ADCs are made of three core components — a monoclonal antibody, a chemical linker, and a cytotoxic payload — that together act as a targeted "biological missile" for delivering potent drugs directly to cancer cells.
The Three Core Components
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Monoclonal antibody: A humanized or fully human IgG that binds a tumor-associated antigen on the cancer cell surface (e.g., HER2, TROP2, CD30, Nectin-4). It provides specificity and, ideally, gets internalized after binding.
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Linker: A chemical bridge that covalently attaches the payload to the antibody, typically via cysteine or lysine residues. Linkers are either cleavable (peptide, hydrazone, disulfide — designed to break in the tumor/lysosomal environment) or non-cleavable (stable thioethers that require full antibody degradation to release payload).
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Cytotoxic payload: An ultra-potent small molecule, roughly 100–1,000x more potent than standard chemotherapy, since only a small fraction of the dose reaches the tumor. Major classes include microtubule inhibitors (MMAE, DM1/DM4, MMAF), DNA-damaging agents (calicheamicin, PBD dimers), and topoisomerase I inhibitors (SN-38, DXd/exatecan).
A key design metric is the drug-antibody ratio (DAR) — typically 2 to 8 payload molecules per antibody — which balances potency against aggregation and pharmacokinetic stability.
Mechanism of Action
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Target binding: After IV infusion, the antibody portion binds its specific antigen on the cancer cell surface.
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Internalization: The ADC-antigen complex is taken into the cell via receptor-mediated endocytosis, forming an endosome that matures and fuses with a lysosome.
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Linker cleavage / antibody degradation: In the lysosome, acidic pH and proteases (e.g., cathepsins) cleave the linker (for cleavable linkers) or degrade the entire antibody (for non-cleavable linkers), liberating the active payload or a payload-amino acid adduct.
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Payload action: The released drug diffuses into the cytosol or nucleus and kills the cell — by binding microtubules to block mitosis, damaging/crosslinking DNA, or inhibiting topoisomerase I to cause replication-associated breaks.
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Bystander effect: If the payload is membrane-permeable and the linker is cleavable, released drug can diffuse out and kill neighboring antigen-low or antigen-negative tumor cells, which is especially valuable in heterogeneous solid tumors.
This design allows ADCs to combine an antibody's precision with a small molecule's killing power, achieving a wider therapeutic window than conventional chemotherapy — though the "how" of linker chemistry ultimately governs efficacy, bystander activity, and off-target toxicity.
Reviews:
(1) Dumontet, C., Reichert, J. M., Senter, P. D., Lambert, J. M., & Beck, A. (2023). Antibody–drug conjugates come of age in oncology. In Nature Reviews Drug Discovery (Vol. 22, Issue 8, pp. 641–661). Nature Research. https://doi.org/10.1038/s41573-023-00709-2