Antibody-drug conjugate (ADC)
An antibody-drug conjugate is a guided missile: an antibody homes to the tumour cell, is swallowed, and releases a chemotherapy so potent it could never be given on its own.
Fifteen-plus ADCs are approved. Components: antibody (target, internalisation), linker (cleavable or not, stability), payload (tubulin inhibitors MMAE/DM1; TOP1 inhibitors DXd/SN-38; PBD dimers; calicheamicin), and drug-to-antibody ratio (DAR). Third-generation ADCs (T-DXd, sacituzumab govitecan, Dato-DXd, enfortumab vedotin) with high DAR and bystander-capable TOP1 payloads changed breast, lung, and bladder cancer. Key issues: target heterogeneity, payload cross-resistance, ILD and ocular toxicities, and sequencing multiple ADCs.
How it works
Antigen binding → receptor-mediated endocytosis → lysosomal degradation or linker cleavage → payload release → tumour cell death and, with permeable payloads, killing of neighbouring antigen-negative cells.
- Widens the therapeutic index of chemotherapy 100-fold
- Works in 'low' antigen expressers via bystander effect
- Active after chemotherapy resistance
- Payload-class toxicities are systemic (neutropenia, ILD, neuropathy, ocular)
- Resistance via antigen loss, efflux, TOP1/SLFN11 changes
- Manufacturing cost
ARX788 is a HER2 ADC with a precisely placed, non-cleavable payload that beat lapatinib-capecitabine in China and showed activity in brain metastases.
A myeloma ADC that was withdrawn in 2022 then came back in 2025 after strong trials in earlier lines.
The ADC that made the modern field credible (2011), for Hodgkin lymphoma and CD30+ lymphomas.
Datopotamab deruxtecan (Datroway) is the second TROP2 ADC and shares Enhertu's payload. In 2026 it became a first-line option for triple-negative breast cancer patients who cannot receive immunotherapy.
Disitamab vedotin is a Chinese HER2 ADC approved for gastric and bladder cancer, now in global trials with Pfizer.
Enfortumab vedotin is an ADC against Nectin-4 that, combined with pembrolizumab, nearly doubled survival in advanced bladder cancer.
Gemtuzumab ozogamicin (Mylotarg) was the very first ADC: approved in 2000, withdrawn in 2010 for toxicity, and re-approved in 2017 at a lower fractionated dose. Its history is cautionary and instructive.
Ifinatamab deruxtecan is a B7-H3 ADC showing some of the best response rates ever seen in relapsed small-cell lung cancer.
Inotuzumab ozogamicin is an antibody carrying a DNA-cutting toxin to CD22 on leukaemia cells. It gets far more relapsed ALL patients into remission than chemotherapy and bridges them to transplant.
Izalontamab brengitecan is the first bispecific ADC to succeed in a phase 3 trial, hitting two growth receptors at once in triple-negative breast cancer.
Loncastuximab tesirine (Zynlonta) is a CD19 ADC with a DNA-crosslinking payload for relapsed large B-cell lymphoma.
A folate-receptor ADC designed to work across low and high receptor levels, in a pivotal ovarian cancer trial.
Mirvetuximab soravtansine (Elahere) is the first ADC for ovarian cancer, for tumours with high folate receptor alpha.
An immunotoxin for hairy cell leukaemia that produced lasting remissions in relapsed patients but was withdrawn from sale in 2023 for commercial reasons.
A HER3-directed ADC with Enhertu's payload, active in lung and all subtypes of breast cancer, but with a bumpy regulatory road.
Pivekimab sunirine is an antibody-drug conjugate against CD123, approved in 2026 for blastic plasmacytoid dendritic cell neoplasm as the second targeted drug for this rare cancer.
Polatuzumab vedotin is an ADC against CD79b that, swapped into the classic R-CHOP regimen, became the first improvement on frontline lymphoma therapy in twenty years.
Puxitatug samrotecan is a B7-H4 ADC targeting a checkpoint-like protein enriched in breast, ovarian, and endometrial cancers.
Raludotatug deruxtecan is a CDH6 ADC in phase 3 for platinum-resistant ovarian cancer.
Rinatabart sesutecan is a next-generation folate-receptor ADC with a topoisomerase payload that responds in both ovarian and endometrial cancer regardless of receptor level.
Rovalpituzumab tesirine (Rova-T) was the first drug against DLL3 in small-cell lung cancer. AbbVie bought it for $5.8B and abandoned it after two failed phase 3 trials. The target later worked with a different weapon.
The first TROP2-targeted ADC. It delivers a strong chemotherapy directly to breast and bladder cancer cells and is now a first-line option in triple-negative breast cancer.
Sacituzumab tirumotecan is a third TROP2 ADC from China, licensed to Merck for a very large global programme. It is approved in China; in the US it has a priority voucher but not yet approval.
Sonesitatug vedotin is a Claudin 18.2 ADC in phase 3 for gastric cancer, licensed by AstraZeneca from KYM Biosciences.
