Incorporation of a Novel CD16-Specific Single-Domain Antibody into Multispecific Natural Killer Cell Engagers With Potent ADCC,Molecular Pharmaceutics

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Incorporation of a Novel CD16-Specific Single-Domain Antibody into Multispecific Natural Killer Cell Engagers With Potent ADCC
Molecular Pharmaceutics ( IF 4.5 ) Pub Date : 2021-05-17 , DOI: 10.1021/acs.molpharmaceut.1c00208
Henk van Faassen ₁ , Dong-Hyeon Jo ₂ , Shannon Ryan ₁ , Michael J Lowden ₁ , Shalini Raphael ₁ , C Roger MacKenzie ₁ , Seung-Hwan Lee ₂ , Greg Hussack ₁ , Kevin A Henry _{1,

2}

Affiliation

Multispecific antibodies that bridge immune effector and tumor cells have shown promising preclinical and clinical efficacies. Here, we isolated and characterized novel llama single-domain antibodies (sdAbs) against CD16. One sdAb, NRC-sdAb048, bound recombinant human and cynomolgus monkey CD16 ectodomains with equivalent affinity (K_D: 1 nM) but did not recognize murine CD16. Binding was similar for human CD16a expressed on NK cells and CD16b (NA2) expressed on neutrophils but dramatically weaker (K_D: ∼6 μM) for the CD16b (NA1) allotype. The sdAb stained primary human peripheral blood NK cells. Irrespective of fusion orientation and linker length, bispecific sdAb–sdAb and sdAb–scFv dimers (anti-CD16/EGFR, anti-CD16/HER2, and anti-CD16/CD19) retained full binding affinity for each target, coengaged both antigens simultaneously, elicited ADCC against target antigen-expressing tumor cells in a reporter bioassay, and triggered target-specific activation and degranulation of primary NK cells as measured via interferon-γ and CD107a expression. These molecules may have applications in cancer immunotherapy.

中文翻译：

将新型 CD16 特异性单域抗体整合到具有强效 ADCC 的多特异性自然杀伤细胞接合剂中

连接免疫效应子和肿瘤细胞的多特异性抗体已显示出有希望的临床前和临床疗效。在这里，我们分离并表征了针对 CD16 的新型美洲驼单域抗体 (sdAb)。一种 sdAb，NRC-sdAb048，以相同的亲和力（K _D：1 nM）结合重组人和食蟹猴 CD16 胞外域，但不识别鼠 CD16。NK 细胞上表达的人 CD16a 和中性粒细胞上表达的 CD16b (NA2) 的结合相似，但显着较弱 ( K _D: ∼6 μM) 用于 CD16b (NA1) 同种异型。sdAb 染色原代人外周血 NK 细胞。无论融合方向和接头长度如何，双特异性 sdAb–sdAb 和 sdAb–scFv 二聚体（抗 CD16/EGFR、抗 CD16/HER2 和抗 CD16/CD19）保持对每个靶标的完全结合亲和力，同时共接合两种抗原，在报告生物测定中引发针对表达靶抗原的肿瘤细胞的 ADCC，并通过干扰素-γ 和 CD107a 表达触发原代 NK 细胞的靶特异性激活和脱颗粒。这些分子可能在癌症免疫治疗中有应用。

更新日期：2021-06-07

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