified as IgG (e.g., IgG1, IgG2, IgG3, IgG4), IgA (e.g., IgA1, IgA2), IgD, IgE, or IgM. The light chain may be kappa (κ) or lambda (λ).

[0109] In some embodiments, the immunoglobulin heavy chain constant sequence is human immunoglobulin G1 constant (IGHG1; UniProt: P01857-1, v1; SEQ ID NO: 440). Positions 1 to 98 of SEQ ID NO: 440 form the CH1 region (SEQ ID NO: 441). SEQ ID NO: 4 Positions 99 to 110 of SEQ ID NO: 440 form the hinge region between the CH1 and CH2 regions (SEQ ID NO: 442). Positions 111 to 223 of SEQ ID NO: 440 form the CH2 region (SEQ ID NO: 443). Positions 224 to 330 of SEQ ID NO: 440 form the CH3 region (SEQ ID NO: 444).

[0110] In some embodiments, the CH1 region comprises or consists of SEQ ID NO: 441, or a sequence having at least 60%, preferably 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% amino acid sequence identity to the amino acid sequence of SEQ ID NO: 441. In some embodiments, the CH1-CH2 hinge region comprises or consists of SEQ ID NO: 442, or a sequence having at least 60%, preferably 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% amino acid sequence identity to the amino acid sequence of SEQ ID NO: 442. In some embodiments, the CH2 region comprises or consists of SEQ ID NO: 443, or a sequence having at least 60%, preferably 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% amino acid sequence identity to the amino acid sequence of SEQ ID NO: 443. In some embodiments, the CH3 region comprises or consists of SEQ ID NO: 444, or a sequence having at least 60%, preferably 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% amino acid sequence identity to the amino acid sequence of SEQ ID NO: 444.

[0111] It will be appreciated that the CH3 region may be provided with additional substitutions in accordance with modifications to the Fc region of the antigen-binding molecule as described herein. In some embodiments, the CH3 region comprises or consists of SEQ ID NO: 447, or a sequence having at least 60%, preferably 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% amino acid sequence identity to the amino acid sequence of SEQ ID NO: 447. In some embodiments, the CH3 region comprises or consists of SEQ ID NO: 448, or a sequence having at least 60%, preferably 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% amino acid sequence identity to the amino acid sequence of SEQ ID NO: 448.

[0112] In some embodiments, the antigen-binding molecule of the present invention comprises one or more regions of an immunoglobulin light chain constant sequence. In some embodiments, the immunoglobulin light chain constant sequence is human immunoglobulin kappa constant (IGKC; Cκ; UniProt: P01834-1, v2; SEQ ID NO: 445). In some embodiments, the immunoglobulin light chain constant sequence is human immunoglobulin lambda constant (IGLC; Cγ), such as IGLC1, IGLC2, IGLC3, IGLC6, or IGLC7. In some embodiments, the CL region comprises or consists of SEQ ID NO: 445, or a sequence having at least 60%, preferably 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% amino acid sequence identity to the amino acid sequence of SEQ ID NO: 445.

[0113] In some embodiments, the antigen-binding molecules described herein comprise or consist of an IgG (e.g., IgG1, IgG2, IgG3, IgG4), IgA (e.g., IgA1, IgA2), IgD, IgE, or IgM that binds to CD122. In some embodiments, the antigen-binding molecules described herein comprise or consist of an IgG (e.g., IgG1, IgG2, IgG3, IgG4), IgA (e.g., IgA1, IgA2), IgD, IgE, or IgM that binds to CD132.

[0114] The antigen-binding molecules according to the present invention may be provided in any suitable format. An aspect of the present invention relates to a multispecific antigen-binding molecule. By "multispecific" is meant that the antigen-binding molecule exhibits specific binding to more than one target. In particular, the antigen-binding molecule binds to CD122 and CD132 and is therefore at least bispecific. The term "bispecific" means that the antigen-binding molecule can bind to at least two distinct antigenic determinants.

[0115] The multispecific antigen-binding molecules described herein exhibit at least monovalent binding to CD122 and also exhibit at least monovalent binding to CD132. Valency refers to the number of binding sites in an antigen-binding molecule for a given antigenic determinant. For example, bispecific antigen-binding molecules in the form of scFv-KiH-Fc, CrossMab, and Duobody are provided herein that are monovalent for binding to CD122 and monovalent for binding to CD132.

[0116] In some embodiments, the antigen binding molecule comprises one binding site for CD122 and one binding site for CD132. In some embodiments, the antigen binding molecule comprises more than one binding site (e.g., two or three) for CD122. In some embodiments, the antigen binding molecule comprises more than one binding site (e.g., two, three) for CD132. In some embodiments, the antigen binding molecule comprises more than one binding site (e.g., two, three) for CD122 and more than one binding site (e.g., two, three) for CD132.

[0117] In some embodiments, the antigen-binding molecule is multivalent (e.g., bivalent, trivalent) with respect to CD122. In some embodiments, the antigen-binding molecule is multivalent (e.g., bivalent, trivalent) with respect to CD132. In some embodiments, the antigen-binding molecule is multivalent (e.g., bivalent, trivalent) with respect to CD122 and multivalent (e.g., bivalent, trivalent) with respect to CD132.

[0118] In some embodiments, the antigen binding molecule comprises two binding sites for CD122. In some embodiments, the antigen binding molecule comprises two binding sites for CD132. In some embodiments, the antigen binding molecule comprises two binding sites for CD122 and two binding sites for CD132.

[0119] Multispecific antigen-binding molecules according to the present invention may be provided in any suitable format, such as those described in Kontermann MAbs 2012, 4(2): 182-197, which is incorporated herein by reference in its entirety. For example, the antigen-binding molecule may be a bispecific antibody conjugate (e.g., IgG2, F(ab')2, or CovX-Body), a bispecific IgG or IgG-like molecule (e.g., IgG, scFv4-Ig, IgG-scFv, scFv-IgG, DVD-Ig, IgG-sVD, sVD-IgG, 2in1-IgG, mAb 2, or Tandemab common LC), asymmetric bispecific IgG or IgG-like molecules (e.g., kih IgG, kih IgG common LC, CrossMab, kih IgG-scFab, mAb-Fv, charge pair or SEED-body), small molecule bispecific antibody molecules (e.g., Diabody (Db), dsDb, DART, scDb, tandAbs, tandem scFv (taFv), tandem dAb / VHH, triple body, triple head, Fab-scFv, or F(ab')2-scFv2), bispecific Fc and C H 3. Fusion proteins (e.g., taFv-Fc, Di-diabody, scDb-C) H 3. scFv-Fc-scFv, HCAb-VHH, scFv-kih-Fc, or scFv-kih-C H 3), or bispecific fusion proteins (e.g., scFv2-albumin, scDb-albumin, taFv-toxin, DNL-F ab3, DNL-Fab4-IgG, DNL-Fab4-IgG-cytokine 2). See, in particular, Figure 2 in Kontermann MAbs 2012, 4(2): 182-19. See also Brinkmann and Kontermann, MAbs (2017) 9(2):182-212 (incorporated herein in its entirety), in particular Figure 2.

[0120] Those skilled in the art can design and prepare bispecific antigen-binding molecules. Methods for producing bispecific antigen-binding molecules include chemically crosslinking antigen-binding molecules or antibody fragments, for example, with a reducible disulfide or non-reducible thioether bond, as described in Segal and Bast, 2001. Production of Bispecific Antigen-binding Molecules. Current Protocols in Immunology. 14:IV:2.13:2.13.1-2.13.16, the entire contents of which are incorporated herein by reference. For example, Fab fragments can be chemically crosslinked through the SH-groups in the hinge region using N-succinimidyl-3-(-2-pyridyldithio)-propionate (SPDP) to generate disulfide-linked bispecific F(ab)2 heterodimers.

[0121] Other methods for producing bispecific antigen-binding molecules include fusing antibody-producing hybridomas, e.g., with polyethylene glycol, to produce quadroma cells capable of secreting bispecific antibodies, as described, e.g., in D. M. and Bast, B. J. 2001. Production of bispecific antigen-binding molecules. Current Protocols in Immunology. 14:IV:2.13:2.13.1-2.13.16.

[0122] See also, for example, Antibody Engineering: Methods and Protocols, 2nd Edition (Humana Press, 2012), Chapter 40: Production of Bispecific Antigen-binding Molecules: Diabodies and Tandem scFv (Hornig and Farber-Schwarz), or French, How to make bispecific antigen-binding molecules, Methods Mol. The bispecific antigen-binding molecules according to the present invention may be produced recombinantly, for example, by expression from a nucleic acid construct encoding a polypeptide related to the antigen-binding molecule, as described in Med. 2000; 40:333-339.

[0123] For example, a DNA construct encoding the light and heavy chain variable domains of two antigen-binding fragments (i.e., the light and heavy chain variable domains for the antigen-binding fragment capable of binding to CD122 or CD132, and the light and heavy chain variable domains for the antigen-binding fragment capable of binding to another target protein), and containing sequences encoding a suitable linker or dimerization domain between the antigen-binding fragments, may be prepared by molecular cloning techniques. Recombinant bispecific antibodies may then be produced by expression (e.g., in vitro) of the constructs in suitable host cells (e.g., mammalian host cells), and the expressed recombinant bispecific antibodies may then be purified, if desired.

[0124] In some embodiments, the antigen binding molecule comprises an Fv, scFv or Fab fragment specific for CD122 and an Fv, scFv or Fab fragment specific for CD132.

[0125] In some embodiments, the antigen binding molecule according to the present invention comprises: A polypeptide comprising a VH, a CH2 domain, and a CH3 domain Polypeptides containing VL and CL domains a CD122 binding region comprising: A polypeptide comprising a VH, a CH2 domain, and a CH3 domain Polypeptides containing VL and CL domains The CD132 binding region comprises:

[0126] In some embodiments, the antigen binding molecule according to the present invention comprises: A polypeptide comprising a VH, a CH1 domain, a CH2 domain, and a CH3 domain Polypeptides containing VL and CL domains a CD122 binding region comprising: A polypeptide comprising a VH, a CH1 domain, a CH2 domain, and a CH3 domain Polypeptides containing VL and CL domains The CD132 binding region comprises:

[0127] In some embodiments, the antigen binding molecule according to the present invention comprises: A polypeptide comprising a VL, a VH, a CH2 domain, and a CH3 domain a CD122 binding region comprising: A polypeptide comprising a VL, a VH, a CH2 domain, and a CH3 domain The CD132 binding region comprises:

[0128] In some embodiments, the antigen binding molecule according to the present invention comprises: A polypeptide comprising a VH, a VL, a CH2 domain, and a CH3 domain a CD122 binding region comprising: A polypeptide comprising a VH, a VL, a CH2 domain, and a CH3 domain The CD132 binding region comprises:

[0129] In some embodiments, the antigen binding molecule according to the present invention comprises: A polypeptide comprising a VL, a VH, a CH1 domain, a CH2 domain, and a CH3 domain a CD122 binding region comprising: A polypeptide comprising a VL, a VH, a CH1 domain, a CH2 domain, and a CH3 domain The CD132 binding region comprises:

[0130] In some embodiments, the antigen binding molecule according to the present invention comprises: A polypeptide comprising a VH, a VL, a CH1 domain, a CH2 domain, and a CH3 domain a CD122 binding region comprising: A polypeptide comprising a VH, a VL, a CH1 domain, a CH2 domain, and a CH3 domain The CD132 binding region comprises:

[0131] The variable regions of the heavy and light chains of the Fab fragments of the antigen-binding molecules of the present invention may be exchanged, or the constant regions of the heavy (i.e., CH1) and light (CL) chains (i.e., Fab light chain = VL-CH1; Fab heavy chain = VH-CL). Fab fragments formed by the association of polypeptides containing such structures are referred to as "cross-Fab" or "crossover Fab" fragments. In some embodiments, the antigen-binding molecules comprise or consist of a cross-Fab region that binds to CD122. In some embodiments, the antigen-binding molecules comprise or consist of a cross-Fab region that binds to CD132.

[0132] In some embodiments, the antigen binding molecule comprises a cross-Fab fragment specific for CD122 and / or a cross-Fab fragment specific for CD132. In some embodiments, the antigen binding molecule according to the present invention comprises: A polypeptide comprising a VH, a CL domain, a CH2 domain, and a CH3 domain Polypeptides Comprising VL and CH1 Domains a CD122 binding region comprising: A polypeptide comprising a VH, a CL domain, a CH2 domain, and a CH3 domain Polypeptides Comprising VL and CH1 Domains The CD132 binding region comprises:

[0133] In some embodiments, the antigen binding molecules of the present invention comprise an Fc region. In IgG, IgA, and IgD isotypes, the Fc region is composed of CH2 and CH3 regions from one polypeptide and CH2 and CH3 regions from another polypeptide. The CH2 and CH3 regions from the two polypeptides together form the Fc region. In IgM and IgE isotypes, the Fc region contains three constant domains (CH2, CH3, and CH4), and the CH2-CH4 regions from the two polypeptides together form the Fc region.

[0134] The Fc region provides for interactions with Fc receptors and other molecules of the immune system to elicit functional effects. IgG Fc-mediated effector functions are described, for example, in Jefferis et al., Immunol Rev 1998 163:59-76 (incorporated herein in its entirety) and is caused by Fc-mediated recruitment and activation of immune cells (e.g., macrophages, dendritic cells, NK cells, and T cells) through interactions between the Fc region and Fc receptors expressed by immune cells, recruitment of complement pathway components through binding of the Fc region to the complement protein C1q, and consequent activation of the complement cascade.

[0135] In some embodiments, the antigen-binding molecule comprises a polypeptide comprising an amino acid sequence having at least 70%, preferably 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% amino acid sequence identity to SEQ ID NO: 444. In some embodiments, the antigen-binding molecule comprises a polypeptide comprising an amino acid sequence having at least 70%, preferably 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% amino acid sequence identity to SEQ ID NO: 446. In some embodiments, an antigen-binding molecule comprises more than one polypeptide (e.g., two polypeptides), each comprising an amino acid sequence having at least 70%, preferably 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% amino acid sequence identity to SEQ ID NO: 444. In some embodiments, an antigen-binding molecule comprises more than one polypeptide (e.g., two polypeptides), each comprising an amino acid sequence having at least 70%, preferably 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% amino acid sequence identity to SEQ ID NO: 446.

[0136] In some embodiments, the antigen-binding molecules of the present invention comprise an Fc region containing a modification that reduces antibody effector functions, including Fc receptor binding, antibody-dependent cellular cytotoxicity (ADCC), antibody-dependent cell-mediated phagocytosis (ADCP), complement-dependent cytotoxicity (CDC), membrane attack complex (MAC) formation, cell degranulation, cytokine and / or chemokine production, and antigen processing and presentation.

[0137] Modifications to antibody Fc regions that affect Fc-mediated functions are known in the art, such as those described in Wang et al., Protein Cell (2018) 9(1):63-73, which is incorporated herein by reference in its entirety. In particular, exemplary Fc region modifications known to affect antibody effector function are described in Wang et al., Protein Cell (2018) 9(1):63-73. Summarized in Table 1 in Cell (2018) 9(1):63-73.

[0138] The substitution combination "L234A / L235A" and corresponding substitutions (e.g., F234A / L235A in human IgG4) are known to disrupt Fc binding to Fcγ receptors and inhibit ADCC, ADCP, and also reduce C1q binding and therefore CDC (Schlothauer et al., Protein Engineering, Design and Selection (2016), 29(10):457-466, incorporated herein by reference in its entirety).

