Abstract 5318: Humanized STC10 is a monoclonal antibody to BTN1A1, a novel immunotherapeutic target to be evaluated in a planned phase 1 study

Abstract

Abstract Butyrophilin 1A1 (BTN1A1) is a novel immune checkpoint protein that exhibits an expression pattern mutually exclusive to that of PD-1/PD-L1 and may represent a promising therapeutic target for tumors that are anti-PD-1/PD-L1 antibody refractory. BTN1A1 was identified as a potential stress-inducible candidate immune checkpoint using the STCube in vivo immune target discovery platform. Additional analyses revealed that BTN1A1 was highly expressed in multiple human tumor types including urothelial carcinoma and NSCLC, with no overlap between BTN1A1 and PD-1/PDL-1 expression patterns. Mouse studies demonstrated that an anti-BTN1A1 antibody exhibited antitumor activity both as a single agent and in combination with anti-PD-1/PD-L1 or radiation therapy. A humanized anti-BTN1A1 antibody, hSTC810, was developed and found to suppress tumor growth in A549 CDX humanized murine models. Further studies identified Galectin 9 (Gal9) as a BTN1A1 receptor that can form a three protein complex with BTN1A1 and PD-1, thereby suppressing T cell receptor signaling and T cell activation. As high Gal9 expression levels are correlated with poor prognosis in multiple cancers, our results highlight this BTN1A1-Gal9-PD-1 axis as a novel therapeutic target for immunotherapeutic drug development. Given these findings, a first in human study of hSTC810 is in development to evaluate the safety profile of this therapy and to identify a dose for its further evaluation as an anticancer therapy. PK modeling including allometric scaling was performed to conduct simulations to predict the PK profile of hSTC810 after IV administration in humans and to identify possible doses needed to achieve tumor concentrations corresponding to the minimum anticipated biological effect level (MABEL) of 20% receptor occupancy (RO), 80% RO, or 95% RO. The partition coefficient was used to predict concentrations at the tumor site based on predicted serum concentrations. Simulations were performed for 100 subjects after the administration of multiple Q2W doses. The dose of 0.1 mg/kg was predicted to have <20% RO, 0.3 mg/kg to have ~21-35% RO, 1 mg/kg to have ~47-65% RO and 15 mg/kg to have ~93-96% RO at steady state. We anticipate beginning study enrollment in the first quarter of 2022 at sites in the United States sand South Korea. The study is a standard 3+3 dose-escalation with a dose of 0.3 mg/kg for a single patient followed by a starting dose of 1 mg/kg. Citation Format: Lynn Jackson Howie, Ezra M. Chung, Young-Seung Kim, Yujin Jung, Hyunjin Jung, Stephen Yoo. Humanized STC10 is a monoclonal antibody to BTN1A1, a novel immunotherapeutic target to be evaluated in a planned phase 1 study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5318.