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Background Tumor-targeted therapies such as CAR T cells and CD3-bispecific antibodies have significantly improved treatment outcomes for patients with non-Hodgkin lymphoma. However, patients with aggressive disease experience high refractory relapse rates suggesting that novel combination treatment strategies are required to achieve durable tumor rejection. Odronextamab, a CD20xCD3 bispecific antibody, has been approved in the EU for the treatment of relapsed/refractory follicular lymphoma and diffuse large B cell lymphoma (DLBCL), however, there remains a need to improve depth and durability of response to odronextamab monotherapy. Maximal T cell activation and cytotoxicity requires engagement of the T cell receptor/CD3 complex (‘signal 1’) and additional engagement of a costimulatory receptor such as CD28 (‘signal 2’). Therefore, to enhance odronextamab efficacy, we aimed to further enhance T cell activation to promote durable immunity by engaging ‘signal 2’.Methods We developed an investigational CD22xCD28 bispecific antibody, REGN5837, and are assessing its ability to cross-link CD22-expressing tumor cells with CD28-expressing T cells and provide ‘signal 2’ to enhance anti-tumor immunity.Results Here we demonstrate that REGN5837 potently augments odronextamab-mediated T cell activation and cytolytic activity in vitro. Preclinical models indicate REGN5837 enhances odronextamab-mediated anti-tumor activity and leads to expansion of reprogrammable T cells. Importantly, primate studies show REGN5837 has limited activity and no toxicity as a monotherapy but enhances T cell activation when dosed in combination with odronextamab.Conclusions These data highlight a potential chemotherapy-free approach for DLBCL treatment in REGN5837 plus odronextamab, and this combination is currently under evaluation in a Phase 1 clinical trial for aggressive relapsed/refractory DLBCL ( NCT05685173).Ethics Approval All procedures were carried out in accordance with the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health. The protocols were approved by the Regeneron Pharmaceuticals Institutional Animal Care and Use Committee (IACUC), and all animals were maintained under pathogen-free conditions.