[0139] In some embodiments, the antigen binding molecules of the present invention comprise an Fc region comprising a modification corresponding to the substitution combination L234A / L235A. In some embodiments, the antigen-binding molecules of the present invention comprise an Fc region containing modifications in one or more of the CH2 and CH3 regions that promote assembly of the Fc regions. Recombinant co-expression and subsequent assembly of the component polypeptides of the antigen-binding molecule leads to several possible combinations. To improve the yield of the bispecific antigen-binding molecules of the present invention during recombinant production, it is preferable to introduce a modification(s) in the Fc region that promotes assembly of the desired combination of polypeptides. Suitable modifications are described, for example, in Ha et al., Front. Immunol (2016), the entire contents of which are incorporated herein by reference. 7:394.

[0140] In some embodiments, the antigen binding molecules of the present invention are in the following formats: KiH, KiH, as shown in Table 1 of Ha et al., Front. Immnol (2016) 7:394. s-s , HA-TF, ZW1, 7.8.60, DD-KK, EW-RVT, EW-RVT s-s , SEED, or A107.

[0141] In some embodiments, the bispecific antigen-binding molecules of the present invention can be prepared using the methods described, for example, in US Pat. No. 7,695,936 and Carter, J Immunol Meth 248, 7-15 (2001), are provided with an Fc region containing a "knob-into-hole" or "KiH" modification. In such embodiments, one CH3 region of the Fc region contains a "knob" modification and the other CH3 region contains a "hole" modification. The "knob" and "hole" modifications are positioned within each CH3 region such that the "knob" can be positioned in the "hole" to promote heterodimerization (and inhibit homodimerization) of the polypeptides and / or stabilize the heterodimer. Knobs are constructed by replacing amino acids with larger side chains (e.g., tyrosine or tryptophan). Holes are generated by replacing amino acids with larger side chains (e.g., alanine or threonine).

[0142] In some embodiments, one CH3 region of the Fc region of the antigen-binding molecule of the present invention comprises the substitution T366W (the numbering of positions / substitutions in the Fc region herein is according to the EU numbering system as described in Kabat et al., Sequences of Proteins of Immunological Interest, 5th ed., Public Health Service, National Institutes of Health, Bethesda, MD, 1991), and the other CH3 region of the Fc region comprises the substitution T366W. In some embodiments, the CH3 region of one of the Fc regions of the antigen binding molecule comprises the substitution T366W, and the CH3 region of the other of the Fc regions comprises the substitution T366S and L368A. In some embodiments, the CH3 region of one of the Fc regions of the antigen binding molecule comprises the substitution T366W, and the CH3 region of the other of the Fc regions comprises the substitution Y407V, T366S, and L368A.

[0143] In some embodiments, one CH3 region contains the substitution S354C, and the other CH3 region of the Fc region contains the substitution Y349C. The introduction of these cysteine ​​residues results in the formation of disulfide bridges between the two CH3 regions of the Fc region, further stabilizing the heterodimer (Carter (2001), J Immunol Methods 248, 7-15).

[0144] In some embodiments, the Fc region is S-S In some embodiments, one CH3 region comprises the substitutions T366W and S354C, and the other CH3 region of the Fc region comprises the substitutions T366S, L368A, Y407V, and Y349C.

[0145] In some embodiments, one CH3 region contains the substitutions K392D and K409D, and the other CH3 region of the Fc region contains the substitutions E356K and D399K. "DDKK" knob-into-hole technology is described, for example, in WO 2014 / 131694 A1 and promotes assembly of heavy chains providing complementary amino acid residues.

[0146] In some embodiments, the antigen-binding molecules of the present invention comprise a modified Fc region, referred to as the "Duobody" format, as described in Labrijn et al., Proc Natl Acad Sci USA (2013) 110(13):5145-50. In some embodiments, one CH3 region of the Fc region comprises the substitution K409R, and the other CH3 region of the Fc region comprises the substitution K405L.

[0147] In some embodiments, the antigen-binding molecules of the present invention comprise an Fc region modified in the so-called "EEE-RRR" format, as described in Strop et al., J Mol Biol. (2012) 420(3):204-19. In some embodiments, one CH3 region of the Fc region comprises substitutions D221E, P228E, and L368E, and the other CH3 region of the Fc region comprises substitutions D221R, P228R, and K409R.

[0148] In some embodiments, the antigen binding molecule comprises an Fc region comprising the "EW-RVT" modification described in Choi et al., Mol Cancer Ther (2013) 12(12):2748-59. In some embodiments, one CH3 region comprises substitutions K360E and K409W, and the other CH3 region of the Fc region comprises substitutions Q347R, D399V, and F405T.

[0149] In some embodiments, the antigen-binding molecules of the present invention comprise an Fc region containing a "SEED" modification as described in Davis et al., Protein Eng Des Sel (2010) 23(4):195-202, in which the β-chain portions of human IgG1 CH3 and IgA CH3 are exchanged.

[0150] In some embodiments, one CH3 region comprises substitutions S364H and F405A, and the other CH3 region of the Fc region comprises substitutions Y349T and T394F (see, e.g., Moore et al., MAbs (2011) 3(6):546-57).

[0151] In some embodiments, one CH3 region comprises substitutions T350V, L351Y, F405A, and Y407V, and the other CH3 region of the Fc region comprises substitutions T350V, T366L, K392L, and T394W (see, e.g., Von Kreudenstein et al., MAbs (2013) 5(5):646-54).

[0152] In some embodiments, one CH3 region comprises substitutions K360D, D399M, and Y407A, and the other CH3 region of the Fc region comprises substitutions E345R, Q347R, T366V, and K409V (see, e.g., Leaver-Fay et al., Structure (2016) 24(4):641-51).

[0153] In some embodiments, one CH3 region contains substitutions K370E and K409W, and the other CH3 region of the Fc region contains substitutions E357N, D399V, and F405T (see, e.g., Choi et al., PLoS One (2015) 10(12):e0145349).

[0154] In certain embodiments, the antigen binding molecule comprises a KiH Fc region. S-S Contains the Fc region. In some embodiments, the antigen-binding molecule comprises a polypeptide comprising a CH3 region comprising a W at a position corresponding to 366. In some embodiments, the antigen-binding molecule comprises a polypeptide comprising a CH3 region comprising a W at a position corresponding to 366 and a C at a position corresponding to 354.

[0155] In some embodiments, the antigen binding molecule comprises a polypeptide comprising a CH3 region comprising an S at a position corresponding to 366 and an A at a position corresponding to 368. In some embodiments, the antigen binding molecule comprises a polypeptide comprising a CH3 region comprising an S at a position corresponding to 366, an A at a position corresponding to 368, and a Y at a position corresponding to 407. In some embodiments, the antigen binding molecule comprises a polypeptide comprising a CH3 region comprising an S at a position corresponding to 366, an A at a position corresponding to 368, a Y at a position corresponding to 407, and a C at a position corresponding to 349.

[0156] In some embodiments, the antigen-binding molecule comprises: (a) a polypeptide comprising a CH3 region comprising a W at a position corresponding to 366 and a C at a position corresponding to 354; and (b) a polypeptide comprising a CH3 region comprising an S at a position corresponding to 366, an A at a position corresponding to 368, a Y at a position corresponding to 407, and a C at a position corresponding to 349.

[0157] In some embodiments, the antigen-binding molecule comprises a polypeptide comprising an amino acid sequence having at least 70%, preferably 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% amino acid sequence identity to SEQ ID NO: 259. In some embodiments, the antigen-binding molecule comprises a polypeptide comprising an amino acid sequence having at least 70%, preferably 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% amino acid sequence identity to SEQ ID NO: 451.

[0158] In some embodiments, the antigen-binding molecule comprises a polypeptide comprising an amino acid sequence having at least 70%, preferably 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% amino acid sequence identity to SEQ ID NO: 447. In some embodiments, the antigen-binding molecule comprises a polypeptide comprising an amino acid sequence having at least 70%, preferably 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% amino acid sequence identity to SEQ ID NO: 448 ... Prototype binding molecules include polypeptides comprising an amino acid sequence having at least 70%, preferably 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% amino acid sequence identity to SEQ ID NO:447, and polypeptides comprising an amino acid sequence having at least 70%, preferably 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% amino acid sequence identity to SEQ ID NO:448.

[0159] In some embodiments, the antigen-binding molecule comprises a polypeptide comprising an amino acid sequence having at least 70%, preferably 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% amino acid sequence identity to SEQ ID NO: 449. In some embodiments, the antigen-binding molecule comprises a polypeptide comprising an amino acid sequence having at least 70%, preferably 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% amino acid sequence identity to SEQ ID NO: 450. In some embodiments, the antigen-binding molecule comprises a polypeptide comprising an amino acid sequence having at least 70%, preferably 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% amino acid sequence identity to SEQ ID NO: 449, and a polypeptide comprising an amino acid sequence having at least 70%, preferably 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% amino acid sequence identity to SEQ ID NO: 450.

[0160] In some embodiments, the antigen-binding molecule comprises a polypeptide comprising an amino acid sequence having at least 70%, preferably 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% amino acid sequence identity to SEQ ID NO: 452. In some embodiments, the antigen-binding molecule comprises a polypeptide comprising an amino acid sequence having at least 70%, preferably 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% amino acid sequence identity to SEQ ID NO: 453. In some embodiments, the antigen-binding molecule comprises a polypeptide comprising an amino acid sequence having at least 70%, preferably 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% amino acid sequence identity to SEQ ID NO: 452, and a polypeptide comprising an amino acid sequence having at least 70%, preferably 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% amino acid sequence identity to SEQ ID NO: 453.

[0161] The present invention also provides polypeptide components of the antigen-binding molecules described herein. The polypeptides may be provided in isolated or substantially purified form. The antigen-binding molecule of the present invention may be or may comprise a complex of polypeptides.

[0162] As used herein, it will be appreciated that where a polypeptide comprises more than one domain or region, the multiple domains / regions may be present in the same polypeptide chain, i.e., a polypeptide may comprise more than one domain or region in a fusion polypeptide comprising the domains / regions.

[0163] In some embodiments, a polypeptide according to the invention comprises or consists of a VH as described herein. In some embodiments, a polypeptide according to the invention comprises or consists of a VL as described herein.

[0164] In some embodiments, the polypeptide further comprises one or more antibody heavy chain constants. In some embodiments, the polypeptide further comprises one or more antibody light chain constant regions (CL). In some embodiments, the polypeptide comprises a CH1, CH2 and / or CH3 region of an immunoglobulin (Ig).

[0165] In some embodiments, the polypeptide comprises one or more regions of an immunoglobulin heavy chain constant sequence. In some embodiments, the polypeptide comprises a CH1 region as described herein. In some embodiments, the polypeptide comprises a CH1-CH2 hinge region as described herein. In some embodiments, the polypeptide comprises a CH2 region as described herein. In some embodiments, the polypeptide comprises a CH3 region as described herein.

[0166] In some embodiments, the polypeptides contain the following amino acid substitutions / combinations of amino acid substitutions (see, for example, Ha et al., Front. Immunol., incorporated herein by reference). (2016) 7:394) containing any one of the following CH3 regions: T366W; T366S, L368A, and Y407V; T366W and S354C; T366S, L368A, Y407V, and Y349C; S364H and F405A; Y349T and T394F; T350V, L351Y, F405A, and Y407V; T350V, T366L, K392L, and T394W; K360D, D 399M and Y407A; E345R, Q347R, T366V and K409V; K409D and K392D; D399K and E356K; K360E and K409W; Q347R, D399V and F405T; K360E, K409W and Y349C; Q347R, D399V, F405T and S354C; K370E and K409W; and E357N, D399V and F405T.

[0167] In some embodiments, the CH2 and / or CH3 region of the polypeptide comprises one or more amino acid substitutions to promote association of the polypeptide with another polypeptide that comprises a CH2 and / or CH3 region.

[0168] In some embodiments, the polypeptide comprises one or more regions of an immunoglobulin light chain constant sequence. In some embodiments, the polypeptide comprises a CL region as described herein.

[0169] Also provided by the present invention are antigen-binding molecules comprising a polypeptide according to the present invention. In some embodiments, the antigen-binding molecules and polypeptides of the present invention comprise one or more linker sequences between amino acid sequences. The linker sequence may be provided at one or both ends of one or more of the VH, VL, CH1-CH2 hinge region, CH2 region, and CH3 region of the antigen-binding molecule / polypeptide.

[0170] Linker sequences are known to those skilled in the art and are described, for example, in Chen et al., Adv Drug Deliv Rev (2013) 65(10): 1357-1369, the entire contents of which are incorporated herein by reference. In some embodiments, the linker sequence may be a flexible linker sequence. A flexible linker sequence allows relative movement of the amino acid sequences connected by the linker sequence. Flexible linkers are known to those skilled in the art, and some are identified in Chen et al., Adv Drug Deliv Rev (2013) 65(10): 1357-1369. Flexible linker sequences often contain a high proportion of glycine and / or serine residues.

[0171] In some embodiments, the linker sequence comprises at least one glycine residue and / or at least one serine residue. In some embodiments, the linker sequence comprises one or more copies (e.g., two, three, or four copies) of the amino acid sequence of SEQ ID NO: 330, 331, 332, 333, 454, or 455.

[0172] The antigen-binding molecules and polypeptides of the present invention may further comprise additional amino acids or amino acid sequences. For example, the antigen-binding molecules and polypeptides may comprise an amino acid sequence(s) that facilitates the expression, folding, transport, processing, purification, or detection of the antigen-binding molecule / polypeptide. For example, the antigen-binding molecules / polypeptides may optionally comprise a sequence encoding His (e.g., 6xHis), Myc, GST, MBP, FLAG, HA, E, or biotin tag at the N- or C-terminus of the antigen-binding molecule / polypeptide. In some embodiments, the antigen-binding molecules / polypeptides comprise a detectable moiety, such as a fluorescent, luminescent, immunodetectable, radioactive, chemical, nucleic acid, or enzyme label.

[0173] The antigen-binding molecules and polypeptides of the present invention may further comprise a signal peptide (also known as a leader sequence or signal sequence). A signal peptide usually consists of a sequence of 5 to 30 hydrophobic amino acids that forms a single alpha helix. Secreted proteins and proteins expressed on the cell surface often contain signal peptides.

[0174] The signal peptide may be present at the N-terminus of the antigen-binding molecule / polypeptide and may be present in a newly synthesized antigen-binding molecule / polypeptide. The signal peptide provides efficient transport and secretion of the antigen-binding molecule / polypeptide. The signal peptide is often removed by cleavage and therefore is not included in the mature antigen-binding molecule / polypeptide secreted from cells expressing the antigen-binding molecule / polypeptide.

