Abstract 4354: Safety and tolerability of NPX372, a novel B7-H7:CD3 bispecific T cell engaging antibody

Abstract BACKGROUND: B7-H7 is a B7 family member upregulated on tumor cells of many histologic subtypes with a very restricted normal tissue expression and is, therefore, being explored as a novel tumor targeting antigen. NextPoint Therapeutics has developed a T cell engager bispecific antibody, NXP372, which simultaneously recognizes B7-H7 and CD3 from both human and non-human primates, providing T cell activation in the proximity of B7-H7. NPX372 induced T cell activation and T cell-mediated killing of B7-H7+ tumor cells in vitro and B7-H7 levels correlated with cytotoxic potency. In addition, NPX372 induced cytokine production in primary T cell cultures with B7-H7+ tumor cells. Finally, NPX372 demonstrated dose-dependent anti-tumor activity in a B7-H7+ tumor model in vivo at clinically relevant doses (1). METHODS: Affinity to human and monkey B7-H7 and CD3 was evaluated by cell binding using flow cytometry and an Octet binding assay, respectively. Immunohistochemistry was used to evaluate human and monkey B7-H7 tissue expression. To evaluate the tolerability of NPX372, we performed a dose escalation toxicokinetic study in cynomolgus monkeys. Animals were evaluated for 4 weeks after a single or step-up intravenous dose(s) of NPX372. Clinical observations, hematology, chemistry, cytokine, immunophenotyping, and PK samples were collected. At completion, pathology evaluation of selected tissues was performed. RESULTS: Expression of B7-H7 is predominant in the luminal epithelium of the gastrointestinal tract (GI) in both monkey and human. NPX372 affinity to NHP and human B7-H7 is similar as measured by on-cell binding. Octet binding confirmed cross-reactivity to NHP CD3. NPX372 was well tolerated up to 100 µg/kg after single IV dose and up to 300ug/kg in a step-up dosing. On-target GI toxicity was observed at the highest dose of 1000 µg/kg, lasting ∼5 days. Pathological assessment of small and large intestinal epithelium was normal at time of scheduled evaluation 28 days after dosing, supporting reversibility of the adverse effects. Clinical chemistry, coagulation, and hematology lab parameters were normal, with minor increases in C-reactive protein in one animal each treated at 300 and 1000 µg/kg. No evidence of cytokine release syndrome was observed, although small increases in G-CSF, IL-1RA, IL-8, MCP-1 and MIP-1β cytokines were noted. One animal dosed at 1000 µg/kg showed a transient increase in IFNγ. Immunophenotyping data showed dose-proportional activation of T cells (by upregulation of CD25). PK exposure was also dose-proportional. CONCLUSION: These data demonstrate on-target activity of NXP372 in monkeys, with doses tolerated up to 1000 µg/Kg, which covers a dose range that is effective in preclinical models. The totality of the data suggests that NXP372 may be a safe and effective drug to further develop toward human clinical studies. References 1) Rausch et al. Abstract SITC 2024 Citation Format: Silvia Ferrati, Matthew Rausch, Katalin Kis-Toth, Bijan A. Etemad-Gilbertson, Leena Gandhi, Tatiana Novobrantseva. Safety and tolerability of NPX372, a novel B7-H7:CD3 bispecific T cell engaging antibody [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 4354.