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VHH3-US11 CAR19 is an experimental allogeneic chimeric antigen receptor (CAR)-T cell therapy designed for the treatment of B-cell malignancies. The therapy utilizes a tricistronic gamma-retroviral vector to express an anti-CD19 CAR alongside a novel protein-based system for immune evasion and safety. This system consists of the VHH3-US11 fusion protein, which combines an anti-CD3 single-domain antibody (VHH) with the human cytomegalovirus (HCMV) US11 protein. The VHH3 component binds to the CD3 epsilon chain, leading to the internal sequestration and downregulation of the T-cell receptor (TCR) complex, thereby preventing graft-versus-host disease (GvHD). Simultaneously, the US11 component facilitates the ubiquitination and proteasomal degradation of Major Histocompatibility Complex class I (MHC-I) molecules, protecting the allogeneic cells from host CD8+ T-cell-mediated rejection. This approach allows for the generation of off-the-shelf CAR-T cells without the need for complex genome-editing techniques like CRISPR, potentially reducing manufacturing costs and genotoxicity risks.
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