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

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. Editor's summary: Current treatments for B cell–specific non-Hodgkin lymphoma (B-NHL) target CD20⁺ cancerous B cells but have limited efficacy in relapsed or refractory patients. Demaria et al. developed an antibody-based molecule that targets B-NHL by engaging natural killer (NK) cells with antitumor activity. This tetraspecific NK cell engager (CD20-NKCE-IL2v) is composed of four components, including three components that activate NK cells: an anti-NKp46 antibody fragment, an IgG1 Fc fragment, and a variant of IL-2 that targets the IL-2R without engaging the alpha subunit. An additional anti-CD20 antibody fragment targets B-NHL cells. The authors tested mouse and human versions of CD20-NKCE-IL2v and confirmed specific NK cell activation and antitumor activity at well-tolerated doses in mice and nonhuman primates, thus suggesting investigation of this molecule as a potential B-NHL therapeutic. —Christiana N. Fogg [ABSTRACT FROM AUTHOR]