OutMARCH-ing cancer: Towards innovative membrane protein degrader modalities for cancer treatment

The OutMARCH project pioneers a paradigm-shifting protein degradation technology aimed at transforming the therapeutic landscape for cancer and beyond. By engineering a novel class of bispecific antibodies—SureTACs—that harness membrane-bound E3 ubiquitin ligases to selectively degrade disease-driving surface proteins. This groundbreaking lysosomal-targeting approach offers greater selectivity, durability, and breadth than conventional blocking therapies and, moreover, enables the targeting of previously 'undruggable' proteins. Central to our innovation is the utilization of the MARCH family of membrane-bound E3 ligases—an unconventional class of enzymes with remarkable substrate promiscuity and cancer-selective expression profiles. These properties make MARCH E3s ideal effectors for tissue-specific protein degradation, reducing off-target toxicity and overcoming treatment resistance. To unlock their therapeutic potential, we will develop a modular platform combining antibody engineering, innovative screening technologies, and machine-learning-guided design. The result will be a new class of biologics that direct the body’s own cellular machinery to dispose of harmful proteins.Our initial focus is on two urgent oncology needs: therapy-resistant B-cell lymphomas and difficult-to-treat gastrointestinal cancers. Both cancer types rely on critical cell surface signaling hubs that evade traditional drug targeting. By degrading cancer-driving proteins at the cell surface, we aim to drive tumor-specific protein elimination to achieve durable anti-cancer effects. Using AI-guided antibody design and optimized E3-target pairing screens, OutMARCH will establish the first programmable, modular membrane degrader platform. While currently focused on oncology, this platform has broad potential across autoimmunity, transplantation, and chronic inflammation—paving the way for a new era of programmable degradation in precision medicine.