LBPO.ET01 · 实验与分子治疗 · Late-Breaking
一种新型CD16A纳米抗体平台克服Fc多态性局限，实现强效广谱的NK细胞衔接器疗法
A novel CD16A-nanobody platform overcomes Fc polymorphism limitations for potent and broad-spectrum NK cell engager therapeutics
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摘要 Abstract
中文摘要
CD16A（FcγRIIIA）是自然杀伤（NK）细胞上介导抗体依赖性细胞毒性（ADCC）的关键激活受体，而ADCC是治疗性抗体清除肿瘤细胞的重要机制。IgG1-Fc和低岩藻糖Fc形式对常见的CD16A-158F等位基因（约85%人群携带）均表现出较差的亲和力，这对广泛而强效的NK细胞介导的肿瘤杀伤构成了重大障碍。基于CD16A的NK细胞衔接器通过高亲和力CD16A结合结构域直接桥连NK细胞与肿瘤抗原，从而克服这一局限，实现强效的、不依赖Fc的ADCC。在此，我们提出了一个优化的NK衔接器平台，该平台以优化的抗体形式整合了一种专有的CD16A纳米抗体。该平台在多个项目中（包括PD-L1/CD16A双特异性抗体和CDH17/EGFR/CD16A三特异性抗体）表现出优于低岩藻糖Fc增强形式的体外和体内疗效。B117-1抗体形式实现了50-100倍更高的CD16A亲合力，对CD16A-158V和CD16A-158F等位基因均具有强结合。相比之下，amivantamab尽管具有低岩藻糖Fc增强，但在携带CD16A-158F等位基因的供体中表现出显著较弱的ADCC活性。广泛的形式筛选表明，NK细胞激活在很大程度上受肿瘤抗原结合Fab与抗CD16A纳米抗体之间空间距离的影响：距离越长，越会削弱庞大的CD45磷酸酶从免疫突触中的排除，从而导致细胞毒性显著降低。因此，广泛采用的Morrison型抗体的表现始终逊于具有更短CD16A-TAA-Fab间距的构架。在来自45名HLA多样化健康供体的PBMC中进行的免疫原性评估显示，整合了CD16A纳米抗体平台的IBI3019的抗药抗体（ADA）率较低。其ADA率与trastuzumab相当，并显著低于atezolizumab。CD16A纳米抗体可无缝整合到抗体构架中，相较于scFv形式具有更优越的稳定性，并具有类似于标准双特异性抗体的简便CMC生产工艺，无需专门的糖工程或授权许可。这一多功能、高性能平台代表了新一代NK细胞衔接器，可提供广泛的患者覆盖率和卓越的治疗潜力。
查看英文原文 English abstract
CD16A (FcgammaRIIIA) is the key activating receptor on natural killer (NK) cells mediating antibody-dependent cellular cytotoxicity (ADCC), an important mechanism for therapeutic antibodies to eliminate tumor cells. Both IgG1-Fc and low-fucose Fc formats exhibit poor affinity for the common CD16A-158F allele, found in ~85% of the population, creating a major barrier to broad and potent NK cell-mediated tumor killing. CD16A-based NK cell engagers overcome this limitation by directly bridging NK cells to tumor antigens with high-affinity CD16A-binding domains, enabling potent, Fc-independent ADCC. Here, we present an optimized NK engager platform incorporating a proprietary CD16A nanobody in an optimized antibody format. This platform demonstrates superior in vitro and in vivo efficacy compared to low-fucose Fc-enhanced formats across multiple programs, including PD-L1/CD16A bispecific and CDH17/EGFR/CD16A trispecific antibodies. The B117-1 antibody format achieves 50-100-fold higher CD16A avidity, with strong binding to both CD16A-158V and CD16A-158F alleles. In contrast, amivantamab, despite its low-fucose Fc enhancement, exhibits significantly weaker ADCC activity in donors carrying CD16A-158F alleles. Extensive format screening revealed that NK cell activation is heavily influenced by the spatial distance between the tumor antigen-binding Fab and the anti-CD16A nanobody: longer distance impairs the bulky CD45 phosphatase exclusion from the immunological synapse, leading to significantly reduced cytotoxicity. Consequently, the widely adopted Morrison-type antibody consistently underperformed compared to architectures with shorter CD16A-TAA-Fab spacing. Immunogenicity assessment in PBMCs from 45 HLA-diverse healthy donors showed low anti-drug antibody (ADA) rates for IBI3019, which incorporates the CD16A nanobody platform. The ADA rate is comparable to that of trastuzumab and significantly lower than atezolizumab. The CD16A nanobody integrates seamlessly into the antibody architecture, offering superior stability over scFv formats and straightforward CMC manufacturing akin to standard bispecifics, without specialized glycoengineering or licensing. This versatile, high-performance platform exemplifies the next-generation NK cell engagers, delivering broad patient coverage and superior therapeutic potential.
利益披露 Disclosure
T. Chia, None..
J. Liu, None..
S. Lin, None..
W. Dai, None..
M. Wu, None..
Z. Wu, None.