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Immunotherapeutic strategies, albeit of proven therapeutic relevance, have been scarcely explored against this target. Therefore, this work aimed at engineering an anti-nucleolin VHH-based antibody capable of triggering anticancer immune responses. Herein, anti-nucleolin VHHs have been generated upon grafting F3 peptide-derived nucleolin-binding sequences onto a VHH CDR1 or CDR3. One of these nucleolin-binding CDR3-grafted VHH was subsequently fused to a human IgG1 Fc region, enabling a significant antibody-dependent cell-mediated cytotoxicity (ADCC). The generated anti-nucleolin VHH revealed increased binding and antiproliferative effects against cancer cells, relative to the parental VHH, while the VHH-Fc counterpart presented increased cytotoxicity relative to the corresponding VHH. This VHH-Fc also triggered an ADCC effect, in the nanomolar range, against a nucleolin-overexpressing cancer cell line. This effect was evidenced by a 2 or 1.7-fold increase of cell death, in the presence of PBMCs, relative to the parental VHH-Fc or the VHH counterpart, respectively. Overall, these formats represent the first anti-nucleolin VHHs and the first anti-nucleolin antibody with ADCC activity that have been successfully developed.<\/jats:p>","DOI":"10.1038\/s41598-018-25816-8","type":"journal-article","created":{"date-parts":[[2018,5,4]],"date-time":"2018-05-04T09:06:44Z","timestamp":1525424804000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":18,"title":["Anticancer activity and antibody-dependent cell-mediated cytotoxicity of novel anti-nucleolin antibodies"],"prefix":"10.1038","volume":"8","author":[{"given":"Sofia","family":"Romano","sequence":"first","affiliation":[]},{"given":"Vera","family":"Moura","sequence":"additional","affiliation":[]},{"given":"S\u00e9rgio","family":"Sim\u00f5es","sequence":"additional","affiliation":[]},{"given":"Jo\u00e3o Nuno","family":"Moreira","sequence":"additional","affiliation":[]},{"given":"Jo\u00e3o","family":"Gon\u00e7alves","sequence":"additional","affiliation":[]}],"member":"297","published-online":{"date-parts":[[2018,5,10]]},"reference":[{"key":"25816_CR1","doi-asserted-by":"publisher","first-page":"1911","DOI":"10.1096\/fasebj.13.14.1911","volume":"13","author":"M Srivastava","year":"1999","unstructured":"Srivastava, M. & Pollard, H. 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