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With Nectin-4 Expressing Advanced Malignancies: phase 1/2, active","href":"/trials/nct04561362/"},{"record":"nct06225596","field":"status","kind":"trial","state":"development","label":"Study BT8009-230 in Participants With Locally Advanced or Metastatic Urothelial Cancer (Duravelo-2): phase 2, active","href":"/trials/nct06225596/"},{"record":"nct06840483","field":"status","kind":"trial","state":"development","label":"Study of Zelenectide Pevedotin in Participants With Advanced Breast Cancer: phase 2, active","href":"/trials/nct06840483/"},{"record":"nct06933329","field":"status","kind":"trial","state":"development","label":"Zelenectide Pevedotin in NECTIN4 Amplified Advanced or Metastatic Non-small Cell Lung Cancer: phase 2, active","href":"/trials/nct06933329/"},{"record":"registry:zelenectide-pevedotin","kind":"registry","state":"development","label":"ClinicalTrials.gov: 4 recruiting, active or planned studies (fetched 2026-09-21)","href":"/drugs/zelenectide-pevedotin/#registry"}],"reasons":[{"drugId":"zelenectide-pevedotin","drugName":"Zelenectide pevedotin","drugRoute":"/drugs/zelenectide-pevedotin/","drugState":"development","record":"zelenectide-pevedotin","kind":"event","label":"US 2026-03: withdrawal","href":"https://www.oncologypipeline.com/apexonco/bicycle-finally-falls","quote":"Programme deprioritised after regulatory feedback on Duravelo-2 design"}]},{"id":"zilovertamab-vedotin","name":"Zilovertamab vedotin","route":"/drugs/zilovertamab-vedotin/","status":"phase-3","modality":"ADC","state":"development","confidence":"high","fields":["targets","payload registry","linker","modality","mechanism"],"components":{"target":{"id":"ror1","name":"ROR1","href":"/targets/ror1/","confidence":"high","from":["targets"],"detail":null},"payload":{"id":"mmae","name":"MMAE","href":"/terms/mmae/","confidence":"high","from":["payload registry"],"detail":null},"payloadClass":{"id":"tubulin-inhibitor-payloads","name":"Tubulin inhibitor","href":"/terms/tubulin-inhibitor-payloads/","confidence":"high","from":["payload registry"],"detail":null},"linker":{"id":"cleavable","name":"Cleavable","href":"/terms/linker/","confidence":"high","from":["linker"],"detail":"Cleavable"},"carrier":{"id":"monoclonal-antibody","name":"Monoclonal antibody","href":"/technologies/monoclonal-antibody/","confidence":"high","from":["modality","mechanism"],"detail":null}},"evidence":[{"record":"zilovertamab-vedotin","field":"status","kind":"drug","state":"development","label":"Drug record status: phase 3","href":"/drugs/zilovertamab-vedotin/"},{"record":"nct06890884","field":"status","kind":"trial","state":"development","label":"A Clinical Study of Zilovertamab Vedotin (MK-2140) Plus Rituximab Plus Cyclophosphamide, Doxorubicin, and Prednisone (R-CHP) Versus Polatuzumab Vedotin Plus R-CHP in People With Diffuse Large B-cell Lymphoma (DLBCL) (MK-2140-011/waveLINE-011): phase 2, recruiting","href":"/trials/nct06890884/"},{"record":"nct05458297","field":"status","kind":"trial","state":"development","label":"A Study of Zilovertamab Vedotin (MK-2140) as Monotherapy and in Combination in Participants With Aggressive and Indolent B-cell Malignancies (MK-2140-: phase 2, active","href":"/trials/nct05458297/"},{"record":"nct05406401","field":"status","kind":"trial","state":"development","label":"A Study of Zilovertamab Vedotin (MK-2140) in Combination With Cyclophosphamide, Doxorubicin, and Prednisone Plus Rituximab or Rituximab Biosimilar (Truxima) (R-CHP) in Participants With Diffuse Large B-Cell Lymphoma (DLBCL) (MK-2140-007): phase 2, active","href":"/trials/nct05406401/"},{"record":"nct06717347","field":"status","kind":"trial","state":"development","label":"A Study to Evaluate Zilovertamab Vedotin (MK-2140) Combination With Rituximab Plus Cyclophosphamide, Doxorubicin, and Prednisone (R-CHP) Versus Rituxi: phase 3, recruiting","href":"/trials/nct06717347/"},{"record":"nct05562830","field":"status","kind":"trial","state":"development","label":"A Substudy of Investigational Agents in Programmed Cell Death-1/Ligand 1 (PD-1/L1) Refractory Locally Advanced or Metastatic Urothelial Carcinoma (mUC) (MK-3475-04A): phase 1/2, recruiting","href":"/trials/nct05562830/"},{"record":"nct06395103","field":"status","kind":"trial","state":"development","label":"Substudy 01A: Zilovertamab Vedotin in Pediatric and Young Adult Participants With Hematologic Malignancies or Solid Tumors (MK-9999-01A/LIGHTBEAM-U01): phase 1/2, recruiting","href":"/trials/nct06395103/"},{"record":"waveline-003","field":"status","kind":"trial","state":"development","label":"waveLINE-003: phase 2/3, recruiting","href":"/trials/waveline-003/"},{"record":"registry:zilovertamab-vedotin","kind":"registry","state":"development","label":"ClinicalTrials.gov: 7 recruiting, active or planned studies (fetched 2026-09-21)","href":"/drugs/zilovertamab-vedotin/#registry"}],"reasons":[]},{"id":"zl-1310","name":"ZL-1310","route":"/drugs/zl-1310/","status":"phase-3","modality":"ADC","state":"development","confidence":"high","fields":["targets","modality","mechanism"],"components":{"target":{"id":"dll3","name":"DLL3","href":"/targets/dll3/","confidence":"high","from":["targets"],"detail":null},"carrier":{"id":"monoclonal-antibody","name":"Monoclonal antibody","href":"/technologies/monoclonal-antibody/","confidence":"high","from":["modality","mechanism"],"detail":null}},"evidence":[{"record":"zl-1310","field":"status","kind":"drug","state":"development","label":"Drug record status: phase 3","href":"/drugs/zl-1310/"},{"record":"nct06885281","field":"status","kind":"trial","state":"development","label":"A Study of ZL-1310 in Participants With Selected Solid Tumors: phase 1/2, recruiting","href":"/trials/nct06885281/"},{"record":"dllevate","field":"status","kind":"trial","state":"development","label":"A Study of ZL-1310 Versus Investigator's Choice of Therapy in Participants With Relapsed Small Cell Lung Cancer (DLLEVATE): phase 3, recruiting","href":"/trials/dllevate/"},{"record":"registry:zl-1310","kind":"registry","state":"development","label":"ClinicalTrials.gov: 4 recruiting, active or planned studies (fetched 2026-09-21)","href":"/drugs/zl-1310/#registry"}],"reasons":[]}],"unresolved":[{"id":"amt-116","name":"AMT-116","route":"/drugs/amt-116/","format":"adc","modality":"Antibody-drug conjugate","missing":["target","payloadClass","payload","linker","dar"],"why":"No target on the record: the targets field is empty and the modality and mechanism text name none the corpus knows."},{"id":"azd5335","name":"AZD5335","route":"/drugs/azd5335/","format":"adc","modality":"ADC","missing":["target","payloadClass","payload","linker","dar"],"why":"No target on the record: the targets field is empty and the modality and mechanism text name none the corpus knows."},{"id":"fda018-adc","name":"FDA018-ADC","route":"/drugs/fda018-adc/","format":"adc","modality":"ADC","missing":["target","payloadClass","payload","linker","dar"],"why":"No target on the record: the targets field is empty and the modality and mechanism text name none the corpus knows."