ARTICLE ABSTRACT
Exatecan is a very potent inhibitor of topoisomerase I and anticancer agent. It has been intensively studied as a single agent, a large macromolecular-conjugate and as the payload component of antigen-dependent antibody-drug conjugates. The present work describes an antigen-independent conjugate of exatecan with polyethylene glycol (PEG) that slowly releases free exatecan. Exatecan was conjugated to a 4-arm 40kDa PEG through a β-eliminative cleavable linker. Pharmacokinetic studies in mice showed that the conjugate has an apparent circulating half-life of 12 h, which reflects a composite of both the rate of renal elimination (half-life ~18 h) and release of exatecan (half-life ~40 h). Remarkably, a single low dose of 10 μmol/kg PEG-Exa – only ~0.2 μmol/mouse – caused complete suppression of tumor growth of BRCA1-deficient MX-1 xenografts lasting over 40 d. A single low dose of 2.5 μmol/kg PEG-exatecan administered with low but efficacious doses of the PARPi talazoparib showed strong synergy and caused significant tumor regression. Further, the same low, single dose of PEG-exatecan administered with the ATRi VX970 at doses of the DNA damage response inhibitor that do not affect tumor growth show high tumor regression, strong synergy and synthetic lethality.
