抗 LMB-100 的抗体可被靶向 OX40 和 CTLA4 的单抗增强，但不能被靶向 PD1 或 PDL-1 的单抗增强。
Anti-drug antibodies to LMB-100 are enhanced by mAbs targeting OX40 and CTLA4 but not by mAbs targeting PD1 or PDL-1.
机构信息
Laboratory of Molecular Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892-4264, USA.
Laboratory of Molecular Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892-4264, USA.
出版信息
Cell Immunol. 2018 Dec;334:38-41. doi: 10.1016/j.cellimm.2018.08.016. Epub 2018 Aug 28.
Abstract
LMB-100 is a recombinant immunotoxin being developed for cancer treatment that is composed of a Fab that binds to mesothelin and a portion of Pseudomonas exotoxin A. LMB-100 is in clinical trials for the treatment of mesothelioma and pancreatic cancer. To determine if check point modulating antibodies enhance the formation of anti-drug antibodies (ADA) against LMB-100, we treated mice with LMB-100 and four different immune modulating monoclonal antibodies that have different mechanisms of action; anti-CTLA4, anti-OX40, anti-PD-1 and anti-PDL-1. We found that anti-PD-1 and anti PDL-1 do not increase the formation of ADA, but anti-CTLA-4 and anti-OX-40 do increase the onset of ADA. These results indicate that combining anti-CTLA-4 and anti-OX-40 with antibodies and other protein-based therapeutics may enhance ADA formation in humans.
摘要
LMB-100 是一种正在开发用于癌症治疗的重组免疫毒素，由与间皮素结合的 Fab 和部分绿脓杆菌外毒素 A 组成。LMB-100 正在进行治疗间皮瘤和胰腺癌的临床试验。为了确定检查点调节抗体是否增强了针对 LMB-100 的抗药物抗体 (ADA) 的形成，我们用 LMB-100 和四种不同的免疫调节单克隆抗体治疗小鼠，这些抗体具有不同的作用机制；抗 CTLA4、抗 OX40、抗 PD-1 和抗 PDL-1。我们发现抗 PD-1 和抗 PDL-1 不会增加 ADA 的形成，但抗 CTLA-4 和抗 OX-40 确实会增加 ADA 的发病。这些结果表明，将抗 CTLA-4 和抗 OX-40 与抗体和其他基于蛋白质的治疗药物联合使用，可能会增强人类的 ADA 形成。
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Oncoimmunology. 2018 Feb 1;7(5):e1424674. doi: 10.1080/2162402X.2018.1424674. eCollection 2018.
2
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Ther Adv Med Oncol. 2018 Apr 6;10:1758835918762094. doi: 10.1177/1758835918762094. eCollection 2018.
3
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Proc Natl Acad Sci U S A. 2018 Jan 23;115(4):E733-E742. doi: 10.1073/pnas.1717063115. Epub 2018 Jan 8.
4
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5
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Nat Med. 2016 Dec;22(12):1402-1410. doi: 10.1038/nm.4200. Epub 2016 Oct 24.
6
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7
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