[0175] Signal peptides are known for many proteins and are recorded in databases such as GenBank, UniProt, Swiss-Prot, TrEMBL, Protein Information Resource, Protein Data Bank, Ensembl, and InterPro, and / or can be identified using, for example, SignalP (Petersen et al., 2011 Nature Methods 8: 785-786) or Signal-BLAST (Frank and Sippl, 2008 Bioinformatics 24: These can be identified / predicted using amino acid sequence analysis tools such as GABA, GABA-1, GABA-2, GABA-3, GABA-4, GABA-5, GABA-6, GABA-7, GABA-8, GABA-9, GABA-10, GABA-11, GABA-12, GABA-13, GABA-14, GABA-15, GABA-16, GABA-

[0176] Functional properties of antigen-binding molecules The antigen-binding molecules described herein may be characterized with respect to specific functional properties. In some embodiments, the antigen-binding molecules described herein have the following properties: binds to CD122; binds to CD132; binds to CD122-expressing cells; binds to CD132-expressing cells; stimulates signaling by a polypeptide complex containing CD122 and CD132; stimulates proliferation of cells expressing CD122 and CD132; preferentially stimulates the proliferation of effector T cells and / or NK cells over regulatory T cells; Expression of one or more immune checkpoint proteins (e.g., PD-1) Decrease; Enhancement of the anti-cancer activity of cancer antigen-specific immune cells, for example, in vivo; Improved thermal stability when compared to antigen-binding molecules described, for example, in WO 2017 / 021540 A1 You may have one or more of the following traits:

[0177] In some embodiments, the degree of binding of the antigen-binding molecule to a non-target is less than about 10% of the binding of the antibody to the target, as measured, for example, by ELISA, SPR, Bio-Layer Interferometry (BLI), Microscale Thermophoresis (MST), or radioimmunoassay (RIA). Alternatively, binding specificity may be reflected in terms of binding affinity, where the antigen-binding molecules described herein bind to CD122 and / or CD132 with an affinity at least 0.1 orders of magnitude greater than their affinity to a non-target molecule. In some embodiments, the antigen-binding molecules described herein bind to CD122 and / or CD132 with an affinity at least 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.5, or 2.0 orders of magnitude greater than their affinity to another non-target molecule.

[0178] The binding affinity of an antigen-binding molecule to its target is determined by the dissociation constant (K D) by methods known in the art, for example, ELISA, surface plasmon resonance (SPR; see, for example, Hearty et al., Methods Mol Biol (2012) 907:411-442; or Rich et al., Anal Biochem. 2008 Feb 1; 373(1):112-20), Bio-Layer Interferometry (see, for example, Lad et al., (2015) J Biomol Screen 20(4): 498-507; or Concepcion et al., Comb Chem High Throughput Screen. 2009 Sep; 12(8):791-800), microscale thermal diffusion (MST) analysis (see, e.g., Jerabek-Willemsen et al., Assay Drug Dev Technol. 2011 Aug; 9(4): 342-353) or by radiolabeled antigen binding assay (RIA).

[0179] In some embodiments, the antigen binding molecule described herein has a K of 10 μM or less, preferably one of: ≦5 μM, ≦2 μM, ≦1 μM, ≦500 nM, ≦100 nM, ≦75 nM, ≦50 nM, ≦40 nM, ≦30 nM, ≦20 nM, ≦15 nM, ≦12.5 nM, ≦10 nM, ≦9 nM, ≦8 nM, ≦7 nM, ≦6 nM, ≦5 nM, ≦4 nM, ≦3 nM, ≦2 nM, ≦1 nM, ≦500 pM. D In some embodiments, the antigen-binding molecules described herein have a K of 10 μM or less, preferably one of: ≦5 μM, ≦2 μM, ≦1 μM, ≦500 nM, ≦100 nM, ≦75 nM, ≦50 nM, ≦40 nM, ≦30 nM, ≦20 nM, ≦15 nM, ≦12.5 nM, ≦10 nM, ≦9 nM, ≦8 nM, ≦7 nM, ≦6 nM, ≦5 nM, ≦4 nM, ≦3 nM, ≦2 nM, ≦1 nM, ≦500 pM. D and binds to CD132.

[0180] In some embodiments, the antigen-binding molecules described herein have an EC50 of 1000 ng / ml or less (e.g., as determined by ELISA), preferably ≦900 ng / ml, ≦800 ng / ml, ≦700 ng / ml, ≦600 ng / ml, ≦500 ng / ml, ≦400 ng / ml, ≦300 ng / ml, ≦200 ng / ml, ≦100 ng / ml, ≦90 ng / ml, ≦80 ng / ml, ≦70 ng / ml, ≦60 ng / ml, ≦50 ng / ml, ≦40 ng / ml, ≦30 ng / ml, ≦20 ng / ml, ≦15 ng / ml, ≦10 ng / ml, ≦7.5 ng / ml, ≦5 ng / ml, ≦2.5 ng / ml In some embodiments, the antigen-binding molecule described herein binds to CD122 with a binding affinity of ≦900 ng / ml, ≦800 ng / ml, ≦700 ng / ml, ≦600 ng / ml, ≦500 ng / ml, ≦400 ng / ml, ≦300 ng / ml, ≦200 ng / ml, ≦100 ng / ml, ≦90 ng / ml, ≦80 ng / ml, ≦70 ng / ml, ≦60 ng / ml, ≦50 ng / ml, ≦40 ng / ml, ≦30 ng / ml, ≦20 ng / ml, ≦15 ng / ml, ≦10 ng / ml, ≦7.5 ng / ml, ≦5 ng / ml, ≦2.5 ng / ml, or ≦1 ng / ml.

[0181] The affinity of binding to CD122 and / or CD132 may be analyzed in vitro by ELISA assay. Suitable assays are well known in the art and may be performed by those skilled in the art, for example, as described in Antibody Engineering, vol.1 (2nd edition), Springer Protocols, Springer (2010), Part 5, pp657-665.

[0182] In some embodiments, the binding affinity of the antigen-binding molecules of the present invention for CD122 is greater than the binding affinity of the antigen-binding molecules described in WO 2017 / 021540 A1. In some embodiments, the antigen-binding molecules described herein have a K of binding to CD122 greater than that of the antigen-binding molecules described in WO 2017 / 021540 A1. D less than 1 time, for example, ≦0.9 times, ≦0.85 times, ≦0.8 times, ≦0.75 times, ≦0.7 times, ≦0.65 times, ≦0.6 times, ≦0.55 times, ≦0.5 times, ≦0.45 times, ≦0.4 times, ≦0.35 times, ≦0.3 times, ≦0.25 times, ≦0.2 times, ≦0.15 times, or ≦0.1 times D In some embodiments, the binding affinity of the antigen-binding molecules of the present invention for CD132 is greater than the binding affinity of the antigen-binding molecules described in WO 2017 / 021540 A1. In some embodiments, the antigen-binding molecules described herein have a K of binding to CD132 greater than that of the antigen-binding molecules described in WO 2017 / 021540 A1. D less than 1 time, for example, ≦0.9 times, ≦0.85 times, ≦0.8 times, ≦0.75 times, ≦0.7 times, ≦0.65 times, ≦0.6 times, ≦0.55 times, ≦0.5 times, ≦0.45 times, ≦0.4 times, ≦0.35 times, ≦0.3 times, ≦0.25 times, ≦0.2 times, ≦0.15 times, or ≦0.1 times D and binds to CD132.

[0183] The antigen binding molecules described herein preferably bind to CD122 at a region of CD122 that is accessible to antigen binding molecules (i.e., extracellular antigen binding molecules) when CD122 is expressed on the cell surface (i.e., in or on the cell membrane). In some embodiments, the antigen binding molecules described herein are capable of binding to CD122 when CD122 is expressed on the cell surface. The antigen binding molecules described herein preferably bind to CD132 at a region of CD132 that is accessible to antigen binding molecules (i.e., extracellular antigen binding molecules) when CD132 is expressed on the cell surface (i.e., in or on the cell membrane). In some embodiments, the antigen binding molecules described herein are capable of binding to CD132 when CD132 is expressed on the cell surface.

[0184] For example, the antigen-binding molecule may bind to CD122- and / or CD132-expressing cells, e.g., cells that express CD122 and CD132 on the cell surface, such as immune cells, lymphocytes, T cells (CD4+ T cells, CD8+ T cells), or NK cells.

[0185] The ability of an antigen-binding molecule to bind to a specific cell type may be analyzed by contacting cells with the antigen-binding molecule and detecting the antigen-binding molecule bound to the cells, for example, after a washing step to remove unbound antigen-binding molecule. The ability of an antigen-binding molecule to bind to CD132-expressing cells and / or CD122-expressing cells can be assayed using flow cytometry and immunofluorescence microscopy. The assay may be performed by methods such as, for example, those described in the experimental examples of this application.

[0186] The antigen-binding molecules of the present invention can stimulate signaling through the medium-affinity IL-2 receptor (i.e., a polypeptide complex comprising CD122 and CD132, but not CD25). The antigen-binding molecules are preferably agonists of signaling through the medium-affinity IL-2 receptor.

[0187] The ability of a given antigen-binding molecule to stimulate signaling through the medium-affinity IL-2 receptor may be assessed, for example, in an in vitro assay, such as that described in Example 4 herein. Briefly, cells expressing CD122 and CD132 on the cell surface may be contacted with the antigen-binding molecule, and activation of intracellular signaling may be determined by detecting an increase in the level of phosphorylated STAT5 (i.e., pSTAT5). pSTAT5 may be detected using antibody- or reporter-based methods as described herein.

[0188] In some embodiments, the antigen-binding molecules of the present invention are capable of increasing the amount of pSTAT5 by more than 1-fold, for example, ≧1.01-fold, ≧1.02-fold, ≧1.03-fold, ≧1.04-fold, ≧1.05-fold, ≧1.1-fold, ≧1.2-fold, ≧1.3-fold, ≧1.4-fold, ≧1.5-fold, ≧1.6-fold, ≧1.7-fold, ≧1.8-fold, ≧1.9-fold, ≧2-fold, ≧3-fold, ≧4-fold, ≧5-fold, ≧6-fold, ≧7-fold, ≧8-fold, ≧9-fold, ≧10-fold, ≧20-fold, ≧30-fold, ≧40-fold, ≧50-fold, ≧60-fold, ≧70-fold, ≧80-fold, ≧90-fold, or up to ≧100-fold the level of pSTAT5 detected in a comparable assay after culturing in the absence of the antigen-binding molecule or in the presence of a suitable control antigen-binding molecule (e.g., an isotype-matched control antigen-binding molecule).

[0189] In some embodiments, the antigen binding molecules of the present invention activate signaling through the medium affinity IL-2 receptor to a greater extent than the antigen binding molecules described in WO 2017 / 021540 A1. In some embodiments, when cells expressing CD122 and CD132 are cultured in the presence of an antigen binding molecule described in the invention, the amount of pSTAT5 increases in a comparative assay by more than 1-fold, for example, ≥1.01-fold, ≥1.02-fold, ≥1.03-fold, ≥1.04-fold, ≥1.05-fold, ≥1.06-fold, ≥1.07-fold, ≥1.08-fold, ≥1.09-fold, ≥1.1-fold, ≥1.2-fold, ≥1.3-fold, ≥1.4-fold, ≥1.5-fold, ≥1.6-fold, ≥1.7-fold, ≥1.8-fold, ≥1.9-fold, ≥2-fold, ≥3-fold, ≥4-fold, ≥5-fold, ≥6-fold, ≥7-fold, ≥8-fold, ≥9-fold, or ≥10-fold the level of pSTAT5 detected after culture in the presence of an antigen binding molecule described in WO 2017 / 021540 A1.

[0190] In some embodiments, the antigen binding molecules of the present invention are capable of increasing the proliferation of cells expressing CD122 and CD132. Cell proliferation may be determined by analyzing cell division over time. 3 Cell division may also be analyzed by in vitro analysis of H-thymidine incorporation or by CFSE dilution assay, for example, as described in Fulcher and Wong, Immunol Cell Biol (1999) 77(6): 559-564, which are incorporated herein in their entireties. Cell division may also be analyzed by analysis of 5-ethynyl-2'-deoxyuridine (EdU) incorporation by a suitable assay, for example, as described in Buck et al., Biotechniques. 2008 Jun; 44(7): 927-9, and Sali and Mitchison, PNAS USA 2008 Feb 19; 105(7): 2415-2420, both of which are incorporated herein in their entireties, or by Alamar Blue dilution assay, as described in Example 3 herein (e.g., Rampersad et al., Sensors (Basel). ( 2012) 12(9):12347-12360), proliferating cells may be identified.

[0191] In some embodiments, the antigen-binding molecules of the present invention increase the number or proportion of proliferating cells by more than 1-fold, for example, ≥ 1.01-fold, ≥ 1.02-fold, ≥ 1.03-fold, ≥ 1.04-fold, ≥ 1.05-fold, ≥ 1.06-fold, or ≥ 1.07-fold, compared to the number / proportion of proliferating cells detected after culturing in the absence of the antigen-binding molecule or in the presence of an appropriate control antigen-binding molecule (e.g., an isotype-matched control antigen-binding molecule) in a comparative assay. fold, ≧1.07-fold, ≧1.08-fold, ≧1.09-fold, ≧1.1-fold, ≧1.2-fold, ≧1.3-fold, ≧1.4-fold, ≧1.5-fold, ≧1.6-fold, ≧1.7-fold, ≧1.8-fold, ≧1.9-fold, ≧2-fold, ≧3-fold, ≧4-fold, ≧5-fold, ≧6-fold, ≧7-fold, ≧8-fold, ≧9-fold, ≧10-fold, ≧20-fold, ≧30-fold, ≧40-fold, ≧50-fold, ≧60-fold, ≧70-fold, ≧80-fold, ≧90-fold, or ≧100-fold.

[0192] In some embodiments, the antigen binding molecules of the present invention increase the number or proportion of proliferating cells to a greater extent than the antigen binding molecules described in WO 2017 / 021540 A1. In some embodiments, culturing cells expressing CD122 and CD132 in the presence of an antigen binding molecule of the invention increases the number / proportion of proliferating cells in a comparative assay by more than 1-fold, for example, ≥1.01-fold, ≥1.02-fold, ≥1.03-fold, ≥1.04-fold, ≥1.05-fold, ≥1.06-fold, ≥1.07-fold, ≥1.08-fold, ≥1.09-fold, ≥1.1-fold, ≥1.2-fold, ≥1.3-fold, ≥1.4-fold, ≥1.5-fold, ≥1.6-fold, ≥1.7-fold, ≥1.8-fold, ≥1.9-fold, ≥2-fold, ≥3-fold, ≥4-fold, ≥5-fold, ≥6-fold, ≥7-fold, ≥8-fold, ≥9-fold, or ≥10-fold, the number / proportion of proliferating cells detected after culturing in the presence of an antigen binding molecule described in WO 2017 / 021540 A1.

[0193] In some embodiments, when cultured in the presence of an antigen-binding molecule of the present invention, the number of cells detected after culture in the absence of the antigen-binding molecule or in the presence of a suitable control antigen-binding molecule (e.g., an isotype-matched control antigen-binding molecule) is more than 1-fold, e.g., ≥ 1.01-fold, ≥ 1.02-fold, ≥ 1.03-fold, ≥ 1.04-fold, ≥ 1.05-fold, ≥ 1.06-fold, ≥ 1.07-fold, ≥ 1.08-fold, ≥ 1.09-fold, ≥ 1.100-fold, ≥ 1.110-fold, ≥ 1.120-fold, ≥ 1.130-fold, ≥ 1.140-fold, ≥ 1.150-fold, ≥ 1.160-fold, ≥ 1.170-fold, ≥ 1.180-fold, ≥ 1.190-fold, ≥ 1.210-fold, ≥ 1.220-fold, ≥ 1.230-fold, ≥ 1.240-fold, ≥ 1.250-fold, ≥ 1.260-fold, ≥ 1.270-fold, ≥ 1.280-fold, ≥ 1.290-fold, ≥ 1.300-fold, ≥ 1.310-fold, ≥ 1.320-fold, ≥ 1.330-fold, ≥ 1.340-fold, ≥ 1.350-fold, ≥ 1.360-fold, ≥ 1.370-fold, ≥ 1.380-fold, ≥ 1.390-fold, ≥ 1.400-fold, ≥ 1.410-fold This results in an expansion of cells expressing CD122 and CD132 to a cell number that is ≥ 0.1 fold, ≥ 1.2 fold, ≥ 1.3 fold, ≥ 1.4 fold, ≥ 1.5 fold, ≥ 1.6 fold, ≥ 1.7 fold, ≥ 1.8 fold, ≥ 1.9 fold, ≥ 2 fold, ≥ 3 fold, ≥ 4 fold, ≥ 5 fold, ≥ 6 fold, ≥ 7 fold, ≥ 8 fold, ≥ 9 fold, ≥ 10 fold, ≥ 20 fold, ≥ 30 fold, ≥ 40 fold, ≥ 50 fold, ≥ 60 fold, ≥ 70 fold, ≥ 80 fold, ≥ 90 fold, or ≥ 100 fold.

