Despite advances in targeted therapies, relapsed/refractory B-cell non-Hodgkin lymphoma (R/R B-NHL) remains incurable in the majority of patients. Thus, there is a critical need to expand the treatment options for R/R B-NHL to improve patient outcomes. In this study, we characterized JNJ-80948543, a novel trispecific T-cell engager (TCE), designed to target CD79b+ and/or CD20+ lymphoma cells and bind to CD3 T cells with low affinity. By engaging two tumor-antigens, JNJ-80948543 may enhance tumor binding through avidity effects, potentially improving eradication of heterogeneous cell populations and reducing the risk of antigen escape. Preclinical data confirmed potent T-cell-mediated cytotoxicity against CD79b+ and/or CD20+ cells, with increased potency upon dual antigen engagement, consistent with an avidity effect. To mitigate cytokine release syndrome and T-cell exhaustion commonly associated with TCEs, JNJ-80948543 was designed with a low-affinity CD3 arm. In vitro, JNJ-80948543 achieved effective cytotoxicity with lower cytokine release compared to a matched high-affinity CD3 trispecific, JNJ-80948556. Despite reduced cytokine secretion by JNJ-80948543, both antibodies demonstrated comparable antitumor activity in xenograft mouse model. Collectively, the selectivity, potent cytotoxicity, tumor growth inhibition, and favorable cytokine profile of JNJ-80948543 supports its clinical development. Phase 1 clinical trials are ongoing to evaluate JNJ-80948543 as a monotherapy (NCT05424822) and in combination with a co-stimulatory bispecific antibody (NCT06139406) in patients with R/R B-NHL.
Kuchnio et al. (Thu,) studied this question.