Soluble CTLA-4 mutants ameliorate immune-related adverse events but preserve efficacy of CTLA-4- and PD-1-targeted immunotherapy.
Soluble CTLA-4 mutants ameliorate immune-related adverse events but preserve efficacy of CTLA-4- and PD-1-targeted immunotherapy.
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DOI：
10.1126/scitranslmed.abm5663
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发表时间：
2023-03
影响因子：
17.1
通讯作者：
中科院分区：
文献类型：
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作者：
免疫检查点抑制剂（ICI），如nivolumab和ipilimumab，不仅在广泛的人类癌症中引起抗肿瘤反应，而且还引起严重的免疫相关不良事件（irAE），包括死亡。一个很大程度上未得到满足的医疗需求是在不消除ICI免疫抑制作用的情况下治疗irAE。尽管阿巴西普已用于治疗irAE，但其存在中和用于癌症治疗的抗细胞毒性T淋巴细胞相关蛋白4（CTLA-4）单克隆抗体的风险，从而降低抗CTLA-4免疫治疗的疗效。为了避免这种警告，我们比较了野生型阿巴西普和CTLA-4-IG突变体与临床批准的抗CTLA-4抗体的结合以及它们对irAE和抗CTLA-4和抗PD-1抗体赋予的免疫疗法的作用。在这里，我们报告了阿巴西普中和抗CTLA-4抗体的治疗效果，而与B7-1和B7-2结合但不与临床抗CTLA-4抗体结合的突变体，包括临床使用的贝拉西普，消除了irAE而不影响癌症免疫治疗。我们的数据表明，抗CTLA-4诱导的irAE可以通过提供可溶性CTLA-4变体来纠正，并且临床上可用的贝拉西普可能成为一种广泛适用的药物，以消除irAE，同时保留靶向CTLA-4的ICI的治疗功效。
Immune checkpoint inhibitors (ICIs), such as nivolumab and ipilimumab, not only elicit antitumor responses in a wide range of human cancers but also cause severe immune-related adverse events (irAEs), including death. A largely unmet medical need is to treat irAEs without abrogating the immunotherapeutic effect of ICIs. Although abatacept has been used to treat irAEs, it risks neutralizing the anti–cytotoxic T lymphocyte–associated protein 4 (CTLA-4) monoclonal antibodies administered for cancer therapy, thereby reducing the efficacy of anti–CTLA-4 immunotherapy. To avoid this caveat, we compared wild-type abatacept and mutants of CTLA-4–Ig for their binding to clinically approved anti–CTLA-4 antibodies and for their effect on both irAEs and immunotherapy conferred by anti–CTLA-4 and anti–PD-1 antibodies. Here, we report that whereas abatacept neutralized the therapeutic effect of anti–CTLA-4 antibodies, the mutants that bound to B7-1 and B7-2, but not to clinical anti-CTLA-4 antibodies, including clinically used belatacept, abrogated irAEs without affecting cancer immunotherapy. Our data demonstrate that anti–CTLA-4–induced irAEs can be corrected by provision of soluble CTLA-4 variants and that the clinically available belatacept may emerge as a broadly applicable drug to abrogate irAEs while preserving the therapeutic efficacy of CTLA-4–targeting ICIs.
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DOI：
10.1084/jem.178.5.1789
发表时间：
1993-11-01
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Wu Y;Guo Y;Liu Y
通讯作者：
Liu Y
影响因子：
158.5
作者：
Larkin, J.;Chiarion-Sileni, V.;Wolchok, J. D.
通讯作者：
Wolchok, J. D.
影响因子：
56.9
作者：
LINSLEY, PS;WALLACE, PM;TEPPER, MA
通讯作者：
TEPPER, MA
DOI：
10.1056/nejmoa1801946
发表时间：
2018-05-31
期刊：
The New England journal of medicine
影响因子：
--
作者：
Hellmann MD;Ciuleanu TE;Pluzanski A;Lee JS;Otterson GA;Audigier-Valette C;Minenza E;Linardou H;Burgers S;Salman P;Borghaei H;Ramalingam SS;Brahmer J;Reck M;O'Byrne KJ;Geese WJ;Green G;Chang H;Szustakowski J;Bhagavatheeswaran P;Healey D;Fu Y;Nathan F;Paz-Ares L
通讯作者：
Paz-Ares L
影响因子：
44.1
作者：
Du X;Liu M;Su J;Zhang P;Tang F;Ye P;Devenport M;Wang X;Zhang Y;Liu Y;Zheng P
通讯作者：
Zheng P