The Rise of Antibody-Drug Conjugates: A Paradigm Shift in Oncology

Introduction

Antibody-drug conjugates (ADCs) are at the forefront of oncological innovation, combining the precision of targeted therapy with the destructive power of chemotherapy. By leveraging advancements in antibody engineering, linker technologies, and payload development, ADCs are transforming cancer treatment paradigms. This blog explores their development, mechanisms, and clinical impact, highlighting recent breakthroughs and ongoing challenges [1].

A Brief History of ADCs

The concept of ADCs dates back to the 1980s, but their potential was limited by early technological hurdles, including unstable linkers and ineffective payloads. Advances in molecular biology and bioconjugation have overcome these barriers, leading to the development of clinically viable ADCs [2].

ADC Mechanism of Action

ADCs operate through a three-component design:

1. Antibody: Specifically targets tumour-associated antigens, such as HER2 or CD30, expressed on cancer cells [3].
2. Linker: Connects the antibody to the cytotoxic payload and ensures its stability in circulation. Types of linkers include cleavable (pH-sensitive, enzyme-sensitive) and non-cleavable [4].
3. Payload: A highly potent cytotoxic drug that disrupts key cellular processes, such as DNA replication or microtubule function [4].

Upon binding to the target antigen, the ADC is internalised into the cancer cell and trafficked to the lysosome, where the linker is degraded, releasing the payload to induce cell death [3].

Recent FDA Approvals and Clinical Successes

ADCs have achieved remarkable milestones in recent years, with approvals for various cancer types:

• Enhertu (trastuzumab deruxtecan): Approved for HER2-positive breast and gastric cancers, this ADC delivers a topoisomerase inhibitor payload, demonstrating impressive efficacy in refractory cases [5].
• Trodelvy (sacituzumab govitecan): Targets Trop-2 and is used in triple-negative breast cancer and urothelial carcinoma. Its innovative design addresses tumour heterogeneity effectively [6].

Other promising ADCs include Blenrep (belantamab mafodotin) for multiple myeloma and Polivy (polatuzumab vedotin) for diffuse large B-cell lymphoma [6].

Advantages of ADCs Over Traditional Chemotherapy

• Targeted Action: Minimises off-target toxicity by delivering the payload directly to cancer cells [7].
• Enhanced Efficacy: The combination of antibody specificity and potent payloads increases therapeutic outcomes [7].
• Reduced Side Effects: Sparing healthy tissues results in improved tolerability [8].

Challenges in ADC Development

Despite their promise, ADCs face several hurdles:

• Resistance Mechanisms: Cancer cells may downregulate antigen expression or develop efflux pumps to expel the payload [9].
• Toxicity: Off-target effects can still occur due to premature payload release or low specificity [9].
• Manufacturing Complexity: Producing ADCs requires expertise in biologics and small-molecule chemistry, making scalability a challenge [10].

Future Directions in ADC Research

1. Improved Linkers: Designing linkers that are stable in circulation but release payloads efficiently at the tumour site [11].
2. Novel Payloads: Developing payloads with unique mechanisms of action to overcome resistance [11].
3. Combination Therapies: Exploring ADCs alongside immunotherapies, such as checkpoint inhibitors, to enhance efficacy [12].
4. Broader Applications: Expanding ADC use beyond oncology into autoimmune disorders and infectious diseases [13].

Conclusion

ADCs represent a paradigm shift in oncology, offering hope to patients with refractory and advanced cancers. As technology evolves, their therapeutic potential continues to expand, paving the way for a future where cancer treatments are not only more effective but also more precise and patient-friendly [13].

References

1. Chari RV. Targeted cancer therapy: conferring specificity to cytotoxic drugs. Acc Chem Res. 2008;41(1):98-107.
2. FDA. FDA-approved drugs. [Internet]. Available from: https://www.fda.gov.
3. Jain N, Smith SW, Ghone S. Current ADC technologies. J Control Release. 2015;207:123-37.
4. Beck A, Wurch T. Antibody-drug conjugates in oncology. Nat Rev Drug Discov. 2015;14(7):465-84.
5. FDA. Enhertu approval. [Internet]. Available from: https://www.fda.gov.
6. Seagen. Antibody-drug conjugate approvals. [Internet]. Available from: https://www.seagen.com.
7. Lambert JM, Morris CQ. Antibody-drug conjugates for targeted cancer therapy. Trends Biotechnol. 2019;37(8):862-74.
8. Teicher BA, Chari RV. Antibody-drug conjugate therapeutics. Clin Cancer Res. 2011;17(20):6389-97.
9. Jain N. Resistance mechanisms in ADCs. J Control Release. 2021;329:1-10.
10. Beck A. Manufacturing challenges in ADCs. Nat Biotechnol. 2018;36(11):1055-66.
11. Smith SW. Innovations in linker technology for ADCs. J Med Chem. 2020;63(5):2345-56.
12. Liu R, Sun D. Combining ADCs with checkpoint inhibitors. Cancer Lett. 2020;469:77-85.
13. Chari RV, Beck A. Expanding ADC applications beyond oncology. Trends Biotechnol. 2021;39(7):700-12.