Abstract 3300: Development of a diagnostic antibody for anti-BTN1A1 therapy, a novel immune checkpoint inhibitor mutually exclusive of PD-L1/PD-1

Abstract

Abstract Butyrophilin 1A1 (BTN1A1) is currently undergoing investigation in Phase 1 clinical trials as a novel immune checkpoint protein for the treatment of solid tumors. BTN1A1 exhibits a mutually exclusive expression pattern to that of PD-1/PD-L1, making anti-BTN1A1 antibody therapy an attractive option for cancer patients with PD-L1 refractory or relapsed disease. While current cancer immunotherapies have shown some efficacy against late-stage disease, there remains a major unmet medical need as a large number of patients fail to respond to current treatments. BTN1A1 has been studied at length in preclinical models to characterize its immunomodulatory functions, revealing its ability to inhibit the proliferation of activated T cells and the ability of these cells to kill tumor cells in vitro. In vivo, BTN1A1-overexpressing tumor models exhibit accelerated growth, whereas the growth of BTN1A1-deficient tumors is impaired in immunocompetent settings, supporting a role for this protein in the regulation of immune evasion. Here in, we present the development of a diagnostic antibody for use in the anti-BTN1A1 therapy clinical trials to enable the immunohistochemical (IHC) detection of human BTN1A1. A high-quality BTN1A1 antibody may help predict which patients are more likely to respond to BTN1A1 antibody-based cancer therapy, similar to the PD-L1 companion diagnostic test for anti-PD-L1/PD-1 therapy. The characterization of the developed BTN1A1 antibody was conducted via ELISA, Western blotting, confocal microscopy, and flow cytometry to demonstrate its overall performance. Validation was performed using formalin-fixed paraffin-embedded human tumor tissue samples to determine the analytical sensitivity and specificity of the IHC assay. This antibody was also found to be of value for imaging mass cytometry and flow cytometry experiments elucidating applicable clinical features of both human tumor tissues and immune cells. Specifically, the developed antibody can detect the robust expression of BTN1A1 on both cancer cells and immune cells, while also revealing the mutually exclusive expression of BTN1A1 and PD-L1. Finally, we demonstrate the capability of a BTN1A1 antibody that can be used to identify BTN1A1-positive patients with a high degree of analytical sensitivity and specificity. Citation Format: Stephen S. Yoo. Development of a diagnostic antibody for anti-BTN1A1 therapy, a novel immune checkpoint inhibitor mutually exclusive of PD-L1/PD-1 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3300.