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Adv."],"published-print":{"date-parts":[[2026,1,2]]},"abstract":"<jats:p>\n                    Antibody-drug conjugates (ADCs) require antibodies with both high specificity and efficient internalization, features often overlooked by conventional discovery pipelines that rely on preselected antigens and recombinant proteins. Here, we describe an integrated phenotypic platform that combines target-unbiased live-cell biopanning with in situ chemical cross-linking and mass spectrometry to concurrently identify internalizing antibodies and their membrane-bound cognate antigens in a native cellular context. Using this approach, we identified 2E7, an antibody with rapid internalization and specificity for the integrin \u03b13\u03b21 (\n                    <jats:italic toggle=\"yes\">ITGA3B1<\/jats:italic>\n                    ) heterodimer. Integrated transcriptomic and proteomic analyses revealed pronounced overexpression of\n                    <jats:italic toggle=\"yes\">ITGA3B1<\/jats:italic>\n                    across multiple solid tumors, with particularly elevated levels in aggressive bladder cancer subtypes. A 2E7-MMAE (monomethyl auristatin E) ADC exhibited potent, dose-dependent antitumor activity in bladder cancer xenograft models, leading to tumor regression and prolonging survival. This study establishes a generalizable framework for function-first ADC discovery and nominates\n                    <jats:italic toggle=\"yes\">ITGA3B1<\/jats:italic>\n                    as a promising therapeutic target in bladder cancer.\n                  <\/jats:p>","DOI":"10.1126\/sciadv.ady0041","type":"journal-article","created":{"date-parts":[[2026,1,1]],"date-time":"2026-01-01T19:00:49Z","timestamp":1767294049000},"update-policy":"https:\/\/doi.org\/10.34133\/aaas_crossmark","source":"Crossref","is-referenced-by-count":2,"title":["Phenotypic discovery and therapeutic evaluation of an\n                    <i>ITGA3B1<\/i>\n                    -targeting antibody-drug conjugate for bladder cancer"],"prefix":"10.1126","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0009-0008-4229-7195","authenticated-orcid":true,"given":"Junghyeon","family":"Lee","sequence":"first","affiliation":[{"name":"Department of Systems Immunology, Division of Biomedical Convergence, College of Biomedical Science, Kangwon National University, Chuncheon 24341, Republic of Korea."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5179-8604","authenticated-orcid":true,"given":"Hyeryeon","family":"Jung","sequence":"additional","affiliation":[{"name":"Department of Systems Immunology, Division of Biomedical Convergence, College of Biomedical Science, Kangwon National University, Chuncheon 24341, Republic of Korea."},{"name":"Department of Molecular Medicine and Biopharmaceutical Sciences, Graduate School of Convergence Science and Technology, Seoul National University, Seoul 03080, Republic of Korea."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-9931-1000","authenticated-orcid":true,"given":"Eunhee G.","family":"Kim","sequence":"additional","affiliation":[{"name":"Department of Systems Immunology, Division of Biomedical Convergence, College of Biomedical Science, Kangwon National 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