Abstract 4345: BH3120, a PD-L1x4-1BB bispecific antibody, exhibits favorable safety profiles in distinct in vivo and ex vivo liver toxicity evaluations

Abstract BH3120 is a novel bivalent PD-L1/4-1BB bispecific antibody targeting both inhibitory (PD-1/PD-L1) and co-stimulatory (4-1BB clustering) signaling. In multiple non-clinical safety evaluations, BH3120 consistently showed minimal modulation of T cell functions in the blood or normal tissues resulting in favorable safety profiles. Clinical evaluation of BH3120 as a monotherapy and in combination with a PD-1 inhibitor is underway (NCT06234397). While early stage clinical evaluations of 4-1BB agonists as a monotherapy or in combination with PD-1/PD-L1 inhibitors are generally associated with certain level of liver abnormalities, the potential biomarkers or patient’s backgrounds that can pre-determine the risk of liver toxicity have not been discussed in details. In the meantime, treatment discontinuation or disruption, and administration of corticosteroid due to liver toxicity would be the limitations of 4-1BB agonists in tumor management, and the mode of action and impact of 4-1BB agonists on liver inflammation need to be further investigated. To understand potential risks of liver toxicity with BH3120, sensitive in vivo and ex vivo models for liver toxicity evaluations were established: a mice model with mild liver inflammation induced by Concanavalin A, and human liver organoids co-cultured with immune cells to mimic the histological and physiological changes in patient's liver tissues. In both models, BH3120 was not associated with significant elevation of liver inflammation markers, indicating minimal risk of liver toxicity that is in line with the safety results we previously reported. The property of BH3120 to minimize systemic immune modulation enables de-coupling of anti-tumor efficacy from systemic toxicities, and would provide flexibility in combination with different anti-tumor treatments. Citation Format: Jing Wang, Jiangcheng Xu, Jun Wang, Jiangwang Liu, Kyoungwoo Lee. BH3120, a PD-L1x4-1BB bispecific antibody, exhibits favorable safety profiles in distinct in vivo and ex vivo liver toxicity evaluations [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 4345.