ADC Payloads: Expanding Beyond Microtubules and DNA-Damaging Agents

Introduction

Antibody-drug conjugates (ADCs) represent a rapidly advancing therapeutic class that combines the precision of monoclonal antibodies (mAbs) with the potency of cytotoxic agents. These ADC drugs have achieved multiple FDA approvals, with hundreds of ongoing clinical trials exploring new targets, mechanisms, and payload designs.

Historically, drug conjugates relied heavily on microtubule inhibitors and DNA-damaging agents, but emerging research has shifted toward novel ADC payloads with innovative mechanisms of action. This diversification is driving a new era in targeted cancer therapy, enabling better tumor targeting, reduced toxicity, and expanded therapeutic applications beyond oncology.

Key Drivers of ADC Advancement

The success of ADCs stems from advancements in multiple areas, including:

• Identification and validation of new tumor-specific targets that improve selectivity and minimize off-target toxicity.

• Optimization of monoclonal antibodies for ADC development, ensuring efficient tumor binding and internalization.

• Use of PEG linkers and advanced conjugation chemistries that allow for higher drug-to-antibody ratios (DARs) while preserving pharmacokinetics similar to naked antibodies.

• Expansion of cytotoxic payloads beyond traditional tubulin inhibitors and DNA-damaging agents.

This diversification is driving the next phase of ADC development, offering new mechanisms that could overcome drug resistance and expand 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 Fam-trastuzumab deruxtecan, 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 in cancer therapy 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 payloads. 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. Such ADCs may also incorporate dual payloads, combining kinase inhibitors with Tubulin inhibitors or Bcl-xL inhibitors to amplify antitumor activity and reduce adaptive resistance.

PROTAC-Based ADCs

PROTAC-based drug conjugates are an emerging innovation in ADC development. 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 ADC drugs aim to provide localized immunosuppression, reducing systemic steroid-related side effects.

Antimicrobial ADCs

Antimicrobial antibody-drug conjugates (ADCs) are emerging as a promising strategy to combat antibiotic resistance. These drug conjugates combine the specificity of monoclonal antibodies with the potency of antimicrobial agents, enabling precise delivery to infected cells. One notable example is an anti-S. aureus antibody–antibiotic conjugate that links an antibody to a highly potent antibiotic, which becomes activated only after release within the proteolytic environment of the phagolysosome.

This targeted activation significantly improves efficacy and minimizes systemic toxicity. The conjugate demonstrated superiority over vancomycin in treating bacteraemia, providing strong evidence that intracellular S. aureus contributes to invasive infections. Additionally, innovative payloads such as Toll-like receptor agonists, STING agonists, and Pseudomonas Exotoxin A are being investigated for their ability to trigger immune activation and enhance antitumor activity, further broadening the therapeutic potential of Antibody–drug conjugates beyond oncology.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 This broadens the ADC landscape to chronic diseases, highlighting the flexibility of antibody–drug conjugate platforms.

Broadening the ADC Frontier

The diversification of ADC payloads marks a turning point in biopharmaceutical innovation. By moving beyond microtubule inhibitors and DNA-damaging agents, researchers are developing next-generation ADCs with enhanced selectivity, reduced toxicity, and expanded disease applications—from oncology to autoimmunity and infectious diseases.

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.

References:

1. 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

2. 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

3. 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

4. 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