2. Academic Validation
  3. Phenotypic discovery and therapeutic evaluation of an ITGA3B1-targeting antibody-drug conjugate for bladder cancer

Phenotypic discovery and therapeutic evaluation of an ITGA3B1-targeting antibody-drug conjugate for bladder cancer

  • Sci Adv. 2026 Jan 2;12(1):eady0041. doi: 10.1126/sciadv.ady0041.
Junghyeon Lee 1,  Hyeryeon Jung 1 2,  Eunhee G Kim 1,  Jinsung Ahn 2,  Michael C Haffner 3 4,  Peter S Nelson 3,  Kwang Pyo Kim 5 6,  John K Lee 3 7 8,  Eugene C Yi 2 9,  Kristine M Kim 1 10
Affiliations

Affiliations

  • 1 Department of Systems Immunology, Division of Biomedical Convergence, College of Biomedical Science, Kangwon National University, Chuncheon 24341, Republic of Korea.
  • 2 Department of Molecular Medicine and Biopharmaceutical Sciences, Graduate School of Convergence Science and Technology, Seoul National University, Seoul 03080, Republic of Korea.
  • 3 Division of Human Biology, Fred Hutchinson Cancer Center, Seattle, WA, USA.
  • 4 Department of Laboratory Medicine and Pathology, University of Washington, Seattle, WA, USA.
  • 5 Department of Applied Chemistry, Department of Applied Chemistry, Institute of Natural Science, Kyung Hee University, Yongin, Republic of Korea.
  • 6 Department of Biomedical Science and Technology, Kyung Hee Medical Science Research Institute, Kyung Hee University, Seoul, Republic of Korea.
  • 7 Division of Hematology/Oncology, Department of Medicine, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA.
  • 8 Parker Institute for Cancer Immunotherapy at UCLA, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA.
  • 9 Institute of Medical and Biological Engineering, Seoul National University Medical Research Center, Seoul 03080, Republic of Korea.
  • 10 Department of Bio-Health Convergence, Kangwon National University, Chuncheon 24341, Republic of Korea.
PMID: 41477868 DOI: 10.1126/sciadv.ady0041
Abstract

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 α3β1 (ITGA3B1) heterodimer. Integrated transcriptomic and proteomic analyses revealed pronounced overexpression of ITGA3B1 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 ITGA3B1 as a promising therapeutic target in bladder Cancer.

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