新策略可避免细胞疗法免受到CD64过表达抗体介导的杀伤，这一成果由加州大学Tobias Deuse研究团队经过不懈努力而取得。相关论文发表在2023年1月2日出版的《自然—生物技术》杂志上。
研究人员提出了一种保护细胞疗法免受抗体介导杀伤的策略，该策略依赖于IgG受体CD64的工程化过表达。研究表明，在体外和ADCC小鼠中，人与小鼠iPSC来源内皮细胞（iEC）中CD64过表达可抵抗由IgG抗体产生的抗体依赖性细胞毒性（ADCC）和补体依赖性细胞毒性。当CD64表达与已知能降低细胞免疫效果的遗传修饰相结合时，B2M−/−CIITA−/−CD47/CD64转基因iEC在体外和人源化小鼠中对IgG抗体介导的以及细胞免疫杀伤均具有抗性。
机理研究表明，CD64或其细胞内截短类似物CD64t可有效捕获单体IgG并占据其Fc，IgG结合并占据其靶抗原。在该方法的三个应用中，人CD64t工程化甲状腺上皮细胞、胰腺β细胞和CAR-T细胞可耐受临床相关水平的移植物定向抗体，并完全逃避了抗体介导的杀伤。
研究人员表示，用于治疗癌症或再生医学的同种异体细胞疗法易受到抗体介导杀伤的影响，这会降低其疗效。
附：英文原文
Title: Protection of cell therapeutics from antibody-mediated killing by CD64 overexpression
Author: Gravina, Alessia, Tediashvili, Grigol, Rajalingam, Raja, Quandt, Zoe, Deisenroth, Chad, Schrepfer, Sonja, Deuse, Tobias
Issue&Volume: 2023-01-02
Abstract: Allogeneic cell therapeutics for cancer therapy or regenerative medicine are susceptible to antibody-mediated killing, which diminishes their efficacy. Here we report a strategy to protect cells from antibody-mediated killing that relies on engineered overexpression of the IgG receptor CD64. We show that human and mouse iPSC-derived endothelial cells (iECs) overexpressing CD64 escape antibody-dependent cellular cytotoxicity (ADCC) and complement-dependent cytotoxicity from IgG antibodies in vitro and in ADCC-enabled mice. When CD64 expression was combined with hypoimmune genetic modifications known to protect against cellular immunity, B2M/CIITA/ CD47/CD64-transgenic iECs were resistant to both IgG antibody-mediated and cellular immune killing in vitro and in humanized mice. Mechanistic studies demonstrated that CD64 or its intracellularly truncated analog CD64t effectively capture monomeric IgG and occupy their Fc, and the IgG bind and occupy their target antigens. In three applications of the approach, human CD64t-engineered thyroid epithelial cells, pancreatic beta cells and CAR T cells withstood clinically relevant levels of graft-directed antibodies and fully evaded antibody-mediated killing.
DOI: 10.1038/s41587-022-01540-7
Source: https://www.nature.com/articles/s41587-022-01540-7
Nature Biotechnology：《自然—生物技术》，创刊于1996年。隶属于施普林格·自然出版集团，最新IF：68.164
官方网址：https://www.nature.com/nbt/
投稿链接：https://mts-nbt.nature.com/cgi-bin/main.plex
本期文章：《自然—生物技术》：Online/在线发表
