Rapidly internalizing receptor

Rapidly internalizing receptors are a functional class of cell-surface proteins characterized by their ability to undergo efficient and continuous endocytosis, often independent of ligand binding or triggered by specific therapeutic agents [1, 2, 6]. In the context of drug discovery, these receptors—such as the Transferrin Receptor (TfR1/CD71), Asialoglycoprotein Receptor (ASGPR), and CD63—are highly valued as "shuttles" for the intracellular delivery of complex payloads, including Antibody-Drug Conjugates (ADCs), radionuclides, and oligonucleotide therapeutics [3, 4, 10]. By hijacking the natural endocytic machinery of these receptors, researchers can overcome the limitations of poorly internalizing primary disease targets, ensuring that cytotoxic or genetic payloads reach their intracellular sites of action [1, 2, 12]. This strategy is particularly prominent in the development of bispecific ADCs, where one arm binds a tumor-specific antigen and the other engages a rapidly internalizing receptor to facilitate uptake [2, 7, 10]. Additionally, GalNAc-conjugated RNA therapies rely on the high-capacity internalization of ASGPR in hepatocytes to achieve liver-specific gene silencing [4, 8, 9]. While highly effective for delivery, targeting these receptors requires careful consideration of safety, as off-target uptake in healthy tissues expressing the receptor can lead to systemic toxicities [6, 9].

Other names

Shuttle receptorEndocytic receptorFast-internalizing receptorInternalizing antigen

Receptor-mediated endocytosis followed by lysosomal trafficking and payload release.