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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.
This roadmap traces antibody-drug conjugates from the first attempts with murine antibodies and the unstable first approved ADC, gemtuzumab ozogamicin, through the second generation that proved the class with brentuximab vedotin and T-DM1. The third generation brought TOP1 payloads and bystander killing with trastuzumab deruxtecan and sacituzumab govitecan, then moved into earlier lines, new targets and ADC plus PD-1 combinations. The emerging fourth generation arrives as bispecific ADCs led by izalontamab brengitecan, then dual-payload, degrader, immune-stimulating and masked ADCs, before a speculative era of imaging-guided therapy. Each generation fixed the previous one's weakness; the route is linked from TNBC, HR-positive and HER2-positive breast cancer, NSCLC and ovarian cancer.
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ozogamicin (2000) becomes the first approved ADC with a calicheamicin payload and an unstable hydrazone linker; withdrawn in 2010 for toxicity, re-approved 2017 with fractionated dosing.
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.
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).
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.
Numbers are from the trial as recorded here; see the source links in the table below. This is orientation, not medical advice: ask your team how closely the trial population matches you.
Numbers are from the trial as recorded here; see the source links in the table below. This is orientation, not medical advice: ask your team how closely the trial population matches you.
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.
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.
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.
Every era's records, trial outcomes and papers, and every watch item, as JSON.
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.
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Shares AK146D1, Dual-payload ADC, ASCENT-04 / KEYNOTE-D19, TROP2 PET.
Shares Mirvetuximab soravtansine, Enfortumab vedotin, Trastuzumab emtansine, Izalontamab brengitecan.
Shares ADC sequencing, A randomised trial of antibody-drug conjugate sequence in metastatic triple-negative breast cancer, Datopotamab deruxtecan, Sacituzumab govitecan.
Shares Tilatamig samrotecan, AK146D1, ADC sequencing, Izalontamab brengitecan.
Shares EV-302 / KEYNOTE-A39, ASCENT-04 / KEYNOTE-D19, Enfortumab vedotin, Sacituzumab govitecan.
Shares BL-B01D1-307, Dual-payload ADC, ASCENT-04 / KEYNOTE-D19, TROP2 PET.
Shares Tilatamig samrotecan, AK146D1, ADC sequencing, Izalontamab brengitecan.
Shares ASCENT-04 / KEYNOTE-D19, TROP2 PET, Immuno-PET, Datopotamab deruxtecan.