The Human Agonistic CD40 Antibody ADC-1013 Eradicates Bladder Tumors and Generates T-cell-Dependent Tumor Immunity
The Human Agonistic CD40 Antibody ADC-1013 Eradicates Bladder Tumors and Generates T-cell-Dependent Tumor Immunity
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DOI：
10.1158/1078-0432.ccr-14-0913
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发表时间：
2015-03-01
影响因子：
11.5
通讯作者：
Ellmark, Peter
中科院分区：
文献类型：
--
作者：
Mangsbo, Sara M.;Broos, Sissela;Ellmark, Peter
目的：局部给予免疫激活抗体可提高疗效，减少与癌症全身免疫治疗相关的免疫相关不良事件。在这里，我们报告的发展和亲和力成熟的完全人激动性CD 40抗体（IgG 1），ADC-1013。实验设计：我们已经使用分子工程，以产生一个激动性抗体与CD 40的高亲和力。在人和鼠体外模型中研究ADC-1013的功能活性。在两个单独的膀胱癌模型中，无论是使用人类异种移植肿瘤免疫缺陷NSG小鼠和使用一种新的人类CD 40转基因mouse.Results的同基因膀胱癌模型的体内效果进行了研究：ADC-1013的树突状细胞（DC）的激活导致共刺激分子CD 80和CD 86的上调，和IL 12的分泌。ADC-1013还激活来自人CD 40转基因小鼠的DC，并且肽脉冲和ADC-1013刺激的DC在体外诱导抗原特异性T细胞增殖。在体内，在hCD 40阴性的同基因膀胱癌模型中用ADC-1013治疗诱导显著的抗肿瘤作用和长期肿瘤特异性免疫。此外，ADC-1013在移植到免疫缺陷NSG小鼠的人膀胱癌中表现出显着的抗肿瘤作用。结论：我们的数据表明ADC-1013诱导持久的抗肿瘤反应和由CD 40刺激介导的免疫记忆。据我们所知，ADC-1013代表了第一个开发用于癌症局部免疫治疗的免疫调节抗体。(C)2014年AACR。
Purpose: Local administration of immune-activating antibodies may increase the efficacy and reduce the immune-related adverse events associated with systemic immunotherapy of cancer. Here, we report the development and affinity maturation of a fully human agonistic CD40 antibody (IgG1), ADC-1013.Experimental Design: We have used molecular engineering to generate an agonistic antibody with high affinity for CD40. The functional activity of ADC-1013 was investigated in human and murine in vitro models. The in vivo effect was investigated in two separate bladder cancer models, both using human xenograft tumors in immune deficient NSG mice and using a syngeneic bladder cancer model in a novel human CD40 transgenic mouse.Results: Activation of dendritic cells (DC) by ADC-1013 results in upregulation of the costimulatory molecules CD80 and CD86, and secretion of IL12. ADC-1013 also activates DCs from human CD40 transgenic mice, and peptide-pulsed and ADC-1013-stimulated DCs induce antigen-specific T-cell proliferation in vitro. In vivo, treatment with ADC-1013 in a syngeneic bladder cancer model, negative for hCD40, induces significant antitumor effects and long-term tumor-specific immunity. Furthermore, ADC-1013 demonstrates significant antitumor effects in a human bladder cancer transplanted into immunodeficient NSG mice.Conclusions: Our data demonstrate that ADC-1013 induces long-lasting antitumor responses and immunologic memory mediated by CD40 stimulation. To the best of our knowledge, ADC-1013 represents the first immunomodulatory antibody developed for local immunotherapy of cancer. (C) 2014 AACR.