Antibody–drug conjugates (ADCs) now have multiple FDA approvals and hundreds of clinical trials exploring novel targets and indications. The success of ADCs stems from advancements in multiple areas, including:
Identification and validation of new tumor-specific targets.
Selection of monoclonal antibodies (mAbs) optimized for ADC design, ensuring efficient tumor binding and internalization.
Improved conjugation technologies that allow for higher drug-to-antibody ratios (DARs) while preserving pharmacokinetics similar to naked antibodies.
Expansion of cytotoxic payloads beyond traditional microtubule inhibitors and DNA-damaging agents.
The diversification of ADC payloads is driving the next phase of ADC development, offering new mechanisms of action that could overcome resistance and expand ADC applications to previously untargeted cancers.1
New Payloads with Novel Mechanisms of Action
Historically, most ADC payloads have been derived from conventional chemotherapy agents such as auristatins, maytansinoids, and DNA-damaging drugs. However, emerging payload classes with novel mechanisms of action are being explored to enhance efficacy and target resistant tumors.
Topoisomerase I Inhibitors and the Bystander Effect
Topoisomerase I inhibitors, such as DXd (deruxtecan) and SN-38, have demonstrated a strong bystander effect, being able to kill adjacent tumor cells even if they do not directly express the target antigen. This feature is particularly valuable for treating tumors with heterogeneous antigen expression, a common challenge in solid tumor therapy.
Targeting Quiescent Tumor Cells
Many ADC payloads primarily affect actively dividing cells. However, a significant portion of the tumor cell population exists in a quiescent state, escaping the effects of cytotoxic agents. Quiescent cancer cells are nonproliferating cells arrested in the G0 phase, which are associated with cancer recurrence since they can re-enter a proliferative state when conditions are favorable.2 Emerging payloads aim to target these dormant cancer cells, reducing the risk of relapse and improving long-term outcomes.
Kinase Inhibitors as ADC Payloads
Small-molecule kinase inhibitors have revolutionized targeted cancer therapy, but their systemic toxicity limits their clinical use. Kinases are enzymes that regulate cellular processes by phosphorylating proteins and biomolecules, influencing their activity, localization, and interactions. Their role in intracellular signaling and homeostasis makes them critical in processes like growth and apoptosis, with dysregulation linked to diseases such as cancer.3 Coupling kinase inhibitors to antibodies via ADC technology could enhance their specificity, reducing off-target effects while maintaining efficacy.
PROTAC-Based ADCs
Proteolysis-targeting chimeras (PROTACs) are a novel class of molecules that promote targeted protein degradation. Unlike conventional inhibitors, PROTACs work at substoichiometric levels, meaning they can achieve therapeutic effects with lower doses. Integrating PROTACs as ADC payloads could further enhance the therapeutic index of ADCs while reducing toxicity.
Related: Antibodies X PROTACs
ADC Applications Beyond Oncology
ADC Payloads for Autoimmune Diseases
The development of ADCs for autoimmune diseases has gained traction, with promising candidates in clinical trials. ABBV-3373 and ABBV-154, two ADCs delivering a glucocorticoid receptor modulator (GRM), are being evaluated for rheumatoid arthritis and Crohn’s disease. These ADCs aim to provide localized immunosuppression, reducing systemic steroid-related side effects.
Antimicrobial ADCs
Antibiotic-conjugated antibodies have also shown potential to overcoming antibiotic resistance. One antibody–antibiotic conjugate consists of an anti-S. aureus antibody conjugated to a highly efficacious antibiotic that is activated only after it is released in the proteolytic environment of the phagolysosome. It was shown to be superior to vancomycin for treatment of bacteraemia and provides direct evidence that intracellular S. aureus represents an important component of invasive infections.4
Metabolic Disease Applications
Non-cytotoxic ADC payloads are also being explored, such as an LXR agonist–ADC targeting lipid metabolism for the treatment of atherosclerosis. This approach could enable precise modulation of metabolic pathways while minimizing systemic toxicity.1
As ADC technology evolves, the integration of novel payloads and improved delivery strategies will expand their therapeutic potential. From oncology to autoimmune diseases and infectious diseases, next-generation ADCs are poised to transform multiple fields of medicine.
At Biointron, we are dedicated to accelerating antibody discovery, optimization, and production. Our team of experts can provide customized solutions that meet your specific research needs, including ADCs from our Abinvivo catalog. Contact us to learn more about our services and how we can help accelerate your research and drug development projects.
Conilh, L., Lenka Sadilkova, Viricel, W., & Dumontet, C. (2023). Payload diversification: a key step in the development of antibody–drug conjugates. Journal of Hematology & Oncology, 16(1). https://doi.org/10.1186/s13045-022-01397-y
Lindell, E., Zhong, L., & Zhang, X. (2023). Quiescent Cancer Cells—A Potential Therapeutic Target to Overcome Tumor Resistance and Relapse. International Journal of Molecular Sciences, 24(4), 3762. https://doi.org/10.3390/ijms24043762
Ayala-Aguilera, C. C., Valero, T., Álvaro Lorente-Macías, Baillache, D. J., Croke, S., & Asier Unciti-Broceta. (2021). Small Molecule Kinase Inhibitor Drugs (1995–2021): Medical Indication, Pharmacology, and Synthesis. Journal of Medicinal Chemistry, 65(2), 1047–1131. https://doi.org/10.1021/acs.jmedchem.1c00963
Lehar, S. M., Pillow, T., Xu, M., Staben, L., Kajihara, K. K., Vandlen, R., DePalatis, L., Raab, H., Hazenbos, W. L., Hiroshi Morisaki, J., Kim, J., Park, S., Darwish, M., Lee, B., Hernandez, H., Loyet, K. M., Lupardus, P., Fong, R., Yan, D., . . . Mariathasan, S. (2015). Novel antibody–antibiotic conjugate eliminates intracellular S. Aureus. Nature, 527(7578), 323-328. https://doi.org/10.1038/nature16057
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