Abstract 5756: Preclinical evaluation of BH4601, a novel tetravalent PD-L1 and B7H3 bispecific antibody-drug conjugate (ADC) with Topo1 inhibitor for the treatment of solid tumors

Abstract PD-L1 and B7-H3, members of the B7 superfamily, are frequently overexpressed across various tumor types. While antibody-drug conjugates (ADCs) targeting either PD-L1 or B7-H3 individually have demonstrated modest clinical efficacy, their co-expression in multiple malignancies presents a compelling rationale for dual-targeting strategies. This bispecific approach broadens the scope of tumor targeting and simultaneously alleviates T-cell suppression, potentially leading to enhanced therapeutic efficacy. The dual-targeting strategy addresses the compensatory upregulation observed between these targets—where suppression of B7-H3 leads to PD-L1 upregulation, and vice versa. A novel bispecific antibody concurrently targeting PD-L1 and B7-H3 was conjugated with a topoisomerase I inhibitor (XYD-295) and BH4601 was generated. In vitro evaluations revealed that BH4601 exhibits excellent target binding and internalization activities, as well as potent PD-1/PD-L1 blockade. Effective tumor control was demonstrated in multiple in vivo models, accompanied by significant T-cell activation. All animals remained well-tolerated at efficacious dose levels. By simultaneously engaging both PD-L1 and B7H3 pathways, BH4601 achieves enhanced tumor-specific distribution and efficient tumor cell internalization, potentially improving both efficacy and safety profiles compared to its parental ADCs. Citation Format: Jun Wang, Pengfei Rong, Jing Wang, Yang Liu, Mengrui Zhao, Jie Feng, Lijuan Li, Yue Wang, Aihong Zhang, Dongyang Li, Hongjuan Zhang, Jingmei Cai, Xiaochun Li, Jiangcheng Xu, Jiawang Liu, Hui Ding, Fangxing Ouyang, Kyoungwoo Lee. Preclinical evaluation of BH4601, a novel tetravalent PD-L1 and B7H3 bispecific antibody-drug conjugate (ADC) with Topo1 inhibitor for the treatment of solid tumors abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 5756.