[0194] In some embodiments, the antigen binding molecules of the present invention cause expansion of cells expressing CD122 and CD132 to a greater extent than the antigen binding molecules described in WO 2017 / 021540 A1. In some embodiments, culturing cells expressing CD122 and CD132 in the presence of an antigen binding molecule of the invention causes an expansion of the cells to a number of cells that is more than 1-fold, e.g., ≥ 1.01-fold, ≥ 1.02-fold, ≥ 1.03-fold, ≥ 1.04-fold, ≥ 1.05-fold, ≥ 1.1-fold, ≥ 1.2-fold, ≥ 1.3-fold, ≥ 1.4-fold, ≥ 1.5-fold, ≥ 1.6-fold, ≥ 1.7-fold, ≥ 1.8-fold, ≥ 1.9-fold, ≥ 2-fold, ≥ 3-fold, ≥ 4-fold, ≥ 5-fold, ≥ 6-fold, ≥ 7-fold, ≥ 8-fold, ≥ 9-fold, or ≥ 10-fold the number of cells detected after culturing in the presence of an antigen binding molecule described in WO 2017 / 021540 A1 in a comparative assay.

[0195] In some embodiments, the antigen binding molecules of the present invention stimulate the proliferation / expansion of one or more of the following cell types rather than (i.e., preferentially over) regulatory T cells (e.g., CD4+CD25+FoxP3+ T cells): antigen-specific T cells (e.g., virus-specific T cells), antigen-specific CD4 T cells, antigen-specific CD8 T cells, effector memory CD4 T cells, effector memory CD8 T cells, central memory CD4 T cells, central memory CD8 T cells, cytotoxic CD8+ T cells (i.e., CTLs), NK cells, antigen-specific NK cells, or cells containing / expressing a chimeric antigen receptor (CAR) or a nucleic acid encoding a CAR.

[0196] In some embodiments, the antigen binding molecules of the present invention are capable of reducing the expression of one or more immune checkpoint proteins. In some embodiments, the antigen binding molecules are capable of reducing the expression of one or more immune checkpoint proteins by immune cells, such as T cells. Immune checkpoint proteins are well known to those skilled in the art and include, for example, PD-1, CTLA-4, LAG-3, TIM-3, VISTA, TIGIT, and BTLA.

[0197] In some embodiments, the antigen-binding molecules of the present invention are capable of reducing the expression of PD-1. The ability of the antigen-binding molecule to reduce the expression of an immune checkpoint protein may be analyzed by contacting a population of immune cells with the antigen-binding molecule and then analyzing the expression of the immune checkpoint protein, for example, by flow cytometry. Cells may be contacted in vivo, for example, by administering the antigen-binding molecule to a subject, or cells obtained from a subject may be contacted with the antigen-binding molecule in vitro or ex vivo.

[0198] In some embodiments, the antigen-binding molecules of the present invention cause a decrease in the level of PD-1 expression by T cells in a given assay to less than 1-fold, e.g., <0.99-fold, <0.95-fold, <0.9-fold, <0.85-fold, <0.8-fold, <0.75-fold, <0.7-fold, <0.65-fold, <0.6-fold, <0.55-fold, <0.5-fold, <0.45-fold, <0.4-fold, <0.35-fold, <0.3-fold, <0.25-fold, <0.2-fold, <0.15-fold, <0.1-fold, <0.05-fold, or <0.01-fold the level of PD-1 expression by T cells observed in the absence of the antigen-binding molecule (or in the presence of a suitable control antigen-binding molecule).

[0199] In some embodiments, the antigen-binding molecules of the present invention enhance the anti-cancer activity of cancer antigen-specific immune cells, for example, in vivo. For example, the ability of antigen-binding molecules to enhance anti-cancer immune responses may be analyzed as described in Example 9 herein.

[0200] In some embodiments, the antigen-binding molecules of the present invention may exhibit improved thermal stability, for example, when compared to the antigen-binding molecules described in WO 2017 / 021540 A1.

[0201] The thermal stability of the antigen-binding molecule may be analyzed by methods well known to those skilled in the art, including differential scanning fluorimetry and differential scanning calorimetry (DSC), for example, as described in He et al., J. Pharm. Sci. (2010), which is incorporated herein by reference in its entirety.

[0202] In some embodiments, such assays involve the use of a method according to WO 2017 / 021540 T determined for the antigen-binding molecule described in A1 m a value of 1, greater than 1x, e.g., ≥1.01x, ≥1.02x, ≥1.03x, ≥1.04x, ≥1.05x, ≥1.06x, ≥1.07x, ≥1.08x, ≥1.09x, ≥1.1x, ≥1.2x, ≥1.3x, ≥1.4x, ≥1.5x, ≥1.6x, ≥1.7x, ≥1.8x, ≥1.9x, ≥2x, ≥3x, ≥4x, ≥5x, ≥6x, ≥7x, ≥8x, ≥9x, or ≥10x Tm An antigen-binding molecule of the present invention having a value of 1 may be determined.

[0203] Membrane-anchored antigen-binding molecules In some embodiments, the antigen-binding molecule of the present invention further comprises a cell membrane anchor region. As used herein, the term "cell membrane anchor region" refers to a region that binds to the cell membrane of a cell expressing the antigen-binding molecule. The "anchoring" may be reversible or irreversible.

[0204] In some embodiments, the cell membrane anchor region is a transmembrane domain. A transmembrane domain refers to any three-dimensional structure formed by an amino acid sequence that is thermodynamically stable in a biological membrane, such as a cell membrane.

[0205] A transmembrane domain may comprise or consist of an amino acid sequence forming a hydrophobic alpha helix or beta barrel. The amino acid sequence of a transmembrane domain may be, or may be derived from, the amino acid sequence of a transmembrane domain of a protein that contains a transmembrane domain. Transmembrane domains are recorded in databases such as GenBank, UniProt, Swiss-Prot, TrEMBL, Protein Information Resource, Protein Data Bank, Ensembl, and InterPro, and / or may be identified / predicted using amino acid sequence analysis tools such as TMHMM (Krogh et al., 2001 J Mol Biol 305: 567-580).

[0206] In some embodiments, the amino acid sequence of the transmembrane domain may be or consist of the amino acid sequence of the transmembrane domain of a protein expressed on the cell surface. In some embodiments, the protein expressed on the cell surface is a receptor or ligand, e.g., an immune receptor or ligand. In some embodiments, the amino acid sequence of the transmembrane domain is selected from the group consisting of ICOS, ICOSL, CD86, CTLA-4, CD28, CD80, MHC class I alpha, MHC class II alpha, MHC class II beta, CD3 epsilon, CD3 delta, CD3 gamma, CD3 zeta, and TCR alpha. The amino acid sequence may be or may be derived from the amino acid sequence of the transmembrane domain of one of TCRβ, CD4, CD8α, CD8β, CD40, CD40L, PD-1, PD-L1, PD-L2, 4-1BB, 4-1BBL, OX40, OX40L, GITR, GITRL, TIM-3, Galectin 9, LAG3, CD27, CD70, LIGHT, HVEM, TIM-4, TIM-1, ICAM1, LFA-1, LFA-3, CD2, BTLA, CD160, LILRB4, LILRB2, VTCN1, CD2, CD48, 2B4, SLAM, CD30, CD30L, DR3, TL1A, CD226, CD155, CD112 and CD276.

[0207] In some embodiments, the cell membrane anchor region may be a lipid anchor region. In some embodiments, the lipid anchor region comprises or consists of a lipid anchor (e.g., a GPI anchor). A "lipid anchor" refers to a moiety that can associate (e.g., covalently) with a lipid component of a biological membrane (e.g., a cell membrane). Through such association, a protein having a lipid anchor attached thereto is "anchored" to the cell membrane. A lipid anchor typically comprises a lipophilic group. Lipid anchors, their lipophilic groups, and protein modifications for attaching lipid anchors are described with reference to examples in Resh 2013, Curr Biol. 23(10): R431-R435, which is incorporated herein by reference in its entirety. A lipid anchor may comprise or consist of an isoprenyl, myristoyl, palmitoyl, fatty acyl, diacylglycerol, steroyl, or phospholipid group, or a glycosylphosphatidylinositol (GPI) anchor.

[0208] In some embodiments, the lipid anchor region comprises or consists of a lipid anchor signal sequence. A "lipid anchor signal sequence" refers to an amino acid sequence that directs the processing of a protein attached to a lipid anchor. After such processing, the antigen-binding molecule contains a lipid anchor.

[0209] Chimeric antigen receptor (CAR) The present invention also provides a chimeric antigen receptor (CAR) comprising an antigen-binding molecule according to the present invention.

[0210] Chimeric antigen receptors (CARs) are recombinant receptors that provide both antigen binding and T cell activation functions. CAR structure and operation are reviewed, for example, in Dotti et al., Immunol Rev (2014) 257(1), the entire contents of which are incorporated herein by reference.

[0211] CARs comprise an antigen-binding region linked to a cell membrane anchor region and a signal transduction region. An optional hinge region may provide separation between the antigen-binding region and the cell membrane anchor region and may act as a flexible linker. The antigen-binding region of a CAR may be based on the antigen-binding region of an antibody specific for the antigen to which the CAR is targeted, or other agents capable of binding to the target. For example, the antigen-binding domain of a CAR may comprise the amino acid sequence of the complementarity-determining region (CDR) of an antibody that specifically binds to a target protein, or the complete light and heavy chain variable region amino acid sequences. The antigen-binding domain of a CAR may also target antigens based on other protein:protein interactions, such as ligand:receptor binding; for example, a CAR targeting IL-13Rα2 has been developed using an antigen-binding domain based on IL-13 (see, e.g., Kahlon et al. 2004 Cancer Res 64(24): 9160-9166).

[0212] The antigen-binding region of the CAR of the present invention can be provided in any suitable format, such as scFv, Fab, etc. A membrane anchor region is provided between the antigen binding region and the signal transduction region of the CAR. The membrane anchor region anchors the CAR to the cell membrane of the cell expressing the CAR, so that the antigen binding region is in the extracellular space and the signal transduction region is inside the cell. In some embodiments, the CAR of the present invention comprises a membrane anchor region that comprises, consists of, or is derived from the transmembrane amino acid sequence of one of CD3-zeta, CD4, CD8, or CD28. As used herein, a region "derived from" a reference amino acid sequence includes an amino acid sequence that has at least 60%, for example, at least 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity with the reference sequence.

[0213] The signaling region of the CAR enables T cell activation. The CAR signaling region may include the amino acid sequence of the intracellular domain of CD3-zeta, which provides an immunoreceptor tyrosine-based activation motif (ITAM) for phosphorylation and activation of CAR-expressing T cells. Signaling regions containing sequences from other ITAM-containing proteins have also been used in CARs, such as domains containing the ITAM-containing region of FcγRI (Haynes et al., 2001 J Immunol 166(1):182-187). CARs containing a signaling region derived from the intracellular domain of CD3-zeta are often referred to as first-generation CARs. The signaling region of the CAR may also include a costimulatory sequence derived from the signaling region of a costimulatory molecule to promote the activation of CAR-expressing T cells upon binding to a target protein. Suitable costimulatory molecules include CD28, OX40, 4-1BB, ICOS, and CD27. CARs with signaling regions containing additional costimulatory sequences are often referred to as second-generation CARs.

[0214] In some cases, CARs are engineered to provide costimulation of different intracellular signaling pathways. For example, signaling associated with CD28 costimulation preferentially activates the phosphatidylinositol 3-kinase (PI3K) pathway, while 4-1BB-mediated signaling preferentially activates the phosphatidylinositol 3-kinase (PI3K) pathway. The signal transduction is via TNF receptor-associated factor (TRAF) adaptor proteins. Thus, the signal transduction region of CAR sometimes contains costimulatory sequences derived from the signal transduction regions of more than one costimulatory molecule. CARs that contain signal transduction regions that include multiple costimulatory sequences are often referred to as third-generation CARs. In some embodiments, the CARs of the present invention contain one or more costimulatory sequences that include, consist of, or are derived from the amino acid sequences of one or more intracellular domains of CD28, OX40, 4-1BB, ICOS, and CD27.

[0215] The optional hinge region may provide separation between the antigen-binding domain and the transmembrane domain and may act as a flexible linker. The hinge region may be a flexible domain that allows the binding moieties to orient in different directions. The hinge region may be derived from the CH2CH3 region of IgG1 or an immunoglobulin. In some embodiments, the CAR of the present invention comprises a hinge region that comprises, consists of, or is derived from the amino acid sequence of the hinge region of IgG1 or the CH2CH3 region of an immunoglobulin. CARs may also be combined with costimulatory ligands, chimeric costimulatory receptors, or cytokines to further enhance T cell potency, specificity, and safety (Sadelain et al., The basic principles of chimeric antigen receptor (CAR) design. Cancer Discov. 2013 April; 3(4): 388-398. doi:10.1158 / 2159-8290.CD-12-0548, specifically incorporated herein by reference).

[0216] Also provided are cells containing the CARs described in the present invention.The CARs described in the present invention can be used to generate CAR-expressing immune cells, such as CAR-T or CAR-NK cells.Engineering of CARs into immune cells can be performed during in vitro culture for transduction and expansion, such as during T cell expansion for adoptive T cell therapy.

[0217] Nucleic acids and expression vectors The present invention provides nucleic acids encoding antigen-binding molecules or CARs according to the present invention. In some embodiments, the nucleic acids are purified or isolated, e.g., from other nucleic acids or naturally occurring biological materials.

[0218] The present invention also provides a vector comprising a nucleic acid encoding an antigen-binding molecule or CAR according to the present invention. The nucleic acids and / or vectors described herein can also be provided for introduction into cells, such as primary human immune cells. Suitable vectors include plasmids, binary vectors, DNA vectors, mRNA vectors, viral vectors (e.g., gammaretroviral vectors (e.g., murine leukemia virus (MLV)-derived vectors), lentiviral vectors, adenoviral vectors, adeno-associated viral vectors, vaccinia viral vectors, and herpes viral vectors), transposon-based vectors, and artificial chromosomes (e.g., yeast artificial chromosomes), such as those described in Maus et al., Annu Rev Immunol (2014) 32:189-225 or Morgan and Boyerinas, Biomedicines 2016 4, 9, both of which are incorporated herein by reference in their entirety. In some embodiments, the viral vector can be a lentiviral, retroviral, adenoviral, or herpes simplex viral vector. In some embodiments, the lentiviral vector can be or be derived from pELNS. In some embodiments, the vector can be a CRISPR / Cas9-encoding vector.

