Glossary

The hydrazone linker is acid-sensitive and breaks in the lysosome's low pH. It was used in the calicheamicin ADCs, but is too leaky for most modern designs.

The open question of whether a second ADC works after the first one fails, especially when both carry the same type of payload.

When a released payload leaks out of the targeted cell and kills its neighbours, including cells that lack the target.

Calicheamicin is an enediyne antibiotic used as an antibody-drug conjugate payload: it binds the minor groove of DNA and cuts both strands at picomolar concentrations, about a thousand times more cytotoxic than conventional chemotherapy. That is why it is only given attached to an antibody (Mylotarg, Besponsa), and why liver toxicity, including veno-occlusive disease, is its defining risk.

CL2A is the deliberately fragile linker in Trodelvy: it releases SN-38 in the acidic tumour environment as well as inside cells, feeding the bystander effect.

DM1 is the maytansine-derived payload in Kadcyla: a tubulin blocker held by a non-cleavable linker, so it stays in the cell it entered.

DM4 is a maytansinoid payload released in a form that can cross membranes, giving mirvetuximab soravtansine a bystander effect that DM1 lacks.

DNA alkylator payloads chemically damage DNA regardless of whether the cell is dividing, and are aimed at slow-growing and resistant tumours.

DNA cleaver payloads are natural products that cut both strands of DNA. They are used in the two oldest approved ADCs, both for leukaemias.

PBD dimers (tesirine, talirine) are DNA crosslinkers that kill at picomolar concentrations, so ADCs need a drug-to-antibody ratio of only about two. Fluid retention and skin and liver toxicity have ended most programmes; loncastuximab tesirine is the approved example.

The drug-to-antibody ratio (DAR) is how many payload molecules ride on each antibody, typically 2 to 8.

Duocarmycins are a DNA-alkylating payload family that damages DNA directly rather than through cell division, so they work in slow-growing tumours.

DXd is the topoisomerase poison inside Enhertu and Dato-DXd: about ten times stronger than SN-38, it spreads to neighbouring cells and leaves the body quickly once released.

Exatecan is a camptothecin that blocks topoisomerase I; it was too toxic to use as a free chemotherapy, but attached to an antibody that toxicity becomes useful, and it is the parent of deruxtecan and most next-generation ADC payloads. The family shares resistance mechanisms, so switching between exatecan ADCs after progression often disappoints.

Hydrophilic next-generation linkers have built-in sugars or polyethylene glycol that let ADCs carry more payload without clumping, and they resist efflux pumps.

The linker is the chemical tether between antibody and payload. It must hold in the blood and let go inside the tumour.

The non-cleavable maleimidocaproyl (mc) linker is a tether with no cleavage site: the payload is released only when the antibody is fully digested.

The mc-Val-Cit-PABC linker is the workhorse of the vedotin ADCs: a valine-citrulline dipeptide cut by cathepsin B, releasing MMAE with a bystander effect.

MMAE is the tubulin-blocking payload in brentuximab, enfortumab, polatuzumab and tisotumab vedotin, four approved ADCs: it halts cell division and, being membrane permeable, leaks into neighbouring tumour cells. Nerve damage and low neutrophil counts are its signature side effects.

MMAF is a charged cousin of MMAE that cannot cross membranes, so it kills only the targeted cell and spares neighbours. Eye side effects are characteristic.

The payload is the poison an ADC carries, usually a chemotherapy far too toxic to give on its own.

The PBD dimer SG3199 crosslinks DNA in the minor groove without distorting it, so cells fail to detect the damage; it kills at picomolar concentrations, so ADCs need only a low drug-to-antibody ratio. Fluid retention, skin reactions and light sensitivity stopped several programmes; loncastuximab tesirine in large B-cell lymphoma is the approved example.

SMCC is the non-cleavable thioether linker in Kadcyla: the payload is freed only when the whole antibody is digested, so nothing leaks to neighbours.

SN-38 is the active form of the chemotherapy irinotecan and the payload of sacituzumab govitecan. It blocks topoisomerase I so DNA breaks during copying, but it kills cells only at nanomolar concentrations, so the ADC carries roughly eight copies per antibody and uses a linker that releases it in the tumour; slow metabolisers (UGT1A1*28) get more diarrhoea.

Sulfo-SPDB is a hindered disulfide linker that is stable in blood but is cut by the reducing environment inside cells, then converted to a membrane-crossing form.

T030 is the belotecan-derived topoisomerase payload in sacituzumab tirumotecan, designed to be less affected by the pumps that eject SN-38.

The GGFG tetrapeptide (glycine-glycine-phenylalanine-glycine) is the tether between antibody and payload in Enhertu and Dato-DXd. Lysosomal cathepsins cut it inside the cancer cell, and it holds in circulation well enough to allow eight payloads per antibody, a load earlier linkers could not carry safely.

Topoisomerase-I inhibitor payloads are the payload class behind Enhertu, Trodelvy and Dato-DXd: poisons that trap the enzyme that untwists DNA, so dividing cells break their own DNA.

Tubulin inhibitor payloads were the first generation of modern ADC payloads: drugs that jam the cell's scaffolding so it cannot divide. Nerve and eye side effects are typical.

The Val-Ala dipeptide linker is easier to manufacture and less prone to aggregation than valine-citrulline, and is used with PBD payloads.

A birth variation in which the bile duct and pancreatic duct join outside the wall of the bowel, so pancreatic juice flows back up into the bile ducts and gallbladder and irritates their lining for life. It carries a high risk of gallbladder cancer, and removing the gallbladder is advised once it is found.

