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| Home > Publications database > T-Cell Receptor Single-Chain Antibody IgG1-Fc Fusion Proteins as Bispecific Engagers for Natural Killer and T Cells. |
| Home > Publications database > T-Cell Receptor Single-Chain Antibody IgG1-Fc Fusion Proteins as Bispecific Engagers for Natural Killer and T Cells. |
| Journal Article | DKFZ-2026-02288 |
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2026
MDPI
Basel
Abstract: Soluble variants of recombinant T cell receptors (TCRs) have become attractive tools for the retargeting of cytotoxic T cells toward intracellular tumor or viral antigens by combining them with CD3-binding antibodies in bispecific T cell engagers; however, TCR-based NK cell engagers have not been studied so far. Here, we developed TCR-based bispecific agents for the redirection of NK cells utilizing a bivalent IgG1-like format. Trifunctional NK engagers included an Fc part with enhanced binding to FcγRIII/CD16A and single-chain (scFv) antibodies recognizing either NKp46 or CD16A, activating NK cell receptors. HCMV pp65/HLA-A2 reactive TCR-scFv-Fc fusion proteins incorporating an affinity-matured TCR and anti-NKp46 scFv activated peripheral blood NK cells and induced cytotoxicity in an antigen-specific manner. For T cell redirection, TCR-scFv-Fc fusion proteins included an scFv antibody recognizing CD3ε. Compared with NK cell engagers, T cell engagers showed similar sensitivity but lower peptide selectivity. For two TCRs recognizing melanoma-associated peptides, affinity-matured TCR-scFv-Fc fusion proteins enabled NK and T cell redirection and activation, and killing of tumor target cells loaded with exogenous peptides. Our results expand the versatility of the soluble TCR technology to NK cell engagers; however, they still require improvement in sensitivity to target tumor cells with low peptide/MHC-I complex densities.
Keyword(s): Humans (MeSH) ; Killer Cells, Natural: immunology (MeSH) ; Killer Cells, Natural: metabolism (MeSH) ; Immunoglobulin G: metabolism (MeSH) ; Immunoglobulin G: immunology (MeSH) ; Recombinant Fusion Proteins: metabolism (MeSH) ; T-Lymphocytes: immunology (MeSH) ; Antibodies, Bispecific: immunology (MeSH) ; Receptors, Antigen, T-Cell: metabolism (MeSH) ; Receptors, Antigen, T-Cell: immunology (MeSH) ; Single-Chain Antibodies: metabolism (MeSH) ; Single-Chain Antibodies: immunology (MeSH) ; Immunoglobulin Fc Fragments: metabolism (MeSH) ; Receptors, IgG: metabolism (MeSH) ; ADCC ; T cell costimulation ; T cell receptor (TCR) ; TCR-based NK cell engager ; TCR-based T cell engager ; bispecific antibodies ; peptide/MHC-I complexes ; tumor immunology ; Immunoglobulin G ; Recombinant Fusion Proteins ; Antibodies, Bispecific ; Receptors, Antigen, T-Cell ; Single-Chain Antibodies ; Immunoglobulin Fc Fragments ; Receptors, IgG
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