Abstract 3411: Transcriptional modulations of tumor microenvironment by BH3120, a PD-L1x4-1BB bispecific antibody, in patient-derived organotypic tumor spheroids (PDOTS) model

Abstract BH3120 is an heterodimeric IgG like bispecific antibody in clinical stage targeting PD-L1 (CD274) and 4-1BB (CD137) simultaneously. It binds 4-1BB with moderate affinity while binds PD-L1 with relatively higher affinity, with the aim to focuss PD-L1 binding dependent 4-1BB agonism in tumor microenvironment. De-coupling of immune modulation between tumor and normal tissues were confirmed in multiple non-clinical studies, and the results were consistent with favorable safety profiles. In the meantime, BH3120 shows synergistic anti-tumor efficacy with PD-1 inhibitors without systemic safety concerns in vivo. To understand how BH3120 and the combination with a PD-1 inhibitor modulate the tumor microenvironment, ex vivo studies with patient-derived organotypic tumor spheroids (PDOTS) were generated from freshly obtained tumor tissues of non-small cell lung cancer (NSCLC) patients, and cultured in microfluidic devices containing extracellular matrix. After incubation of the test articles in the ex vivo model, anti-tumor activities and immune modulations were observed by RNA analysis as the response to BH3120, a PD-1 inhibitor, and the combination. In responding tumor spheroids, multiple genes were significantly upregulated or down-regulated. In particular, RNAs representing CD4+ T cell, CD8+ T cell, NK cell, and B cell signals, and certain co-stimulators, proinflammatory cytokines, and chemokines were notably increased. Combination of BH3120 and PD-1 inhibitor resulted in the relevant genetic modulations with high magnitudes implicating potential synergism in RNA level. Citation Format: Jun Wang, Jiangcheng Xu, Jing Wang, Jiawang Liu, Kyoungwoo Lee. Transcriptional modulations of tumor microenvironment by BH3120, a PD-L1x4-1BB bispecific antibody, in patient-derived organotypic tumor spheroids (PDOTS) model [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 3411.