},{"id":"hs-20093","name":"HS-20093","route":"/drugs/hs-20093/","format":"adc","modality":"antibody-drug conjugate (ADC), per the sponsor's pipeline page; form not stated in the registry record","missing":["target","payloadClass","payload","linker","dar"],"why":"No target on the record: the targets field is empty and the modality and mechanism text name none the corpus knows."},{"id":"melflufen","name":"Melphalan flufenamide","route":"/drugs/melflufen/","format":"adc","modality":"Peptide-drug conjugate","missing":["target","payload","linker","dar"],"why":"No target on the record: the targets field is empty and the modality and mechanism text name none the corpus knows."},{"id":"mhb036c","name":"MHB036C","route":"/drugs/mhb036c/","format":"adc","modality":"Antibody-drug conjugate","missing":["target","payloadClass","payload","linker","dar"],"why":"No target on the record: the targets field is empty and the modality and mechanism text name none the corpus knows."},{"id":"mitazalimab","name":"Mitazalimab","route":"/drugs/mitazalimab/","format":"adc","modality":"Antibody-drug conjugate","missing":["target","payloadClass","payload","linker","dar"],"why":"No target on the record: the targets field is empty and the modality and mechanism text name none the corpus knows."},{"id":"mrg003","name":"MRG003","route":"/drugs/mrg003/","format":"adc","modality":"ADC","missing":["target","payloadClass","payload","linker","dar"],"why":"No target on the record: the targets field is empty and the modality and mechanism text name none the corpus knows."},{"id":"obi-902","name":"OBI-902","route":"/drugs/obi-902/","format":"adc","modality":"Antibody-drug conjugate","missing":["target","payloadClass","payload","linker","dar"],"why":"No target on the record: the targets field is empty and the modality and mechanism text name none the corpus knows."},{"id":"obi-992","name":"OBI-992","route":"/drugs/obi-992/","format":"adc","modality":"Antibody-drug conjugate","missing":["target","payloadClass","payload","linker","dar"],"why":"No target on the record: the targets field is empty and the modality and mechanism text name none the corpus knows."},{"id":"shr-a1912","name":"SHR-A1912","route":"/drugs/shr-a1912/","format":"adc","modality":"antibody-drug conjugate (ADC), per the sponsor's pipeline page; form not stated in the registry record","missing":["target","payloadClass","payload","linker","dar"],"why":"No target on the record: the targets field is empty and the modality and mechanism text name none the corpus knows."},{"id":"shr-a1921","name":"SHR-A1921","route":"/drugs/shr-a1921/","format":"adc","modality":"antibody-drug conjugate (ADC), per the sponsor's pipeline page; form not stated in the registry record","missing":["target","payloadClass","payload","linker","dar"],"why":"No target on the record: the targets field is empty and the modality and mechanism text name none the corpus knows."},{"id":"shr-a2102","name":"SHR-A2102","route":"/drugs/shr-a2102/","format":"adc","modality":"antibody-drug conjugate (ADC), per the sponsor's pipeline page; form not stated in the registry record","missing":["target","payloadClass","payload","linker","dar"],"why":"No target on the record: the targets field is empty and the modality and mechanism text name none the corpus knows."},{"id":"skb105","name":"SKB105","route":"/drugs/skb105/","format":"adc","modality":"Antibody-drug conjugate","missing":["target","payloadClass","payload","linker","dar"],"why":"No target on the record: the targets field is empty and the modality and mechanism text name none the corpus knows."},{"id":"upifitamab-rilsodotin","name":"Upifitamab rilsodotin","route":"/drugs/upifitamab-rilsodotin/","format":"adc","modality":"Antibody-drug conjugate","missing":["target","payload","linker","dar"],"why":"No target on the record: the targets field is empty and the modality and mechanism text name none the corpus knows."}],"stopped":[{"drugId":"anetumab-ravtansine","drugName":"Anetumab ravtansine","drugRoute":"/drugs/anetumab-ravtansine/","drugState":"stopped","record":"anetumab-ravtansine","kind":"drug","label":"Drug record status: negative","href":"/drugs/anetumab-ravtansine/","quote":"Anetumab ravtansine was the first antibody-drug conjugate tested in a randomised trial in mesothelioma, aimed at the mesothelin protein that nearly all mesotheliomas carry; it was no better than vinorelbine chemotherapy as second-line treatment, and is now being tried with pembrolizumab."},{"drugId":"anetumab-ravtansine","drugName":"Anetumab ravtansine","drugRoute":"/drugs/anetumab-ravtansine/","drugState":"stopped","record":"anetumab-vs-vinorelbine-mpm","kind":"trial","label":"Anetumab ravtansine versus vinorelbine in relapsed mesothelin-positive pleural mesothelioma: phase 2, negative","href":"/trials/anetumab-vs-vinorelbine-mpm/","quote":"PFS 4.3 vs 4.5 months, HR 1.22; primary endpoint not met."},{"drugId":"depatuxizumab-mafodotin","drugName":"Depatuxizumab mafodotin","drugRoute":"/drugs/depatuxizumab-mafodotin/","drugState":"stopped","record":"depatuxizumab-mafodotin","kind":"drug","label":"Drug record status: negative","href":"/drugs/depatuxizumab-mafodotin/","quote":"Depatuxizumab mafodotin carried a cell-killing payload to glioblastomas with extra copies of the EGFR gene. It caused serious eye problems and, in the phase 3 INTELLANCE-1 trial, did not help patients live longer, so development stopped in 2019."},{"drugId":"depatuxizumab-mafodotin","drugName":"Depatuxizumab mafodotin","drugRoute":"/drugs/depatuxizumab-mafodotin/","drugState":"stopped","record":"intellance-1","kind":"trial","label":"INTELLANCE-1: phase 3, negative","href":"/trials/intellance-1/","quote":"Depatuxizumab mafodotin added to radiotherapy and temozolomide did not improve overall survival in EGFR-amplified glioblastoma; stopped for futility."},{"drugId":"moxetumomab-pasudotox","drugName":"Moxetumomab pasudotox","drugRoute":"/drugs/moxetumomab-pasudotox/","drugState":"stopped","record":"moxetumomab-pasudotox","kind":"drug","label":"Drug record status: withdrawn","href":"/drugs/moxetumomab-pasudotox/","quote":"An immunotoxin for hairy cell leukaemia that produced lasting remissions in relapsed patients but was withdrawn from sale in 2023 for commercial reasons."},{"drugId":"moxetumomab-pasudotox","drugName":"Moxetumomab pasudotox","drugRoute":"/drugs/moxetumomab-pasudotox/","drugState":"stopped","record":"moxetumomab-pasudotox","kind":"regional","label":"FDA (US): withdrawn 2023","href":"/regulatory/regions/","quote":"Lumoxiti accelerated approval Sep 2018; discontinued by AstraZeneca and withdrawn 2023"},{"drugId":"moxetumomab-pasudotox","drugName":"Moxetumomab pasudotox","drugRoute":"/drugs/moxetumomab-pasudotox/","drugState":"stopped","record":"moxetumomab-pasudotox","kind":"regional","label":"EMA / European Commission (EU): withdrawn 2021","href":"https://www.ema.europa.eu/en/medicines/human/EPAR/lumoxiti","quote":"Authorised 8 Feb 2021; marketing authorisation withdrawn at the holder's request 23 Jul 2021"},{"drugId":"rovalpituzumab-tesirine","drugName":"Rovalpituzumab tesirine","drugRoute":"/drugs/rovalpituzumab-tesirine/","drugState":"stopped","record":"rovalpituzumab-tesirine","kind":"drug","label":"Drug record status: withdrawn","href":"/drugs/rovalpituzumab-tesirine/","quote":"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."