The endosomal-lysosomal system in ADC design and cancer therapy

ABSTRACT

Introduction

This discourse delves into the intricate connections between the endosomal-lysosomal system and antibody-drug conjugates (ADCs), shedding light on an essential yet less understood dimension of targeted therapy. While ADCs have revolutionized cancer treatment, resistance remains a formidable challenge, often involving diverse and overlapping mechanisms.

Areas covered

This discourse highlights the roles of various components within the endosomal machinery, including Rab proteins, in ADC resistance development. It also explores how the transferrin–transferrin receptor and epidermal growth factor-epidermal growth factor receptor complexes, known for their roles in recycling and degradation process, respectively, can offer valuable insights for ADC design. Selected strategies to enhance lysosomal targeting are discussed, and potentially offer solutions to improve ADC efficacy.

Expert opinion

By harnessing these different insights that connect ADCs with the endosomal-lysosomal system, the field may benefit to shape the next-generation of ADC design for increased efficacy and improved patient outcomes.

KEYWORDS:

• Antibody-drug conjugates
• plasma membrane
• internalization
• endosome
• lysosome
• transferrin receptor
• epidermal growth factor receptor
• Rab proteins

Article highlights

• ADCs efficacy relies on intricate interactions with the endosomal-lysosomal system.

• ADC resistance mechanisms now include dysregulated endosomal-lysosomal processes.

• Rab GTPases play crucial roles in regulating endosomal-lysosomal dynamics and their functions are significantly altered in cancer cells.

• Effective ADC design can draw parallels and insights between well-established recycling and degradation systems (TfR and EGFR).

• Emerging strategies are demonstrating that enhancing lysosomal targeting are essential for ADC therapeutic success in the clinic.

• Improved understanding of the endosomal-lysosomal system may hold the key to overcoming resistance and enhancing ADC treatment outcomes.

Declaration of interest

JV Leyton has consulted for Merck and PinotBio in the past 5 years and owns options from Defence Therapeutics Inc. The author has no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This paper was funded by the Canadian Institutes of Health Research.