一种基于StarLinker™的新型CLDN18.2/PD-L1双特异性双载荷ADC(CAN017)可克服肿瘤异质性

Introduction: Antibody-drug conjugates (ADCs) against the tumor-specific antigen Claudin18.2 (CLDN18.2) have now reached the clinic to treat gastrointestinal (GI) cancers (gastric, pancreatic, esophageal). PD-L1 is an immune checkpoint inhibitor and its antibodies have been approved mainly for lung and hepatocellular cancers. However, their utilities are limited by tumor heterogeneity and resistance leading to disease progression. Now we report to employ the StarLinker TM technology to engineer a first-in-class bispecific ADC (CAN017) targeting CLDN18.2 and PD-L1 bearing two different cytotoxic payloads, and assessed its antitumoral effects in vivo compared with mono-payload ADCs or single-target ADCs. Methods: CanWell's StarLinker TM technology, which ensures stable conjugation, controlled drug-to-antibody ratio (DAR), and efficient on-target release via a cleavable linker, was used to construct an ADC by conjugating a humanized bispecific antibody targeting CLDN18.2 and PD-L1 with two distinct cytotoxic payloads. The binding, cytotoxicity of this ADC against tumor cell lines expressing CLDN18.2 only, PD-L1 only, and both targets were separately tested. The DMPK profiles of CAN017 were measured in vivo and in vitro . Furthermore, the antitumor efficacy of CAN017 was evaluated in mouse CDX and PDX tumor models, which overexpress only CLDN18.2, PD-L1 or both targets. We also compare CAN017 with single-target ADCs as references and unconjugated bispecific antibody. Results: In vitro studies confirmed the high-affinity binding of CAN017 to both CLDN18.2 and PD-L1 expressing cells, and potent cytotoxic activity across all tested cell lines. CAN017 demonstrated superior cell-killing activity over single-payload or single-target ADC controls. The compound also exhibited excellent plasma stability and a favorable pharmacokinetic (PK) profile. Moreover, CAN017 showed outstanding anti-tumor activities in all tested CDX and PDX models. Notably, it achieved superior tumor growth inhibitions not only in CLDN18.2+/PD-L1+ tumor models with complete tumor regression and significantly prolonging progression-free survival, but also surprisingly in the models in which tumor cells only express single target (CLDN18.2 or PD-L1). CAN017 has demonstrated its potential to overcome tumor heterogeneity and enhance therapeutic efficacy. The results from non-human primate (NHP) toxicology studies will be presented. Conclusion: The CLDN18.2/PD-L1 bispecific dual-payload ADC (CAN017), enabled by the StarLinker TM technology, shown superior antitumoral effects in various preclinical tumor models. Coupling with its preliminary excellent DMPK and safety profiles, it provides a strong path to become a potent next-generation ADC for the treatments of advanced solid tumors, particularly pancreatic and GI cancers.