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However, these products are incapable of breaking the infamous pattern of patient relapse. Two contributing factors are the use of BCMA as a target molecule and the artificial scFv format that is responsible for antigen recognition. Tackling both points of improvement in the present study, we used previously characterized VHHs that specifically target the idiotype of murine 5T33 MM cells. This idiotype represents one of the most promising yet challenging MM target antigens, as it is highly cancer- but also patient-specific. These VHHs were incorporated into VHH-based CAR modules, the format of which has advantages compared to scFv-based CARs. This allowed a side-by-side comparison of the influence of the targeting domain on T cell activation. Surprisingly, VHHs previously selected as lead compounds for targeted MM radiotherapy are not the best (CAR-) T cell activators. Moreover, the majority of the evaluated VHHs are incapable of inducing any T cell activation. As such, we highlight the importance of specific VHH selection, depending on its intended use, and thereby raise an important shortcoming of current common CAR development approaches.<\/jats:p>","DOI":"10.3390\/ijms25115634","type":"journal-article","created":{"date-parts":[[2024,5,22]],"date-time":"2024-05-22T10:00:11Z","timestamp":1716372011000},"page":"5634","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["Anti-Idiotypic VHHs and VHH-CAR-T Cells to Tackle Multiple Myeloma: Different Applications Call for Different Antigen-Binding Moieties"],"prefix":"10.3390","volume":"25","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8996-4671","authenticated-orcid":false,"given":"Heleen","family":"Hanssens","sequence":"first","affiliation":[{"name":"Molecular Imaging and Therapy Research Group (MITH), Department of Biomedical Sciences, Vrije Universiteit Brussel, Laarbeeklaan 103\/K0, 1090 Brussels, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fien","family":"Meeus","sequence":"additional","affiliation":[{"name":"Laboratory for Molecular and Cellular Therapy (LMCT), Translational Oncology Research Center, Department of Biomedical Sciences, Vrije Universiteit Brussel, Laarbeeklaan 103\/E2, 1090 Brussels, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emma L.","family":"Gesquiere","sequence":"additional","affiliation":[{"name":"Molecular Imaging and Therapy Research Group (MITH), Department of Biomedical Sciences, Vrije Universiteit Brussel, Laarbeeklaan 103\/K0, 1090 Brussels, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3753-1895","authenticated-orcid":false,"given":"Janik","family":"Puttemans","sequence":"additional","affiliation":[{"name":"Molecular Imaging and Therapy Research Group (MITH), Department of Biomedical Sciences, Vrije Universiteit Brussel, Laarbeeklaan 103\/K0, 1090 Brussels, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1882-4740","authenticated-orcid":false,"given":"Yannick","family":"De Vlaeminck","sequence":"additional","affiliation":[{"name":"Laboratory for Molecular and Cellular Therapy (LMCT), Translational Oncology Research Center, Department of Biomedical Sciences, Vrije Universiteit Brussel, Laarbeeklaan 103\/E2, 1090 Brussels, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1313-6121","authenticated-orcid":false,"given":"Kim","family":"De Veirman","sequence":"additional","affiliation":[{"name":"Laboratory for Hematology and Immunology (HEIM), Translational Oncology Research Center, Department of Biomedical Sciences, Vrije Universiteit Brussel, Laarbeeklaan 103\/D0, 1090 Brussels, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4331-3480","authenticated-orcid":false,"given":"Karine","family":"Breckpot","sequence":"additional","affiliation":[{"name":"Laboratory for Molecular and Cellular Therapy (LMCT), Translational Oncology Research Center, Department of Biomedical Sciences, Vrije Universiteit Brussel, Laarbeeklaan 103\/E2, 1090 Brussels, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9220-4833","authenticated-orcid":false,"given":"Nick","family":"Devoogdt","sequence":"additional","affiliation":[{"name":"Molecular Imaging and Therapy Research Group (MITH), Department of Biomedical Sciences, Vrije Universiteit Brussel, Laarbeeklaan 103\/K0, 1090 Brussels, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,5,22]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"17046","DOI":"10.1038\/nrdp.2017.46","article-title":"Multiple myeloma","volume":"3","author":"Kumar","year":"2017","journal-title":"Nat. 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