},{"drugId":"trastuzumab-duocarmazine","drugName":"Trastuzumab duocarmazine","drugRoute":"/drugs/trastuzumab-duocarmazine/","drugState":"stopped","record":"trastuzumab-duocarmazine","kind":"drug","label":"Drug record status: withdrawn","href":"/drugs/trastuzumab-duocarmazine/","quote":"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."},{"drugId":"trastuzumab-duocarmazine","drugName":"Trastuzumab duocarmazine","drugRoute":"/drugs/trastuzumab-duocarmazine/","drugState":"stopped","record":"trastuzumab-duocarmazine","kind":"regional","label":"FDA (US): rejected 2023","href":"/regulatory/regions/","quote":"Complete response letter May 2023 (Byondis)"},{"drugId":"trastuzumab-duocarmazine","drugName":"Trastuzumab duocarmazine","drugRoute":"/drugs/trastuzumab-duocarmazine/","drugState":"stopped","record":"trastuzumab-duocarmazine","kind":"regional","label":"EMA / European Commission (EU): withdrawn","href":"https://www.ema.europa.eu/en/medicines/human/EPAR/jivadco","quote":"Marketing authorisation application withdrawn before a CHMP opinion"},{"drugId":"tusamitamab-ravtansine","drugName":"Tusamitamab ravtansine","drugRoute":"/drugs/tusamitamab-ravtansine/","drugState":"stopped","record":"tusamitamab-ravtansine","kind":"drug","label":"Drug record status: withdrawn","href":"/drugs/tusamitamab-ravtansine/","quote":"Tusamitamab ravtansine was Sanofi's ADC against the classic CEA tumour marker, stopped for futility in lung cancer in 2023."},{"drugId":"patritumab-deruxtecan","drugName":"Patritumab deruxtecan","drugRoute":"/drugs/patritumab-deruxtecan/","drugState":"development","record":"patritumab-deruxtecan","kind":"regional","label":"FDA (US): withdrawn 2025","href":"/regulatory/regions/","quote":"BLA withdrawn May 2025 after CRL (manufacturing) and HERTHENA-Lung02 OS miss"},{"drugId":"patritumab-deruxtecan","drugName":"Patritumab deruxtecan","drugRoute":"/drugs/patritumab-deruxtecan/","drugState":"development","record":"patritumab-deruxtecan","kind":"event","label":"US 2024-06-26: complete response letter","href":"https://www.fda.gov/drugs/resources-information-approved-drugs/oncology-cancer-hematologic-malignancies-approval-notifications","quote":"Complete response letter citing third-party manufacturing inspection"},{"drugId":"patritumab-deruxtecan","drugName":"Patritumab deruxtecan","drugRoute":"/drugs/patritumab-deruxtecan/","drugState":"development","record":"patritumab-deruxtecan","kind":"event","label":"US 2025-05: withdrawal","href":"https://www.fda.gov/drugs/resources-information-approved-drugs/oncology-cancer-hematologic-malignancies-approval-notifications","quote":"BLA withdrawn after HERTHENA-Lung02 met PFS but not OS"},{"drugId":"zelenectide-pevedotin","drugName":"Zelenectide pevedotin","drugRoute":"/drugs/zelenectide-pevedotin/","drugState":"development","record":"zelenectide-pevedotin","kind":"event","label":"US 2026-03: withdrawal","href":"https://www.oncologypipeline.com/apexonco/bicycle-finally-falls","quote":"Programme deprioritised after regulatory feedback on Duravelo-2 design"},{"drugId":"belantamab-mafodotin","drugName":"Belantamab mafodotin","drugRoute":"/drugs/belantamab-mafodotin/","drugState":"approved","record":"belantamab-mafodotin","kind":"event","label":"US 2022-11-22: withdrawal","href":"https://www.fda.gov/drugs/resources-information-approved-drugs/oncology-cancer-hematologic-malignancies-approval-notifications","quote":"Withdrawn after DREAMM-3 failed to confirm benefit"},{"drugId":"belantamab-mafodotin","drugName":"Belantamab mafodotin","drugRoute":"/drugs/belantamab-mafodotin/","drugState":"approved","record":"belantamab-mafodotin","kind":"event","label":"US 2025-07-23: complete response letter","href":"https://www.fda.gov/drugs/resources-information-approved-drugs/oncology-cancer-hematologic-malignancies-approval-notifications","quote":"Complete response letter on combination filing; resubmitted"},{"drugId":"gemtuzumab-ozogamicin","drugName":"Gemtuzumab ozogamicin","drugRoute":"/drugs/gemtuzumab-ozogamicin/","drugState":"approved","record":"gemtuzumab-ozogamicin","kind":"event","label":"US 2010-06-21: withdrawal","href":"https://www.fda.gov/drugs/resources-information-approved-drugs/oncology-cancer-hematologic-malignancies-approval-notifications","quote":"Voluntary withdrawal after confirmatory trial showed no benefit and excess deaths"},{"drugId":"sacituzumab-govitecan","drugName":"Sacituzumab govitecan","drugRoute":"/drugs/sacituzumab-govitecan/","drugState":"approved","record":"sacituzumab-govitecan","kind":"event","label":"US 2024-11: withdrawal","href":"https://www.fda.gov/drugs/resources-information-approved-drugs/oncology-cancer-hematologic-malignancies-approval-notifications","quote":"Urothelial cancer indication voluntarily withdrawn after TROPiCS-04"},{"drugId":"trastuzumab-emtansine","drugName":"Trastuzumab emtansine","drugRoute":"/drugs/trastuzumab-emtansine/","drugState":"approved","record":"gatsby","kind":"trial","label":"GATSBY: phase 2/3, negative","href":"/trials/gatsby/","quote":"Trastuzumab emtansine did not improve overall survival over taxane chemotherapy in previously treated HER2-positive gastric cancer."},{"drugId":"trastuzumab-emtansine","drugName":"Trastuzumab emtansine","drugRoute":"/drugs/trastuzumab-emtansine/","drugState":"approved","record":"kristine","kind":"trial","label":"KRISTINE: phase 3, negative","href":"/trials/kristine/","quote":"Pathological complete response 44.4% (T-DM1 + pertuzumab) vs 55.7% (TCHP); more locoregional progression before surgery with T-DM1."