Human plasma cells engineered to secrete bispecifics drive effective invivo leukemia killing.

Abstract

Bispecific antibodies are an important tool for the management and treatment of acute leukemias. As a next step toward clinical translation of engineered plasma cells, we describe approaches for secretion of bispecific antibodies by human plasma cells. We show that human plasma cells expressing either fragment crystallizable domain-deficient anti-CD19×anti-CD3 (blinatumomab) or anti-CD33×anti-CD3 bispecific antibodies mediate Tcell activation and direct Tcell killing of B acute lymphoblastic leukemia or acute myeloid leukemia cell lines invitro. We demonstrate that knockout of the self-expressed antigen, CD19, boosts anti-CD19-bispecific secretion by plasma cells and prevents self-targeting. Plasma cells secreting anti-CD19-bispecific antibodies elicited invivo control of acute lymphoblastic leukemia patient-derived xenografts in immunodeficient mice co-engrafted with autologous Tcells. In these studies, we found that leukemic control elicited by engineered plasma cells was similar to CD19-targeted chimeric antigen receptor-expressing Tcells. Finally, the steady-state concentration of anti-CD19 bispecifics in serum 1month after cell delivery and tumor eradication was comparable with that observed in patients treated with a steady-state infusion of blinatumomab. These findings support further development of ePCs for use as a durable delivery system for the treatment of acute leukemias, and potentially other cancers.