Bi-functional integrin degraders cause stronger anti-proliferative effects than a blocking antibody by modulating distinct downstream signaling

Integrins play a critical role in signaling events that regulate cell adhesion, migration, and proliferation, processes that, when dysregulated, contribute to cancer progression. Recently, innovative approaches that target extracellular proteins for degradation have suggested potential in cancer treatment by removing specific cell surface receptors and trafficking them to the lysosome for breakdown. In this context, two integrin degraders were engineered, each exploiting different lysosomal targeting pathways: the asialoglycoprotein receptor (ASGPR) and zinc and ring finger 3 (ZNRF3), respectively. Both degraders use a pan-selective human αv antibody that fully blocks ligand binding, effectively internalizing and degrading αv integrins <i>in vitro</i> and <i>in vivo</i>. Degrading cell-surface αv integrins, rather than merely blocking their interactions with the extracellular matrix (ECM), produces a stronger anti-proliferative effect by more robustly modulating oncogenic signaling pathways. Notably, these degraders exploit distinct mechanisms, including the first reporting of more profound changes in tumor-promoting integrin signaling cascades compared to ligand blocking alone, highlighting a novel avenue for integrin-targeted drug development. This strategy leads to greater suppression of tumor cell growth making it a promising and potentially superior approach to cancer therapy. Similar to other reports, <i>in vivo</i> efficacy has yet to be shown with extracellular or membrane-targeted protein degraders. Through careful pharmacokinetics characterizations, we showed that lack of <i>in vivo</i> efficacy may be due to insufficient exposure and target engagement. Our study provides useful lessons for the field to fully realize the full potential for the next generation of degrader therapeutics.