}],"proposed":[{"id":"adc-nectin4-top1","format":"adc","name":"Nectin-4 ADC with a topoisomerase-I payload","a":"nectin4","b":"topoisomerase-i-payloads","raw":{"a":"nectin4","b":"topoisomerase-i-payloads"},"matched":true,"unmatched":[],"rationale":"Nectin-4 is validated with a tubulin payload (enfortumab-vedotin) and the topoisomerase-I class is the best-validated ADC payload in the corpus (trastuzumab-deruxtecan, sacituzumab-govitecan, datopotamab-deruxtecan). The corpus holds a Nectin-4 x TROP2 bispecific ADC with a topoisomerase payload (ak146d1) and a Nectin-4 ADC in phase 3 whose payload the record does not state (shr-a2102), so the mono-specific Nectin-4 x topoisomerase-I cell reads as untried when the search shows it is occupied. Nectin-4 internalises (enfortumab-vedotin relies on it) and is expressed in breast, lung and pancreatic cancers beyond bladder; a topoisomerase-I payload would swap the neuropathy and skin toxicity of MMAE for the neutropenia and ILD class effects of camptothecins.","caveat":"The corpus record for SHR-A2102 needs its payload class filled in; the open question is no longer whether the cell is tried but whether a topoisomerase-I Nectin-4 ADC works after enfortumab vedotin progression.","status":"already in development (missed by decomposer)","statusLabel":"Already in development","score":{"total":84,"burden":34,"worldDeaths":2704168,"validationA":15,"validationB":15,"plausibility":20},"evidence":[{"label":"Paper: Zhong R et al. (2026-09-01)","url":"https://doi.org/10.1016/s1470-2045(26)00238-x","quote":"<h4>Background</h4>SHR-A2102 is a new antibody-drug conjugate consisting of a fully human nectin-4-directed monoclonal antibody bound to a topoisomerase I inhibitor payload via a cleavable linker.","kind":"paper"},{"label":"Paper: Lopez M et al. (2024-11-01)","url":"https://doi.org/10.1158/2767-9764.crc-24-0176","quote":"<h4>Significance</h4>ETx-22, a novel ADC combining a tumor nectin-4-specific antibody and an innovative linker to exatecan, demonstrates significant and durable responses in low-target-expressing tumor models that are resistant to MMAE-based EV and has a better toxicity profile.","kind":"paper"}],"refs":["ak146d1","datopotamab-deruxtecan","enfortumab-vedotin","sacituzumab-govitecan","shr-a2102","trastuzumab-deruxtecan"],"cancers":["urothelial","tnbc","nsclc","breast-hr-positive"],"proposedBy":"OnCo open pipeline","on":"2026-09-23"},{"id":"adc-met-top1","format":"adc","name":"MET ADC with a topoisomerase-I payload","a":"met","b":"topoisomerase-i-payloads","raw":{"a":"met","b":"topoisomerase-i-payloads"},"matched":true,"unmatched":[],"rationale":"MET is validated by an approved tubulin ADC (telisotuzumab-vedotin) and kinase inhibitors (capmatinib, tepotinib), and topoisomerase-I payloads are approved on five antigens (trastuzumab-deruxtecan). The corpus holds a MET ADC in phase 3 whose payload the record does not state (telisotuzumab-adizutecan), so the MET x topoisomerase-I cell reads as untried when it is probably not. MET internalises and is over-expressed across lung, colorectal and gastric cancers beyond the amplified subset; a bystander-capable topoisomerase-I payload could reach MET-intermediate tumours that telisotuzumab-vedotin does not.","caveat":"The corpus record for the phase-3 MET ADC needs its payload class filled in; if it is a topoisomerase-I inhibitor this cell is already occupied and the open question is how it sequences with the tubulin ADC.","status":"already in development (missed by decomposer)","statusLabel":"Already in development","score":{"total":83,"burden":35,"worldDeaths":3381663,"validationA":15,"validationB":15,"plausibility":18},"evidence":[{"label":"Paper: Sharma MR et al. (2026-05-01)","url":"https://doi.org/10.1200/jco-25-01525","quote":"<h4>Purpose</h4>The antibody-drug conjugate Temab-A comprises the c-Met-targeting antibody telisotuzumab conjugated to a novel topoisomerase 1 inhibitor payload, adizutecan.","kind":"paper"}],"refs":["capmatinib","telisotuzumab-adizutecan","telisotuzumab-vedotin","tepotinib","trastuzumab-deruxtecan"],"cancers":["met-altered-nsclc","nsclc","colorectal","gastric"],"proposedBy":"OnCo open pipeline","on":"2026-09-23"},{"id":"adc-cldn18-2-top1","format":"adc","name":"Claudin 18.2 ADC with a topoisomerase-I payload","a":"cldn18-2","b":"topoisomerase-i-payloads","raw":{"a":"cldn18-2","b":"topoisomerase-i-payloads"},"matched":true,"unmatched":[],"rationale":"Claudin 18.2 is validated by an approved antibody (zolbetuximab) and an approved CAR-T (satricabtagene-autoleucel), and the corpus holds a Claudin 18.2 ADC with a tubulin payload in phase 3 (cmg901). Several corpus Claudin 18.2 ADCs in phase 2 and 3 do not state their payload (ibi343, azd4360, xnw27011), so the Claudin 18.2 x topoisomerase-I cell reads as untried when it is almost certainly occupied. Claudin 18.2 is buried in tight junctions of normal stomach but exposed on cancer cells, giving a tumour-selective epitope; expression is heterogeneous, so a bystander-capable topoisomerase-I payload is the natural class.","caveat":"This row is a data-quality flag as much as a proposal: the payload fields on the corpus Claudin 18.2 ADC records need filling before the engine can count this cell as in development.","status":"already in development (missed by decomposer)","statusLabel":"Already in development","score":{"total":82,"burden":32,"worldDeaths":1572975,"validationA":15,"validationB":15,"plausibility":20},"evidence":[{"label":"Paper: Ruan DY et al. (2025-07-16)","url":"https://doi.org/10.1038/s41591-025-03781-w","quote":"SHR-A1904 is an antibody-drug conjugate comprising CLDN18.2-targeting monoclonal antibody, a DNA topoisomerase I inhibitor payload and a cleavable peptide-based linker.","kind":"paper"},{"label":"Trial: Zhejiang University (2025-01-13)","url":"https://clinicaltrials.gov/study/NCT06770439","quote":"This study is a phase II study to evaluate the safety, tolerability and efficacy of IBI343 combined with chemotherapy in patients with advanced pancreatic cancer, including Part1 (safe lead-in phase) and Part2 (extension phase).","kind":"trial"}],"refs":["azd4360","cmg901","ibi343","satricabtagene-autoleucel","xnw27011","zolbetuximab","lm-302"],"cancers":["gastric-cldn18-2-positive","gastric","pancreatic","oesophageal-adenocarcinoma"],"proposedBy":"OnCo open pipeline","on":"2026-09-23"},{"id":"adc-egfr-top1","format":"adc","name":"EGFR ADC with a topoisomerase-I payload","a":"egfr","b":"topoisomerase-i-payloads","raw":{"a":"egfr","b":"topoisomerase-i-payloads"},"matched":true,"unmatched":[],"rationale":"EGFR is validated by antibodies (cetuximab, amivantamab) and kinase inhibitors (osimertinib), and the corpus holds an EGFR ADC with a tubulin payload in phase 3 (mrg003) plus two bispecific EGFR ADCs with topoisomerase-I payloads (izalontamab-brengitecan, tilatamig-samrotecan). There is no mono-specific EGFR topoisomerase-I ADC in the corpus, the simplest construct in the family. EGFR internalises on antibody binding and is over-expressed in squamous cancers, but its expression on skin and gut means an EGFR ADC inherits cetuximab's rash plus payload toxicity; the corpus bispecific EGFR ADCs (izalontamab-brengitecan) use a second arm partly to bias delivery towards tumour.","caveat":"The bispecific EGFR ADCs exist partly because a mono-specific EGFR ADC risks skin and gut toxicity at active doses; this proposal asks whether the simpler molecule can find a window, and depatuxizumab-mafodotin's failure in glioblastoma is a warning.","status":"no public evidence","statusLabel":"No public evidence","score":{"total":82,"burden":36,"worldDeaths":3649307,"validationA":15,"validationB":15,"plausibility":16},"evidence":[],"refs":["amivantamab","cetuximab","izalontamab-brengitecan","mrg003","osimertinib","tilatamig-samrotecan"],"cancers":["head-and-neck","nsclc","colorectal","egfr-mutant-nsclc","esophageal"],"proposedBy":"OnCo open pipeline","on":"2026-09-23"},{"id":"adc-dll3-top1","format":"adc","name":"DLL3 