B lymphocyte protein factories produced by hematopoietic stem cell gene editing
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.
Authors
- Leonidas Stamatatos (ORCID: https://orcid.org/0000-0002-1106-7097)
- Michel C. Nussenzweig (ORCID: https://orcid.org/0000-0003-0592-8564)
- Esen Sefik (ORCID: https://orcid.org/0000-0002-6807-3498)
- Patrick C. Wilson (ORCID: https://orcid.org/0000-0002-3537-1245)
- Hedda Wardemann (ORCID: https://orcid.org/0000-0003-3921-5933)
- Harald Hartweger (ORCID: https://orcid.org/0000-0002-1118-1818)
- Elena A. Levashina (ORCID: https://orcid.org/0000-0003-4605-906X)
- Sachie Kanatani (ORCID: https://orcid.org/0000-0002-7072-0447)
- Jean‐Philippe Julien (ORCID: https://orcid.org/0000-0001-7602-3995)
- Jordan J. Clark (ORCID: https://orcid.org/0000-0003-1790-7883)
- Pengcheng Zhou (ORCID: https://orcid.org/0000-0002-7736-2902)
- Maximilian Loewe (ORCID: https://orcid.org/0000-0003-2935-3750)
- Thomas Hägglöf (ORCID: https://orcid.org/0000-0002-7751-0928)
- R A Flavell
- Florian Krammer (ORCID: https://orcid.org/0000-0003-4121-776X)
- Photini Sinnis (ORCID: https://orcid.org/0000-0003-2954-7547)
- Anna Gazumyan (ORCID: https://orcid.org/0000-0002-5976-9717)
- Giulia Costa (ORCID: https://orcid.org/0000-0001-7387-6589)
- Michael S. Seaman (ORCID: https://orcid.org/0000-0001-6444-3562)
- Mila Janković (ORCID: https://orcid.org/0000-0001-9696-5234)
- Sean A. Nelson (ORCID: https://orcid.org/0000-0002-9000-3496)
- Gabriella Lima dos Reis
- Chiara Ruprecht
- Philippe Laffont
- Laurine Binet
- Tianli Xiao
- Brianna Hernandez
- Kai-Hui Yao
Institutions
- Beth Israel Deaconess Medical Center (US)
- Howard Hughes Medical Institute (US)
- Johns Hopkins University (US)
- German Cancer Research Center (DE)
- University of Toronto (CA)
- University of Washington (US)
- Cornell University (US)
- Heidelberg University (DE)
- Hospital for Sick Children (CA)
- Yale University (US)
- University of Chicago (US)
- Max Planck Institute for Infection Biology (DE)
- Fred Hutch Cancer Center (US)
- Weill Cornell Medicine (US)
- Medical University of Vienna (AT)
- Rockefeller University (US)
- Icahn School of Medicine at Mount Sinai (US)
Publication Details
- Journal
- Science
- Published
- 2026-04-16
- DOI
- https://doi.org/10.1126/science.adz8994
- Citations
- 1
- Primary Topic
- CRISPR and Genetic Engineering
- Type
- article
- Field-Weighted Citation Impact
- 12.65
Funders
- Hemophilia Association of New York
- National Institutes of Health