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Summary  Polatuzumab vedotin (Pola) is an antibody–drug conjugate that targets the B‐cell antigen CD79b and delivers monomethyl auristatin E (MMAE). It is approved in combination with bendamustine and rituximab (Rit) for relapsed/refractory diffuse large B‐cell lymphoma (r/r DLBCL). Understanding the molecular basis of Pola combination therapy with Rit, the key component for the treatment of DLBCL, is important to establish the effective treatment strategies against r/r DLBCL. Here, we examined the rationale for the combination of Pola with Rit using Pola‐refractory cells. We found that treatment with Pola increased CD20 expression and sensitivity to Rit‐induced complement‐dependent cytotoxicity (CDC) in several Pola‐refractory cells. Pola treatment increased phosphorylation of AKT and ERK and both AKT‐ and MEK‐specific inhibitors attenuated the Pola‐induced increase of CD20 and CDC sensitivity, suggesting that these phosphorylation events were required for this combination efficacy. It was revealed that anti‐CD79b antibody increased the phosphorylation of AKT but inhibited the phosphorylation of ERK. In contrast, MMAE potentiated phosphorylation of ERK but slightly attenuated the phosphorylation of AKT. Pola also increased CD20 expression on Pola‐refractory xenografted tumours and significantly enhanced antitumour activity in combination with Rit. In conclusion, these results could provide a novel rationale for the combination of Pola plus Rit.

The molecular rationale for the combination of polatuzumab vedotin plus rituximab in diffuse large B‐cell lymphoma