ADC with a topoisomerase-I payload","a":"dll3","b":"topoisomerase-i-payloads","raw":{"a":"dll3","b":"topoisomerase-i-payloads"},"matched":true,"unmatched":[],"rationale":"DLL3 is validated by an approved T-cell engager (tarlatamab) and a PBD ADC that reached phase 3 and was withdrawn for toxicity (rovalpituzumab-tesirine), while topoisomerase-I payloads are approved on five antigens (trastuzumab-deruxtecan, sacituzumab-govitecan). The corpus has a DLL3 ADC in phase 3 whose payload the record does not state (zl-1310), so the decomposer classes the DLL3 x topoisomerase-I cell as untried. DLL3 is tumour-restricted (no normal-tissue surface expression) and internalises, but at low density; a bystander-capable topoisomerase-I payload at DAR 8 fits low-density antigens far better than the DAR-2 PBD that failed with rovalpituzumab-tesirine.","caveat":"The corpus DLL3 ADC record needs its payload filled in before this cell can be marked as in development; if the payload is a camptothecin, this proposal is already being tested rather than open.","status":"already in development (missed by decomposer)","statusLabel":"Already in development","score":{"total":81,"burden":33,"worldDeaths":2214899,"validationA":15,"validationB":15,"plausibility":18},"evidence":[{"label":"Trial: Zai Lab (Shanghai) Co., Ltd. (2025-10-20)","url":"https://clinicaltrials.gov/study/NCT07218146","quote":"The purpose of this study is to evaluate the efficacy and safety of ZL-1310 compared to Investigator's Choice Therapy in participants with relapsed Small Cell Lung Cancer.","kind":"trial"}],"refs":["rovalpituzumab-tesirine","sacituzumab-govitecan","tarlatamab","trastuzumab-deruxtecan","zl-1310"],"cancers":["sclc","extensive-stage-sclc","prostate-nepc","extrapulmonary-nec"],"proposedBy":"OnCo open pipeline","on":"2026-09-23"},{"id":"adc-trop2-tubulin","format":"adc","name":"TROP2 ADC with a tubulin-inhibitor payload","a":"trop2","b":"tubulin-inhibitor-payloads","raw":{"a":"trop2","b":"tubulin-inhibitor-payloads"},"matched":true,"unmatched":[],"rationale":"TROP2 carries three approved topoisomerase-I ADCs (sacituzumab-govitecan, datopotamab-deruxtecan, sacituzumab-tirumotecan) and no tubulin-payload ADC in the corpus, while tubulin payloads are approved on Nectin-4 (enfortumab-vedotin) and HER2 (trastuzumab-emtansine). A tubulin-payload TROP2 ADC would give a second mechanism for the same antigen after topoisomerase-I failure, the sequencing already used across HER2 ADCs. TROP2 internalises and recycles quickly, which suits a permeable auristatin with bystander killing (bystander-effect); TROP2 on skin and mucosa predicts the rash and stomatitis already seen with the topoisomerase ADCs.","caveat":"Earlier TROP2 auristatin conjugates were stopped in phase 1; the class may need a lower DAR or site-specific conjugation to be tolerable, and that history is the first thing to read.","status":"clinical evidence","statusLabel":"Clinical evidence","score":{"total":80,"burden":34,"worldDeaths":2704168,"validationA":15,"validationB":15,"plausibility":16},"evidence":[{"label":"Trial: Pfizer (2014-04-24)","url":"https://clinicaltrials.gov/study/NCT02122146","quote":"To assess the safety and tolerability at increasing dose levels of PF-06664178 in patients with advanced solid tumors in order to determine the maximum tolerated dose and select the recommended Phase 2 dose.","kind":"trial"},{"label":"Paper: King GT et al. (2018-01-15)","url":"https://doi.org/10.1007/s10637-018-0560-6","quote":"A phase 1, dose-escalation study of PF-06664178, an anti-Trop-2/Aur0101 antibody-drug conjugate in patients with advanced or metastatic solid tumors.","kind":"paper"},{"label":"Paper: Sun LP et al. (2023-10-26)","url":"https://doi.org/10.1021/acs.jmedchem.3c01210","quote":"Herein, we first prepared a novel anti-TROP2 antibody-drug conjugate (ADC) hIMB1636-MMAE using hIMB1636 antibody chemically coupled to monomethyl auristatin E (MMAE) via a Valine-Citrulline linker and then reported its characteristics and antitumor activity.","kind":"paper"}],"refs":["bystander-effect","datopotamab-deruxtecan","enfortumab-vedotin","sacituzumab-govitecan","sacituzumab-tirumotecan","trastuzumab-emtansine"],"cancers":["tnbc","nsclc","urothelial","breast-hr-positive"],"proposedBy":"OnCo open pipeline","on":"2026-09-23"},{"id":"adc-sstr2-top1","format":"adc","name":"Somatostatin receptor 2 ADC with a topoisomerase-I payload","a":"sstr2","b":"topoisomerase-i-payloads","raw":{"a":"sstr2","b":"topoisomerase-i-payloads"},"matched":true,"unmatched":[],"rationale":"SSTR2 is validated by an approved radioligand (lutathera) and a phase-3 alpha emitter (ryz101), and topoisomerase-I payloads are the best-validated ADC class (trastuzumab-deruxtecan). No corpus product pairs SSTR2 with a cytotoxic payload, although the corpus already carries a bystander-capable topoisomerase payload family (topoisomerase-i-payloads) suited to heterogeneous receptor expression. SSTR2 is a G-protein-coupled receptor that internalises on agonist binding (the basis of lutathera); antibody-format ADCs against GPCRs are hard, so a peptide-drug conjugate with a camptothecin is the more plausible construct, and neuroendocrine tumours divide slowly.","caveat":"Well-differentiated neuroendocrine tumours have low proliferation and replication-dependent poisons may add little to radioligand therapy; the better fit may be SSTR2-positive small-cell lung cancer, where cells divide fast.","status":"clinical evidence","statusLabel":"Clinical evidence","score":{"total":77,"burden":33,"worldDeaths":1817469,"validationA":15,"validationB":15,"plausibility":14},"evidence":[{"label":"Trial: Tarveda Therapeutics (2016-10-18)","url":"https://clinicaltrials.gov/study/NCT02936323","quote":"Protocol PEN-221-001 is an open-label, multicenter Phase 1/2a study evaluating PEN-221 in patients with SSTR2 expressing advanced gastroenteropancreatic (GEP) or lung or thymus or other neuroendocrine tumors or small cell lung cancer or large cell neuroendocrine carcinoma of the lung.","kind":"trial"},{"label":"Paper: White BH et al. (2019-02-28)","url":"https://doi.org/10.1021/acs.jmedchem.8b02036","quote":"Discovery of an SSTR2-Targeting Maytansinoid Conjugate (PEN-221) with Potent Activity in Vitro and in Vivo.","kind":"paper"},{"label":"Paper: Whalen KA et al. (2019-11-01), neighbouring cell","url":"https://doi.org/10.1158/1535-7163.mct-19-0022","quote":"Targeting the Somatostatin Receptor 2 with the Miniaturized Drug Conjugate, PEN-221: A Potent and Novel Therapeutic for the Treatment of Small Cell Lung Cancer.","kind":"paper","adjacent":true}],"refs":["lutathera","ryz101","topoisomerase-i-payloads","trastuzumab-deruxtecan"],"cancers":["neuroendocrine","pancreatic-net","lung-net","sclc"],"proposedBy":"OnCo open pipeline","on":"2026-09-23"},{"id":"adc-her2-pbd-dimer","format":"adc","name":"HER2 ADC with a PBD dimer payload","a":"her2","b":"pbd-dimer-payloads","raw":{"a":"her2","b":"pbd-dimer-payloads"},"matched":true,"unmatched":[],"rationale":"HER2 