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

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.