Cross-species higher sensitivities of FcγRIIIA/FcγRIV to afucosylated IgG for enhanced ADCC.
Cross-species higher sensitivities of FcγRIIIA/FcγRIV to afucosylated IgG for enhanced ADCC.
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DOI：
10.1093/abt/tbab016
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发表时间：
2021-07
影响因子：
--
通讯作者：
Gao W
中科院分区：
文献类型：
--
作者：
Mao C;Near R;Zhong X;Gao W
用缺乏α-（1，6）-岩藻糖基转移酶（FUT 8）的中国仓鼠卵巢（CHO）细胞表达无岩藻糖基化人IgG 1抗体越来越被接受为增强治疗性抗体的抗体依赖性细胞毒性（ADCC）的常规方法，特别是对于抗癌方案。然而，在依赖于小鼠和灵长类动物以外的疾病模型的临床前研究中，例如，对于那些代表性不足的物种，不太清楚这种无岩藻糖基化抗体是否可以显示增强的治疗指数。这是因为尚未对来自这些种属的人FcγRIIIA或小鼠FcγRIV的直系同源物进行充分表征。我们建立了一种基于腺苷酸酶的ADCC试验，使用表达来自人、小鼠、大鼠、仓鼠、豚鼠、雪貂、兔、猫、狗、猪和猴的FcγRIIIA/FcγRIV的Jurkat报告细胞，还使用野生型和Fut 8 −/− CHO细胞或杂交瘤产生人、小鼠、仓鼠、兔和猪IgG。我们证实，与野生型IgG相比，无岩藻糖基化IgG通过FcγRIIIA/FcγRIV的刺激增强是一种跨种属现象。因此，在这些代表性不足的动物模型中进行的下一代无岩藻糖基化治疗性IgG和Fc融合蛋白的疗效和毒理学研究应有望产生用于治疗人类疾病的可翻译数据，从而扩大这类新的糖工程生物制剂的应用。
Expressing afucosylated human IgG1 antibodies with Chinese hamster ovary (CHO) cells deficient of α-(1,6)-fucosyltransferase (FUT8) is being more and more accepted as a routine method to enhance antibody-dependent cellular cytotoxicity (ADCC) of therapeutic antibodies, especially for anti-cancer regimens. However, in pre-clinical studies relying on disease models other than mice and primates, e.g., those underrepresented species for infectious diseases, it is less clear whether such afucosylated antibodies can demonstrate enhanced therapeutic index. This is because the orthologues of human FcγRIIIA or mouse FcγRIV from those species have not been well characterized. We set up a luciferase-based ADCC assay with Jurkat reporter cells expressing FcγRIIIA/FcγRIV from human, mouse, rat, hamster, guinea pig, ferret, rabbit, cat, dog, pig and monkey, and also produced human, mouse, hamster, rabbit and pig IgG from wild type and Fut8−/− CHO cells or hybridomas. We confirmed that enhanced stimulation through FcγRIIIA/FcγRIV by afucosylated IgG, as compared with wild type IgG, is a cross-species phenomenon. Thus, efficacy and toxicology studies of the next generation afucosylated therapeutic IgG and Fc fusion proteins in these underrepresented animal models should be expected to generate translatable data for treating human diseases, leading to the expanded applications of this new class of glycoengineered biologics.