Humanized mice enable in vivo evaluation of engineered plasma cell biology and therapeutic function.

Engineered plasma cells (ePCs) offer a durable strategy for in vivo delivery of therapeutic antibodies, but standard immunodeficient mouse models lack human immune factors critical for PC survival and function. We utilized a humanized mouse model in which NOD.Cg-Prkdc scid Il2rg tm1Wjl /SzJ (NSG) mice were engrafted with human CD34+ stem cells as recipients for infusions with autologous ePCs. In this setting, ePCs localized to PC niches and stably secreted antibodies for over 3 months. To improve the selection of antibodies for secretion, we developed a B cell receptor surface display screen that identified candidate antibody sequences with high secretion potential. An anti-severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) antibody (clone 297) selected by this method showed robust secretion both in vitro and in vivo, and serum from ePC-engrafted mice potently neutralized SARS-CoV-2 pseudovirus. Together, these findings establish a physiologically relevant model for testing human ePCs, and offer a generalizable strategy for optimizing antibody selection to support long-term therapeutic delivery.