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 present an integrated phenotypic platform that combines target-unbiased live-cell biopanning with in situ chemical crosslinking and mass spectrometry to concurrently identify internalizing 49 antibodies and their membrane-bound cognate antigens in a physiologic context.