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July 18th, 2025
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Seattle Children\'s Research Institute
molecular biology
biorxiv

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

Hill, T. F.Open in Google Scholar•Helmers, A. E.Open in Google Scholar•Cheng, R. Y.Open in Google Scholar•Singh, S.Open in Google Scholar•Homad, L. J.Open in Google Scholar•Narvekar, P.Open in Google Scholar•Asher, G. D.Open in Google Scholar•Camp, N. D.Open in Google Scholar•Suchland, E. R.Open in Google Scholar•Ott, A. R.Open in Google Scholaret al.

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 plasma cell survival and function. We utilized a humanized mouse model in which NOD.Cg-Prkdcscid Il2rgtm1Wjl/SzJ (NSG) mice were engrafted with human CD34+ stem cells as recipients for infusions with autologous ePCs. In this setting, ePCs localized to plasma cell niches and stably secreted antibodies for over three 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-SARS-CoV-2 antibody (clone 297) selected by this method showed robust secretion both in vitro and 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.

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