Gene‑edited stem cells enable sustained antibody production with a single injection
Limitations of repeated dosing, is one enough?
Antibody drugs that require a single injection to maintain therapeutic effect currently need to be administered each time. Consequently, cost and patient inconvenience increase dramatically. There is great anticipation that cell‑based therapies could solve this problem.
Designing anti‑antibody insertion into HSPCs with CRISPR
We used CRISPR/Cas9 and homology‑directed repair (HDR) to precisely insert an antibody‑expression cassette into a safe‑harbor locus. The edited hematopoietic stem and progenitor cells and their progeny differentiate into B cells that secrete a monoclonal antibody.
Demonstration of sustained antibody production in mouse models
When edited mouse HSPCs were transplanted into immunocompetent mice, serum antibody concentrations remained at therapeutic levels for several months. In addition, we attached a destabilization domain to the antibody, allowing secretion to be modulated with a small‑molecule drug.
Future of personalized one‑shot therapy
This platform could provide long‑term antibody therapy with a single cell infusion. A modular system that can rapidly deploy antibodies for various diseases and be adjusted as needed is anticipated.
Monoclonal antibodies represent half of the top ten selling drugs. Their proven efficacy, however, generally requires repeated administration for prolonged periods of time. In contrast, cell-based therapies offer a different set of pharmacokinetics and pharmacodynamics than traditional medicines, including the potential to have lifetime durability after a single infusion. Here, we describe a genome-engineered stem cell-based platform for continuous antibody production from a single dose. Using CRISPR/Cas9 homology-directed repair mediated editing, we precisely integrated therapeutic antibody expression cassettes into a safe-harbor locus of hematopoietic stem and progenitor cells (HSPCs). Upon differentiation, these gene-targeted HSPCs generate B cells that secrete monoclonal antibodies. We validated this platform using two clinically approved antibodies, achieving efficient targeted integration of the gene-targeted antibodies (GT-Ab) in human HSPCs that successfully engraft in immunodeficient mice. Direct engineering of human B cells demonstrated robust secretion of therapeutic antibodies. To evaluate in vivo antibody production, we transplanted engineered GT-Ab murine HSPCs into immunocompetent mice, achieving durable serum antibody concentrations within the therapeutic range over several months. Lastly, by fusing the antibody to a destabilization domain, we enabled tunable antibody secretion via small molecule regulation. This modular platform establishes a potentially curative approach for chronic diseases currently reliant on repeated antibody administration, offering durable antibody production from a single treatment.
This study addresses the inconvenience and cost associated with the need for repeated antibody injections. If a single cell infusion can produce antibodies for a lifetime or extended period, the therapeutic burden in daily life will be dramatically reduced.