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

• Published in: Cancer research communications 2023-05, Vol.3 (5), p.908-916
• Main Authors: Fontaine, Shaun D, Carreras, Christopher W, Reid, Ralph R, Ashley, Gary W, Santi, Daniel V
• Format: Article
• Language: English
• Subjects: Animals; Antineoplastic Agents - pharmacology; Breast Cancer; Camptothecin - pharmacology; Chemotherapy; DNA Damage; Dna Damage And Repair; Humans; Mice; Neoplasms - drug therapy; Pharmacology; Poly(ADP-ribose) Polymerase Inhibitors - pharmacology; Polyethylene Glycols - pharmacology; Small Molecule Agents
• ISSN: 2767-9764; 2767-9764
• DOI: 10.1158/2767-9764.CRC-22-0517

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. A circulating conjugate that slowly releases Exa is described. It is efficacious after a single dose and synergistic with ATR and PARP inhibitors.