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首页> 外文期刊>Nature cancer. >Bispecific antibodies increase the therapeutic window of CD40 agonists through selective dendritic cell targeting
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Bispecific antibodies increase the therapeutic window of CD40 agonists through selective dendritic cell targeting

机译：双特异性抗体增加治疗窗口的CD40通过选择性受体激动剂树突细胞定位

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Therapeutic use of agonistic anti-CD40 antibodies is a potentially powerful approach for activation of the immune response to eradicate tumors. However, the translation of this approach to clinical practice has been substantially restricted due to the severe dose-limiting toxicities observed in multiple clinical trials. Here, we demonstrate that conventional type 1 dendritic cells are essential for triggering antitumor immunity but not the toxicity of CD40 agonists, while macrophages, platelets and monocytes lead to toxic events. Therefore, we designed bispecific antibodies that target CD40 activation preferentially to dendritic cells, by coupling the CD40 agonist arm with CD11c-, DEC-205- or CLEC9A-targeting arms. These bispecific reagents demonstrate a superior safety profile compared to their parental CD40 monospecific antibody while triggering potent antitumor activity. We suggest such cell-selective bispecific agonistic antibodies as a drug platform to bypass the dose-limiting toxicities of anti-CD40, and of additional types of agonistic antibodies used for cancer immunotherapy.
机译：治疗使用织anti-CD40抗体是一个潜在的强大的方法来激活吗根除肿瘤的免疫反应。然而,这种方法的翻译临床实践已经充分由于严重的dose-limiting限制多个临床试验中观察到的毒性。在这里,我们表明,传统的1型树突细胞引发至关重要抗肿瘤免疫力但不是CD40的毒性受体激动剂,而巨噬细胞、血小板和单核细胞导致有毒事件。设计目标CD40双特异性抗体树突状细胞激活优先,耦合与CD11c CD40兴奋剂的手臂,12月- 205或CLEC9A-targeting武器。双特异性试剂展示出优越的安全他们的父母CD40相比概要文件单一的抗体而引发的抗肿瘤活性。cell-selective双特异性抗体争胜一种药物绕过dose-limiting平台anti-CD40毒性,额外的类型织抗体用于癌症免疫疗法。

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