肿瘤细胞治疗研究
英文原题：A MICA/B GAALIE-mutant antibody elicits potent natural killer cell-driven immunity in solid and hematologic malignancy models.
抑制MICA/B脱落的抗体在癌症免疫治疗中具有前景，目前正处于1期临床试验阶段。
抑制MICA/B脱落的抗MICA/B抗体在癌症免疫治疗中具有前景，目前正处于1期临床试验阶段。尽管抑制MICA/B脱落通过NKG2D接合促进自然杀伤（NK）细胞驱动的免疫，但Fc段能够介导抗体依赖性细胞毒性。因此，我们通过GAALIE突变对抗MICA/B抗体（克隆7C6）的Fc段进行工程改造，以增加其与Fc激活受体的结合亲和力。7C6-GAALIE抑制MICA/B脱落，并有效触发NK细胞对肿瘤细胞的效应功能。此外，我们建立了一个转移性前列腺癌模型，并据此正式证明，在Fc gamma受体人源化小鼠中，7C6-GAALIE在抑制转移方面优于作为野生型人IgG1的7C6。在黑色素瘤和白血病模型中，7C6-GAALIE的治疗效果比作为野生型人IgG1的7C6更为一致。因此，本研究通过Fc优化增强抗体引发NK细胞驱动免疫的能力，为下一代抗MICA/B抗体用于癌症免疫治疗建立了概念验证。
Anti-MICA/B antibodies that inhibit the shedding hold promise for cancer immunotherapy and are in phase 1 clinical trials. Although MICA/B-shedding inhibition promotes natural killer (NK) cell-driven immunity by NKG2D engagement, the Fc enables antibody-dependent cellular cytotoxicity. We, therefore, engineer the Fc of an anti-MICA/B antibody (clone 7C6) through GAALIE mutations that increase the binding affinity to Fc-activating receptors. 7C6-GAALIE inhibits MICA/B shedding and potently triggers NK cell-effector functions against tumor cells. Furthermore, we establish a model of metastatic prostate cancer with which we formally demonstrate that 7C6-GAALIE is superior to 7C6 as wild-type human IgG1 in inhibiting metastases in Fc gamma receptor-humanized mice. In melanoma and leukemia models, 7C6-GAALIE had a therapeutic efficacy more consistent than that with 7C6 as wild-type human IgG1. Therefore, this study establishes the proof of concept of a next-generation anti-MICA/B antibody for cancer immunotherapy through an Fc optimization that enhances the antibody's ability to elicit NK cell-driven immunity.
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