用于靶向PD-L1的抗体药物偶联物的新型ATR抑制剂载荷

Ataxia telangiectasia and Rad3-related kinase (ATR) is essential to the faithful replication of DNA in rapidly dividing cells such as cancer cell lines. ATR is activated in response to single-strand DNA breaks that result from increased replication stress caused by defects in DNA repair mechanisms and/or damaged DNA. ATR stabilizes and restarts the stressed replication forks, suppresses origin firing, activates cell cycle checkpoints, and facilitates DNA repair. In fact, ATR activity contributes to the tolerance of chronic replication stress in cells transformed by oncogenes rendering cancer cells more dependent on ATR activity for survival. Systemic exposure to ATR inhibitors (ATRis) in clinical studies have demonstrated dose-limiting toxicities that reduce their clinical utility. Therefore, precision antibody-drug conjugates (ADCs) for targeted delivery of ATR payloads could bypass the systemic toxicities associated with oral administration. There is significant overlap between cancers with ATRi sensitizing defects in DNA repair mechanisms with those expressing high levels of PD-L1 surface antigens including stomach, breast, lung and colon cancers. Our personalized antibody-drug conjugate approach couples surface targeted therapeutics to tumors with increased sensitivity to the delivered payload to improve the therapeutic index. We have discovered multiple derivatizable proprietary ATRis with desirable physicochemical properties that demonstrate low nM potency in cancer cell lines with ATRi sensitizing mutations. Furthermore, the ATRi payloads maintained in vitro cytotoxic potency in cells harbouring clinically relevant acquired resistance mutations in Topoisomerase 1, whereas exatecan did not. Once conjugated to the anti-PD-L1 monoclonal antibody, the resulting ADCs demonstrated selective picomolar cellular growth inhibition and excellent metabolic stability in mouse plasma. Preclinical in vivo studies in mice demonstrate robust efficacy and selectivity with PD-L1-ATRi as single agent relative to IgG-ATRi. The in vitro and in vivo data presented herein demonstrate the efficacy of an ADC with an ATRi mono-payload and illustrate the potential for combinations with standard of care chemotherapeutic agents such as gemcitabine or PARP inhibitors.