A novel loncastuximab-based cucurmosin immunotoxin with high potency in vitro against lymphoma.

Loncastuximab is a humanized monoclonal antibody targeting CD19 for the treatment of diffuse large B-cell lymphoma. Chemoimmunotherapies still leave many patients unresponsive to treatment or retreatment following relapse, with complete remission rates being low. The main purpose of this study was to broaden the therapeutic window of loncastuximab by conjugating it with recombinant cucurmosin to form an immunotoxin called L-CUS_245C. L-CUS_245C was chemically conjugated, and the purification of L-CUS_245C was evaluated by SDS-PAGE. Thiazolyl blue tetrazolium bromide assay showed remarkable cytotoxicity of L-CUS_245C, with IC₅₀ values in the picomolar range, against CD19-positive cancer cells, while it exhibited no significant inhibitory effect on the proliferation of CD19-negative cells (P < .01). Mechanistic studies demonstrated that L-CUS_245C induces apoptosis in positive cancer cells via mitochondrial membrane potential disruption. Synergistic effects were observed when L-CUS_245C was combined with I-CUS_245C, enhancing proliferation inhibition in CD19-positive cells. These results indicate the therapeutic potential of L-CUS_245C for CD19-targeted therapy, offering a promising strategy to improve treatment efficacy and patient prognosis. SIGNIFICANCE STATEMENT: We propose applying CUS_245C, conjugating with loncastuximab, to prepare L-CUS_245C. At the same time, we hope that L-CUS_245C can play an objective therapeutic role in diffuse large B-cell lymphoma, achieving the effect of reducing the recurrence rate of the disease and thereby improving prognosis.