Development of Antibody-Based Strategies for Targeted Degradation of Membrane and Extracellular Proteins.

Abstract

Membrane and extracellular proteins are essential components in various biological processes that ensure cellular function and homeostasis. Their dysregulation is linked to a wide range of diseases, making them pivotal therapeutic targets. Recent innovations in therapeutic strategies have concentrated on targeted protein degradation, particularly via the endocytosis-lysosome pathway, offering a novel approach to restoring balance within cellular systems. This review elucidates recent advancements in antibody-based therapeutics designed for the targeted degradation of membrane and extracellular proteins, specifically emphasizing three key mechanisms: lysosomal targeting receptors, transmembrane E3 ligases, and lysosome-sorting signals that facilitate the degradation of disease-relevant proteins. We focus on various construction strategies for these antibody-based therapeutics, highlighting the potential of antibody-ligand conjugates, bispecific antibodies, and antibody fusion proteins. By leveraging the natural endocytic pathway for efficient protein internalization and subsequent lysosomal degradation, these antibody-based platforms hold significant promise for developing targeted therapies for a variety of diseases. Through this review, we aim to provide insights into the exciting field of antibody-enabled lysosomal degradation and its implications for future therapeutic interventions.