[0219] In some embodiments, the nucleic acids described herein comprise or consist of a nucleic acid sequence having at least 60%, 65%, 70%, 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to one of SEQ ID NOs: 335-433, or to a nucleic acid sequence that, as a result of codon degeneracy, encodes the same amino acid sequence as one of SEQ ID NOs: 335-433.

[0220] Cells containing / expressing antigen-binding molecules / CARs The present invention also provides cells containing or expressing an antigen-binding molecule or CAR according to the invention. Also provided are cells containing or expressing a nucleic acid or expression vector according to the invention.

[0221] The cell may be a eukaryotic cell, e.g., a mammalian cell. The mammal may be a human or a non-human mammal (e.g., a rabbit, guinea pig, rat, mouse or other rodent (including any animal in the order Rodentia), cat, dog, pig, sheep, goat, cow (including a cow, e.g., a dairy cow, or any animal in the order Bos), horse (including any animal in the order Equidae), donkey, and non-human primate).

[0222] In some embodiments, the cells may be derived from or obtained from a human subject. The cell may be an immune cell. The cell may be a cell of hematopoietic origin, such as a neutrophil, eosinophil, basophil, dendritic cell, lymphocyte, or monocyte. The lymphocyte may be, for example, a T cell, a B cell, a NK cell, a NKT cell, or an innate lymphoid cell (ILC), or a precursor thereof. The cell may express, for example, a CD3 polypeptide (e.g., CD3γ CD3ε CD3ζ or CD3δ), a TCR polypeptide (TCRα or TCRβ), CD27, CD28, CD4, or CD8. In some embodiments, the cell is a T cell. In some embodiments, the T cell is a CD3+ T cell. In some embodiments, the T cell is a CD3+, CD8+ T cell. In some embodiments, the T cell is a cytotoxic T cell (e.g., a cytotoxic T lymphocyte (CTL)).

[0223] In some embodiments, the cell is an antigen-specific T cell. In some embodiments herein, an "antigen-specific" T cell is a cell that exhibits a particular functional property of a T cell in response to an antigen for which the T cell is specific or a cell expressing said antigen. In some embodiments, the property is a functional property associated with an effector T cell, e.g., a cytotoxic T cell. In some embodiments, an antigen-specific T cell may exhibit one or more of the following properties: cytotoxicity, e.g., against cells containing / expressing the antigen for which the T cell is specific; proliferation, IFNγ expression, CD107a expression, IL-2 expression, TNFα expression, perforin expression, granzyme expression, granulysin expression, and / or FAS ligand (FASL) expression, e.g., in response to the antigen for which the T cell is specific or a cell containing / expressing the antigen for which the T cell is specific. In some embodiments, the antigen for which the T cells are specific may be a peptide or polypeptide of a virus, such as Epstein-Barr virus (EBV), influenza virus, measles virus, hepatitis B virus (HBV), hepatitis C virus (HCV), human immunodeficiency virus (HIV), lymphocytic choriomeningitis virus (LCMV), herpes simplex virus (HSV), or human papillomavirus (HPV).

[0224] The present invention also provides a method for producing a cell containing a nucleic acid or expression vector according to the present invention, the method comprising the step of introducing the nucleic acid or expression vector according to the present invention into a cell. The present invention also provides a method for producing a cell that expresses an antigen-binding molecule or CAR according to the present invention. Also provided are methods for producing the nucleic acid or vector described herein, the methods comprising introducing the nucleic acid or vector described herein into a cell. In some embodiments, the methods further comprise culturing the cell under conditions suitable for expression of the nucleic acid or expression vector by the cell. In some embodiments, the methods are performed in vitro.

[0225] In some embodiments, introducing the isolated nucleic acid or expression vector described herein into a cell comprises transduction, e.g., retroviral transduction. Thus, in some embodiments, the isolated nucleic acid or expression vector is contained in a viral vector, or the vector is a viral vector. In some embodiments, the method comprises introducing the nucleic acid or expression vector described herein by electroporation, e.g., as described in Koh et al., Molecular Therapy - Nucleic Acids (2013) 2, e114, which is incorporated herein in its entirety.

[0226] The present invention also provides cells obtained or obtainable by the methods according to the invention. Production of antigen-binding molecules and CARs The antigen-binding molecules and CARs according to the present invention may be prepared according to methods for producing polypeptides known to those skilled in the art.

[0227] The polypeptide(s) of interest may be prepared by chemical synthesis, for example, liquid phase or solid phase synthesis. For example, peptides / polypeptides may be synthesized using the method described in Chandrudu et al., Molecules (2013), 18: 4373-4388, the entire contents of which are incorporated herein by reference. Alternatively, the antigen-binding molecules and CARs of the present invention may be produced by recombinant expression. Molecular biology techniques suitable for recombinant production are well known in the art, and are described, for example, in Green and Sambrook, Molecular Cloning: A New Approach, the entire contents of which are incorporated herein by reference. Laboratory Manual (4th ed.), Cold Spring Harbor Press, 2012.

[0228] Expression may be from a nucleotide sequence. The nucleotide sequence may be contained in a vector. As used herein, a "vector" refers to an oligonucleotide molecule (DNA or RNA) used as a vehicle to transfer exogenous genetic material into a cell. The vector may be an expression vector for expressing foreign genetic material in a cell. Such a vector may include a promoter sequence operably linked to a nucleotide sequence encoding the sequence to be expressed. The vector may also include a termination codon and an expression enhancer. Any suitable vector, promoter, enhancer, and termination codon known in the art may be used to express a peptide or polypeptide from a vector according to the present invention. In some embodiments, the vector may be a plasmid, MAC, virus, etc. In some embodiments, the vector may be a eukaryotic expression vector, e.g., a vector containing elements necessary for protein expression from the vector in a eukaryotic cell. In some embodiments, the vector may be a mammalian expression vector, e.g., including a cytomegalovirus (CMV) or SV40 promoter to drive protein expression.

[0229] The term "operably linked" can include the situation where a selected nucleotide sequence and a regulatory nucleotide sequence (e.g., a promoter and / or enhancer) are covalently linked (thereby forming an expression cassette) in such a manner as to achieve expression of the nucleotide sequence under the influence or control of the regulatory sequences. Thus, a regulatory sequence can be linked to a selected nucleotide sequence if the regulatory sequence is capable of effecting transcription of the nucleotide sequence. The resulting transcript may then be translated into a desired peptide or polypeptide.

[0230] In some cases, the antigen-binding molecule according to the present invention is composed of more than one polypeptide chain. In such cases, production of the antigen-binding molecule may involve transcription and translation of more than one polypeptide chain, followed by assembly of the polypeptide chains to form the antigen-binding molecule.

[0231] For recombinant production according to the present invention, any cell suitable for expressing a polypeptide may be used. The cell may be a prokaryotic or eukaryotic cell. In some embodiments, the cell is a prokaryotic cell, such as an archaeal or bacterial cell. In some embodiments, the bacterium may be a gram-negative bacterium, such as a bacterium of the Enterobacteriaceae family, such as Escherichia coli.

[0232] In some embodiments, the cell is a eukaryotic cell, such as a yeast cell, a plant cell, an insect cell, or a mammalian cell, such as a CHO, HEK, HeLa, or COS cell. In some cases, the cells are not prokaryotic because prokaryotic cells do not allow for the same folding or post-translational modifications as eukaryotic cells. Furthermore, much higher expression levels are possible in eukaryotic cells, and with the appropriate tag, it may be easier to purify proteins from eukaryotic cells. Specific plasmids that enhance protein secretion into the medium are also available.

[0233] Production may involve the culture or fermentation of eukaryotic cells modified to express the peptide or polypeptide. Culture or fermentation may be carried out in a bioreactor provided with an appropriate supply of nutrients, air / oxygen, and / or growth factors. The secreted protein may be collected from the cells by partitioning the medium / fermentation broth, extracting the protein content, and separating the individual proteins to isolate the secreted peptide or polypeptide. Culture, fermentation, and separation techniques are well known to those of skill in the art and are described, for example, in Green and Sambrook, Molecular Cloning: A Laboratory Manual (4th ed.; incorporated herein by reference).

[0234] A bioreactor contains one or more vessels in which cells can be cultured. Cultivation in a bioreactor can occur continuously, with continuous flow of reactants into the reactor and continuous flow of cultured cells out of the reactor. Alternatively, cultivation can occur in batches. Bioreactors monitor and regulate environmental conditions, such as pH, oxygen, flow rates into and out of the vessel, and agitation within the vessel, to provide optimal conditions for the cells being cultured.

[0235] After culturing the cells that express antigen binding molecule or CAR, preferably isolate the polypeptide of interest.Can use any suitable method known in the art for separating proteins from cell culture.To isolate polypeptide from culture, it may be necessary to first separate cultured cells from the medium containing the polypeptide of interest.If the polypeptide of interest is secreted from cells, the cells can be separated from the medium containing the secreted polypeptide of interest by centrifugation.If the polypeptide of interest is accumulated within cells, it may be necessary to disrupt the cells before centrifugation, for example, by using ultrasound, rapid freeze-thawing or osmotic lysis.Centrifugation will produce a pellet containing cultured cells, or a supernatant containing cell debris of cultured cells and medium and the polypeptide of interest.

[0236] The supernatant or medium, which may also contain other proteins and non-protein components, is then It may also be desirable to isolate the polypeptide of interest. A common approach to separating protein components from the supernatant or medium is by precipitation. Proteins of different solubilities are precipitated with different concentrations of a precipitant, such as ammonium sulfate. For example, low concentrations of the precipitant extract water-soluble proteins. Thus, by adding different, increasing concentrations of the precipitant, proteins of different solubilities can be distinguished. Dialysis can then be used to remove the ammonium sulfate from the separated proteins.

[0237] Other methods for distinguishing between different proteins are known in the art, such as ion exchange chromatography and size chromatography, which may be used as an alternative to precipitation or may follow precipitation.

[0238] Once the polypeptide of interest has been isolated from the culture, it may be desirable or necessary to concentrate the peptide or polypeptide. Several methods for concentrating proteins are known in the art, such as ultrafiltration or lyophilization.

[0239] Generation / expansion of immune cell populations The antigen-binding molecules of the present invention also find use in methods for generating / expanding immune cell populations. Essentially, the antigen-binding molecules of the present invention find use in generating / expanding populations of cell types that express CD122 and CD132 (e.g., on the cell surface).

[0240] The cell can be, for example, a T cell, an antigen-specific T cell (e.g., a virus-specific T cell), an antigen-specific CD4 T cell, an antigen-specific CD8 T cell, an effector memory CD4 T cell, an effector memory CD8 T cell, a central memory CD4 T cell, a central memory CD8 T cell, a cytotoxic CD8+ T cell (i.e., a CTL), an NK cell, or an antigen-specific NK cell.

[0241] The cells may be antigen-specific immune cells, such as antigen-specific T cells. For example, the cells may be specific for a peptide / polypeptide of a virus, such as adenovirus, Epstein-Barr virus (EBV), cytomegalovirus (CMV), human papillomavirus (HPV), influenza virus, measles virus, hepatitis B virus (HBV), hepatitis C virus (HCV), human immunodeficiency virus (HIV), lymphocytic choriomeningitis virus (LCMV), or herpes simplex virus (HSV). The virus-specific immune cells may be adenovirus-specific T cells (AdVST), Epstein-Barr virus-specific T cells (EBVST), cytomegalovirus-specific T cells (CMVST), human papillomavirus-specific T cells (HPVST), influenza virus-specific T cells, measles virus-specific T cells, hepatitis B virus-specific T cells (HBVST), hepatitis C virus-specific T cells (HCVST), human immunodeficiency virus-specific T cells (HIVST), lymphocytic choriomeningitis virus-specific T cells (LCMVST), or herpes simplex virus-specific T cells (HSVST).

[0242] The cells may comprise / express a chimeric antigen receptor (CAR) or a nucleic acid encoding a CAR. The cells may comprise / express a TGFβ decoy receptor or a nucleic acid encoding a TGFβ decoy receptor.

[0243] The method includes contacting cells expressing CD122 and CD132 in the presence of an antigen-binding molecule according to the present invention, whereby the cells expressing CD122 and CD132 are stimulated by the antigen-binding molecule to undergo cell division (i.e., proliferation), resulting in an increase in cell number.

[0244] In some embodiments, the method comprises generating / expanding the cells in vitro. In some embodiments, the method comprises generating / expanding the cells ex vivo. In some embodiments, the method comprises culturing the cells in vitro in the presence of an antigen-binding molecule according to the present invention.

[0245] Cell culture may be carried out using a suitable medium for in vitro culture of immune cells and under appropriate environmental conditions (e.g., temperature, pH, humidity, atmospheric conditions, agitation, etc.) well known to those skilled in the art of cell culture. Cell culture may be maintained at 37°C in a humidified atmosphere containing 5% CO2. Culture may be carried out in any vessel appropriate for the culture volume, such as a well of a cell culture plate, a cell culture flask, a bioreactor, etc. Cell cultures may be established and / or maintained at any suitable density, as can be readily determined by one skilled in the art. In some embodiments, cells are cultured in a bioreactor. In some embodiments, cells are cultured in a bioreactor as described in Somerville and Dudley, Oncoimmunology (2012) 1(8):1435-1437, which is incorporated herein by reference in its entirety. In some embodiments, cells are cultured in a GRex cell culture vessel, such as a GRex flask or a GRex 100 bioreactor.

[0246] In some embodiments, immune cells expressing CD122 and CD132 may be generated or expanded from within an immune cell population. It will be appreciated that the immune cell population comprises immune cells expressing CD122 and CD132. The immune cell population expressing CD122 and CD132 generated / expanded according to the methods of the present invention comprises at least one immune cell expressing CD122 and CD132.

[0247] In some embodiments, immune cells expressing CD122 and CD132 may be generated or expanded from within a PBMC population. The method may involve the expansion of T cells (e.g., antigen-specific T cells) from within an immune cell (e.g., PBMC, PBL) population. The immune cells (e.g., PBMC, PBL) used in the methods of the present invention may be obtained fresh or thawed from a previously obtained and frozen sample of immune cells.

[0248] In embodiments of the methods disclosed herein, generating or expanding an immune cell population may involve culturing a PBMC population. In some embodiments, the immune cell population may be generated / expanded from within a T cell population (e.g., a T cell population of heterogeneous type and / or specificity), which may be obtained from a blood sample or PBMC population. Culturing an immune cell population to generate / expand cells expressing CD122 and CD132 may result in an increase in the number of cells expressing CD122 and CD132 and / or an increase in the proportion of such cells in the cell population at the end of the culture.

[0249] In some embodiments, the method includes treating cells to increase CD122 and / or CD132 expression (e.g., surface expression) and expand cells expressing CD122 and CD132. For example, T cell activation (e.g., by stimulation with anti-CD3 (e.g., clone OKT3) and anti-CD28) induces upregulation of CD122 and CD132. Antigen-specific T cells also have upregulated expression of CD122 and CD132. In some embodiments, the method includes contacting immune cells with an antigen or a cell presenting the antigen.

[0250] In some embodiments, the cell population is generated / expanded in vivo after administration of an antigen-binding molecule according to the present invention (or administration of cells expressing the antigen-binding molecule) to a subject. Compositions and Formulations The invention described herein also provides compositions comprising the antigen-binding molecules, nucleic acids, expression vectors and cells described herein.

