Human anti-CAIX antibodies mediate immune cell inhibition of renal cell carcinoma in vitro and in a humanized mouse model in vivo.
Human anti-CAIX antibodies mediate immune cell inhibition of renal cell carcinoma in vitro and in a humanized mouse model in vivo.
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DOI：
10.1186/s12943-015-0384-3
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发表时间：
2015-06-11
期刊：
影响因子：
37.3
通讯作者：
Marasco WA
中科院分区：
文献类型：
--
作者：
Chang DK;Moniz RJ;Xu Z;Sun J;Signoretti S;Zhu Q;Marasco WA
碳酸酐酶（CA） IX是一种受缺氧诱导因子（HIF）上调的表面表达蛋白，是一种在肾细胞癌（RCC）中过度表达的原型肿瘤相关抗原。针对CAIX的治疗方法主要集中在CAIX抑制剂和包括单克隆抗体（mab）在内的特异性免疫疗法的开发上。然而，目前用于表征全人源抗caix单克隆抗体抗肿瘤特性的体内小鼠模型存在明显的局限性，因为人体效应细胞在体内杀伤肿瘤细胞中的作用尚未得到直接评估。体外通过抗体依赖细胞介导的细胞毒性（ADCC）、补体依赖细胞毒性（CDC）和抗体依赖细胞吞噬（ADCP），以及CAIX+ RCC细胞运动、伤口愈合、迁移和增殖，检测了人抗CAIX单克隆抗体对免疫细胞或补体杀伤CAIX+ RCC肿瘤细胞的作用。采用新型原位RCC异种人源化动物模型，检测抗caix单克隆抗体介导的体内治疗活性，并进行组织学和FACS染色分析。我们的研究表明，人类抗caix单克隆抗体能够抑制CA酶活性，导致免疫介导的RCC杀伤，包括自然杀伤（NK）细胞介导的ADCC、CDC和巨噬细胞介导的ADCP。在RCC细胞系上，杀伤活性与CAIX表达水平呈正相关。此外，Fc工程抗caix单克隆抗体被证明可以增强ADCC对RCC的活性。我们还证明了这些抗caix单克隆抗体在体外抑制RCC细胞的迁移。最后，通过在NOD/SCID/IL2Rγ−/−小鼠中使用异体人外周血单个核细胞建立新的原位RCC模型，我们发现抗CAIX单克隆抗体能够在体内介导人体免疫反应，包括肿瘤NK细胞浸润和T细胞活化，从而抑制CAIX+肿瘤的生长。我们的研究结果表明，这些新的人类抗CAIX单克隆抗体在靶向杀死hif驱动的CAIX+RCC的未满足的医疗需求方面具有治疗潜力。原位肿瘤异种移植人源化小鼠为评估全人源单克隆抗体在RCC治疗中的体内抗肿瘤能力提供了一种改进的模型。本文的在线版本（doi:10.1186/s12943-015-0384-3）包含补充材料，可供授权用户使用。
Carbonic anhydrase (CA) IX is a surface-expressed protein that is upregulated by the hypoxia inducible factor (HIF) and represents a prototypic tumor-associated antigen that is overexpressed on renal cell carcinoma (RCC). Therapeutic approaches targeting CAIX have focused on the development of CAIX inhibitors and specific immunotherapies including monoclonal antibodies (mAbs). However, current in vivo mouse models used to characterize the anti-tumor properties of fully human anti-CAIX mAbs have significant limitations since the role of human effector cells in tumor cell killing in vivo is not directly evaluated. The role of human anti-CAIX mAbs on CAIX+ RCC tumor cell killing by immunocytes or complement was tested in vitro by antibody-dependent cell-mediated cytotoxicity (ADCC), complement-dependent cytotoxicity (CDC) and antibody-dependent cellular phagocytosis (ADCP) as well as on CAIX+ RCC cellular motility, wound healing, migration and proliferation. The in vivo therapeutic activity mediated by anti-CAIX mAbs was determined by using a novel orthotopic RCC xenograft humanized animal model and analyzed by histology and FACS staining. Our studies demonstrate the capacity of human anti-CAIX mAbs that inhibit CA enzymatic activity to result in immune-mediated killing of RCC, including nature killer (NK) cell-mediated ADCC, CDC, and macrophage-mediated ADCP. The killing activity correlated positively with the level of CAIX expression on RCC tumor cell lines. In addition, Fc engineering of anti-CAIX mAbs was shown to enhance the ADCC activity against RCC. We also demonstrate that these anti-CAIX mAbs inhibit migration of RCC cells in vitro. Finally, through the implementation of a novel orthotopic RCC model utilizing allogeneic human peripheral blood mononuclear cells in NOD/SCID/IL2Rγ−/− mice, we show that anti-CAIX mAbs are capable of mediating human immune response in vivo including tumor infiltration of NK cells and activation of T cells, resulting in inhibition of CAIX+ tumor growth. Our findings demonstrate that these novel human anti-CAIX mAbs have therapeutic potential in the unmet medical need of targeted killing of HIF-driven CAIX+RCC. The orthotopic tumor xenografted humanized mouse provides an improved model to evaluate the in vivo anti-tumor capabilities of fully human mAbs for RCC therapy. The online version of this article (doi:10.1186/s12943-015-0384-3) contains supplementary material, which is available to authorized users.
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