Types of Payloads for Antibody-Drug Conjugates (ADCs)

Antibody-drug conjugates (ADCs) are a class of biopharmaceuticals designed to deliver cytotoxic drugs selectively to target cells, typically cancer cells, by exploiting the specificity of monoclonal antibodies (mAbs) for antigens expressed on the cell surface. The design of ADCs combines the specificity of mAbs with the potent cytotoxicity of small-molecule drugs, linked via a stable and cleavable linker. The choice of payload is critical to the efficacy and safety of ADCs. Here, we provide a detailed overview of the types of payloads used in ADCs.

1. Microtubule Inhibitors

Microtubule inhibitors disrupt the microtubule network, which is essential for cell division. By preventing microtubule polymerization or depolymerization, these agents can induce cell cycle arrest and apoptosis. Common microtubule inhibitors used as ADC payloads include: 

• Auristatins: 

• MMAE (Monomethyl auristatin E): A synthetic antineoplastic agent that inhibits tubulin polymerization, leading to cell cycle arrest in the G2/M phase and subsequent apoptosis. 

• MMAF (Monomethyl auristatin F): Similar to MMAE but with a different structure that affects its potency and solubility. 

• Maytansinoids 

• DM1 (Emtansine): A derivative of maytansine that binds to tubulin and inhibits microtubule assembly, causing cell death. 

• DM4 (Ravtansine): Another maytansine derivative with similar mechanisms of action but differing pharmacokinetics and efficacy profiles. 

2. DNA-Damaging Agents 

These agents target the DNA within cancer cells, causing breaks, cross-links, or other forms of damage that prevent replication and transcription, leading to cell death. Common DNA-damaging payloads include: 

• Calicheamicins 

• Calicheamicin γ1: A potent enediyne antibiotic that induces double-stranded DNA breaks. It is highly cytotoxic and effective at inducing apoptosis. 

• Pyrrolobenzodiazepines (PBDs) 

• PBD dimers: DNA cross-linking agents that form covalent bonds with guanine residues in DNA, disrupting its function and leading to cell death. 

• Duocarmycins 

• Duocarmycin analogs: Alkylating agents that bind to the minor groove of DNA and cause irreversible alkylation, leading to DNA strand breaks and apoptosis. 

3. Topoisomerase Inhibitors

Topoisomerase inhibitors interfere with the action of topoisomerases, enzymes crucial for DNA replication and transcription. By stabilizing the topoisomerase-DNA complex, these inhibitors induce DNA breaks and cell death. Notable topoisomerase inhibitors used in ADCs include: 

• Camptothecins 

• SN-38: The active metabolite of irinotecan, which inhibits topoisomerase I, causing single-strand breaks in DNA that lead to cell death. 

• Doxorubicins 

• Doxorubicin: An anthracycline antibiotic that intercalates into DNA and inhibits topoisomerase II, leading to double-strand breaks and apoptosis. 

4. Other Cytotoxic Agents

Beyond the traditional classes, there are other cytotoxic agents used as ADC payloads, exploiting unique mechanisms of action. 

• Amanitins 

• α-Amanitin: A toxin derived from the Amanita mushroom that inhibits RNA polymerase II, blocking mRNA synthesis and leading to cell death. 

• Tubulysins 

• Tubulysin analogs: Potent cytotoxic agents that inhibit tubulin polymerization, disrupting microtubule function and inducing apoptosis. 

The selection of payloads for ADCs is a critical determinant of their therapeutic potential and safety profile. The payload must be highly potent to ensure that it can kill target cells effectively at the low concentrations achieved by ADCs in the tumor microenvironment. Additionally, the payload must be conjugatable to the antibody and remain stable in the bloodstream while being releasable once inside the target cell. Advances in ADC technology continue to expand the repertoire of payloads, improving the efficacy and reducing the toxicity of these targeted therapies.

References

1. Beck, A., Goetsch, L., Dumontet, C., & Corvaïa, N. (2017). Strategies and challenges for the next generation of antibody-drug conjugates. Nature Reviews Drug Discovery, 16(5), 315-337. 

2. Lambert, J. M., & Berkenblit, A. (2018). Antibody-drug conjugates for cancer treatment. Annual Review of Medicine, 69, 191-207. 

3. Peters, C., & Brown, S. (2015). Antibody-drug conjugates as novel anti-cancer chemotherapeutics. Bioscience Reports, 35(4), e00225.