B cells and their differentiated progeny, plasma cells, are attractive targets for the development of cellular therapies owing to their central role in antibody production. A study in Science by Hartweger et al. now describes a strategy that transplants engineered hematopoietic stem and progenitor cells (HSPCs) into mice to produce B cell precursors that can then be expanded through immunization to secrete therapeutic antibodies.
The HSPCs were gene edited to encode an anti-HIV broadly neutralizing antibody, called 3BNC117, within the immunoglobulin heavy chain locus. Transplantation of as low as a few hundred HSPCs into mice was sufficient to establish 3BNC117-expressing B cells that expanded upon immunization with the cognate HIV-1 antigen to produce high levels of anti-HIV antibody. While antibody levels slowly declined over time, boosting with a second dose of HIV-1 antigen stimulated production, after which they were maintained for at least 9 months. A combination of two antibodies targeting non-overlapping epitopes on the HIV-1 could also be produced by engineering two populations of HSPCs that were then mixed for transplantation. Findings were comparable in mice transplanted with HSPCs encoding anti-malaria parasite or anti-influenza A antibodies, the latter protecting mice from a lethal influenza infection.
