Engineered plasma cells: a novel platform for long-term delivery of biologics to treat leukemia and other diseases

Abstract

Advances in genome-engineering have enabled the generation of human plasma cells that secrete therapeutic proteins and are capable of long-term in vivo engraftment in humanized mouse models. To assist the clinical translation of engineered plasma cells (ePCs), we present three key studies evaluating: a) engineering approaches for optimized expression and secretion of non-immunoglobulin G (IgG)-like bispecific antibodies by human plasma cells to treat leukemias in vivo; b) a humanized mouse model to assess engraftment function and pharmacokinetics of adoptively transferred autologous ePC; and c) a novel B cell signaling BCR/Ab-screening method to evaluate highly expressed monoclonal antibodies for secretion by ePCs. We show that human ePCs expressing either anti-CD19 x anti-CD3 (blinatumomab) or anti-CD33 x anti-CD3 bispecific antibodies mediate T cell activation and direct T cell killing of specific primary human cell subsets and leukemia cell lines in vitro and in vivo. We demonstrate that the presence of autologous human hematopoietic cells in immunodeficient mice permits the establishment of a robust model for studying the in vivo biology and potential therapeutic benefit of long-lived human ePCs. Finally, we developed a B cell signaling-based method for the screening of BCRs for use as recombinant monoclonal antibody therapy and in engineered B cells and ePCs. Collectively, these findings support further development of ePCs for use as a durable system for the treatment of acute leukemias, and potentially other diseases.