NK cells offer a promising alternative to T cell therapies in cancer. We evaluated IPH6501, a clinical-stage, tetraspecific NK cell engager (NKCE) armed with a non-alpha IL-2 variant (IL-2v), which targets CD20 and was developed for treating B cell non-Hodgkin lymphoma (B-NHL). CD20-NKCE-IL2v boosts NK cell proliferation and cytotoxicity, showing activity against a range of B-NHL cell lines, including those with low CD20 density. Whereas it presented reduced toxicities compared with those commonly associated with T cell therapies, CD20-NKCE-IL2v showed greater killing efficacy over a T cell engager targeting CD20 in in vitro preclinical models. CD20-NKCE-IL2v also increased the cell surface expression of NK cell–activating receptors, leading to activity against CD20-negative tumor cells. In vivo studies in nonhuman primates and tumor mouse models further validated its efficacy and revealed that CD20-NKCE-IL2v induces peripheral NK cell homing at the tumor site. CD20-NKCE-IL2v emerges as a potential alternative in the treatment landscape of B-NHL.

中文翻译：

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配备非 α IL-2 变体的四特异性接合器利用自然杀伤细胞对抗 B 细胞非霍奇金淋巴瘤


NK 细胞为癌症中的 T 细胞疗法提供了一种有前途的替代方案。我们评估了 IPH6501，这是一种临床阶段的四特异性 NK 细胞接合器 （NKCE），配备非 α IL-2 变体 （IL-2v），靶向 CD20，专为治疗 B 细胞非霍奇金淋巴瘤 （B-NHL） 而开发。CD20-NKCE-IL2v 可促进 NK 细胞增殖和细胞毒性，显示出对一系列 B-NHL 细胞系的活性，包括那些 CD20 密度低的细胞系。虽然与通常与 T 细胞疗法相关的毒性相比，CD20-NKCE-IL2v 的毒性较低，但在体外临床前模型中，CD20-NKCE-IL2v 显示出比靶向 CD20 的 T 细胞接合器更高的杀伤效果。CD20-NKCE-IL2v 还增加了 NK 细胞激活受体的细胞表面表达，导致对 CD20 阴性肿瘤细胞的活性。在非人灵长类动物和肿瘤小鼠模型中的体内研究进一步验证了其疗效，并揭示了 CD20-NKCE-IL2v 诱导肿瘤部位的外周 NK 细胞归巢。CD20-NKCE-IL2v 成为 B-NHL 治疗领域的潜在替代方案。