ADC roadmap: from Mylotarg to bispecific and dual-payload ADCs
Twenty-five years of trying to make chemotherapy hit only cancer cells, from the unstable first ADC to today's third-generation blockbusters and the fourth generation now in trials.
The ADC field failed for a decade, worked in blood cancers, then broke through in solid tumours once linkers, payloads, and DAR were engineered together. Each generation fixed the previous one's weakness; the next generation is attacking heterogeneity and payload resistance.
- 1980s-2000historic
Concept and first attempt
Murine antibodies with conventional chemotherapy payloads (doxorubicin) fail: immunogenic, too little drug delivered. Gemtuzumab ozogamicin (2000) becomes the first approved ADC with a calicheamicin payload and an unstable hydrazone linker; withdrawn in 2010 for toxicity, re-approved 2017 with fractionated dosing.
- 2011-2013historic
Second generation proves the class
Brentuximab vedotin (2011, vc-MMAE, Hodgkin) and T-DM1 (2013, non-cleavable SMCC-DM1, HER2+ breast) succeed with humanised antibodies, ultra-potent tubulin payloads, and more stable linkers. Heterogeneous DAR, no bystander effect for T-DM1, and payload-driven neuropathy remain.
- 2019-2022current
Third generation: TOP1 payloads and bystander killing
Trastuzumab deruxtecan (DAR 8, cleavable GGFG linker, DXd) and sacituzumab govitecan (DAR ~7.6, SN-38) show that a permeable topoisomerase-I payload at high DAR works in low-antigen and heterogeneous tumours. Enfortumab vedotin (Nectin-4) transforms bladder cancer. HER2-low becomes a diagnosis. ADCs beat chemotherapy head-to-head and beat an older ADC (DESTINY-Breast03).
- 2023-2026current
Third generation matures: earlier lines, more targets, combinations
Dato-DXd, mirvetuximab, telisotuzumab vedotin approved; T-DXd reaches early-stage breast cancer and tumour-agnostic HER2 IHC3+; ADC + PD-1 combinations become first-line standards (EV-302, ASCENT-04). New targets validated: FRα, TF, c-MET, B7-H3, CDH6, CLDN18.2. Problems surface: ILD, ocular toxicity, TOP1 cross-resistance, ADC sequencing.
- 2026-2028emerging
Fourth generation, wave 1: bispecific ADCs
Izalontamab brengitecan (EGFR×HER3) posts the first positive phase 3 for a bispecific ADC (TNBC and ESCC, 2026). Eight bsADC phase 3 trials started in 2025; c-MET×EGFR (tilatamig samrotecan), Nectin-4×TROP2 (AK146D1, AVZO-103), HER2 biparatopic, PD-L1×B7-H3 follow. Bispecific ADCs offer better internalisation and tumour selectivity and address heterogeneity.
- 2026-2030emerging
Fourth generation, wave 2: new payload logic
The second wave brings dual-payload ADCs (TOP1 + orthogonal mechanism) to pre-empt cross-resistance; degrader-antibody conjugates (non-genotoxic payloads reaching intracellular targets); immune-stimulating conjugates (TLR/STING); masked/conditionally active ADCs unlocking EGFR, EpCAM, CD71; peptide-drug conjugates; radio-ADCs with 225Ac/177Lu. Homogeneous site-specific conjugation and hydrophilic linkers are the enabling chemistry.
- 2028+speculative30%–55%likely
Speculative: imaging-guided, adaptive ADC therapy
Antigen PET (TROP2, HER2, B7-H3) to select and sequence ADCs; ctDNA and payload-resistance biomarkers (SLFN11, TOP1) to switch payload class; AI-designed antibodies and linkers; personalised payload selection from ex vivo testing; ADCs as neoadjuvant chemotherapy replacements across common cancers.
Probability ranges are named estimates that the claim is borne out on roughly a five-year horizon. They are meant to be argued with: propose a revision with your name and reasoning via a pull request to src/data/confidence.ts.
Story
topConcept and first attempt
Murine antibodies with conventional chemotherapy payloads (doxorubicin) fail: immunogenic, too little drug delivered. Gemtuzumab ozogamicin (2000) becomes the first approved ADC with a calicheamicin payload and an unstable hydrazone linker; withdrawn in 2010 for toxicity, re-approved 2017 with fractionated dosing.
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.
CD33 is a myeloid marker and the target of the very first ADC ever approved, in 2000.
Second generation proves the class
Brentuximab vedotin (2011, vc-MMAE, Hodgkin) and T-DM1 (2013, non-cleavable SMCC-DM1, HER2+ breast) succeed with humanised antibodies, ultra-potent tubulin payloads, and more stable linkers. Heterogeneous DAR, no bystander effect for T-DM1, and payload-driven neuropathy remain.
The ADC that made the modern field credible (2011), for Hodgkin lymphoma and CD30+ lymphomas.
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.
