Agonistic CD40 antibodies and cancer therapy.
Agonistic CD40 antibodies and cancer therapy.
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DOI：
10.1158/1078-0432.ccr-12-2064
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发表时间：
2013-03-01
期刊：
影响因子：
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通讯作者：
Glennie MJ
中科院分区：
文献类型：
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作者：
Vonderheide RH;Glennie MJ
最近在癌症免疫治疗方面取得的成功重新激活了一种假设，即免疫系统可以控制许多癌症，即使不是大多数癌症，在某些情况下，会产生许多小分子药物所没有的持久反应。激动性CD40单克隆抗体（mAb）提供了一种新的治疗选择，具有通过多种机制产生抗癌免疫的潜力。CD40是一种肿瘤坏死因子受体超家族成员，广泛表达于抗原呈递细胞（APC），如树突状细胞、B细胞和单核细胞，以及许多非免疫细胞和一系列肿瘤。激动性CD40单抗已被证明可以激活APC，促进抗肿瘤T细胞反应，并培养细胞毒性骨髓细胞，在缺乏T细胞免疫的情况下具有控制癌症的潜力。因此，激动性CD40单抗与阻断阴性免疫检查点（如抗ctla -4或抗pd -1）的单抗有本质区别。在单药研究和联合化疗中，激动性CD40 mAb的初步临床试验显示，在没有致残毒性方面，结果非常有希望；然而，关于剂量、时间表、给药途径和配方仍有许多问题。最近关于IgG同型和Fcγ受体（Fcγ r）在单抗交联中所起作用的发现，以及对作用机制的见解，特别是关于骨髓细胞的作用，预计将有助于设计更有效的下一代CD40激动剂。在这里，我们将回顾临床前和临床数据，并讨论该领域面临的主要问题。
Recent success in cancer immunotherapy has reinvigorated the hypothesis that the immune system can control many if not most cancers, in some cases producing durable responses in a way not seen with many small molecule drugs. Agonistic CD40 monoclonal antibodies (mAb) offer a new therapeutic option which has the potential to generate anti-cancer immunity by various mechanisms. CD40 is a tumor necrosis factor receptor superfamily member expressed broadly on antigen-presenting cells (APC) such as dendritic cells, B cells, and monocytes as well as many non-immune cells and a range of tumors. Agonistic CD40 mAb have been shown to activate APC and promote anti-tumor T cell responses and to foster cytotoxic myeloid cells with the potential to control cancer in the absence of T-cell immunity. Thus, agonistic CD40 mAb are fundamentally different from mAb which block negative immune checkpoint such as anti-CTLA-4 or anti-PD-1. Initial clinical trials of agonistic CD40 mAb have shown highly promising results in the absence of disabling toxicity, both in single-agent studies and in combination with chemotherapy; however, numerous questions remain regarding dose, schedule, route of administration, and formulation. Recent findings regarding the role played by the IgG isotype and the Fc gamma receptor (FcγR) in mAb crosslinking, together with insights into mechanisms of action, particularly with regards to the role of myeloid cells, are predicted to help design next-generation CD40 agonistic reagents with greater efficacy. Here, we will review the preclinical and clinical data and discuss the major issues facing the field.