Laboratory of Molecular Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892.
Laboratory of Cellular Oncology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892.
Proc Natl Acad Sci U S A. 2018 Jan 23;115(4):E733-E742. doi: 10.1073/pnas.1717063115. Epub 2018 Jan 8.
Protein-based drugs are very active in treating cancer, but their efficacy can be limited by the formation of neutralizing antidrug antibodies (ADAs). Recombinant immunotoxins are proteins that are very effective in patients with leukemia, where immunity is suppressed, but induce ADAs, which compromise their activity, in patients with intact immunity. Here we induced a specific, durable, and transferable immune tolerance to recombinant immunotoxins by combining them with nanoparticles containing rapamycin (SVP-R). SVP-R mitigated the formation of inhibitory ADAs in naïve and sensitized mice, resulting in restoration of antitumor activity. The immune tolerance is mediated by colocalization of the SVP-R and immunotoxin to dendritic cells and macrophages in the spleen and is abrogated by depletion of regulatory T cells. Tolerance induced by SVPs was not blocked by checkpoint inhibitors or costimulatory agonist monoclonal antibodies that by themselves enhance ADA formation.
基于蛋白质的药物在治疗癌症方面非常有效，但它们的疗效可能会受到中和性抗药物抗体 (ADA) 的形成的限制。重组免疫毒素是一种在白血病患者中非常有效的蛋白质，因为这些患者的免疫受到抑制，但在具有完整免疫功能的患者中会引起 ADA，从而降低其活性。在这里，我们通过将其与含有雷帕霉素的纳米颗粒 (SVP-R) 结合，诱导了对重组免疫毒素的特异性、持久和可转移的免疫耐受。SVP-R 减轻了在幼稚和致敏小鼠中抑制性 ADA 的形成，从而恢复了抗肿瘤活性。免疫耐受是由 SVP-R 和免疫毒素在脾脏中的树突状细胞和巨噬细胞中的共定位介导的，并且可以通过耗尽调节性 T 细胞来消除。SVPs 诱导的耐受性不受检查点抑制剂或共刺激激动型单克隆抗体的阻断，这些抑制剂或抗体本身会增强 ADA 的形成。