[0251] The antigen-binding molecules, nucleic acids, expression vectors, and cells described herein may be formulated as pharmaceutical compositions or medicaments for clinical use, and these may include pharmaceutically acceptable carriers, diluents, excipients, or adjuvants. Compositions may be formulated for local, parenteral, systemic, intracavitary, intravenous, intraarterial, intramuscular, intrathecal, intraocular, intraconjunctival, intratumoral, subcutaneous, intradermal, intrathecal, oral, or transdermal administration routes, which may include injection or infusion. Suitable formulations may contain the antigen-binding molecules in a sterile or isotonic medium. Medicaments and pharmaceutical compositions may also be formulated in liquid form, including gels. Liquid formulations may be formulated for administration by injection or infusion (e.g., via a catheter) into selected regions of the human or animal body.

[0252] In some embodiments, the antigen binding molecules, nucleic acids, expression vectors, CARs, compositions or cells according to the invention are formulated for injection or infusion, for example, into a blood vessel or tumor. In accordance with the invention described herein, there is also provided a method for producing a pharmaceutically useful composition, which may comprise one or more steps selected from the steps of: isolating an antigen-binding molecule, nucleic acid, expression vector, or cell described herein; and / or mixing an antigen-binding molecule, nucleic acid, expression vector, or cell described herein with a pharmaceutically acceptable carrier, adjuvant, excipient, or diluent.

[0253] For example, a further aspect of the invention described herein relates to a method for formulating or producing a medicament or pharmaceutical composition for use in treating cancer, the method comprising the step of formulating the pharmaceutical composition or medicament by mixing an antigen-binding molecule, nucleic acid, expression vector or cell described herein with a pharmaceutically acceptable carrier, adjuvant, excipient or diluent.

[0254] Therapeutic and prophylactic applications The antigen binding molecules, CARs, nucleic acids, expression vectors, cells and compositions described herein find use in therapeutic and prophylactic methods.

[0255] The invention described herein provides antigen-binding molecules, nucleic acids, expression vectors, cells, and compositions described herein for use in methods of medical treatment or prevention. The invention described herein also provides use of the antigen-binding molecules, nucleic acids, expression vectors, cells, and compositions described herein in the manufacture of a medicament for treating or preventing a disease or condition. The invention described herein also provides a method of treating or preventing a disease or condition, comprising the step of administering to a subject a therapeutically or prophylactically effective amount of an antigen-binding molecule, nucleic acid, expression vector, cell, or composition described herein.

[0256] "Treatment" may be, for example, a reduction in the development or progression of a disease / condition, a reduction in the symptoms of a disease / condition, or a reduction in the pathology of a disease / condition. Treating or alleviating a disease / condition may be effective to prevent the progression of the disease / condition, for example, to prevent the condition from worsening or to slow the rate of development. In some embodiments, treatment or alleviation may lead to an improvement in the disease / condition, for example, a reduction in the symptoms of the disease / condition, or a reduction in some other correlate of the severity / activity of the disease / condition. Prevention of a disease / condition may refer to preventing the condition from worsening, or preventing the development of a disease / condition, for example, preventing an early stage disease / condition from progressing to a later, chronic stage.

[0257] The articles of the invention can be used in the treatment of any disease / condition that would benefit from an increase in the number / frequency of immune cells, such as T cells (especially effector T cells) and / or NK cells. In particular, the antigen-binding molecules and pharmaceutical compositions described herein find use in the treatment or prevention of T cell dysfunction disorders, cancer and infectious diseases.

[0258] It will be appreciated that the therapeutic and prophylactic utility of the present invention extends to the treatment of any subject who would benefit from an increase in the number (i.e., population expansion) of cells expressing CD122 and CD132 (e.g., effector T cells and / or NK cells).

[0259] T-cell dysfunction disorders A T cell dysfunction disorder may be a disease or condition in which normal T cell function is impaired, resulting in downregulation of a subject's immune response to pathogenic antigens, for example, caused by infection with exogenous pathogens, such as microorganisms, bacteria, and viruses, or produced by the host in certain disease states, such as those in certain types of cancer (e.g., types of tumor-associated antigens).

[0260] T cell dysfunction disorders may include T cell exhaustion or T cell anergy. T cell exhaustion includes a state in which CD8+ T cells are unable to proliferate or exert T cell effector functions, such as cytotoxicity and cytokine (e.g., IFNγ) secretion, in response to antigen stimulation. Exhausted T cells may also be characterized by persistent expression of one or more markers of T cell exhaustion, such as PD-1, CTLA-4, LAG-3, and TIM-3. Thus, in some cases, the antigen-binding molecules and pharmaceutical compositions described herein find use in the treatment and prevention of T cell dysfunction disorders, cancer, and infectious diseases, in which treatment with the antigen-binding molecules and pharmaceutical compositions results in decreased expression by T cells of one or more markers of T cell exhaustion. In some cases, treatment results in decreased expression by T cells of PD-1.

[0261] T cell dysfunction disorders can manifest as infection or an inability to mount an effective immune response to infection. The infection may be chronic, persistent, subclinical, or indolent, and may be the result of a bacterial, viral, fungal, or parasitic infection. As such, treatment may be provided to patients with bacterial, viral, or fungal infections. Examples of bacterial infections include infection with Helicobacter pylori. Examples of viral infections include infection with HIV, hepatitis B, or hepatitis C.

[0262] T cell dysfunction disorders may be associated with cancer, such as tumor immune escape. Many human tumors express tumor-associated antigens that can be recognized by T cells and induce an immune response.

[0263] cancer Cancers without signs of T cell dysfunction may also be treated, but the use of the antigen-binding molecules, cells, or compositions described herein stimulates the proliferation and expansion of T cells (particularly effector T cells) and enables the subject to mount an effective immune response.

[0264] Cancers to be treated / prevented in accordance with the invention described herein may be any unwanted cell proliferation (or any disease manifested by unwanted cell proliferation), neoplasms, or tumors. Cancers may be benign or malignant, and may be primary or secondary (metastatic). Neoplasms or tumors may be any abnormal growth or proliferation of cells and may be located in any tissue. Cancers may be, for example, cancers of the adrenal gland, adrenal medulla, anus, appendix, bladder, blood, bone, bone marrow, brain, breast, cecum, central nervous system (including or excluding the brain), cerebellum, cervix, colon, duodenum, endometrium, epithelial cells (e.g., renal epithelium), gallbladder, esophagus, glial cells, heart, ileum, jejunum, kidney, lacrimal gland, larynx, liver, lung, lymph, lymph node, lymphoblast, maxilla, mediastinum, mesentery, uterine muscle, nasopharynx, omentum, oral cavity, ovary, pancreas, The tissue / cells may be from the parotid gland, peripheral nervous system, peritoneum, pleura, prostate, salivary gland, sigmoid colon, skin, small intestine, parenchyma, spleen, stomach, testis, thymus, thyroid, tongue, tonsils, trachea, uterus, vulva, and white blood cells.

[0265] In some embodiments, the cancer to be treated may be a cancer of a tissue selected from the group consisting of colon, rectum, nasopharynx, cervix, oropharynx, stomach, liver, head and neck, oral cavity, esophagus, lips, mouth, tongue, tonsils, nose, throat, salivary glands, sinus, pharynx, larynx, prostate, lung, bladder, skin, kidney, ovary, or mesothelium.

[0266] The tumor to be treated may be a nervous system or non-nervous system tumor. Nervous system tumors may originate from either the central or peripheral nervous system, such as glioma, medulloblastoma, meningioma, neurofibroma, ependymoma, schwannoma, neurofibrosarcoma, astrocytoma, and oligodendroglioma. Non-nervous system cancers / tumors may originate from any other non-nervous tissue, including melanoma, mesothelioma, lymphoma, myeloma, leukemia, non-Hodgkin's lymphoma (NHL), Hodgkin's lymphoma, chronic myeloid leukemia (CML), acute myeloid leukemia (AML), myelodysplastic syndrome (MDS), cutaneous T-cell lymphoma (CTCL), chronic lymphocytic leukemia (CLL), hepatocellular carcinoma, epidermoid carcinoma, prostate cancer, breast cancer, lung cancer, colon cancer, ovarian cancer, pancreatic cancer, thymic cancer, NSCLC, hematological cancer, and sarcoma.

[0267] In some embodiments, the cancer to be treated may be colon cancer, colon carcinoma, colorectal cancer, nasopharyngeal cancer, cervical cancer, oropharyngeal cancer, gastric cancer, hepatocellular carcinoma, head and neck cancer, head and neck squamous cell carcinoma (HNSCC), oral cancer, laryngeal cancer, prostate cancer, lung cancer, small cell lung cancer, non-small cell lung cancer, bladder cancer, urothelial carcinoma, melanoma, advanced melanoma, renal cell carcinoma, ovarian cancer, or mesothelioma.

[0268] In some embodiments, the cancer to be treated / prevented according to the present invention is a virus-associated cancer, such as an EBV-associated cancer or an HPV-associated cancer. "EBV-associated" and "HPV-associated" cancers may be cancers caused or exacerbated by infection with the respective viruses, cancers for which the infection is a risk factor, and / or cancers for which the infection is positively associated with the onset, development, progression, severity, or metastasis.

[0269] EBV-associated cancers that may be treated with cells produced by the methods of the present disclosure include nasopharyngeal carcinoma (NPC) and gastric cancer (GC). HPV-associated medical conditions that may be treated with cells produced by the methods of the present disclosure include at least dysplasia of the genital area(s), cervical intraepithelial neoplasia, vulvar intraepithelial neoplasia, penile intraepithelial neoplasia, anal intraepithelial neoplasia, cervical cancer, anal cancer, vulvar cancer, vaginal cancer, penile cancer, genital cancer, oral papilloma, and oropharyngeal cancer.

[0270] In some embodiments, the cancer to be treated according to various aspects of the present disclosure is one or more of nasopharyngeal carcinoma (NPC; e.g., Epstein-Barr virus (EBV)-positive NPC), cervical cancer (CC; e.g., human papillomavirus (HPV)-positive CC), oropharyngeal carcinoma (OPC; e.g., HPV-positive OPC), gastric cancer (GC; e.g., EBV-positive GC), hepatocellular carcinoma (HCC; e.g., hepatitis B virus (HBV)-positive HCC), lung cancer (e.g., non-small cell lung cancer (NSCLC)), and head and neck cancer (e.g., a cancer arising from tissues of the lip, mouth, nose, sinuses, pharynx, or larynx, e.g., head and neck squamous cell carcinoma (HNSCC).

[0271] Treatment may be aimed at reducing the number of cancer cells, and / or reducing tumor size, and / or inhibiting signaling mediated by immune checkpoint proteins (e.g., PD-1).

[0272] Administration of the antigen binding molecules and compositions described herein may delay or improve the onset of cancer symptoms. Administration of the antigen-binding molecules and compositions described herein may prevent the onset of invasion and / or metastasis. Administration of the antigen-binding molecules and compositions described herein may reduce the severity of cancer symptoms. Administration of the antigen-binding molecules and compositions described herein may delay or prevent the onset of invasion and / or metastasis. Administration of the antigen-binding molecules and compositions described herein may reduce invasion and / or metastasis. Administration of the antigen-binding molecules and compositions described herein may reduce cancer cell survival. Administration of the antigen-binding molecules and compositions described herein may increase non-cancerous cell survival and / or increase subject survival.

[0273] infection The infection may be any infection or infectious disease, such as a bacterial, viral, fungal, or parasitic infection. In some embodiments, it may be particularly desirable to treat chronic / persistent infections, such as those where such infections are associated with T cell dysfunction or T cell exhaustion.

[0274] It is well established that T cell exhaustion is a state of T cell dysfunction that occurs during many chronic infections (including viral, bacterial, and parasitic infections) and in cancer (Wherry Nature Immunology Vol. 12, No. 6, p492-499, June 2011).

[0275] Examples of treatable bacterial infections include Bacillus spp., Bordetella pertussis, Clostridium spp., Corynebacterium spp., Vibrio chloerae, Staphylococcus spp., Streptococcus spp., Escherichia, Klebsiella spp., Proteus spp., Yersinia spp., Erwina spp., Salmonella spp., Listeria spp., Helicobacter pylori, mycobacteria (e.g., Mycobacterium tuberculosis), and Pseudomonas aeruginosa. For example, the bacterial infection may be sepsis or tuberculosis.

[0276] Examples of treatable viral infections include influenza virus, measles virus, hepatitis B virus (HBV), hepatitis C virus (HCV), human immunodeficiency virus (HIV), lymphocytic choriomeningitis virus (LCMV), herpes simplex virus, and human papillomavirus (HPV).

[0277] Examples of treatable fungal infections include infections caused by Alternaria species, Aspergillus species, Candida species, and Histoplasma species. The fungal infection may be fungal septicemia or histoplasmosis.

[0278] Examples of treatable parasitic infections include infections by Plasmodium species (e.g., Plasmodium falciparum, Plasmodium yoeli, Plasmodium ovale, Plasmodium vivax, or Plasmodium chabaudi chabaudi). Parasitic infections can be diseases such as malaria, leishmaniasis, and toxoplasmosis.

[0279] Medical treatments also include those using autologous and / or heterologous cells or immortalized cell lines. These may involve in vivo, ex vivo, and adoptive immunotherapy. Adoption The antigen-binding molecules of the present invention are also useful in combination with methods involving adoptive cell transfer (ACT). In particular, the antigen-binding molecules of the present invention are useful in methods for generating / expanding immune cell populations in vitro or ex vivo, which may then be administered to a subject. The methods for generating / expanding immune cell populations may also be performed in vivo.

[0280] The present invention provides therapeutic or prophylactic methods involving the adoptive transfer of immune cells (e.g., T cells, effector T cells, virus-specific T cells, NK cells) produced (i.e., generated or expanded) according to the methods of the invention. Adoptive cell transfer generally refers to a process in which immune cells are obtained from a subject, typically by drawing a blood sample from which the immune cells are isolated. The immune cells are then typically treated or modified in some way, optionally expanded, and then administered to either the same subject or a different subject. Treatments are typically aimed at providing the subject with a population of immune cells with particular desired properties or at increasing the frequency of immune cells with such properties in the subject.

[0281] The immune cells may be, for example, T cells, antigen-specific T cells (e.g., virus-specific T cells), antigen-specific CD4 T cells, antigen-specific CD8 T cells, effector memory CD4 T cells, effector memory CD8 T cells, central memory CD4 T cells, central memory CD8 T cells, cytotoxic CD8+ T cells (i.e., CTLs), NK cells, or antigen-specific NK cells. The immune cells preferably express CD122 and CD132.

[0282] The cells may be antigen-specific immune cells, such as antigen-specific T cells. For example, the cells may be specific for a peptide / polypeptide of a virus, such as adenovirus, Epstein-Barr virus (EBV), cytomegalovirus (CMV), human papillomavirus (HPV), influenza virus, measles virus, hepatitis B virus (HBV), hepatitis C virus (HCV), human immunodeficiency virus (HIV), lymphocytic choriomeningitis virus (LCMV), or herpes simplex virus (HSV). The virus-specific immune cells may be adenovirus-specific T cells (AdVST), Epstein-Barr virus-specific T cells (EBVST), cytomegalovirus-specific T cells (CMVST), human papillomavirus-specific T cells (HPVST), influenza virus-specific T cells, measles virus-specific T cells, hepatitis B virus-specific T cells (HBVST), hepatitis C virus-specific T cells (HCVST), human immunodeficiency virus-specific T cells (HIVST), lymphocytic choriomeningitis virus-specific T cells (LCMVST), or herpes simplex virus-specific T cells (HSVST).

