Uncoupling therapeutic from immunotherapy-related adverse effects for safer and effective anti-CTLA-4 antibodies in CTLA4 humanized mice.
Uncoupling therapeutic from immunotherapy-related adverse effects for safer and effective anti-CTLA-4 antibodies in CTLA4 humanized mice.
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DOI：
10.1038/s41422-018-0012-z
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发表时间：
2018-04
期刊：
影响因子：
44.1
通讯作者：
Zheng P
中科院分区：
文献类型：
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作者：
Du X;Liu M;Su J;Zhang P;Tang F;Ye P;Devenport M;Wang X;Zhang Y;Liu Y;Zheng P
抗 CTLA-4 单克隆抗体 (mAb) 具有癌症免疫治疗效果 (CITE)，但会引起严重的免疫治疗相关不良事件 (irAE)。靶向 CTLA-4 已显示出显着的长期益处，因此，如果 irAE 能够得到控制，那么它仍然是癌症免疫治疗的一个有价值的工具。概括临床 irAE 和 CITE 的动物模型对于开发更安全的 CTLA-4 靶向试剂非常有价值。在这里，我们报告了一个使用携带人源化 Ctla4 基因的小鼠的模型。在该模型中，临床使用的药物 Ipilimumab 诱发了严重的 irAE，尤其是与抗 PD-1 抗体联合使用时；而另一种单克隆抗体 L3D10 在相同条件下诱导了可比的 CITE 和非常轻微的 irAE。 irAE 与全身 T 细胞激活相对应，导致自身反应性 T 细胞中调节性 T 细胞与效应 T 细胞 (Treg/Teff) 的比率降低。使用人类等位基因纯合或杂合的小鼠，我们发现 irAE 需要双等位基因接合，而 CITE 仅需要单等位基因接合。与单等位基因与双等位基因接合的免疫学区别一样，我们发现 Ctla4 基因的双等位基因接合对于防止自身反应性 T 细胞转化为 Treg 细胞是必要的。 L3D10的人源化导致阻断活性丧失，在不影响治疗效果的情况下进一步提高了安全性。总而言之，我们的数据表明，完整的 CTLA-4 占据、全身性 T 细胞激活和自身反应性 T 细胞的优先扩增对于肿瘤排斥来说是可有可无的，但与 irAE 相关，而阻断 B7-CTLA-4 相互作用既不影响抗 CTLA-4 抗体的安全性，也不影响其有效性。这些数据为临床开发更安全且可能更有效的 CTLA-4 靶向免疫疗法提供了重要见解。
Anti-CTLA-4 monoclonal antibodies (mAbs) confer a cancer immunotherapeutic effect (CITE) but cause severe immunotherapy-related adverse events (irAE). Targeting CTLA-4 has shown remarkable long-term benefit and thus remains a valuable tool for cancer immunotherapy if the irAE can be brought under control. An animal model, which recapitulates clinical irAE and CITE, would be valuable for developing safer CTLA-4-targeting reagents. Here, we report such a model using mice harboring the humanized Ctla4 gene. In this model, the clinically used drug, Ipilimumab, induced severe irAE especially when combined with an anti-PD-1 antibody; whereas another mAb, L3D10, induced comparable CITE with very mild irAE under the same conditions. The irAE corresponded to systemic T cell activation and resulted in reduced ratios of regulatory to effector T cells (Treg/Teff) among autoreactive T cells. Using mice that were either homozygous or heterozygous for the human allele, we found that the irAE required bi-allelic engagement, while CITE only required monoallelic engagement. As with the immunological distinction for monoallelic vs bi-allelic engagement, we found that bi-allelic engagement of the Ctla4 gene was necessary for preventing conversion of autoreactive T cells into Treg cells. Humanization of L3D10, which led to loss of blocking activity, further increased safety without affecting the therapeutic effect. Taken together, our data demonstrate that complete CTLA-4 occupation, systemic T cell activation and preferential expansion of self-reactive T cells are dispensable for tumor rejection but correlate with irAE, while blocking B7-CTLA-4 interaction impacts neither safety nor efficacy of anti-CTLA-4 antibodies. These data provide important insights for the clinical development of safer and potentially more effective CTLA-4-targeting immunotherapy.
DOI：
10.1016/j.clim.2008.08.014
发表时间：
2009-01
期刊：
Clinical immunology (Orlando, Fla.)
影响因子：
--
作者：
Chang X;Zheng P;Liu Y
通讯作者：
Liu Y