INBRX-120, a CD8α-targeted detuned IL-2 that selectively expands and activates tumoricidal effector cells for safe and durable in vivo responses
Background As a major driver of lymphocyte proliferation and activation interleukin 2 (IL-2) is a crucial mediator for antitumor responses. Despite promising activity in a subset of patients, wider therapeutic utility of IL-2 (aldesleukin) has been hampered by severe dose-limiting toxicities, the ex...
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| Format: | Article |
| Language: | English |
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BMJ Publishing Group
2023-01-01
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| Series: | Journal for ImmunoTherapy of Cancer |
| Online Access: | https://jitc.bmj.com/content/11/1/e006116.full |
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| _version_ | 1832582664346927104 |
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| author | Jason Ho Chelsie Macedo Garrett Cyprus Rajay Pandit Anya Polovina Nadja Kern Abrahim Hussain Sae Jeong Ahn William Crago Emily Rowell Florian J Sulzmaier John C Timmer Brendan P Eckelman |
| author_facet | Jason Ho Chelsie Macedo Garrett Cyprus Rajay Pandit Anya Polovina Nadja Kern Abrahim Hussain Sae Jeong Ahn William Crago Emily Rowell Florian J Sulzmaier John C Timmer Brendan P Eckelman |
| author_sort | Jason Ho |
| collection | DOAJ |
| description | Background As a major driver of lymphocyte proliferation and activation interleukin 2 (IL-2) is a crucial mediator for antitumor responses. Despite promising activity in a subset of patients, wider therapeutic utility of IL-2 (aldesleukin) has been hampered by severe dose-limiting toxicities, the expansion of immunosuppressive regulatory T cells and a poor pharmacokinetic (PK) profile. Recent engineering efforts, including non-α IL-2 variants, have lowered the toxicity profile, but have yet to induce meaningful antitumor activity in a wider patient population.Methods We engineered INBRX-120, a CD8α-targeted Cisleukin™ molecule consisting of an affinity tuned IL-2 (IL2-x) connected to two high affinity CD8α-specific single domain antibodies via an effector-silenced Fc domain. To show that this large affinity differential enables directed IL-2 cis-signaling exclusively on CD8α-expressing tumoricidal effector cell populations, INBRX-120 effects on target cell expansion, activation and antitumor activity were tested in vitro. In vivo antitumor efficacy was evaluated in syngeneic mouse models alone or in combination with programmed cell death protein-1 (PD-1) blockade. Preclinical safety, as well as pharmacodynamic (PD) and PK profiling was carried out in non-human primates.Results INBRX-120 effectively expanded and enhanced the cytotoxic capacity of CD8 T cells and natural killer cells towards tumor cells without affecting regulatory T cells in vitro and in vivo. In syngeneic mouse models, INBRX-120 surrogate showed safe, potent, and durable antitumor efficacy alone and in combination with PD-1 blockade. In non-human primates, INBRX-120 expanded and activated CD8α-expressing effector cells, showed a favorable PK profile, and was well tolerated up to a dose of 1 mg/kg.Conclusions Through its unique cis-signaling activity on CD8α-expressing effector cells, INBRX-120 overcomes the major limitations of IL-2-based therapy and effectively harnesses IL-2’s potent intrinsic antitumor activity. This novel therapeutic strategy promises safer clinical activity that could induce meaningful antitumor efficacy in a wider set of patients with various cancer indications. |
| format | Article |
| id | doaj-art-1128664e4a4f45238e95ab92d708e9bf |
| institution | Kabale University |
| issn | 2051-1426 |
| language | English |
| publishDate | 2023-01-01 |
| publisher | BMJ Publishing Group |
| record_format | Article |
| series | Journal for ImmunoTherapy of Cancer |
