BSI-730，一种首创的HER2xPD-L1双特异性ADC，通过选择性杀伤肿瘤细胞和免疫调节在HER2低表达模型中展现出强效抗肿瘤活性

Background: HER2-targeting ADCs approved worldwide benefit patients with HER2-positive/overexpression, yet the efficacy in HER2-low/null setting is limited. HER2-positive cancers often display adaptive resistance to HER2-targeted therapies, driven in part by PD-L1-mediated immunosuppression. Current clinical readouts on HER2-targeting ADCs combined with immune checkpoint modulators and PD-L1-targeting ADCs support the dual targeting design. Engaging HER2 and PD-L1 simultaneously enables enhanced internalization, selective tumor cell killing, and promoted anti-tumor immune response via payload-induced immunogenic cell death, subsequently improving efficacy in HER2-low/null patients. Methods: The HER2xPD-L1 bi-specific antibody was composed of trastuzumab and the humanized anti-PD-L1 antibody identified from A/J mice immunized with PD-L1-ECD-Fc. The in vitro characterization of the bi-specific construct, including simultaneous dual target binding, internalization, and PD-1/PD-L1 signal blocking, has been reported previously. The bi-specific antibody was conjugated to exatecan via a glyco-site-specific conjugation technology in a DAR of 4. The in vitro cytotoxicity of BSI-730 was evaluated across cancer cell lines with various expression levels of HER2 and PD-L1. The anti-tumor activity of BSI-730 was investigated in animal models with low/null HER2 expression. The CMC developability as well as the stability of BSI-730 in mouse and human plasma were also assessed. Results: BSI-730 simultaneously bound to HER2 and PD-L1 with high affinity and showed strong PD-1/PD-L1 signal blocking activity as well as efficient internalization regardless target expression. BSI-730 exhibited potent in vitro cytotoxic activity across cell lines with various expression levels of HER2 and PD-L1. The potency of BSI-730 was higher than and comparable to T-Dxd in HER2-low and high expressing cell lines, respectively. In a HER2-null breast cancer CDX model (MDA-MB-231), a single administration of BSI-730 resulted in a significant anti-tumor activity, which was higher than T-Dxd at the same dose level. BSI-730 possesses favorable CMC developability profile. Conclusion: BSI-730 is a first-in-class HER2xPD-L1 bi-specific ADC tailored for HER2-low/null patients leveraging dual function of selective cell killing and immune modulation. The current pre-clinical data highlight the potential of BSI-730 in HER2-low setting and further pharmacokinetics, toxicity, and IND-enabling studies are underway.