B lymphocyte protein factories produced by hematopoietic stem cell gene editing

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Abstract
Long-term in vivo production of therapeutic proteins and development of vaccines that elicit protective levels of broadly neutralizing antibodies (bNAbs) against major pathogens face challenges. In this study, we report on an alternative gene editing approach using small numbers of hematopoietic stem and progenitor cells (HSPCs) to direct long-term, high-level expression of antibodies or cargo proteins. In mice, edited B lymphocytes derived from transplanted HSPCs were activated by cognate antigen, underwent clonal expansion, and developed into specific antibody-synthesizing or cargo protein–synthesizing plasma cells. These cells produced long-lasting, therapeutic levels of serum antibody against HIV-1, malaria, or an anti-influenza virus bNAb that mediated universal protection from heterologous lethal challenge. Our data provide a paradigm for cell therapy approaches to prevent or treat disease using self-amplifying B cell protein factories.
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Funding Information
  • National Institutes of Health (2P01AI100148-11)
  • National Institutes of Health (AI132359)
  • National Institutes of Health (1UM1AI144462-01)
  • Hemophilia Association of New York (n/a)
  • Canada Research Chair Program (n/a)
  • Bill and Melinda Gate Foundation (INV-081964)
  • Bill and Melinda Gate Foundation (INV-008866)
  • Bill and Melinda Gate Foundation (INV-036842)
  • Bill and Melinda Gate Foundation (INV-002777)
  • Johns Hopkins Malaria Research Institute Fellowship (n/a)
  • Stavros Niarchos Foundation Institute for Global Infectious Disease Research (n/a)

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