Antibody-based targeted protein degradation: Mechanisms, challenges and future directions

Conventional cancer therapies include chemotherapy and immunotherapy. These therapies are frequently compromised by systemic toxicity, limited selectivity, and the emergence of drug resistance. These challenges have driven the search for innovative approaches that move beyond traditional inhibition to achieve selective elimination of disease-driving proteins. In recent years, targeted protein degradation (TPD) has emerged as a transformative strategy that leverages endogenous degradation pathways to eliminate proteins previously considered undruggable. While small-molecule degraders such as proteolysis-targeting chimeras (PROTACs) have received substantial attention, antibody-based TPD represents a rapidly advancing and complementary frontier. Owing to their unparalleled specificity, antibodies offer a versatile platform for directing degradation machinery toward diverse intracellular and extracellular substrates. Multiple antibody-based TPD modalities have been developed, including tripartite motif (TRIM)-Away, sweeping antibody, Seldegs, lysosome-targeting chimeras (LYTACs), antibody-based PROTACs (AbTACs), and covalently engineered nanobody chimeras (GlueTACs). Collectively, these approaches exploit antibody-mediated recognition to enable selective clearance of intracellular, cell-surface, and extracellular proteins. By extending degradation strategies beyond the cytosolic environment, these technologies open new therapeutic opportunities for cancer, autoimmune disorders, and neurodegenerative diseases. This review summarizes the mechanisms, structural innovations, and therapeutic applications of antibody-based TPD technologies. We highlight emerging preclinical evidence, outline the strengths and limitations of each modality, and discuss the translational barriers that must be overcome for clinical implementation. Finally, we propose future research directions that may accelerate the development of antibody-guided degraders into next-generation therapeutics, with the potential to reshape treatment paradigms across a broad spectrum of diseases.