ABSTRACT Monoclonal antibody (mAbs) therapies have proven to be effective treatments for a multitude of clinical applications. Several of these treatments require repeated administration through intravenous infusions leading to high costs and poor patient adherence. A new field has emerged that seeks to generate mAb-secreting plasma cell therapeutics that could be administered once to provide lifelong therapeutic mAb levels as a therapeutic alternative. Plasma cells have high secretory capacities, can last a lifetime and are thought to be relatively quiescent. Advances in gene editing and ex vivo B cell differentiation have enabled the ability to generate plasma cells that secrete an exogenous mAb. However, current gene editing strategies do not fully account for endogenous antibody expression or control for what isotype the exogenous mAb is expressed as. Additionally, the field of gene-edited human plasma cell lacks both large and small animal models to test the engraftment and functionality of these mAb-secreting plasma cells. Aim 1 of this proposal will use a new gene engineering strategy to generate a human plasma cell therapeutic that secretes an engineered IgG mAb against Epstein Barr Virus (EBV) as a proof of concept for future mAb- secreting cell therapies. I will characterize the ability of gene-edited primary plasma cells to produce large quantities of defined mAbs and compare to previously published methods. Human plasma cells are difficult to engraft in small animal models due to the lack of extrinsic survival factors from human stromal and myeloid cells. Aim 2 of this proposal will use a humanized (NSG-huCD34) mouse model to better predict the potential engraftment potential of gene-edited plasma cells therapies. This humanized mouse model also serves as a model for human-tropic EBV infection. I propose to validate the functionality of anti-EBV secreting plasma cells by showing that these cells protect humanized mice against high dose intravenous EBV challenge. This would be the first time that gene-edited primary human plasma cells were shown to protect against a human-tropic disease in a humanized mouse model and would serve as a proof of concept for use of gene-edited plasma cells to provide mAbs. This project is ideal for my training as a young physician scientist due to my strong interest in translational immunology, the complementation of my previous training in chimeric antigen receptor- modified T cell research, the extensive background of Dr. David Rawlings and Dr. Richard James in B cell biology and mentorship, and the quality research and medical education at the University of Washington. The activities detailed in this proposal will provide a strong background for a future career as a physician scientist pursuing translational immunology research.