| spelling | doaj-art-1128664e4a4f45238e95ab92d708e9bf2025-01-29T12:20:10ZengBMJ Publishing GroupJournal for ImmunoTherapy of Cancer2051-14262023-01-0111110.1136/jitc-2022-006116INBRX-120, a CD8α-targeted detuned IL-2 that selectively expands and activates tumoricidal effector cells for safe and durable in vivo responsesJason Ho0Chelsie Macedo1Garrett Cyprus2Rajay Pandit3Anya Polovina4Nadja Kern5Abrahim Hussain6Sae Jeong Ahn7William Crago8Emily Rowell9Florian J Sulzmaier10John C Timmer11Brendan P Eckelman12Inhibrx Inc, La Jolla, California, USAInhibrx Inc, La Jolla, California, USAInhibrx Inc, La Jolla, California, USAInhibrx Inc, La Jolla, California, USAInhibrx Inc, La Jolla, California, USAInhibrx Inc, La Jolla, California, USAInhibrx Inc, La Jolla, California, USAInhibrx Inc, La Jolla, California, USAInhibrx Inc, La Jolla, California, USAInhibrx Inc, La Jolla, California, USAInhibrx Inc, La Jolla, California, USAInhibrx Inc, La Jolla, California, USAInhibrx Inc, La Jolla, California, USABackground As a major driver of lymphocyte proliferation and activation interleukin 2 (IL-2) is a crucial mediator for antitumor responses. Despite promising activity in a subset of patients, wider therapeutic utility of IL-2 (aldesleukin) has been hampered by severe dose-limiting toxicities, the expansion of immunosuppressive regulatory T cells and a poor pharmacokinetic (PK) profile. Recent engineering efforts, including non-α IL-2 variants, have lowered the toxicity profile, but have yet to induce meaningful antitumor activity in a wider patient population.Methods We engineered INBRX-120, a CD8α-targeted Cisleukin™ molecule consisting of an affinity tuned IL-2 (IL2-x) connected to two high affinity CD8α-specific single domain antibodies via an effector-silenced Fc domain. To show that this large affinity differential enables directed IL-2 cis-signaling exclusively on CD8α-expressing tumoricidal effector cell populations, INBRX-120 effects on target cell expansion, activation and antitumor activity were tested in vitro. In vivo antitumor efficacy was evaluated in syngeneic mouse models alone or in combination with programmed cell death protein-1 (PD-1) blockade. Preclinical safety, as well as pharmacodynamic (PD) and PK profiling was carried out in non-human primates.Results INBRX-120 effectively expanded and enhanced the cytotoxic capacity of CD8 T cells and natural killer cells towards tumor cells without affecting regulatory T cells in vitro and in vivo. In syngeneic mouse models, INBRX-120 surrogate showed safe, potent, and durable antitumor efficacy alone and in combination with PD-1 blockade. In non-human primates, INBRX-120 expanded and activated CD8α-expressing effector cells, showed a favorable PK profile, and was well tolerated up to a dose of 1 mg/kg.Conclusions Through its unique cis-signaling activity on CD8α-expressing effector cells, INBRX-120 overcomes the major limitations of IL-2-based therapy and effectively harnesses IL-2’s potent intrinsic antitumor activity. This novel therapeutic strategy promises safer clinical activity that could induce meaningful antitumor efficacy in a wider set of patients with various cancer indications.https://jitc.bmj.com/content/11/1/e006116.full |
| spellingShingle | Jason Ho Chelsie Macedo Garrett Cyprus Rajay Pandit Anya Polovina Nadja Kern Abrahim Hussain Sae Jeong Ahn William Crago Emily Rowell Florian J Sulzmaier John C Timmer Brendan P Eckelman INBRX-120, a CD8α-targeted detuned IL-2 that selectively expands and activates tumoricidal effector cells for safe and durable in vivo responses Journal for ImmunoTherapy of Cancer |
| title | INBRX-120, a CD8α-targeted detuned IL-2 that selectively expands and activates tumoricidal effector cells for safe and durable in vivo responses |
| title_full | INBRX-120, a CD8α-targeted detuned IL-2 that selectively expands and activates tumoricidal effector cells for safe and durable in vivo responses |
| title_fullStr | INBRX-120, a CD8α-targeted detuned IL-2 that selectively expands and activates tumoricidal effector cells for safe and durable in vivo responses |
| title_full_unstemmed | INBRX-120, a CD8α-targeted detuned IL-2 that selectively expands and activates tumoricidal effector cells for safe and durable in vivo responses |
| title_short | INBRX-120, a CD8α-targeted detuned IL-2 that selectively expands and activates tumoricidal effector cells for safe and durable in vivo responses |
| title_sort | inbrx 120 a cd8α targeted detuned il 2 that selectively expands and activates tumoricidal effector cells for safe and durable in vivo responses |
| url | https://jitc.bmj.com/content/11/1/e006116.full |
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