BSI-737——一种同类最佳的B7H3xPD-L1双特异性ADC,通过选择性杀伤和增强抗肿瘤免疫应答实现双重功能以清除肿瘤

Background: B7H3 and PD-L1 are both inhibitory immune checkpoints. The dual targeting of B7H3 and PD-L1, which are prevalently co-expressed in various malignancies, may synergistically enhance anti-tumor immune response. PD-L1-directed ADCs have shown modest efficacy with no target-related safety issues. B7-H3, by comparison, is a clinically validated ADC target that tolerates high-dose exposure without target-mediated toxicity and supports added immune-checkpoint blockade. B7H3xPD-L1 bi-specific ADC may hold promise via bi-specific binding mode, cytotoxic agent-mediated immunogenic cell death, and exacerbated anti-tumor immune response. Methods: The B7H3xPD-L1 bi-specific antibody was composed of humanized anti-PD-L1 and anti-B7H3 antibodies identified from A/J mice immunized with PD-L1-ECD-Fc and HG5042 mice immunized with B7H3-EDC-Fc, respectively. The final bi-specific construct was selected based on simultaneous binding to B7H3 and PD-L1, efficient cell internalization, and strong PD-1/PD-L1 signal blocking. The bi-specific antibody was conjugated to exatecan via a glycol-site-specific conjugation technology in a DAR of 4. The anti-tumor activity of BSI-737 was investigated in cell-derived xenograft models with various expression levels of B7H3 and PD-L1. The CMC developability as well as the stability of BSI-737 in mouse and human plasma were also assessed. Results: BSI-737 simultaneously bound to B7H3 and PD-L1 with high affinity and showed strong PD-1/PD-L1 signal blocking activity. The binding of BSI-737 resulted in efficient antibody-induced internalization across cell lines expressing various levels of B7H3 and PD-L1. When conjugated to exatecan via a cleavable linker in DAR of 4, BSI-737 demonstrated an outstanding anti-tumor activity compared to clinical benchmarks. A single administration of BSI-737 resulted in a complete tumor regression in a CDX model expressing high level of B7H3 with a survival rate of 100% by the end of the study. A significant anti-tumor activity of BSI-737 after a single administration was also observed in a B7H3-medium expressing model. BSI-737 possessed a favorable CMC developability profile. Conclusion: BSI-737 is a B7-H3 × PD-L1 bispecific ADC with best-in-class potential, leveraging dual targeting to enable selective tumor cell killing while amplifying anti-tumor immune responses. The current pre-clinical data highlight the potential of BSI-737 across expression levels of B7H3 and further pharmacokinetics, toxicity, and IND-enabling studies are underway.