How Antibody-Drug Conjugates Work: Targeted Chemotherapy Delivery

The Three Components

The antibody provides selectivity: it binds a protein that is more abundant on tumour cells (HER2, TROP2, Nectin-4, and others). The payload is a cytotoxic drug — typically a microtubule inhibitor or a topoisomerase I inhibitor — that is far too toxic to give systemically on its own. The linker holds them together in the bloodstream and releases the payload at the right place.

The number of payload molecules per antibody (the drug-to-antibody ratio) is a key design parameter.

How Delivery Works

The conjugate circulates, binds its target on a tumour cell, and is taken inside by receptor-mediated internalisation. Inside the cell, the linker is cleaved — by low pH, by lysosomal enzymes, or by reduction — releasing the payload, which then kills the cell by its usual mechanism.

This concentrates a potent drug where the target is expressed and reduces exposure elsewhere, although off-target uptake and payload release in the circulation still cause class-typical toxicities.

The Bystander Effect

Some payloads, once released, are membrane-permeable and can diffuse into neighbouring cells. This 'bystander' killing means an ADC can affect tumour cells that express little or no target antigen, as long as they sit next to antigen-positive cells.

The bystander effect is one reason trastuzumab deruxtecan is active in 'HER2-low' breast cancer, where HER2 is present at levels too low for trastuzumab itself to work.

Toxicity and Resistance

ADC side effects reflect both the antibody target and the payload. Interstitial lung disease with some deruxtecan-based ADCs, ocular effects with certain others, and payload-typical cytopenias, nausea and neuropathy are examples that require specific monitoring.

Resistance can develop through loss or downregulation of the target antigen, impaired internalisation or lysosomal processing, drug-efflux pumps that remove the payload, and payload-target mutations.

How HER2-Low Is Scored, and Why It Matters

HER2-low is defined on the same immunohistochemistry scale used for HER2-positive disease, but from the opposite direction: a score of 1+, or 2+ without gene amplification. It is not a separate assay, and pathologists note that telling 0 apart from 1+ is the least reproducible part of the scale.

The category exists because trastuzumab deruxtecan produces meaningful responses in HER2-low breast cancer through bystander killing, even though HER2 levels are too low for trastuzumab itself. Work is under way on whether an even lower 'HER2-ultralow' group also benefits, which would further blur the positive-versus-negative dichotomy.

Key Takeaways

• ·An ADC couples a targeting antibody, a linker and a potent cytotoxic payload.
• ·It is internalised by target-expressing cells, where the linker releases the payload.
• ·Membrane-permeable payloads enable bystander killing, which underlies activity in HER2-low disease.