[0283] The cells may comprise / express a chimeric antigen receptor (CAR) or a nucleic acid encoding a CAR. The cells may comprise / express a TGFβ decoy receptor or a nucleic acid encoding a TGFβ decoy receptor.

[0284] In some cases, the immune cells are obtained from the patient to be introduced (autologous cell therapy). That is, the cells are obtained from the patient, generated according to the methods described herein, and may then be returned to the same patient. The methods disclosed herein may also be used in allogeneic cell therapy, in which cells obtained from a different individual are introduced into the patient.

[0285] Adoptive T cell transfer can be performed, for example, as described in Chia WK et al., Molecular Therapy (2014), 22(1): 132-139, which is incorporated herein by reference in its entirety. , Kalos and June 2013, Immunity 39(1): 49-60, and Cobbold et al., (2005) J. Exp. Med. 202: 379-386.

[0286] In the present invention, adoptive transfer is performed for the purpose of introducing or increasing the frequency of immune cells in a subject. Accordingly, the present invention provides a method of treating or preventing a disease or condition in a subject, comprising: (a) isolating PBMCs from a subject; (b) generating or expanding a population of immune cells by culture in the presence of an antigen-binding molecule according to the invention; and (c) administering the generated / expanded immune cell population to the subject. The method includes the steps of:

[0287] In some embodiments, the subject from which the PBMCs are isolated is the subject to which the generated / expanded cells are administered (i.e., the adoptive transfer is of autologous cells). In some embodiments, the subject from which the PBMCs are isolated is a different subject from the subject to which the generated / expanded cells are administered (i.e., the adoptive transfer is of allogeneic cells).

[0288] In some embodiments, the method may include one or more of the following steps: collecting blood cells from a subject; isolating PBMCs from the blood sample; generating or expanding an immune cell population by culture in the presence of an antigen-binding molecule described in the present invention; collecting the generated or expanded immune cell population; mixing the generated or expanded immune cell population with an adjuvant, diluent, or carrier; and administering the generated or expanded immune cell population or composition to the subject.

[0289] In some embodiments, the method may further comprise administering to the subject a therapeutically or prophylactically effective amount of an antigen-binding molecule according to the present invention. Those skilled in the art can refer to, for example, Chia WK et al., Molecular Therapy (2014), 22(1): 132-139, Kalos and June 2013, Immunity 39(1): 49-60, and Cobbold et al., (2005) J. Exp. Med. 202: 379-386, one can determine appropriate reagents and methods for adoptive transfer of immune cells generated or expanded according to the methods of the present invention.

[0290] Administration Administration of the antigen-binding molecules or compositions of the present invention is preferably in a "therapeutically effective" or "prophylactically effective" amount, which is an amount sufficient to show benefit to the subject. The actual amount administered, as well as the rate and time course of administration, will depend on the nature and severity of the disease or disorder. Prescribing treatment, e.g., determining dosage, is within the responsibility of medical practitioners and other physicians and will typically take into account the disease / disorder to be treated, the condition of the individual subject, the site of delivery, the method of administration, and other factors known to physicians. Examples of the techniques and protocols mentioned above can be found in Remington's Pharmaceutical Sciences, 20th ed., 2000, published by Lippincott, Williams & Wilkins. It will be appreciated that the articles of the present invention (e.g., antigen-binding molecules or compositions of the present invention) are administered in an amount sufficient to cause an increase in the number (i.e., expansion of the cell population) of cells expressing CD122 and CD132 (e.g., effector T cells, NK cells, and / or CAR-T cells).

[0291] Administration of an antigen-binding molecule includes administration of cells containing / expressing the antigen-binding molecule. Administration may be performed alone or in combination with other treatments, either simultaneously or sequentially, depending on the disease / condition to be treated / prevented. The antigen-binding molecule or composition described herein and an additional agent, e.g., a therapeutic agent, may be administered simultaneously or sequentially. In some embodiments, the method includes an additional therapeutic or prophylactic intervention, e.g., for the treatment / prevention of cancer. In some embodiments, the therapeutic or prophylactic intervention is selected from chemotherapy, immunotherapy, radiation therapy, surgery, vaccination, and / or hormonal therapy.

[0292] Simultaneous administration refers to the administration of an antigen-binding molecule, nucleic acid, vector, cell, or composition and a therapeutic agent together, for example, a pharmaceutical composition containing both agents (combined preparation), or immediately after each other, and optionally via the same administration route, for example, into the same artery, vein, or other blood vessel. Sequential administration refers to the administration of one of the antigen-binding molecule / composition or therapeutic agent followed by the separate administration of the other agent after a predetermined time interval. The two agents do not need to be administered by the same route, although this is the case in some embodiments. The time interval may be any time interval.

[0293] In some embodiments, the antigen-binding molecule is administered in combination with a chimeric antigen receptor (CAR) or CAR-expressing cells (e.g., CAR-T cells). In some embodiments, the antigen-binding molecule is administered in combination with an immune cell population, for example, an immune cell population generated / expanded according to the methods described herein. In some embodiments, the antigen-binding molecule is administered by a method comprising adoptive transfer (ACT), as described herein.

[0294] In some embodiments, the antigen binding molecule is administered in combination with an agent capable of inhibiting signal transduction mediated by immune checkpoint proteins, sometimes referred to as immune checkpoint inhibitors.

[0295] Immune checkpoint proteins help suppress immune responses and thereby protect against autoimmunity, but can also act to inhibit desirable effector immune cell activity, such as T-cell killing of cancer cells or killing of pathogen-infected cells (especially in cases of chronic infection). Inhibition of immune checkpoint protein-mediated signaling is desirable in these settings because it relieves effector immune cells from immune checkpoint protein-mediated inhibition, thereby promoting effector immune responses.

[0296] Agents capable of inhibiting signal transduction mediated by a given immune checkpoint protein include, for example, agents capable of binding to and inhibiting signal transduction mediated by the immune checkpoint protein or a ligand of an immune checkpoint protein; agents capable of decreasing gene / protein expression of the immune checkpoint protein or a ligand of an immune checkpoint protein (e.g., by inhibiting the transcription of a gene(s) encoding the immune checkpoint protein / ligand, inhibiting post-transcriptional processing of RNA encoding the immune checkpoint protein / ligand, decreasing the stability of RNA encoding the immune checkpoint protein / ligand, promoting degradation of RNA encoding the immune checkpoint protein / ligand, inhibiting post-translational processing of the immune checkpoint protein / ligand, decreasing the stability of the immune checkpoint protein / ligand, or promoting degradation of the immune checkpoint protein / ligand), and small molecule inhibitors.

[0297] In some embodiments, the immune checkpoint protein is PD-1, CTLA- In some embodiments, the immune checkpoint protein is selected from PD-1, CTLA-4, LAG-3, and TIM-3.

[0298] In some embodiments, the antigen binding molecules of the present invention are administered in combination with an agent capable of inhibiting PD-1-mediated signal transduction. The agent capable of inhibiting PD-1-mediated signal transduction may be an agent targeted to PD-1 or an agent targeted to a PD-1 ligand, such as PD-L1 or PD-L2. In some embodiments, the agent capable of inhibiting PD-1-mediated signal transduction may be, for example, an antibody capable of binding to PD-1, PD-L1, or PD-L2 and inhibiting PD-1-mediated signal transduction. In some embodiments, the agent capable of inhibiting PD-1-mediated signal transduction is an antibody / fragment described in WO2016 / 068801 or WO2016 / 111645, both of which are incorporated herein by reference in their entirety.

[0299] In some embodiments, the antigen binding molecule of the present invention is administered in combination with an agent capable of inhibiting CTLA-4-mediated signal transduction. The agent capable of inhibiting CTLA-4-mediated signal transduction may be an agent targeted to CTLA-4 or an agent targeted to a CTLA-4 ligand, such as CD80 or CD86. In some embodiments, the agent capable of inhibiting CTLA-4-mediated signal transduction may be, for example, an antibody capable of binding to CTLA-4, CD80, or CD86 and inhibiting CTLA-4-mediated signal transduction. In some embodiments, the agent capable of inhibiting CTLA-4-mediated signal transduction is an antibody / fragment described in WO2017 / 194265, the entire contents of which are incorporated herein by reference.

[0300] In some embodiments, the antigen binding molecules of the present invention are administered in combination with an agent capable of inhibiting LAG-3-mediated signal transduction. The agent capable of inhibiting LAG-3-mediated signal transduction may be an agent targeted to LAG-3 or an agent targeted to a ligand of LAG-3, such as MHC class II. In some embodiments, the agent capable of inhibiting PD-1-mediated signal transduction may be, for example, an antibody capable of binding to LAG-3 or MHC class II and inhibiting LAG-3-mediated signal transduction. In some embodiments, the agent capable of inhibiting LAG-3-mediated signal transduction is an antibody / fragment described in WO2017 / 149143, the entire contents of which are incorporated herein by reference.

[0301] In some embodiments, the antigen binding molecules of the present invention are administered in combination with an agent capable of inhibiting TIM-3-mediated signaling. The agent capable of inhibiting TIM-3-mediated signaling may be an agent targeted to TIM-3 or an agent targeted to a TIM-3 ligand, such as galectin-9. In some embodiments, the agent capable of inhibiting TIM-3-mediated signaling may be, for example, an antibody capable of binding to TIM-3 or galectin-9 and inhibiting TIM-3-mediated signaling. In some embodiments, the agent capable of inhibiting PD-1-mediated signaling is an antibody / fragment described in WO2016 / 068802 or WO2016 / 068803, both of which are incorporated herein by reference in their entirety.

[0302] Chemotherapy and radiotherapy refer to the treatment of cancer with drugs or ionizing radiation (e.g., radiotherapy using X-rays or gamma rays), respectively. Drugs can be chemical entities, such as small molecule drugs, antibiotics, DNA intercalators, protein inhibitors (e.g., kinase inhibitors), or biological agents. The agent may be, for example, an antibody, an antibody fragment, an aptamer, a nucleic acid (e.g., DNA, RNA), a peptide, a polypeptide, or a protein. The agent may be formulated as a pharmaceutical composition or medicament. The formulation may include one or more agents (e.g., one or more active agents) together with one or more pharmaceutically acceptable diluents, excipients, or carriers.

[0303] Treatment can involve the administration of more than one drug.Depending on the condition to be treated, drug can be administered alone or in combination with other treatment, simultaneously or sequentially.For example, chemotherapy can be a combination therapy that involves the administration of two drugs, one or more of which can be intended to treat cancer.

[0304] Chemotherapy may be administered by one or more routes of administration, such as parenteral, intravenous injection, oral, subcutaneous, intradermal, or intratumoral routes. Chemotherapy may be administered according to a therapeutic regimen, which may be a predetermined timetable, plan, scheme, or schedule of chemotherapy administration that may be prepared by a doctor or physician and may be customized for the patient in need of treatment.

[0305] The treatment regimen may indicate one or more of: the type of chemotherapy to be administered to the patient; the dose of each agent or radiation; the time interval between administrations; the length of each treatment; the number and nature of any treatment holidays, if any, etc. For combination therapy, a single treatment regimen may be provided that indicates how each agent is to be administered.

[0306] Chemotherapeutic agents and biologics may be selected from: alkylating agents such as cisplatin, carboplatin, mechlorethamine, cyclophosphamide, chlorambucil, ifosfamide; purine or pyrimidine antimetabolites such as azathioprine or mercaptopurine; alkaloids and terpenoids such as vinca alkaloids (e.g., vincristine, vinblastine, vinorelbine, vindesine), podophyllotoxin, etoposide, teniposide, Taxanes, such as paclitaxel (Taxol™), docetaxel; topoisomerase inhibitors, such as type I topoisomerase inhibitors, camptothecin, irinotecan, and topotecan, or type II topoisomerase inhibitors, amsacrine, etoposide, etoposide phosphate, teniposide; antitumor antibiotics (e.g., anthracycline antibiotics), such as dactinomycin, doxorubicin (Adriamycin™), epirubicin, bleomycin, rapamycin antibody-based agents, such as anti-PD-1 antibodies, anti-PD-L1 antibodies, anti-TIM-3 antibodies, anti-CTLA-4, anti-4-1BB, anti-GITR, anti-CD27, anti-BLTA, anti-OX43, anti-VEGF, anti-TNFα, anti-IL-2, anti-GpIIb / IIIa, anti-CD-52, anti-CD20, anti-RSV, anti-HER2 / neu (erbB2), anti-TNF receptor, anti-EGFR antibodies, monoclonal antibodies or antibody fragments, for example: cetuximab, panitumumab, infliximab, basiliximab; anti-angiogenic agents such as bevacizumab (Avastin®); cancer vaccines such as sipuleucel-T (Provenge®).

