美国洛克菲勒大学Jeffrey V. Ravetch课题组的研究发现，抗CD47抗体的抗肿瘤活性需要Fc-FcγR之间的相互作用。该项研究成果发表在2023年11月16日出版的《癌细胞》上。

研究人员研究了抗CD47抗体的Fc结构域在多个物种匹配模型中对最佳体内抗肿瘤活性的作用，为了解这类新兴治疗性抗体的治疗机制提供了新的见解。研究人员利用一种针对CD47、SIRPα和FcγRs的人源化小鼠模型证明，局部注射Fc工程化抗CD47抗体能增强其与活化FcγRs的结合，促进巨噬细胞和抗原特异性T细胞的肿瘤浸润，同时消耗调节性T细胞。

这些效应提高了长期全身抗肿瘤免疫，并将靶向肿瘤外的毒性降至最低。该研究结果凸显了Fc优化在开发有效抗CD47疗法中的重要性，并为增强该免疫疗法的疗效提供了一种极具吸引力的策略。

据介绍，虽然抗CD47抗体有望用于癌症免疫疗法，但早期临床试验表明其临床疗效有限，这表明仅靠CD47阻断可能不足以有效控制肿瘤。

附：英文原文

Title: The antitumor activities of anti-CD47 antibodies require Fc-FcγR interactions

Author: Juan C. Osorio, Patrick Smith, David A. Knorr, Jeffrey V. Ravetch

Issue&Volume: 2023-11-16

Abstract: While anti-CD47 antibodies hold promise for cancer immunotherapy, early-phase clinical trials have shown limited clinical benefit, suggesting that CD47 blockade alone might be insufficient for effective tumor control. Here, we investigate the contributions of the Fc domain of anti-CD47 antibodies required for optimal in vivo antitumor activity across multiple species-matched models, providing new insights into the mechanisms behind the efficacy of this emerging class of therapeutic antibodies. Using a mouse model humanized for CD47, SIRPα, and FcγRs, we demonstrate that local administration of Fc-engineered anti-CD47 antibodies with enhanced binding to activating FcγRs promotes tumor infiltration of macrophages and antigen-specific T cells, while depleting regulatory T cells. These effects result in improved long-term systemic antitumor immunity and minimal on-target off-tumor toxicity. Our results highlight the importance of Fc optimization in the development of effective anti-CD47 therapies and provide an attractive strategy to enhance the activity of this promising immunotherapy.

DOI: 10.1016/j.ccell.2023.10.007

Source: https://www.cell.com/cancer-cell/fulltext/S1535-6108(23)00363-X