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An anti-CD98 antibody displaying pH-dependent Fc-mediated tumour-specific activity against multiple cancers in CD98-humanized mice
Nature Biomedical Engineering ( IF 26.8 ) Pub Date : 2022-11-24 , DOI: 10.1038/s41551-022-00956-5
Xinxin Tian 1, 2 , Ximing Liu 1, 2 , Jingjin Ding 1, 3 , Fengchao Wang 1 , Kailun Wang 1 , Juan Liu 1 , Zhizhong Wei 1 , Xinyan Hao 1 , Yulu Li 1 , Xin Wei 1 , Huixiang Zhang 1 , Jianhua Sui 1, 4
Affiliation  

The cell-surface glycoprotein CD98—a subunit of the LAT1/CD98 amino acid transporter—is an attractive target for cancer immunotherapies, but its widespread expression has hampered the development of CD98-targeting antibody therapeutics. Here we report that an anti-CD98 antibody, identified via the screening of phage-display libraries of CD98 single-chain variable fragments with mutated complementarity-determining regions, preserves the physiological function of CD98 and elicits broad-spectrum crystallizable-fragment (Fc)-mediated anti-tumour activity (requiring Fcγ receptors for immunoglobulins, macrophages, dendritic cells and CD8+ T cells, as well as other components of the innate and adaptive immune systems) in multiple xenograft and syngeneic tumour models established in CD98-humanized mice. We also show that a variant of the anti-CD98 antibody with pH-dependent binding, generated by solving the structure of the antibody–CD98 complex, displayed enhanced tumour-specific activity and pharmacokinetics. pH-dependent antibody variants targeting widely expressed antigens may lead to superior therapeutic outcomes.



中文翻译:

一种抗 CD98 抗体在 CD98 人源化小鼠中表现出 pH 依赖性 Fc 介导的针对多种癌症的肿瘤特异性活性

细胞表面糖蛋白 CD98(LAT1/CD98 氨基酸转运蛋白的一个亚基)是癌症免疫疗法的一个有吸引力的靶标,但其广泛表达阻碍了靶向 CD98 的抗体疗法的发展。在这里,我们报告了一种抗 CD98 抗体,通过筛选具有突变互补决定区的 CD98 单链可变片段的噬菌体展示文库鉴定,保留了 CD98 的生理功能并引发广谱可结晶片段 (Fc)介导的抗肿瘤活性(需要免疫球蛋白、巨噬细胞、树突状细胞和 CD8 +的 Fcγ 受体在 CD98 人源化小鼠中建立的多种异种移植和同源肿瘤模型中的 T 细胞,以及先天性和适应性免疫系统的其他成分。我们还表明,通过解析抗体-CD98 复合物的结构生成的具有 pH 依赖性结合的抗 CD98 抗体变体显示出增强的肿瘤特异性活性和药代动力学。针对广泛表达的抗原的 pH 依赖性抗体变体可能会带来更好的治疗效果。

更新日期:2022-11-25
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