A Very Long-acting Exatecan and Its Synergism with DNA Damage Response Inhibitors

Exatecan (Exa) 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 current work describes an antigen-independent conjugate of Exa with polyethylene glycol (PEG) that slowly releases free Exa. Exa was conjugated to a 4-arm 40 kDa PEG through a β-eliminative cleavable linker. Pharmacokinetic studies in mice showed that the conjugate has an apparent circulating half-life of 12 hours, which reflects a composite of both the rate of renal elimination (half-life ∼18 hours) and release of Exa (half-life ∼40 hours). Remarkably, a single low dose of 10 μmol/kg PEG-Exa—only approximately 0.2 μmol/mouse—caused complete suppression of tumor growth of BRCA1-deficient MX-1 xenografts lasting over 40 days. A single low dose of 2.5 μmol/kg PEG-Exa administered with low but efficacious doses of the PARP inhibitor talazoparib showed strong synergy and caused significant tumor regression. Furthermore, the same low, single dose of PEG-Exa administered with the ATR inhibitor VX970 at doses of the DNA damage response inhibitor that do not affect tumor growth show high tumor regression, strong synergy, and synthetic lethality. SIGNIFICANCE: A circulating conjugate that slowly releases Exa is described. It is efficacious after a single dose and synergistic with ATR and PARP inhibitors.