PD-L1 targeted antibody-polymer-Epirubicin conjugate prolongs survival in a preclinical murine model of advanced ovarian cancer
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Following successful design of polymer enhanced rituximab-epirubicin (EPI) conjugates targeted to non-Hodgkin lymphoma (Zhang et al. 2017), we developed U6244-051 that consists of anti-PD-L1 antibody (αPD-L1) and semitelechelic N-(2-hydroxypropyl)methacrylamide (HPMA) copolymer-epirubicin (EPI) conjugates (ST-P-EPI); the latter is attached to αPD-L1 via Cu-free azide/alkyne cycloaddition. This new polymer-enhanced antibody-drug conjugate (pADC) not only exhibits a high drug-to-antibody ratio (DAR ∼ 30-40) but also integrates immune checkpoint blockade with long-lasting immunogenic anticancer chemotherapy, providing an innovative chemo-immuno combination modality. The biological properties of U6244-051 were evaluated using ID8-Luc murine ovarian cancer cells in vitro and in vivo. In vitro, U6244-051 treatment induced immunomodulatory changes, including upregulation of calreticulin, PD-L1, and MHC I, suggesting enhanced tumor cell visibility to the immune system. In vivo efficacy was assessed in a syngeneic murine model (C57BL/6J mice inoculated with 5 × 10