is the most validated ADC target in the corpus, carrying a tubulin payload (trastuzumab-emtansine) and two topoisomerase-I payloads (trastuzumab-deruxtecan, trastuzumab-rezetecan), while the PBD dimer class is validated on CD19 (zynlonta). No corpus ADC combines HER2 with a DNA crosslinker, which would offer a mechanism unaffected by the topoisomerase-I resistance now emerging after deruxtecan exposure. HER2 internalises well (trastuzumab-emtansine, trastuzumab-deruxtecan), and a DAR-2 PBD dimer would not depend on high antigen density; but HER2 is expressed on cardiomyocytes and the gut, and PBD dimers carry fluid-retention and liver toxicity (pbd-dimer-payloads), so the therapeutic window is the open question.","caveat":"A HER2 PBD ADC would need a therapeutic window that HER2 expression on normal heart and gut tissue may not allow; the tried-and-stopped history of HER2 PBD conjugates must be read before any new attempt.","status":"clinical evidence","statusLabel":"Clinical evidence","score":{"total":75,"burden":31,"worldDeaths":1326278,"validationA":15,"validationB":15,"plausibility":14},"evidence":[{"label":"Trial: ADC Therapeutics S.A. (2017-04-24)","url":"https://clinicaltrials.gov/study/NCT03125200","quote":"This study evaluated ADCT-502 in participants with Advanced Solid Tumors with HER2 Expression.","kind":"trial"}],"refs":["pbd-dimer-payloads","trastuzumab-deruxtecan","trastuzumab-emtansine","trastuzumab-rezetecan","zynlonta"],"cancers":["breast-her2-positive","gastric-her2-positive","her2-low-metastatic-breast-cancer"],"proposedBy":"OnCo open pipeline","on":"2026-09-23"},{"id":"adc-psma-top1","format":"adc","name":"PSMA ADC with a topoisomerase-I payload","a":"psma","b":"topoisomerase-i-payloads","raw":{"a":"psma","b":"topoisomerase-i-payloads"},"matched":true,"unmatched":[],"rationale":"PSMA is validated by an approved radioligand (pluvicto) and three phase-3 alpha emitters (aaa817, ac225-psma), and topoisomerase-I is the dominant approved ADC payload class (trastuzumab-deruxtecan, sacituzumab-govitecan, datopotamab-deruxtecan). No corpus drug conjugates a PSMA antibody to a topoisomerase-I payload. Topoisomerase-I payloads kill more slowly dividing cells than auristatins and have bystander effect for heterogeneous PSMA expression; prostate cancer has had no camptothecin exposure, so no pre-existing resistance.","caveat":"It would need to hold its own against a radioligand that already delivers a DNA-damaging dose to the same antigen; the likely place is after radioligand progression or in patients whose marrow reserve excludes further radiation.","status":"preclinical evidence","statusLabel":"Preclinical","score":{"total":74,"burden":26,"worldDeaths":397430,"validationA":15,"validationB":15,"plausibility":18},"evidence":[{"label":"Paper: Xu Y et al. (2026-05-29)","url":"https://doi.org/10.1158/1535-7163.mct-26-0395","quote":"GenSci143 comprises a highly active topoisomerase 1 inhibitor payload conjugated to a dual-targeting antibody via a plasma-stable linker to minimize off-target toxicity.","kind":"paper"}],"refs":["aaa817","ac225-psma","datopotamab-deruxtecan","pluvicto","sacituzumab-govitecan","trastuzumab-deruxtecan"],"cancers":["prostate-mcrpc","prostate"],"proposedBy":"OnCo open pipeline","on":"2026-09-23"},{"id":"adc-cd19-top1","format":"adc","name":"CD19 ADC with a topoisomerase-I payload","a":"cd19","b":"topoisomerase-i-payloads","raw":{"a":"cd19","b":"topoisomerase-i-payloads"},"matched":true,"unmatched":[],"rationale":"CD19 is validated as an ADC target with a PBD dimer (zynlonta), as a T-cell engager target (blinatumomab) and as a CAR-T target (tisagenlecleucel), while topoisomerase-I payloads dominate solid-tumour ADCs (trastuzumab-deruxtecan, sacituzumab-govitecan). No corpus ADC pairs CD19 with a topoisomerase-I payload; lymphoma cells proliferate fast enough for replication-dependent poisons to act. CD19 internalises (zynlonta depends on it) and is B-lineage restricted; a topoisomerase-I payload would give a lower-potency, higher-DAR alternative to the PBD dimer whose skin and fluid toxicities limit zynlonta.","caveat":"A CD19 topoisomerase-I ADC would enter a field where CAR-T and CD20 x CD3 bispecifics already work; its niche would be outpatient, off-the-shelf therapy for patients unfit for those.","status":"no public evidence","statusLabel":"No public evidence","score":{"total":73,"burden":27,"worldDeaths":556084,"validationA":15,"validationB":15,"plausibility":16},"evidence":[],"refs":["blinatumomab","sacituzumab-govitecan","tisagenlecleucel","trastuzumab-deruxtecan","zynlonta"],"cancers":["dlbcl","all-leukemia","follicular-lymphoma","mantle-cell-lymphoma"],"proposedBy":"OnCo open pipeline","on":"2026-09-23"},{"id":"adc-psma-tubulin","format":"adc","name":"PSMA ADC with a tubulin-inhibitor payload","a":"psma","b":"tubulin-inhibitor-payloads","raw":{"a":"psma","b":"tubulin-inhibitor-payloads"},"matched":true,"unmatched":[],"rationale":"PSMA is validated by an approved radioligand (pluvicto) and tubulin payloads are approved on Nectin-4 (enfortumab-vedotin) and HER2 (trastuzumab-emtansine). No corpus ADC targets PSMA at all, although PSMA internalises and is the best-characterised antigen in prostate cancer. PSMA internalises through its cytoplasmic tail and is tumour-restricted apart from salivary glands, kidney and small bowel; an ADC would avoid the marrow and salivary dose of the radioligand, though prostate cancer grows slowly and tubulin agents need dividing cells.","caveat":"Two earlier PSMA tubulin ADCs were stopped for neuropathy and neutropenia; a new attempt would need site-specific conjugation or a non-permeable payload to change the window.","status":"clinical evidence","statusLabel":"Clinical evidence","score":{"total":72,"burden":26,"worldDeaths":397430,"validationA":15,"validationB":15,"plausibility":16},"evidence":[{"label":"Trial: Janssen Research & Development, LLC (2020-12-10)","url":"https://clinicaltrials.gov/study/NCT04662580","quote":"This is a phase 1 study to assess the safety and tolerability of ARX517 as monotherapy or combination therapy in adult subjects with metastatic prostate cancer (mPC).","kind":"trial"},{"label":"Paper: Skidmore LK et al. (2024-12-01)","url":"https://doi.org/10.1158/1535-7163.mct-23-0927","quote":"Using our proprietary technology for incorporating synthetic amino acids into proteins at selected sites, we have developed ARX517, an antibody-drug conjugate composed of a humanized anti-PSMA antibody site-specifically conjugated to a tubulin inhibitor at a drug-to-antibody ratio of 2.","kind":"paper"},{"label":"Trial: Progenics Pharmaceuticals, Inc. (2012-09-27)","url":"https://clinicaltrials.gov/study/NCT01695044","quote":"PSMA ADC 2301 is a Phase 2, open-label, study to assess the anti-tumor activity and tolerability of Prostate Specific Membrane Antigen Antibody Drug Conjugate (PSMA ADC) in two groups of subjects with metastatic castration-resistant prostate cancer (mCRPC).","kind":"trial"},{"label":"Paper: Milowsky MI et al. (2016-10-17)","url":"https://doi.org/10.1016/j.urolonc.2016.07.005","quote":"<h4>Background</h4>This phase 1/2 study evaluated the dose-limiting toxicity and maximum tolerated dose of MLN2704, a humanized monoclonal antibody MLN591 targeting prostate-specific membrane antigen, linked to the maytansinoid DM1 in patients with progressive metastatic castration-resistant prostate cancer.