A tetraspecific engager armed with a non-alpha IL-2 variant harnesses natural killer cells against B cell non-Hodgkin lymphoma

IF 17.6 1区医学 Q1 IMMUNOLOGY

Science Immunology Pub Date : 2024-11-15 DOI:10.1126/sciimmunol.adp3720

Olivier Demaria, Guillaume Habif, Marie Vetizou, Laurent Gauthier, Romain Remark, Laura Chiossone, Constance Vagne, Lucas Rebuffet, Rachel Courtois, Caroline Denis, François Le Floch, Marianna Muller, Mathilde Girard-Madoux, Séverine Augier, Julie Lopez, Barbara Carrette, Aurélie Maguer, Jean-Baptiste Vallier, Gwendoline Grondin, William Baron, Justine Galluso, Nadia Yessaad, Marilyn Giordano, Léa Simon, Fabien Chanuc, Audrey Blanchard Alvarez, Ivan Perrot, Cécile Bonnafous, Agnès Represa, Benjamin Rossi, Ariane Morel, Yannis Morel, Carine Paturel, Eric Vivier

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Abstract

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.

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用非αIL-2变体武装的四特异性捕获器利用自然杀伤细胞对抗B细胞非霍奇金淋巴瘤

在癌症治疗中，NK细胞为T细胞疗法提供了一种前景广阔的替代疗法。我们对 IPH6501 进行了评估，它是一种处于临床阶段的四特异性 NK 细胞吞噬剂（NKCE），带有非α IL-2 变体（IL-2v），靶向 CD20，用于治疗 B 细胞非霍奇金淋巴瘤（B-NHL）。CD20-NKCE-IL2v 可促进 NK 细胞的增殖和细胞毒性，对一系列 B-NHL 细胞系（包括 CD20 密度低的细胞系）具有活性。与通常的 T 细胞疗法相比，CD20-NKCE-IL2v 的毒性更低，在体外临床前模型中，CD20-NKCE-IL2v 比以 CD20 为靶点的 T 细胞诱导剂具有更强的杀伤力。CD20-NKCE-IL2v 还能增加细胞表面 NK 细胞激活受体的表达，从而提高对 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进行的体内研究进一步验证了CD20-NKCE-IL2v的疗效，并发现CD20-NKCE-IL2v能诱导外周NK细胞在肿瘤部位归巢。CD20-NKCE-IL2v 成为治疗 B-NHL 的潜在替代疗法。

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来源期刊

Science Immunology Immunology and Microbiology-Immunology

CiteScore

32.90

自引率

2.00%

发文量

183

期刊介绍： Science Immunology is a peer-reviewed journal that publishes original research articles in the field of immunology. The journal encourages the submission of research findings from all areas of immunology, including studies on innate and adaptive immunity, immune cell development and differentiation, immunogenomics, systems immunology, structural immunology, antigen presentation, immunometabolism, and mucosal immunology. Additionally, the journal covers research on immune contributions to health and disease, such as host defense, inflammation, cancer immunology, autoimmunity, allergy, transplantation, and immunodeficiency. Science Immunology maintains the same high-quality standard as other journals in the Science family and aims to facilitate understanding of the immune system by showcasing innovative advances in immunology research from all organisms and model systems, including humans.