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These dramatic changes are due in part to our improved understanding of the molecular features of bladder tumors and the identification of tumor-associated antigens specific to UC, which may serve as druggable targets. Despite notable advances and the clinical success of ADCs in other malignancies, their full potential in UC remains largely unmet. Early clinical success of enfortumab vedotin and sacituzumab govitecan demonstrated antitumor activity; however, there are multiple challenges with these ADCs, including on-target, off-tumor toxicity and difficulty in maintaining sustained responses. Newer-generation ADC constructs, either alone or as part of combination approaches, are currently under investigation. This review examines the historical development, current landscape, and emerging trends in ADC therapy for UC, highlighting both the progress made and obstacles that continue to hinder optimal therapeutic outcomes.<\/jats:p>","DOI":"10.1200\/edbk-25-471924","type":"journal-article","created":{"date-parts":[[2025,2,6]],"date-time":"2025-02-06T20:59:07Z","timestamp":1738875547000},"source":"Crossref","is-referenced-by-count":6,"title":["Unmet Potential of Antibody-Drug Conjugates: An Evaluation of the Past, Present, and Future of Antibody-Drug Conjugate Development in Advanced Urothelial Carcinoma"],"prefix":"10.1200","volume":"45","author":[{"given":"Kevin K.","family":"Zarrabi","sequence":"first","affiliation":[{"name":"Department of Medical Oncology, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Abhiraj","family":"Saxena","sequence":"additional","affiliation":[{"name":"Rutgers Robert Wood Johnson Medical School, Division of Medical Oncology, Rutgers Cancer Institute of New Jersey, Rutgers University, New Brunswick, NJ"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kent W.","family":"Mouw","sequence":"additional","affiliation":[{"name":"Department of Radiation Oncology, Dana-Farber Cancer Institute, Brigham &amp; Women's Hospital, Harvard Medical School, Boston, MA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Vadim S.","family":"Koshkin","sequence":"additional","affiliation":[{"name":"Division of Hematology\/Oncology, Department of Medicine, University of California San Francisco, Helen Diller Family Comprehensive Cancer Center, San Francisco, CA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Terence","family":"Friedlander","sequence":"additional","affiliation":[{"name":"Division of Hematology\/Oncology, Department of Medicine, University of California San Francisco, Helen Diller Family Comprehensive Cancer Center, San Francisco, CA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"233","reference":[{"key":"e_1_3_2_2_2","doi-asserted-by":"publisher","DOI":"10.3322\/caac.21863"},{"key":"e_1_3_2_3_2","volume-title":"Cancer Stat Facts: Bladder Cancer","year":"2024","unstructured":"Cancer Stat Facts: Bladder Cancer. 2024. https:\/\/seer.cancer.gov\/statfacts\/html\/urinb.html"},{"key":"e_1_3_2_4_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.eururo.2023.03.029"},{"key":"e_1_3_2_5_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ctrv.2018.07.002"},{"key":"e_1_3_2_6_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41585-020-00404-6"},{"key":"e_1_3_2_7_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41392-022-00947-7"},{"key":"e_1_3_2_8_2","doi-asserted-by":"publisher","DOI":"10.1038\/nrd.2016.268"},{"key":"e_1_3_2_9_2","doi-asserted-by":"publisher","DOI":"10.3390\/cells11050803"},{"key":"e_1_3_2_10_2","doi-asserted-by":"publisher","DOI":"10.1007\/s00280-022-04459-7"},{"key":"e_1_3_2_11_2","doi-asserted-by":"publisher","DOI":"10.3390\/cancers16132420"},{"key":"e_1_3_2_12_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa2203690"},{"key":"e_1_3_2_13_2","doi-asserted-by":"publisher","DOI":"10.3389\/fonc.2023.1254906"},{"key":"e_1_3_2_14_2","doi-asserted-by":"publisher","DOI":"10.3389\/fonc.2024.1354543"},{"key":"e_1_3_2_15_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41585-020-00394-5"},{"key":"e_1_3_2_16_2","doi-asserted-by":"publisher","DOI":"10.1186\/s13046-015-0144-7"},{"key":"e_1_3_2_17_2","doi-asserted-by":"publisher","DOI":"10.18632\/oncotarget.14206"},{"key":"e_1_3_2_18_2","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.19.02044"},{"key":"e_1_3_2_19_2","doi-asserted-by":"publisher","DOI":"10.1016\/S1470-2045(21)00094-2"},{"key":"e_1_3_2_20_2","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.19.01140"},{"key":"e_1_3_2_21_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa2035807"},{"key":"e_1_3_2_22_2","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.22.02887"},{"key":"e_1_3_2_23_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.eururo.2024.08.012"},{"key":"e_1_3_2_24_2","doi-asserted-by":"publisher","DOI":"10.6004\/jnccn.2024.0024"},{"key":"e_1_3_2_25_2","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2024.42.16_suppl.4502"},{"key":"e_1_3_2_26_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.annonc.2024.08.2073"},{"key":"e_1_3_2_27_2","doi-asserted-by":"publisher","DOI":"10.1002\/cncr.34057"},{"key":"e_1_3_2_28_2","article-title":"Outcomes with enfortumab vedotin in patients with advanced urothelial carcinoma and histology variants: Analysis of the UNITE study","volume":"42","author":"Jindal T","year":"2024","unstructured":"Jindal T, Jiang CY, Alhalabi O, et al: Outcomes with enfortumab vedotin in patients with advanced urothelial carcinoma and histology variants: Analysis of the UNITE study. 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