<h4>Patients and methods</h4>A total of 62 patients received MLN2704 at ascending doses on 4 schedules: week...","kind":"paper"}],"refs":["enfortumab-vedotin","pluvicto","trastuzumab-emtansine"],"cancers":["prostate-mcrpc","prostate"],"proposedBy":"OnCo open pipeline","on":"2026-09-23"},{"id":"adc-cd79b-top1","format":"adc","name":"CD79b ADC with a topoisomerase-I payload","a":"cd79b","b":"topoisomerase-i-payloads","raw":{"a":"cd79b","b":"topoisomerase-i-payloads"},"matched":true,"unmatched":[],"rationale":"CD79b is validated by an approved tubulin ADC used in first-line lymphoma (polatuzumab-vedotin) and the topoisomerase-I class is the most validated payload family (trastuzumab-deruxtecan, sacituzumab-govitecan). No corpus ADC pairs CD79b with a topoisomerase-I payload. CD79b internalises via the B-cell receptor complex (polatuzumab-vedotin) and is B-lineage restricted; a topoisomerase-I payload would avoid the neuropathy of MMAE and could be combined with R-CHP where vincristine was dropped.","caveat":"Polatuzumab already occupies first-line DLBCL; a second CD79b ADC would need a clean advantage, most plausibly activity after polatuzumab failure or a better neuropathy profile in older patients.","status":"no public evidence","statusLabel":"No public evidence","score":{"total":70,"burden":24,"worldDeaths":250679,"validationA":15,"validationB":15,"plausibility":16},"evidence":[],"refs":["polatuzumab-vedotin","sacituzumab-govitecan","trastuzumab-deruxtecan"],"cancers":["dlbcl","follicular-lymphoma","mantle-cell-lymphoma"],"proposedBy":"OnCo open pipeline","on":"2026-09-23"},{"id":"adc-cd22-pbd-dimer","format":"adc","name":"CD22 ADC with a PBD dimer payload","a":"cd22","b":"pbd-dimer-payloads","raw":{"a":"cd22","b":"pbd-dimer-payloads"},"matched":true,"unmatched":[],"rationale":"CD22 is validated with a DNA-cleaving calicheamicin payload (inotuzumab-ozogamicin) and the PBD dimer class is validated on the neighbouring B-cell antigen CD19 (zynlonta). No corpus ADC pairs CD22 with a PBD dimer, even though the two DNA-damaging classes have different resistance mechanisms. CD22 internalises rapidly (inotuzumab-ozogamicin) and both calicheamicin and PBD are DNA-damaging payloads that kill non-dividing blasts; the liver toxicity of both classes (veno-occlusive disease with inotuzumab) is the shared risk.","caveat":"Both payload classes damage liver sinusoids; a CD22 PBD ADC would need to show it does not reproduce the veno-occlusive disease seen with inotuzumab before transplant.","status":"clinical evidence","statusLabel":"Clinical evidence","score":{"total":69,"burden":27,"worldDeaths":556084,"validationA":15,"validationB":15,"plausibility":12},"evidence":[{"label":"Trial: M.D. Anderson Cancer Center (2018-10-09)","url":"https://clinicaltrials.gov/study/NCT03698552","quote":"This phase I/II trial studies the side effects and best dose of ADCT-602 in treating patients with B-cell lymphoblastic leukemia that has come back or does not respond to treatment.","kind":"trial"},{"label":"Paper: Zammarchi F et al. (2024-04-01)","url":"https://doi.org/10.1158/1535-7163.mct-23-0506","quote":"ADCT-602, a Novel PBD Dimer-containing Antibody-Drug Conjugate for Treating CD22-positive Hematologic Malignancies.","kind":"paper"}],"refs":["inotuzumab-ozogamicin","zynlonta"],"cancers":["all-leukemia","dlbcl"],"proposedBy":"OnCo open pipeline","on":"2026-09-23"},{"id":"adc-bcma-top1","format":"adc","name":"BCMA ADC with a topoisomerase-I payload","a":"bcma","b":"topoisomerase-i-payloads","raw":{"a":"bcma","b":"topoisomerase-i-payloads"},"matched":true,"unmatched":[],"rationale":"BCMA is validated across four formats in the corpus, including an ADC with a tubulin payload (belantamab-mafodotin), and the topoisomerase-I class is validated on solid-tumour antigens (trastuzumab-deruxtecan, sacituzumab-govitecan). No corpus ADC pairs BCMA with a topoisomerase-I payload, which would replace the ocular toxicity of MMAF with a different, better-understood profile. BCMA is plasma-cell restricted and internalises (belantamab-mafodotin); a permeable topoisomerase-I payload could avoid the corneal toxicity of MMAF, which is the dose-limiting problem of the approved BCMA ADC, but myeloma cells divide slowly, which blunts replication-dependent poisons.","caveat":"Topoisomerase-I poisons need replicating cells; the low proliferative index of myeloma may make this class less active than in solid tumours, so a preclinical comparison against belantamab is the first step.","status":"no public evidence","statusLabel":"No public evidence","score":{"total":67,"burden":21,"worldDeaths":121388,"validationA":15,"validationB":15,"plausibility":16},"evidence":[],"refs":["belantamab-mafodotin","sacituzumab-govitecan","trastuzumab-deruxtecan"],"cancers":["multiple-myeloma"],"proposedBy":"OnCo open pipeline","on":"2026-09-23"},{"id":"adc-cd123-top1","format":"adc","name":"CD123 ADC with a topoisomerase-I payload","a":"cd123","b":"topoisomerase-i-payloads","raw":{"a":"cd123","b":"topoisomerase-i-payloads"},"matched":true,"unmatched":[],"rationale":"CD123 is validated with a DNA-alkylating ADC (pivekimab-sunirine) and a toxin fusion (tagraxofusp), and the topoisomerase-I class is validated on many solid-tumour antigens (trastuzumab-deruxtecan). No corpus ADC pairs CD123 with a topoisomerase-I payload. CD123 is on leukaemic stem cells and internalises (pivekimab-sunirine, tagraxofusp); a topoisomerase-I payload would be less potent than the IGN alkylator and might widen the window against normal progenitors, at the cost of activity in quiescent stem cells.","caveat":"Quiescent leukaemic stem cells are the therapeutic goal of CD123 targeting, and topoisomerase-I poisons act mainly on replicating cells; this construct may treat bulk disease but miss the stem cell pool.","status":"preclinical evidence","statusLabel":"Preclinical","score":{"total":67,"burden":25,"worldDeaths":305405,"validationA":15,"validationB":15,"plausibility":12},"evidence":[{"label":"Paper: Li B et al. (2016-09-17)","url":"https://doi.org/10.1016/j.bmc.2016.09.043","quote":"Here, we designed and developed an antibody drug conjugate (CD123-CPT) by integrating anti-CD123 antibody with a chemotherapeutic agent, Camptothecin (CPT), via a disulfide linker.","kind":"paper"}],"refs":["pivekimab-sunirine","tagraxofusp","trastuzumab-deruxtecan"],"cancers":["aml","bpdcn"],"proposedBy":"OnCo open pipeline","on":"2026-09-23"},{"id":"adc-cd20-top1","format":"adc","name":"CD20 ADC with a topoisomerase-I