Sulzmaier et al. developed INBRX-120, a cytokine therapy linking single-domain anti-CD8a antibodies to low-affinity IL-2 (nonfunctional without concurrent CD8a binding). INBRX-120 selectively bound, activated, and induced proliferation of CD8+, but not CD4+ T cells from human PBMCs in vitro and in C57 mice. INBRX-120 also enhanced CD8+ T cell and NK cell cytotoxicity comparable to wild-type IL-2, improving MC38 and CT26 tumor growth control and synergizing with anti-PD-1 therapy for long-term survival. In non-human primates, i.v. INBRX-120 was well tolerated, persisted in serum for several days, and expanded CD8+ T, NK, and NKT cells.
Contributed by Alex Najibi
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.
Author Info: (1) Inhibrx Inc, La Jolla, California, USA florian@inhibrx.com. (2) Inhibrx Inc, La Jolla, California, USA. (3) Inhibrx Inc, La Jolla, California, USA. (4) Inhibrx Inc, La Jolla, C
Author Info: (1) Inhibrx Inc, La Jolla, California, USA florian@inhibrx.com. (2) Inhibrx Inc, La Jolla, California, USA. (3) Inhibrx Inc, La Jolla, California, USA. (4) Inhibrx Inc, La Jolla, California, USA. (5) Inhibrx Inc, La Jolla, California, USA. (6) Inhibrx Inc, La Jolla, California, USA. (7) Inhibrx Inc, La Jolla, California, USA. (8) Inhibrx Inc, La Jolla, California, USA. (9) Inhibrx Inc, La Jolla, California, USA. (10) Inhibrx Inc, La Jolla, California, USA. (11) Inhibrx Inc, La Jolla, California, USA. (12) Inhibrx Inc, La Jolla, California, USA. (13) Inhibrx Inc, La Jolla, California, USA.
