{"entity":{"id":"adc-generations","kind":"roadmap","name":"ADC roadmap: from Mylotarg to bispecific and dual-payload ADCs","aka":[],"tldr":"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.","summary":"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.","asOf":"2026-09-04","links":[{"label":"ASCENT: sacituzumab govitecan doubles survival in heavily pretreated metastatic triple-negative breast cancer (New England Journal of Medicine 2021)","url":"https://doi.org/10.1056/NEJMoa2028485"},{"label":"DESTINY-Breast03: trastuzumab deruxtecan beats T-DM1 as second-line treatment of HER2-positive metastatic breast cancer (New England Journal of Medicine 2022)","url":"https://doi.org/10.1056/NEJMoa2115022"}],"tags":[],"related":["drug-discovery-roadmap"],"cancers":[],"sections":["adcs"],"technologies":["adc","bispecific-adc","dual-payload-adc","degrader-antibody-conjugate","immune-stimulating-adc","masked-adc","radioimmunotherapy","site-specific-conjugation"],"targets":[],"drugs":[],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"steps":[{"era":"1980s-2000","title":"Concept and first attempt","description":"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ozogamicin (2000) becomes the first approved ADC with a calicheamicin payload and an unstable hydrazone linker; withdrawn in 2010 for toxicity, re-approved 2017 with fractionated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.","refs":["gemtuzumab-ozogamicin","cd33"],"status":"historic"},{"era":"2011-2013","title":"Second generation proves the class","description":"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.","refs":["brentuximab-vedotin","trastuzumab-emtansine"],"status":"historic"},{"era":"2019-2022","title":"Third generation: TOP1 payloads and bystander killing","description":"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).","refs":["trastuzumab-deruxtecan","sacituzumab-govitecan","enfortumab-vedotin","destiny-breast03","destiny-breast04"],"status":"current"},{"era":"2023-2026","title":"Third generation matures: earlier lines, more targets, combinations","description":"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.","refs":["datopotamab-deruxtecan","mirvetuximab-soravtansine","telisotuzumab-vedotin","ev-302","ascent-04","adc-sequencing"],"status":"current"},{"era":"2026-2028","title":"Fourth generation, wave 1: bispecific ADCs","description":"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.","refs":["izalontamab-brengitecan","bl-b01d1-307","tilatamig-samrotecan","ak146d1","bispecific-adc"],"status":"emerging"},{"era":"2026-2030","title":"Fourth generation, wave 2: new payload logic","description":"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.","refs":["dual-payload-adc","degrader-antibody-conjugate","immune-stimulating-adc","masked-adc","peptide-drug-conjugate","radioimmunotherapy","site-specific-conjugation"],"status":"emerging"},{"era":"2028+","title":"Speculative: imaging-guided, adaptive ADC therapy","description":"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.","refs":["trop2-pet","her2-pet","immuno-pet","ai-drug-design","functional-drug-testing"],"status":"speculative"}],"watch":[]},"route":"/roadmaps/adc-generations/","neighbours":{"roadmap":[{"id":"chemotherapy-roadmap","kind":"roadmap","name":"Chemotherapy roadmap: mustard gas → curative combinations → the warhead inside smarter drugs","route":"/roadmaps/chemotherapy-roadmap/"},{"id":"drug-discovery-roadmap","kind":"roadmap","name":"Drug discovery roadmap: screening in mice → maps of dependency → designing in silico","route":"/roadmaps/drug-discovery-roadmap/"},{"id":"tnbc-roadmap","kind":"roadmap","name":"Triple-negative breast cancer roadmap: from a remainder defined by three negative tests to immunotherapy, antibody-drug conjugates and the residual disease problem","route":"/roadmaps/tnbc-roadmap/"}],"section":[{"id":"adcs","kind":"section","name":"Antibody-Drug Conjugates","route":"/fronts/adcs/"}],"technology":[{"id":"ai-drug-design","kind":"technology","name":"AI-driven drug & target discovery","route":"/technologies/ai-drug-design/"},{"id":"adc","kind":"technology","name":"Antibody-drug conjugate (ADC)","route":"/technologies/adc/"},{"id":"bispecific-adc","kind":"technology","name":"Bispecific