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When T cell-mediated immunity is compromised, HCMV reactivation can lead to increased morbidity and mortality. HCMV antigens are processed and presented as peptides on the cell surface via HLA I complexes to the T cell receptor (TCR) of T cells. The generation of antibodies against HCMV peptides presented on HLA complexes (TCR-like antibodies) has been described, but is without therapeutic applications to date due to the polygenic and polymorphic nature of HLA genes. We set out to obtain antibodies specific for HLA\/HCMV-peptides, covering the majority of HLA alleles present in European populations. Using phage display technology, we selected 10 Fabs, able to bind to HCMV-peptides presented in the 6 different HLA class I alleles A*0101, A*0201, A*2402, B*0702, B*0801 and B*3501. We demonstrate specific binding of all selected Fabs to HLA-typed lymphoblastoid cell lines (EBV-transformed B cells) and lymphocytes loaded with HCMV-peptides. After infection with HCMV, 4\/10 tetramerized Fabs restricted to the alleles HLA-A*0101, HLA-A*0201 and HLA-B*0702 showed binding to infected primary fibroblasts. When linked to the pseudomonas exotoxin A, these Fab antibodies induce highly specific cytotoxicity in HLA matched cell lines loaded with HCMV peptides. TCR-like antibody repertoires therefore represent a promising new treatment modality for viral infections and may also have applications in the treatment of cancers.<\/jats:p>","DOI":"10.1007\/s00262-020-02564-1","type":"journal-article","created":{"date-parts":[[2020,4,16]],"date-time":"2020-04-16T04:15:32Z","timestamp":1587010532000},"page":"1535-1548","update-policy":"http:\/\/dx.doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Characterization of an HLA-restricted and human cytomegalovirus-specific antibody repertoire with therapeutic potential"],"prefix":"10.1007","volume":"69","author":[{"given":"Moritz","family":"Bewarder","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gerhard","family":"Held","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lorenz","family":"Thurner","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Stephan","family":"Stilgenbauer","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sigrun","family":"Smola","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Klaus-Dieter","family":"Preuss","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gabi","family":"Carbon","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Birgit","family":"Bette","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Konstantinos","family":"Christofyllakis","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Joerg Thomas","family":"Bittenbring","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Arne","family":"Felbel","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alexander","family":"Hasse","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Niels","family":"Murawski","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Dominic","family":"Kaddu-Mulindwa","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Frank","family":"Neumann","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2020,4,16]]},"reference":[{"key":"2564_CR1","unstructured":"Bewarder M, Smola S, Preuss D, Bette B, Carbon G, Thurner L, Bittenbring J, Christofyllakis K, Kaddu-Mulindwa D, Held G, Neumann F (2018) HLA restricted, HCMV specific Fab\/single chain fragments bind to HCMV infected primary fibroblasts and exert cytotoxic effects on HCMV-peptide pulsed HEK cells. 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Sci Transl Med 5(174):174ra127. https:\/\/doi.org\/10.1126\/scitranslmed.3004916","journal-title":"Sci Transl Med"}],"container-title":["Cancer Immunology, Immunotherapy"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s00262-020-02564-1.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1007\/s00262-020-02564-1\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s00262-020-02564-1.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,4,15]],"date-time":"2021-04-15T23:36:44Z","timestamp":1618529804000},"score":1,"resource":{"primary":{"URL":"https:\/\/link.springer.com\/10.1007\/s00262-020-02564-1"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,4,16]]},"references-count":45,"journal-issue":{"issue":"8","published-print":{"date-parts":[[2020,8]]}},"alternative-id":["2564"],"URL":"https:\/\/doi.org\/10.1007\/s00262-020-02564-1","relation":{},"ISSN":["0340-7004","1432-0851"],"issn-type":[{"value":"0340-7004","type":"print"},{"value":"1432-0851","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,4,16]]},"assertion":[{"value":"1 September 2019","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"2 April 2020","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"16 April 2020","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Compliance with ethical standards"}},{"value":"The authors declare that they have no conflict of interest.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Conflict of interest"}},{"value":"The study was conducted in accordance with the Helsinki Declaration and approved by the local ethics committee (\u00c4rztekammer des Saarlandes, ID 110\/19). HLA-typed, healthy donors of blood and skin biopsies gave written informed consent prior to study inclusion.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethical approval"}},{"value":"The melanoma cell lines Me 260 and Me 275 were provided by the Ludwig Institute for Cancer Research, Lausanne, Switzerland. The melanoma cell line SK-mel-23 was provided by the Memorial Sloan Kettering Cancer Center, New York, USA. Cell lines A-431 (ATCC\u00ae CRL-1555) and MRC-5 (ATCC\u00ae CCL-171\u2122) were bought from ATCC, Manassas, Virginia, USA.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Cell line authentication"}}]}}