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bioRxiv · 10.1101/2025.04.06.647354

Targeting the ITGA3B1 Complex with A Novel Antibody-Drug Conjugate for Metastatic Bladder Cancer

Jung, H.·Lee, J.·Kim, E. G.·Ahn, J.·Haffner, M.·Nelson, P. S.·Kim, K.·Lee, J. K.·Yi, E. C.·Kim, K. M.
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Abstract

Advances in antibody (Ab) phage display technologies have enabled the development of targeted therapies with enhanced precision and clinical efficacy. Here, we report a phenotypic screening strategy combining target-unbiased live-cell biopanning with in situ chemical crosslinking and mass spectrometry to identify internalizing antibodies and their cognate antigens--key features for effective antibody-drug conjugate (ADC) development. Using this approach, we identified the 2E7 antibody, which exhibits rapid internalization and high specificity for the integrin 3{beta}1 (ITGA3B1) heterodimer, a complex overexpressed in multiple solid tumors, including bladder cancer. We generated an ITGA3B1-targeted ADC by conjugating monomethyl auristatin E (MMAE) to the 2E7 antibody, enabling selective delivery of cytotoxic payloads to ITGA3B1-positive cells. In preclinical bladder cancer models, this ADC demonstrated potent and dose-dependent antitumor efficacy, with significant tumor regression and improved survival. Our findings establish a framework for target discovery using live-cell phenotypic screening and position ITGA3B1 as a promising therapeutic target for ADC-based treatment of advanced bladder cancer. TeaserLive-cell biopanning uncovers ITGA3B1 as a target for ADC development in metastatic bladder cancer.

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Jung, H., Lee, J., Kim, E. G., Ahn, J., Haffner, M., Nelson, P. S., Kim, K., Lee, J. K., Yi, E. C., Kim, K. M.. 2025-04-07. Targeting the ITGA3B1 Complex with A Novel Antibody-Drug Conjugate for Metastatic Bladder Cancer. https://doi.org/10.1101/2025.04.06.647354

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