Cancer spread to the bones, most common in prostate, breast, lung, kidney and thyroid cancer and myeloma. It causes pain, fractures and high calcium, and the complications are counted in trials as 'skeletal-related events'.

Tumour deposits that have travelled to the brain from a cancer elsewhere, ten times more common than cancers that start in the brain, mostly from lung, breast, melanoma and kidney cancer. Because the blood-brain barrier excludes most drugs, whether a medicine reaches and shrinks them now decides which drug is chosen, and trials report intracranial progression separately.

Where the food pipe meets the stomach. Cancers here are classed by how far above or below the junction they centre (Siewert I-III), which decides whether they are treated like oesophageal or stomach cancer.

Head and neck cancer is really several cancers named by exact location: mouth (oral cavity), back of the throat (oropharynx, where HPV cancers arise), voice box (larynx), lower throat (hypopharynx) and behind the nose (nasopharynx). Each behaves and is treated differently.

Cancer cells spreading in the fluid and membranes that bathe the brain and spinal cord, rather than as a solid lump. It causes headaches, nerve palsies and confusion and has been one of the hardest situations to treat.

Whether the cancer has reached the nearby lymph nodes, the filters along the lymphatic drainage. It is the single strongest predictor of whether cancer has escaped the organ, and it drives most decisions about extra treatment after surgery.

Fluid that builds up around the lung (pleural effusion) or in the abdomen (ascites) because cancer cells irritate the lining and block lymph drainage; it causes breathlessness or a swollen, tight belly.

The space in the middle of the chest between the two lungs, containing the heart, great vessels, windpipe, food pipe and the lymph nodes that lung cancer spreads to first.

The thin membrane lining the abdominal cavity and covering the bowel. Cancers of the ovary, stomach, colon, appendix and pancreas seed it with small, poorly vascularised deposits that CT under-detects and drugs reach badly, which is why surgery with heated intraperitoneal chemotherapy (HIPEC) is used in appendiceal and selected ovarian cancers.

The two-layered lining around each lung. Mesothelioma grows from it, lung and breast cancers spread to it, and fluid collecting between its layers causes breathlessness.

Liver cancer growing into the main vein that brings blood from the gut to the liver. It marks advanced disease, rules out most surgery and transplant, and makes some local treatments unsafe.

The space at the back of the abdomen, behind the gut's lining, holding the kidneys, adrenals, pancreas, aorta and the para-aortic lymph nodes. Tumours here grow large before they are felt.

Tiny pouches where the gallbladder lining pushes down into the muscle wall, common in gallbladders damaged by stones and inflammation. They matter in cancer because an early tumour that tracks down into these pouches behaves worse than one that stays on the surface, and mucus trapped in them can be mistaken for cancer under the microscope.

Uberon names anatomical structures (organs, tissues) and the Cell Ontology names cell types, each with a code, so that a tissue label or a cell-type annotation means the same thing across datasets.

A carcinoma arising from gland-forming cells, the kind that make mucus, milk, digestive juices or hormones. The most common type of breast, lung, colon, prostate, pancreas and stomach cancer.

An agonist switches a receptor on, imitating the natural signal; an antagonist sits in the receptor and blocks it without switching it on. Cancer medicine uses both.

When a cell carries extra copies of a gene, sometimes 50 or more instead of the normal two, so it makes far too much of that protein. HER2 amplification in breast cancer is the classic example and is what trastuzumab exploits; MET amplification is a common escape route from EGFR inhibitors in lung cancer.

The growth of new blood vessels. A tumour bigger than a pinhead needs its own blood supply and sends out signals (mainly VEGF) to recruit one; anti-angiogenic drugs cut that supply.

A Y-shaped protein the immune system makes to grab onto one specific target. Manufactured antibodies are now a cornerstone of cancer treatment, either blocking a protein or delivering a payload to it.

Anything an antibody or immune cell can recognise, typically a protein on a cell's surface. In cancer, an antigen is the flag that tells a drug or an immune cell 'this is the cell to attack'.

The cell's built-in self-destruct programme, which tidily dismantles a damaged or unwanted cell without alarming its neighbours. Cancer cells disable it by mutating TP53 or overproducing BCL-2; chemotherapy and radiation work largely by inflicting enough damage to trigger it, and venetoclax removes the BCL-2 shield directly.

The immune cells that make antibodies. They matter in cancer twice over: as the source of every therapeutic antibody, and as the cells that go wrong in most lymphomas, leukaemias and myeloma.

A benign tumour grows but stays put and does not invade; a malignant tumour invades surrounding tissue and can spread. Only malignant tumours are cancer.

The soft tissue inside bones where all blood cells are made. Chemotherapy damages it, causing the low blood counts that limit how much treatment a patient can take.

Cancer of the epithelium, the lining tissue that covers surfaces and forms glands. Around 85% of cancers are carcinomas, including breast, lung, colon, prostate and skin cancers.

The smallest living unit of the body. You are made of roughly 30 trillion of them, and cancer begins when one of them starts dividing when it should not.

The ordered sequence a cell goes through to copy its DNA and split in two, with checkpoints along the way where it pauses to check for damage. Cancer cells run through the checkpoints.

One cell splitting into two identical daughters. Tissues need it for growth and repair; cancer is cell division that no longer stops.

A population of cells, usually taken from a tumour decades ago, that keeps dividing indefinitely in the laboratory. The workhorse of cancer research: cheap, fast and infinitely reproducible, but a distant cousin of a real tumour.