ADC","route":"/technologies/bispecific-adc/"},{"id":"degrader-antibody-conjugate","kind":"technology","name":"Degrader-antibody conjugate (DAC)","route":"/technologies/degrader-antibody-conjugate/"},{"id":"dual-payload-adc","kind":"technology","name":"Dual-payload ADC","route":"/technologies/dual-payload-adc/"},{"id":"functional-drug-testing","kind":"technology","name":"Functional (ex vivo) drug testing","route":"/technologies/functional-drug-testing/"},{"id":"her2-pet","kind":"technology","name":"HER2 PET","route":"/technologies/her2-pet/"},{"id":"immune-stimulating-adc","kind":"technology","name":"Immune-stimulating antibody conjugate (ISAC)","route":"/technologies/immune-stimulating-adc/"},{"id":"immuno-pet","kind":"technology","name":"Immuno-PET","route":"/technologies/immuno-pet/"},{"id":"masked-adc","kind":"technology","name":"Masked / conditionally active ADC","route":"/technologies/masked-adc/"},{"id":"peptide-drug-conjugate","kind":"technology","name":"Peptide-drug & small-molecule-drug conjugates","route":"/technologies/peptide-drug-conjugate/"},{"id":"radioimmunotherapy","kind":"technology","name":"Radio-antibody & radio-ADC","route":"/technologies/radioimmunotherapy/"},{"id":"site-specific-conjugation","kind":"technology","name":"Site-specific conjugation & linker chemistry","route":"/technologies/site-specific-conjugation/"},{"id":"trop2-pet","kind":"technology","name":"TROP2 PET","route":"/technologies/trop2-pet/"}],"drug":[{"id":"ak146d1","kind":"drug","name":"AK146D1","route":"/drugs/ak146d1/"},{"id":"brentuximab-vedotin","kind":"drug","name":"Brentuximab vedotin","route":"/drugs/brentuximab-vedotin/"},{"id":"datopotamab-deruxtecan","kind":"drug","name":"Datopotamab deruxtecan","route":"/drugs/datopotamab-deruxtecan/"},{"id":"enfortumab-vedotin","kind":"drug","name":"Enfortumab vedotin","route":"/drugs/enfortumab-vedotin/"},{"id":"gemtuzumab-ozogamicin","kind":"drug","name":"Gemtuzumab ozogamicin","route":"/drugs/gemtuzumab-ozogamicin/"},{"id":"izalontamab-brengitecan","kind":"drug","name":"Izalontamab brengitecan","route":"/drugs/izalontamab-brengitecan/"},{"id":"mirvetuximab-soravtansine","kind":"drug","name":"Mirvetuximab soravtansine","route":"/drugs/mirvetuximab-soravtansine/"},{"id":"sacituzumab-govitecan","kind":"drug","name":"Sacituzumab govitecan","route":"/drugs/sacituzumab-govitecan/"},{"id":"telisotuzumab-vedotin","kind":"drug","name":"Telisotuzumab vedotin","route":"/drugs/telisotuzumab-vedotin/"},{"id":"tilatamig-samrotecan","kind":"drug","name":"Tilatamig samrotecan","route":"/drugs/tilatamig-samrotecan/"},{"id":"trastuzumab-deruxtecan","kind":"drug","name":"Trastuzumab deruxtecan","route":"/drugs/trastuzumab-deruxtecan/"},{"id":"trastuzumab-emtansine","kind":"drug","name":"Trastuzumab emtansine","route":"/drugs/trastuzumab-emtansine/"}],"target":[{"id":"cd33","kind":"target","name":"CD33","route":"/targets/cd33/"}],"trial":[{"id":"ascent-04","kind":"trial","name":"ASCENT-04 / KEYNOTE-D19","route":"/trials/ascent-04/"},{"id":"bl-b01d1-307","kind":"trial","name":"BL-B01D1-307","route":"/trials/bl-b01d1-307/"},{"id":"destiny-breast03","kind":"trial","name":"DESTINY-Breast03","route":"/trials/destiny-breast03/"},{"id":"destiny-breast04","kind":"trial","name":"DESTINY-Breast04","route":"/trials/destiny-breast04/"},{"id":"ev-302","kind":"trial","name":"EV-302 / KEYNOTE-A39","route":"/trials/ev-302/"}],"term":[{"id":"adc-sequencing","kind":"term","name":"ADC sequencing","route":"/terms/adc-sequencing/"}],"cancer":[{"id":"breast-her2-positive","kind":"cancer","name":"HER2-positive breast cancer","route":"/cancers/breast-her2-positive/"},{"id":"breast-hr-positive","kind":"cancer","name":"HR-positive / HER2-negative breast cancer","route":"/cancers/breast-hr-positive/"},{"id":"nsclc","kind":"cancer","name":"Non-small-cell lung cancer","route":"/cancers/nsclc/"},{"id":"ovarian","kind":"cancer","name":"Ovarian cancer","route":"/cancers/ovarian/"},{"id":"tnbc","kind":"cancer","name":"Triple-negative breast cancer (TNBC)","route":"/cancers/tnbc/"}],"idea":[{"id":"idea-tnbc-adc-sequencing-trial","kind":"idea","name":"A randomised trial of antibody-drug conjugate sequence in metastatic triple-negative breast cancer","route":"/ideas/idea-tnbc-adc-sequencing-trial/"}]}}