A Small Molecule-Drug Conjugate (SMDC) Consisting of a Modified Camptothecin Payload Linked to an αVß3 Binder for the Treatment of Multiple Cancer Types

To improve tumor selectivity of cytotoxic agents, we designed VIP236, a small molecule-drug conjugate consisting of an α_Vβ₃ Integrin binder linked to a modified camptothecin payload (VIP126), which is released by the enzyme neutrophil Elastase (NE) in the tumor microenvironment (TME). The tumor targeting and pharmacokinetics of VIP236 were studied in tumor-bearing mice by in vivo near-infrared imaging and by analyzing tumor and plasma samples. The efficacy of VIP236 was investigated in a panel of Cancer cell lines in vitro, and in MX-1, NCI-H69, and SW480 murine xenograft models. Imaging studies with the α_Vβ₃ binder demonstrated efficient tumor targeting. Administration of VIP126 via VIP236 resulted in a 10-fold improvement in the tumor/plasma ratio of VIP126 compared with VIP126 administered alone. Unlike SN38, VIP126 is not a substrate of P-gp and BCRP drug transporters. VIP236 presented strong cytotoxic activity in the presence of NE. VIP236 treatment resulted in tumor regressions and very good tolerability in all in vivo models tested. VIP236 represents a novel approach for delivering a potent cytotoxic agent by utilizing α_Vβ₃ as a targeting moiety and NE in the TME to release the VIP126 payload-designed for high permeability and low efflux-directly into the tumor stroma.

SMDC; SN38 derivative; VIP126; VIP236; camptothecin payload; neutrophil elastase; small molecule–drug conjugate; topoisomerase 1; tumor microenvironment; αVβ3 integrin.