Third generation: TOP1 payloads and bystander killing
Trastuzumab deruxtecan (DAR 8, cleavable GGFG linker, DXd) and sacituzumab govitecan (DAR ~7.6, SN-38) show that a permeable topoisomerase-I payload at high DAR works in low-antigen and heterogeneous tumours. Enfortumab vedotin (Nectin-4) transforms bladder cancer. HER2-low becomes a diagnosis. ADCs beat chemotherapy head-to-head and beat an older ADC (DESTINY-Breast03).
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.
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.
Enfortumab vedotin is an ADC against Nectin-4 that, combined with pembrolizumab, nearly doubled survival in advanced bladder cancer.
The head-to-head ADC trial where Enhertu beat Kadcyla by a wide margin, showing that payload and bystander effect matter.
Created a new category of breast cancer, HER2-low, by showing Enhertu works in tumours previously called HER2-negative.
Third generation matures: earlier lines, more targets, combinations
Dato-DXd, mirvetuximab, telisotuzumab vedotin approved; T-DXd reaches early-stage breast cancer and tumour-agnostic HER2 IHC3+; ADC + PD-1 combinations become first-line standards (EV-302, ASCENT-04). New targets validated: FRα, TF, c-MET, B7-H3, CDH6, CLDN18.2. Problems surface: ILD, ocular toxicity, TOP1 cross-resistance, ADC sequencing.
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.
Mirvetuximab soravtansine (Elahere) is the first ADC for ovarian cancer, for tumours with high folate receptor alpha.
Telisotuzumab vedotin (Emrelis) is the first c-MET-directed ADC, approved in 2025 for lung cancer with high c-MET protein.
Nearly doubled survival in advanced bladder cancer, ending 40 years of platinum chemotherapy as the standard.
Showed that pairing an ADC with immunotherapy beats chemotherapy plus immunotherapy in first-line PD-L1-positive TNBC.
The open question of whether a second ADC works after the first one fails, especially when both carry the same type of payload.
Fourth generation, wave 1: bispecific ADCs
Izalontamab brengitecan (EGFR×HER3) posts the first positive phase 3 for a bispecific ADC (TNBC and ESCC, 2026). Eight bsADC phase 3 trials started in 2025; c-MET×EGFR (tilatamig samrotecan), Nectin-4×TROP2 (AK146D1, AVZO-103), HER2 biparatopic, PD-L1×B7-H3 follow. Bispecific ADCs offer better internalisation and tumour selectivity and address heterogeneity.
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.
The first phase 3 win for a bispecific ADC, in triple-negative breast cancer, announced February 2026.
AstraZeneca's EGFR×c-MET bispecific ADC, the most advanced in the most crowded next-generation ADC target pair.
AK146D1 is Akeso's Nectin-4 × TROP2 bispecific ADC, combining the two most validated ADC addresses in one molecule.
A bispecific ADC is an ADC whose antibody grabs two different proteins on the cancer cell, so it sticks better to tumour and less to healthy tissue.
Fourth generation, wave 2: new payload logic
The second wave brings dual-payload ADCs (TOP1 + orthogonal mechanism) to pre-empt cross-resistance; degrader-antibody conjugates (non-genotoxic payloads reaching intracellular targets); immune-stimulating conjugates (TLR/STING); masked/conditionally active ADCs unlocking EGFR, EpCAM, CD71; peptide-drug conjugates; radio-ADCs with 225Ac/177Lu. Homogeneous site-specific conjugation and hydrophilic linkers are the enabling chemistry.
A dual-payload ADC is an ADC carrying two different poisons at once, so the tumour cannot escape by becoming resistant to one.
An ADC that delivers a protein-destroying molecule instead of chemotherapy, hitting targets inside the cell that were previously unreachable.
An immune-stimulating antibody conjugate (ISAC) is an ADC whose payload wakes up the immune system inside the tumour rather than poisoning the cell.
An ADC wearing a mask that only comes off inside the tumour, so it ignores the same protein on healthy tissue.
Like an ADC but with a small targeting peptide instead of an antibody, so it penetrates tumours faster and is cheaper to make.
Attaching a radioactive atom to an antibody, so an ADC's targeting is used to deliver radiation instead of chemotherapy.
Site-specific conjugation and linker chemistry decide exactly where and how many payloads attach to the antibody, which determines how safe and effective an ADC is.
Speculative: imaging-guided, adaptive ADC therapy
Antigen PET (TROP2, HER2, B7-H3) to select and sequence ADCs; ctDNA and payload-resistance biomarkers (SLFN11, TOP1) to switch payload class; AI-designed antibodies and linkers; personalised payload selection from ex vivo testing; ADCs as neoadjuvant chemotherapy replacements across common cancers.
An experimental PET scan that shows whether a tumour carries the TROP2 protein, so doctors could pick the right ADC before giving it.
HER2 PET is a PET scan using radiolabelled trastuzumab or smaller HER2 binders to map HER2 across all metastases at once.
PET scans built from radiolabelled antibodies or their fragments, to see any protein an antibody can reach, including immune cells inside tumours.
Using machine learning to pick targets, design molecules and antibodies, and predict which ADC will work.
Growing a patient's own cancer cells in a dish and testing drugs on them directly, instead of guessing from genetics.