[0307] Further chemotherapy agents are: 13-cis-retinoic acid, 2-chlorodeoxyadenosine , 5-azacytidine, 5-fluorouracil, 6-mercaptopurine, 6-thioguanine, Abraxane, Accutane®, Actinomycin-D, Adriamycin®, Adrsil®, Afinitor®, Agrylin®, Ala-Cort®, aldesleukin, alemtuzumab, ALIMTA , alitretinoin, Alkaban-AQ (registered trademark), Alkeran (registered trademark), all-trans retinoic acid, alpha interferon, altretamine, amethopterin, amifostine, aminoglutethimide, anagrelide, anandrone (registered trademark), anastrozole, arabinosylcytosine, Aranesp (registered trademark), Alesia (registered trademark), Arimidex (registered trademark), Aromasin (registered trademark), Alanon (registered trademark), arsenic trioxide, asparaginase, ATRA Avastin (registered trademark), azacitidine, BCG, BCNU, bendamustine, bevacizumab, bexarotene, BEXXAR (registered trademark), bicalutamide, BiCNU, Blenoxan (registered trademark), bleomycin, bortezomib, busulfan, Busulfex (registered trademark), calcium leucovorin, Campath (registered trademark), Camptosar (registered trademark), camptothecin-11, capecitabine, Carac TM , carboplatin, carmustine, Casodex®, CC-5013, CCI-779, CCNU, CDDP, CeeNU, Cervizin®, cetuximab, chlorambucil, cisplatin, citrovorum factor, cladribine, cortisone, Cosmegen®, CPT-11, cyclophosphamide, Citadren®, cytarabine, Citosar-U®, Cytoxan®, Dacogen, dactinomycin, darbepoetin alfa, dasatinib, daunomycin, daunorubicin, daunorubicin hydrochloride, daunorubicin liposomal, Daunoxome®, Decadron, decitabine, Delta-Cortef®, Deltazone®, denileukin, diftitox, Depocyto TM, dexamethasone, dexamethasone acetate, dexamethasone sodium phosphate, dexasone, dexrazoxane, DHAD, DIC, Geodex, docetaxel, Doxil®, doxorubicin, doxorubicin liposomal, droxia TM , DTIC, DTIC-Dome (registered trademark), Duralon (registered trademark), Eligard TM , Elence TM , Eloxatin TM , Elspar (registered trademark), Encit (registered trademark), epirubicin, epoetin alfa, Erbitux, erlotinib, Erwinia L-asparaginase, estramustine, ethyol-etopofos (registered trademark), etoposide, etoposide phosphate, Eurexin (registered trademark), everolimus, Evista (registered trademark), exemestane, Faslodex (registered trademark), Femara (registered trademark), filgrastim, floxuridine, Fludara (registered trademark), fludarabine, Fluoroplex (registered trademark), fluorouracil, floxymesterone, flutamide, folinic acid, FUDR (registered trademark), fulvestrant, gefitinib, gemcitabine, gemtuzumab ozogamicin, Gleevec TM , Gliadel® wafer, goserelin, granulocyte colony-stimulating factor, granulocyte-macrophage colony-stimulating factor, Herceptin®, Hexadrol, Hexalen®, hexamethylmelamine, HMM, Hicamtine®, Hydrea®, Hydrocort® acetate, hydrocortisone, hydrocortisone sodium phosphate, hydrocortisone sodium succinate, hydrocortone phosphate, hydroxyurea, ibritumomab, ibritumomab tiuxe Tan, Idamycin®, Idarubicin, Ifex®, IFN-alpha, Ifosfamide, IL-11, IL-2, Imatinib mesylate, Imidazole carboxamide, Interferon alpha, Interferon alpha-2b (PEG conjugate), Interleukin-2, Interleukin-11, Intron A® (Interferon alpha-2b), Iressa®, Irinotecan, Isotretinoin, Ixabepilone, IxempraTM , Kidrolase, Lanacort®, Lapatinib, L-asparaginase, LCR, Lenalidomide, Letrozole, Leucovorin, Leukeran, Leukine TM , leuprolide, leurocristin, leustatin TM , Liposomal Ara-C, Liquid Pred®, Lomustine, L-PAM, L-Sarcolysin, Lupron®, Lupron Depot®, Matulan®, Maxidex, Mechlorethamine, Mechlorethamine Hydrochloride, Medralon®, Medrol®, Megase®, Megestrol, Megestrol Acetate, Melphalan, Mercaptopurine, Mesna, Mesunex TM , methotrexate, methotrexate sodium, methylprednisolone Rednisolone, Methycortene (registered trademark), Mitomycin, Mitomycin-C, Mitoxantrone, M-Prednisol (registered trademark), MTC, MTX, Mustagen (registered trademark), Mustine, Mutamycin (registered trademark), Myleran (registered trademark), Mirocel TM , Mirotarg (registered trademark), Navelbine (registered trademark), Nelarabine, Neosar (registered trademark), Neulasta TM , Neumega (registered trademark), Neupogen (registered trademark), Nexavar (registered trademark), Nilandrone (registered trademark), Nilutamide, Nipent (registered trademark), Nitrogen Mustard, Novardex (registered trademark), Novantrone (registered trademark), Octreotide, Octreotide Acetate, Oncospar (registered trademark), Oncovin (registered trademark), Ontac (registered trademark), Onxal TM , Oplevelkin, Orapred®, Orazon®, oxaliplatin, paclitaxel, paclitaxel protein-bound, pamidronate, panitumumab, Panretin®, Paraplatin®, Pediapred®, PEG-interferon, pegaspargase, pegfilgrastim, PEG-Intron TM, PEG-L-asparaginase, PEMETREXED, pentostatin, phenylalanine mustard, Platinol®, Platinol-AQ®, prednisolone, prednisone, Prelon®, procarbazine, PROCRIT®, Proleukin®, carmustine implant, Prolif Prospan 20 including Prinetol®, raloxifene, Revlimid®, Rheumatrex®, Rituxan®, rituximab, Roferon-A® (interferon alpha-2a), Lubex®, rubidomycin hydrochloride, Sandostatin®, Sandostatin LAR®, sargramostin, Solu-Cortef®, Solu-Medrol®, sorafenib, Sprycel® TM , STI-571, streptozocin, SU11248, sunitinib, Sutent (registered trademark), tamoxifen, Tarceva (registered trademark), Targretin (registered trademark), Taxol (registered trademark), Taxotere (registered trademark), Temodar (registered trademark), temozolomide, temsirolimus, teniposide, TESPA, thalidomide, Talomide (registered trademark), Terasis (registered trademark), thioguanine, thioguanine tabloid (registered trademark), thiophosphoamide, Thioplex (registered trademark), thiotepa, TICE (registered trademark), Toposar (registered trademark), topotecan, toremifene, Torisel (registered trademark), tositumomab, trastuzumab, Treanda (registered trademark), tretinoin, Trexar TM , Trisenox (registered trademark), TSPA, TYKERB (registered trademark), VCR, Vectivix TM , Velban (registered trademark), Velcade (registered trademark), Bepesid (registered trademark), Vesanoid (registered trademark), Viadur TM , Vidaza (registered trademark), vinblastine, vinblastine sulfate, Vincasar Pfs (registered trademark), vincristine, vinorelbine, vinorelbine tartrate, VLB, VM-26, vorinostat, VP-16, Bumon (registered trademark), Xeloda (registered trademark), Zanosar (registered trademark), Zevalin TM, Zinecard®, Zoladex®, zoledronic acid, Zolinza, Zometa®.

[0308] Multiple doses of the antigen-binding molecule or composition may be provided, one or more or each of which may be accompanied by the simultaneous or sequential administration of another therapeutic agent. The multiple doses may be separated by predetermined time intervals, which may be selected to be one of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, or 31 days, or 1, 2, 3, 4, 5, or 6 months. For example, doses may be administered once every 7, 14, 21, or 28 days (plus or minus 3, 2, or 1 day).

[0309] In some embodiments, the antigen-binding molecule may be conjugated to a drug moiety or a detectable moiety. Detection method The antigen-binding molecules described herein may be used in methods involving the detection of CD122 and / or CD132, or cells expressing CD122 and / or CD132 (e.g., on the cell surface). The methods may be in vitro or in vivo methods. Such methods may involve the detection of a binding complex between the antigen-binding molecule and CD122 and / or CD132, or cells expressing CD122 and / or CD132.

[0310] As such, a method is provided that includes the steps of contacting a sample containing or suspected of containing CD122 and / or CD132, or cells expressing CD122 and / or CD132, and detecting the formation of a complex of an antigen-binding molecule and CD122 and / or CD132, or cells expressing CD122 and / or CD132.

[0311] Suitable method formats are well known in the art and include sandwich assays, immunoassays such as ELISA. The method may involve labeling the antigen-binding molecule, or the target(s), or both with a detectable label, such as a detectable moiety as described herein above. In some embodiments, the detectable moiety is a fluorescent label, a luminescent label, an immunodetectable label, or a radiolabel. In some embodiments, the detectable moiety may be selected from: a radionucleotide, a positron-emitting nuclide (e.g., for positron emission tomography (PET)), an MRI contrast agent, or a fluorescent label. In vitro or in vivo analysis may involve analysis by detecting the appropriately labeled species by positron emission tomography (PET), magnetic resonance imaging (MRI), or fluorescence imaging.

[0312] This type of method can provide the basis for methods for diagnosing and / or evaluating the prognosis of a disease or condition. Such methods can be performed on patient samples in vitro or after processing of the patient sample. Once the sample is collected, the patient does not need to be present to perform the in vitro method, and therefore the method may not be performed on a human or animal body.

[0313] In some embodiments, the method may include detecting or quantifying CD122 and / or CD132, or cells expressing CD122 and / or CD132, for example, in a patient sample. If the method includes quantifying an appropriate factor, the method may further include comparing the detected amount to a standard or reference value as part of the diagnostic or prognostic evaluation. Other diagnostic / prognostic tests may be combined with those described herein to increase the accuracy of the diagnosis or prognosis or to confirm the results obtained by using the tests described herein.

[0314] A sample may be taken from any tissue or body fluid. The sample may comprise or be derived from: a volume of blood; a volume of serum from an individual's blood, which may include the liquid portion of blood obtained after removing fibrin clots and blood cells; a tissue sample or biopsy; pleural effusion; cerebrospinal fluid (CSF); or cells isolated from said individual. In some embodiments, the sample may be obtained from or derived from one or more tissues affected by a disease / condition (e.g., one or more tissues that manifest symptoms of the disease or are involved in the pathogenesis of the disease / disorder).

[0315] Subject The subject to be treated according to the aspects of the invention described herein may be any animal or human. The subject is preferably a mammal, more preferably a human. The subject may also be a non-human mammal, but is more preferably a human. The subject may be male or female. The subject may be a patient. The subject may have been diagnosed with a disease or condition (e.g., cancer) in need of treatment, may be suspected of having such a disease / condition, or may be at risk of developing / obtaining such a disease / condition.

[0316] In the embodiments described herein, the subject is preferably a human subject. In some embodiments, the subject to be treated according to the therapeutic or preventive method of the present invention is a subject who has cancer or is at risk of developing cancer. In the embodiments described herein, the subject may be selected for treatment according to the method based on the characterization of specific markers of such diseases / conditions.

[0317] kit The present invention also provides kits of parts. In some embodiments, the kits may include at least one container containing a predetermined amount of an antigen-binding molecule, nucleic acid, expression vector, CAR, composition, or cell described herein.

[0318] The kit may be provided with instructions for administering the antigen-binding molecule, nucleic acid, expression vector, CAR, composition or cell to a patient to treat a specified disease / condition.

[0319] In some embodiments, the kit may include materials for producing an antigen-binding molecule or composition described herein. The kit may further include instructions for administration to a patient to treat the specified disease / condition. In some embodiments, the kit may include materials and / or instructions for producing the antigen-binding molecules, nucleic acids, expression vectors, CARs, cells, or compositions described herein.

[0320] In some embodiments, the kit may further include at least one container with a predetermined amount of another therapeutic agent (e.g., an anti-infective or chemotherapeutic agent). In such embodiments, the kit may also include a second agent or pharmaceutical composition, such that the two agents or pharmaceutical compositions can be administered simultaneously or separately to provide a combination treatment for a particular disease or condition.

[0321] Sequence identity For the purpose of determining the percent identity between two or more amino acid or nucleic acid sequences, pairwise and multiple sequence alignments can be performed in a variety of ways known to those skilled in the art, for example, using publicly available computer software such as ClustalOmega (Söding, J. 2005, Bioinformatics 21, 951-960), T-coffee (Notredame et al. 2000, J. Mol. Biol. (2000) 302, 205-217), Kalign (Lassmann and Sonnhammer 2005, BMC Bioinformatics, 6(298)) and MAFFT (Katoh and Standley 2013, Molecular Biology and Evolution, 30(4) 772-780). When using such software, it is preferable to use default parameters, for example, regarding gap penalties and extension penalties.

[0322] array

[0323] [Table 2-1]

[0324] [Table 2-2]

[0325] [Table 2-3]

[0326] [Table 2-4]

[0327] [Table 2-5]

[0328]

Table 2-6

[0329]

Table 2-7

[0330]

Table 2-8

[0331]

Table 2-9

[0332]

Table 2-10

[0333]

Table 2-11

[0334]

Table 2-12

[0335]

Table 2-13

[0336]

Table 2-14

[0337]

Table 2-15

[0338]

Table 2-16

[0339]

Table 2-17

[0340]

Table 2-18

[0341]

Table 2-19

[0342]

Table 2-20

[0343]

Table 2-21

[0344]

Table 2-22

[0345]

Table 2-23

[0346]

Table 2-24

[0347]

Table 2-25

[0348]

Table 2-26

[0349]

Table 2-27

[0350]

Table 2-28

[0351]

Table 2-29

[0352]

Table 2-30

[0353]

Table 2-31

[0354]

Table 2-32

[0355]

Table 2-33

[0356]

Table 2-34

[0357]

Table 2-35

[0358]

Table 2-36

[0359]

Table 2-37

[0360]

Table 2-38

[0361]

Table 2-39

[0362]

Table 2-40

[0363]

Table 2-41

[0364]

Table 2-42

[0365]

Table 2-43

[0366]

Table 2-44

[0367]

Table 2-45

[0368]

Table 2-46

[0369] [Table 2-47]

[0370] [Table 2-48]

[0371] [Table 2-49]

[0372] [Table 2-50]

[0373] [Table 2-51]

[0374] The present invention includes combinations of the described aspects and preferred features except where such combinations are clearly impermissible or clearly avoided. The section headings used herein are for organizational purposes only and are not to be construed as limiting the subject matter described.

[0375] Aspects and embodiments of the present invention will now be illustrated, by way of example, with reference to the accompanying figures. Further aspects and embodiments will be apparent to those skilled in the art. All documents mentioned in this text are incorporated herein by reference.

[0376] Throughout this specification, including the claims which follow, unless the context requires otherwise, the word "comprises", and variations such as "comprises" and "comprising", will be understood to imply the inclusion of a stated integer or step or group of steps, but not the exclusion of any o...

Claims

(i) the following CDRs: HC-CDR1 consisting of the amino acid sequence of SEQ ID NO: 196 HC-CDR2 consisting of the amino acid sequence of SEQ ID NO: 204 HC-CDR3 consisting of the amino acid sequence of SEQ ID NO: 212 and a VH region incorporating The following CDRs: LC-CDR1 consisting of the amino acid sequence of SEQ ID NO: 227 LC-CDR2 consisting of the amino acid sequence of SEQ ID NO: 238 LC-CDR3 consisting of the amino acid sequence of SEQ ID NO: 248 A VL region incorporating an antigen-binding portion capable of binding to the common gamma chain (CD132), comprising And, (ii) an antigen-binding portion capable of binding to CD122; An antigen-binding molecule comprising:

2. An antigen-binding portion capable of binding to the common gamma chain (CD132), a VH region comprising an amino acid sequence having at least 85% sequence identity to SEQ ID NO:71; and A VL region comprising an amino acid sequence having at least 85% sequence identity to SEQ ID NO:89; Including, The antigen-binding molecule of claim 1.

3. The antigen-binding molecule of claim 1 or 2, which is an IL-2 receptor agonist.

4. The antigen-binding molecule according to any one of claims 1 to 3, which is capable of reducing PD-1 expression by T cells.

5. A nucleic acid encoding an antigen-binding molecule described in any one of claims 1 to 4.

6. An expression vector comprising the nucleic acid described in claim 5.

7. A cell comprising the antigen-binding molecule of any one of claims 1 to 4, the nucleic acid of claim 5, or the expression vector of claim 6.

8. A method for producing the antigen-binding molecule of any one of claims 1 to 4, comprising the step of culturing a cell containing the nucleic acid of claim 5 or the expression vector of claim 6 under conditions suitable for expression of the antigen-binding molecule from the nucleic acid or the expression vector.

9. A composition comprising the antigen-binding molecule according to any one of claims 1 to 4, the nucleic acid according to claim 5, the expression vector according to claim 6, or the cell according to claim 7.

10. A drug comprising an antigen-binding molecule described in any one of claims 1 to 4.

11. A drug comprising the antigen-binding molecule according to any one of claims 1 to 4 for treating or preventing a T cell dysfunction disorder, cancer or an infectious disease.

12. 12. The method of claim 11, wherein the cancer is selected from the group consisting of colon cancer, colon carcinoma, colorectal cancer, nasopharyngeal cancer, cervical cancer, oropharyngeal cancer, gastric cancer, hepatocellular carcinoma, head and neck cancer, head and neck squamous cell carcinoma (HNSCC), oral cancer, laryngeal cancer, prostate cancer, lung cancer, small cell lung cancer, non-small cell lung cancer, bladder cancer, urothelial carcinoma, melanoma, advanced melanoma, renal cell carcinoma, ovarian cancer or mesothelioma.

13. The agent according to claim 11 or claim 12, wherein the antigen-binding molecule is administered in combination with a therapeutically effective amount of an agent capable of inhibiting signal transduction mediated by an immune checkpoint protein.

14. The method of claim 13, wherein the immune checkpoint protein is PD-1, CTLA-4, LAG-3, TIM-3, VISTA, TIGIT or BTLA.

15. A method for generating or expanding an immune cell population, comprising contacting an immune cell in vitro or ex vivo with an antigen-binding molecule according to any one of claims 1 to 4.

Citation Information

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