LAUSR

Although many patients with diffuse large B cell lymphoma (DLBCL) may achieve a complete response to frontline chemoimmunotherapy, patients with relapsed/refractory disease typically have poor outcomes. Odronextamab, a CD20xCD3 bispecific antibody that provides “signal 1” through the activation of the T cell receptor/CD3 complex, has exhibited early, promising activity for patients with highly refractory DLBCL in phase 1 trials. However, not all patients achieve complete responses, and many relapse, thus representing a high unmet medical need. Here, we investigated whether adding a costimulatory “signal 2” by engaging CD28 receptors on T cells could augment odronextamab activity. We demonstrate that REGN5837, a bispecific antibody that cross-links CD22-expressing tumor cells with CD28-expressing T cells, enhances odronextamab by potentiating T cell activation and cytolytic function. In preclinical DLBCL studies using human immune system–reconstituted animals, REGN5837 promotes the antitumor activity of odronextamab and induces intratumoral expansion of reprogrammable T cells while skewing away from a dysfunctional state. Although REGN5837 monotherapy shows limited activity and no toxicity in primate studies, it augments T cell activation when dosed in combination with odronextamab. In addition, analysis of non-Hodgkin lymphoma clinical samples reveals an increase in CD28+CD8+ T cells after odronextamab treatment, demonstrating the presence of a population that could potentially be targeted by REGN5837. Collectively, our data demonstrate that REGN5837 can markedly enhance the antitumor activity of odronextamab in preclinical NHL models, and the combination of these two bispecific antibodies may provide a chemotherapy-free approach for the treatment of DLBCL. Description REGN5837, a CD22xCD28 bispecific antibody, enhances the antitumor activity of odronextamab in preclinical models of diffuse large B cell lymphoma. Dynamic bispecific duo Bispecific antibodies are being used for cancer immunotherapy because they target two different antigens thus facilitating T cell targeting to tumors. Odronextamab is a CD20xCD3 bispecific antibody that shows promising activity in patients with diffuse large B cell lymphoma (DLBCL), but not all patients achieve complete responses, and there remains a high unmet need in the setting of relapsed/refractory disease. Wei et al. (p. 0000) demonstrate that REGN5837, a CD22xCD28 bispecific antibody, enhanced the antitumor activity of odronextamab in preclinical models of DLBCL and that the combination exhibited no toxicity in primates while augmenting T cell activation. CD28+CD8+ T cells were expanded in non-Hodgkin lymphoma samples from a phase 1 odronextamab trial, suggesting that addition of REGN5837 could enhance antitumor activity. These findings highlight the potential clinical usefulness of a bispecific antibody combination for treating DLBCL.