Implications of receptor-mediated endocytosis and intracellular trafficking dynamics in the development of antibody drug conjugates

Abstract

The use of antibody-drug conjugates (ADCs) as a therapeutic platform to treat cancer has recently gained substantial momentum. This therapeutic modality has the potential to increase the efficacy and reduce the systemic toxicity associated with current therapeutic regimens. The efficacy of ADCs, however, relies on the proper exploitation of intracellular sorting dynamics of the antigen as well as the specificity, selectivity and pharmacokinetic properties of the antibody itself. Our understanding of endocytosis and endosomal trafficking of receptors has appreciably increased in recent years, as improvements in the assays used to study these events have resolved many of the molecular mechanisms regulating these processes. As a result, we now have the knowledge necessary to exploit these pathways efficiently to improve the efficacy of antibody-based therapy. This review discusses some recent studies that have explored how endo/lysosomal dynamics can affect the efficacy of engineered therapeutic antibodies, including ADCs.

Figure 1. Intracellular trafficking through the endo/lysosomal system. The internalized cargo is initially contained within endocytotic vesicles which fuse together to become the early endosome. Cargo can be recycled directly back to the plasma membrane from the early endosome through the “short recycling loop” or retained within the maturing endosome. As the early endosome matures, cargo can be trafficked through the trans-golgi network for repackaging or trafficked back to the plasma membrane through the “long recycling loop.” As the early endosome matures to multivesicular bodies (MVB), the retained cargo is internalized into intraluminal vesicle (ILVs) formed within the fluid phase of the MVB and subsequently delivered to the lysosome. A biochemical event that occurs during the maturation of an early endosome to an MVB is the RAB5 to Rab7 switch. Although the precise role that the Rab5 to Rab7 switch is unknown, it serves as a reliable marker for the transition from an early endosome to a late endosome.

Figure 2. Possible Intracellular trafficking routes of Antibody-Drug Conjugates. If an ADC binds to a receptor which undergoes continual recycling back to the plasma membrane, there is the potential that the ADC may be recycled back to the plasma membrane without delivering the toxic payload, as depicted on the right trafficking route. In certain cell types, the presence of the FcRn can complicate this process, as FcRn binds IgGs and recycles them back to the plasma membrane; as depicted on the right trafficking route. However, in the absence of FcRn, dissociation of the ADC from its receptor within the endosome may lead to lysosomal trafficking of the ADC, where it can release its toxic payload to the cell, as depicted on the left trafficking route.