PO.IM01.07 · 免疫学
一种为与抗体和T细胞衔接器疗法协同联合而工程化设计的通用多受体NK细胞平台
A universal multi-receptor NK cell platform engineered for synergistic combination with antibody and T-cell engager therapies
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
背景：单克隆抗体（mAb）和T细胞衔接器（TCE）将免疫效应细胞重定向至恶性靶标，但其疗效常受到患者T细胞和NK细胞功能障碍的限制。传统的CAR策略靶向单一抗原，需要为每个靶点进行新的构建体设计、GMP生产和独立的监管审批路径。为了结合衔接器和基于细胞的方法的优势，我们开发了PluraliNK细胞，这是一种通过CD3/TCR和Fc依赖性途径活化的通用多受体NK细胞平台。这使得任何已获批的mAb或TCE都能在无需额外工程化改造的情况下实现重定向，创造出一种灵活的即插即用型NK疗法。
方法：使用两个多顺反子载体对NK细胞进行工程化改造，使其表达完整的CD3复合物、用于细胞因子支持的IL-15、用于增强Fc结合的高亲和力CD16A（F158V）以及一种恒定型TCR α/β（iTCR）以稳定CD3并允许CD1d限制性识别。这种双重活化系统使PluraliNK细胞能够响应CD3或CD16介导的信号，并与多种mAb或TCE配对而无需进一步修饰。
结果：当与已获批的mAb（利妥昔单抗、曲妥珠单抗）或TCE（贝林妥欧单抗、格菲妥单抗、埃纳妥单抗）联合使用时，PluraliNK细胞在血液和实体肿瘤模型中均表现出强效的细胞毒性，持续优于mAb/TCE单药治疗或未修饰的NK细胞。该平台支持多种抗体或TCE的同时结合，能够清除异质性肿瘤群体并减少抗原逃逸。双重输入信号增强了活化、连续杀伤和抗耗竭能力，这在具有空间异质性和谱系可塑性的实体瘤中是一大优势。由于PluraliNK的活化依赖于外部mAb或TCE，与组成型活化的CAR构建体相比，该系统提供了额外的安全层。在NSG异种移植模型中，PluraliNK细胞与mAb或TCE联合实现了卓越的肿瘤清除、改善的浸润和增强的体内持久性，且无脱靶毒性。
结论：这种通用NK细胞平台实现了多抗原靶向以及与现有mAb和TCE的整合，在无需抗原特异性CAR重新设计的情况下解决了肿瘤异质性和免疫逃逸问题。PluraliNK细胞联合抗体疗法的首个在人体临床试验已经启动。
查看英文原文 English abstract
Background: Monoclonal antibodies (mAbs) and T-cell engagers (TCEs) redirect immune effector cells toward malignant targets, yet their efficacy is often limited by patient T- and NK-cell dysfunction. Conventional CAR strategies target a single antigen, requiring new construct design, GMP production, and separate regulatory pathways for each target. To combine the strengths of engager- and cell-based approaches, we developed PluraliNK cells, a universal multireceptor NK-cell platform activated through CD3/TCR- and Fc-dependent pathways. This enables redirection by any approved mAb or TCE without additional engineering, creating a flexible plug-and-play NK therapy.
Methods: NK cells were engineered using two polycistronic vectors to express the full CD3 complex, IL-15 for cytokine support, high-affinity CD16A (F158V) for enhanced Fc engagement, and an invariant TCR alpha/beta (iTCR) to stabilize CD3 and permit CD1d-restricted recognition. This dual-activation system allows PluraliNK cells to respond to CD3- or CD16-mediated signals and to pair with diverse mAbs or TCEs without further modification.
Results: PluraliNK cells showed potent cytotoxicity across hematologic and solid tumor models when combined with approved mAbs (rituximab, trastuzumab) or TCEs (blinatumomab, glofitamab, elranatamab), consistently outperforming mAb/TCE monotherapy or unmodified NK cells. The platform supports simultaneous engagement by multiple antibodies or TCEs, enabling clearance of heterogeneous tumor populations and reducing antigen escape. Dual-input signaling enhanced activation, serial killing, and resistance to exhaustion, an advantage in solid tumors with spatial heterogeneity and lineage plasticity. Because PluraliNK activation depends on an external mAb or TCE, the system provides an additional safety layer compared with constitutively active CAR constructs. In NSG xenograft models, PluraliNK cells combined with mAbs or TCEs achieved superior tumor clearance, improved infiltration, and enhanced in vivo persistence without off-target toxicity.
Conclusions: This universal NK-cell platform enables multiantigen targeting and integration with existing mAbs and TCEs, addressing tumor heterogeneity and immune escape without requiring antigen-specific CAR redesign. A first-in-human clinical trial of PluraliNK cells with antibody therapy has been initiated.
利益披露 Disclosure
R. Basar,
Takeda Patent.
Affimed Patent.