Single-Domain Antibodies as Antibody-Drug Conjugates: From Promise to Practice-A Systematic Review

Area of Science:

• Oncology
• Biotechnology
• Immunology

Background:

• Antibody-drug conjugates (ADCs) are potent targeted cancer therapies but face challenges with resistance and side effects.
• Advancements in ADC components are crucial for improving efficacy and safety.

Purpose of the Study:

• To assess single-domain antibodies (VHHs) as alternatives to conventional antibodies in ADCs.
• To review the current status and potential of VHHs in ADC development, focusing on their unique features.

Main Methods:

• A systematic literature review following PRISMA guidelines from 2014 to 2024.
• Searches in major databases (PubMed, Cochrane, ScienceDirect, LILACS) for ADCs and VHHs.
• Rigorous evaluation and synthesis of peer-reviewed articles on VHH-based ADCs.

Main Results:

• VHHs offer superior tissue penetration, stability, and manufacturability compared to conventional antibodies for drug conjugation.
• Their small size allows access to novel epitopes, and some VHHs can cross the blood-brain barrier, aiding brain tumor targeting.
• While VHH-drug conjugates are preclinical, various conjugation methods and linkers are being explored.

Conclusions:

• VHHs' rapid distribution, tumor penetration, and clearance may reduce ADC toxicity by minimizing prolonged exposure.
• Single-domain antibodies are strong candidates for next-generation ADCs, potentially enhancing both treatment efficacy and patient safety.
• Further understanding of ADC mechanisms and toxicities is needed to optimize therapeutic strategies.