Polatuzumab Vedotin Induced CD20 Upregulation Contributes to the Efficacy of Mosunetuzumab in Combination With Polatuzumab Vedotin in Diffuse Large B-Cell Lymphoma Preclinical Models.

Background: Aggressive non-Hodgkin lymphoma (aNHL) often relapses after first-line treatment. Clinical data supports the safety and efficacy of the combination of mosunetuzumab, a CD20×CD3 bispecific antibody, and polatuzumab vedotin, an anti-CD79b antibody drug conjugate (Mosun-Pola) in relapsed/refractory aNHL. This study investigated the molecular mechanism behind the combination effect of Mosun-Pola in human diffuse large B-cell lymphoma (DLBCL) cell lines. Methods: The in vitro Mosun-Pola efficacy in DLBCL cells (SU-DHL-8 and HT) was evaluated by T cell-dependent cellular cytotoxicity (TDCC) assay. CD20-stable-knockdown SU-DHL-8 cells were established using lentiviral short hairpin RNA. Surface and T-cell activation marker proteins expression were determined by flow cytometry. Human T-cell-injected mice or humanized NOD/Shi-scid, IL-2Rγnull (huNOG) mice were used for an in vivo study. Results: An in vitro TDCC assay showed a synergistic effect in SU-DHL-8 and HT cells. Based on our experimental results of suppressing CD20 expression, it was suggested that this combination effect could be caused by an increase in CD20 expression by polatuzumab vedotin. In addition, examining the effects of CD20 upregulation in tumor cells on T-cell activation demonstrated that the combination of Mosun-Pola enhanced T-cell activation markers in both CD4+ and CD8+ T cells during the TDCC reaction. In vivo studies, using human immune system-reconstituted mouse models confirmed that polatuzumab vedotin enhanced CD20 expression in tumors, and the combination of Mosun-Pola showed significantly improved anti-tumor effects compared with single-drug treatments. Conclusion: These findings suggest that polatuzumab vedotin-induced CD20 upregulation provides a molecular rationale to explain the synergistic effect of this combination therapy. Trial Registration: The authors have confirmed clinical trial registration is not needed for this submission.