ProLynx, San Francisco, California.
Cancer Res Commun. 2023 May 24;3(5):908-916. doi: 10.1158/2767-9764.CRC-22-0517. eCollection 2023 May.
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.
埃克替康（Exa）是一种非常有效的拓扑异构酶 I 抑制剂和抗癌药物。它已被作为单药、大的大分子缀合物以及作为抗原依赖性抗体药物偶联物的有效载荷成分进行了深入研究。目前的工作描述了一种与聚乙二醇（PEG）的抗原非依赖性 Exa 缀合物，其可缓慢释放游离的 Exa。Exa 通过β消除可裂解连接子与 4 臂 40 kDa PEG 缀合。在小鼠中的药代动力学研究表明，该缀合物具有 12 小时的表观循环半衰期，这反映了肾脏消除（半衰期约 18 小时）和 Exa 释放（半衰期约 40 小时）的复合速率。值得注意的是，单次低剂量 10 μmol/kg 的 PEG-Exa（约 0.2 μmol/只小鼠）仅导致 BRCA1 缺陷型 MX-1 异种移植物的肿瘤生长完全抑制，持续超过 40 天。单次低剂量 2.5 μmol/kg 的 PEG-Exa 与低但有效的 PARP 抑制剂他拉唑帕利联合使用显示出强烈的协同作用，并导致明显的肿瘤消退。此外，相同的低剂量，单次 PEG-Exa 与 ATR 抑制剂 VX970 联合使用，其剂量不影响肿瘤生长，表现出高肿瘤消退率、强烈的协同作用和合成致死性。
描述了一种缓慢释放 Exa 的循环缀合物。它在单次剂量后有效，并且与 ATR 和 PARP 抑制剂协同作用。
