{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,27]],"date-time":"2026-08-27T09:23:00Z","timestamp":1787822580090,"version":"build-2784847793"},"reference-count":89,"publisher":"MDPI AG","issue":"17","license":[{"start":{"date-parts":[[2026,8,27]],"date-time":"2026-08-27T00:00:00Z","timestamp":1787788800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"National Center for Tumor Diseases","award":["G851"],"award-info":[{"award-number":["G851"]}]},{"award":["G851"],"award-info":[{"award-number":["G851"]}],"id":[{"id":"https:\/\/ror.org\/01txwsw02","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>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 Fc\u03b3RIII\/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 CD3\u03b5. 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.<\/jats:p>","DOI":"10.3390\/cells15171545","type":"journal-article","created":{"date-parts":[[2026,8,27]],"date-time":"2026-08-27T09:00:35Z","timestamp":1787821235000},"page":"1545","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["T-Cell Receptor Single-Chain Antibody IgG1-Fc Fusion Proteins as Bispecific Engagers for Natural Killer and T Cells"],"prefix":"10.3390","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0009-0001-3618-090X","authenticated-orcid":false,"given":"Annkathrin C.","family":"Teschner","sequence":"first","affiliation":[{"name":"Clinical Cooperation Unit Applied Tumor Immunity, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120 Heidelberg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6315-4141","authenticated-orcid":false,"given":"M\u00e1rcia","family":"Gon\u00e7alves","sequence":"additional","affiliation":[{"name":"Clinical Cooperation Unit Applied Tumor Immunity, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120 Heidelberg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6067-9591","authenticated-orcid":false,"given":"Marten","family":"Meyer","sequence":"additional","affiliation":[{"name":"Clinical Cooperation Unit Applied Tumor Immunity, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120 Heidelberg, Germany"},{"name":"Department of Medical Oncology, Heidelberg University Hospital, Heidelberg University, 69120 Heidelberg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Inka","family":"Z\u00f6rnig","sequence":"additional","affiliation":[{"name":"Department of Medical Oncology, Heidelberg University Hospital, Heidelberg University, 69120 Heidelberg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dirk","family":"J\u00e4ger","sequence":"additional","affiliation":[{"name":"Clinical Cooperation Unit Applied Tumor Immunity, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120 Heidelberg, Germany"},{"name":"Department of Medical Oncology, Heidelberg University Hospital, Heidelberg University, 69120 Heidelberg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9475-0122","authenticated-orcid":false,"given":"Frank","family":"Momburg","sequence":"additional","affiliation":[{"name":"Clinical Cooperation Unit Applied Tumor Immunity, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120 Heidelberg, Germany"},{"name":"Department of Medical Oncology, Heidelberg University Hospital, Heidelberg University, 69120 Heidelberg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,8,27]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"301","DOI":"10.1038\/s41573-024-00896-6","article-title":"The present and future of bispecific antibodies for cancer therapy","volume":"23","author":"Klein","year":"2024","journal-title":"Nat. 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