Telisotuzumab vedotin (Emrelis) is the first c-MET-directed ADC, approved in 2025 for lung cancer with high c-MET protein.
Tisotumab vedotin is an ADC against tissue factor, the first to show a survival benefit in recurrent cervical cancer.
SystImmune's HER2 ADC, sharing its payload with iza-bren, now in a 1,450-patient trial to replace Kadcyla after surgery.
Trastuzumab deruxtecan (Enhertu) is the most successful ADC ever. It redefined HER2 by working in tumours with only tiny amounts of the protein, and in 2026 moved into early-stage breast cancer.
A HER2 ADC with a DNA-alkylating payload that beat chemotherapy in a phase 3 trial yet never reached the market, because eye and lung toxicity and a stronger rival arrived first.
Trastuzumab emtansine (Kadcyla, T-DM1) was the first ADC for a solid tumour (2013). It is still standard after surgery for HER2+ breast cancer patients whose tumour did not fully respond to pre-surgery treatment.
Hengrui's HER2 ADC, approved in China for lung cancer and showing Enhertu-scale results in breast cancer, part of a wave of Chinese ADCs heading for global trials.
Tusamitamab ravtansine was Sanofi's ADC against the classic CEA tumour marker, stopped for futility in lung cancer in 2023.
Zilovertamab vedotin is a ROR1-directed ADC in phase 3 for large B-cell lymphoma.
Patients with hormone-receptor-positive metastatic breast cancer that has stopped responding to endocrine therapy can be offered trastuzumab deruxtecan as their first chemotherapy-type treatment if the tumour shows any HER2 staining, rather than waiting until after conventional chemotherapy. Whether to use it before or after chemotherapy is now a choice, since overall survival was not shown to differ and the drug carries a risk of lung inflammation.
Almost every patient newly diagnosed with advanced bladder or urothelial cancer should now be offered enfortumab vedotin plus pembrolizumab rather than chemotherapy, with median survival extended from about 16 months to over two and a half years. Neuropathy and skin toxicity need monitoring and dose adjustment, and patients with severe diabetes or pre-existing neuropathy need care. Platinum chemotherapy remains an option for those who cannot receive the combination.
For hormone-receptor-positive metastatic breast cancer that has already had chemotherapy, Dato-DXd controls the disease for longer with fewer severe side effects than chemotherapy, but does not help patients live longer, so it is not a standard option here. The result is a reminder that progression-free survival is a surrogate; regulators and clinicians should wait for survival data before adopting an ADC in a setting where later therapies are effective.
For HER2-positive metastatic breast cancer that has progressed after trastuzumab and a taxane, trastuzumab deruxtecan is now the standard second-line treatment and T-DM1 has moved later in the sequence. The benefit is large enough that ADC design, not just the target, is understood to be what matters. Patients need lung monitoring because of the risk of pneumonitis.
Patients whose breast cancer was previously called HER2-negative may now be eligible for an effective HER2-directed drug if their tumour has even low-level HER2 staining, so pathology reports must now distinguish HER2-low (1+ or 2+/ISH-negative) from HER2-zero. This applies to metastatic disease after at least one line of chemotherapy; it does not mean these patients benefit from trastuzumab or other older HER2 drugs.
POLARIX gave the first new first-line standard for DLBCL since rituximab was added to CHOP, and pola-R-CHP is now approved and widely used, especially in higher-risk or ABC-type disease. The gain is modest and survival is unchanged, so many clinicians still use R-CHOP in lower-risk or GCB-type patients. Cost and subgroup uncertainty drive ongoing debate.
Sacituzumab govitecan is a standard second-line or later treatment for metastatic triple-negative breast cancer, roughly doubling survival compared with the chemotherapies it was tested against. Patients should expect neutropenia and diarrhoea, which are manageable with growth factor support and loperamide. Trials are now testing it earlier, in first-line combinations with pembrolizumab and after surgery for residual disease.
HER2-positive breast cancer is now routinely treated before surgery so that the pathology result can guide what comes after: patients with no residual cancer continue trastuzumab (with or without pertuzumab), while those with residual disease switch to T-DM1. This model of using the tumour's response as a test has since been copied in triple-negative and other cancers.
ECHELON-1 made a targeted antibody-drug conjugate part of first-line Hodgkin therapy and eventually showed that this saves lives, not just relapses. It set the reference arm against which nivolumab-AVD (SWOG S1826) and BrECADD (HD21) were later compared. Neuropathy is the main price and needs proactive dose modification.
INO-VATE made inotuzumab a standard salvage therapy for adult ALL and a common route to transplant, and, with the TOWER trial of blinatumomab, moved adult ALL from chemotherapy-only salvage to immunotherapy. Both drugs have since been pulled into front-line regimens. The liver toxicity signal shaped how transplant conditioning is chosen after inotuzumab.
Latest papers
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