payload","a":"cd20","b":"topoisomerase-i-payloads","raw":{"a":"cd20","b":"topoisomerase-i-payloads"},"matched":true,"unmatched":[],"rationale":"CD20 is the most validated B-cell antigen in the corpus across naked antibodies (rituximab, obinutuzumab), a radioconjugate (ibritumomab-tiuxetan) and four T-cell engagers (epcoritamab, glofitamab), yet no ADC. Topoisomerase-I payloads with acid-labile linkers release drug in the tumour microenvironment (sacituzumab-govitecan), which is the mechanism a non-internalising antigen would rely on. CD20 barely internalises, which is why no CD20 ADC exists despite four approved CD20 antibodies; a permeable topoisomerase-I payload released extracellularly (as sacituzumab-govitecan partly is) is the only route that makes sense, and it would be a delivery experiment as much as a drug.","caveat":"The whole proposal rests on extracellular payload release working at therapeutic levels; if it does not, CD20's lack of internalisation kills the idea, as it has for tubulin payloads.","status":"no public evidence","statusLabel":"No public evidence","score":{"total":65,"burden":27,"worldDeaths":556084,"validationA":15,"validationB":15,"plausibility":8},"evidence":[],"refs":["epcoritamab","glofitamab","ibritumomab-tiuxetan","obinutuzumab","rituximab","sacituzumab-govitecan"],"cancers":["dlbcl","follicular-lymphoma","mantle-cell-lymphoma","cll"],"proposedBy":"OnCo open pipeline","on":"2026-09-23"},{"id":"adc-cd33-pbd-dimer","format":"adc","name":"CD33 ADC with a PBD dimer payload","a":"cd33","b":"pbd-dimer-payloads","raw":{"a":"cd33","b":"pbd-dimer-payloads"},"matched":true,"unmatched":[],"rationale":"CD33 is validated with a calicheamicin ADC (gemtuzumab-ozogamicin) and PBD dimers are validated on CD19 (zynlonta). The corpus has no CD33 PBD conjugate; a lower-DAR PBD could address the calicheamicin resistance driven by drug efflux in AML blasts. CD33 internalises and is myeloid-restricted, but it sits on normal myeloid progenitors, so any potent DNA-damaging payload will cause deep, prolonged cytopenias; the earlier CD33 PBD programme was stopped for that reason.","caveat":"A CD33 PBD ADC would need a way round the myelosuppression that stopped the earlier attempt, for example as a bridge to transplant rather than a stand-alone therapy.","status":"clinical evidence","statusLabel":"Clinical evidence","score":{"total":65,"burden":25,"worldDeaths":305405,"validationA":15,"validationB":15,"plausibility":10},"evidence":[{"label":"Trial: Seagen Inc. (2016-05-30)","url":"https://clinicaltrials.gov/study/NCT02785900","quote":"The purpose of this study in AML patients is to test whether vadastuximab talirine (SGN-CD33A; 33A) combined with either azacitidine or decitabine improves remission rates and extends overall survival as compared to placebo combined with either azacitidine or decitabine.","kind":"trial"},{"label":"Paper: Stein EM et al. (2017-12-01)","url":"https://doi.org/10.1182/blood-2017-06-789800","quote":"Vadastuximab talirine (SGN-CD33A, 33A) is an antibody-drug conjugate consisting of pyrrolobenzodiazepine dimers linked to a monoclonal antibody targeting CD33, which is expressed in the majority of acute myeloid leukemia (AML) patients.","kind":"paper"}],"refs":["gemtuzumab-ozogamicin","zynlonta"],"cancers":["aml","mds"],"proposedBy":"OnCo open pipeline","on":"2026-09-23"},{"id":"adc-gprc5d-top1","format":"adc","name":"GPRC5D ADC with a topoisomerase-I payload","a":"gprc5d","b":"topoisomerase-i-payloads","raw":{"a":"gprc5d","b":"topoisomerase-i-payloads"},"matched":true,"unmatched":[],"rationale":"GPRC5D is validated by an approved T-cell engager (talquetamab) and a phase-3 CAR-T (arlocabtagene-autoleucel), and the topoisomerase-I payload class is validated on many antigens (trastuzumab-deruxtecan). No corpus product delivers a cytotoxic payload to GPRC5D, which would give patients who have exhausted BCMA and CD3-engaging therapies an off-the-shelf option. GPRC5D is an orphan GPCR restricted to plasma cells and keratinised tissue (talquetamab); a payload delivered by an antibody would spare T-cell engagement toxicities but the receptor's internalisation rate is not established and myeloma proliferates slowly.","caveat":"GPRC5D is expressed in hair follicles, nails and tongue; an ADC would carry the same skin, nail and dysgeusia toxicity as talquetamab, and antigen loss after talquetamab is documented.","status":"no public evidence","statusLabel":"No public evidence","score":{"total":65,"burden":21,"worldDeaths":121388,"validationA":15,"validationB":15,"plausibility":14},"evidence":[],"refs":["arlocabtagene-autoleucel","talquetamab","trastuzumab-deruxtecan"],"cancers":["multiple-myeloma"],"proposedBy":"OnCo open pipeline","on":"2026-09-23"},{"id":"adc-cd38-top1","format":"adc","name":"CD38 ADC with a topoisomerase-I payload","a":"cd38","b":"topoisomerase-i-payloads","raw":{"a":"cd38","b":"topoisomerase-i-payloads"},"matched":true,"unmatched":[],"rationale":"CD38 is validated by two approved antibodies (daratumumab, isatuximab) and the corpus holds a CD38 ADC with a tubulin payload in phase 2 (sti-6129), but no CD38 topoisomerase-I ADC. Topoisomerase-I payloads are the best-validated ADC class (trastuzumab-deruxtecan, sacituzumab-govitecan) and could act on daratumumab-refractory disease that still expresses the antigen. CD38 is expressed at high density on myeloma cells and internalises slowly, which suits a permeable payload with bystander killing; the antigen is also on NK cells and red-cell precursors, so haematological toxicity is the expected limit.","caveat":"Most relapsed myeloma patients have received daratumumab, which down-regulates CD38 for months; the ADC would need antigen to remain, and the low proliferation of myeloma cells may blunt a replication-dependent payload.","status":"no public evidence","statusLabel":"No public evidence","score":{"total":63,"burden":21,"worldDeaths":121388,"validationA":15,"validationB":15,"plausibility":12},"evidence":[],"refs":["daratumumab","isatuximab","sacituzumab-govitecan","sti-6129","trastuzumab-deruxtecan"],"cancers":["multiple-myeloma"],"proposedBy":"OnCo open pipeline","on":"2026-09-23"},{"id":"adc-gd2-top1","format":"adc","name":"GD2 (disialoganglioside) ADC with a topoisomerase-I payload","a":"gd2","b":"topoisomerase-i-payloads","raw":{"a":"gd2","b":"topoisomerase-i-payloads"},"matched":true,"unmatched":[],"rationale":"GD2 is validated by two approved antibodies in neuroblastoma (dinutuximab, naxitamab) and topoisomerase-I payloads are the best-validated ADC class (trastuzumab-deruxtecan); the corpus has no GD2 ADC of any payload class. Children with relapsed neuroblastoma receive irinotecan and temozolomide as standard, so a GD2-directed camptothecin would concentrate a drug already known to be active. GD2 is a glycolipid, not a protein, and internalises poorly; its expression on peripheral nerves causes the pain of dinutuximab, which a cytotoxic payload could worsen. A bystander-capable payload released near the cell is the only plausible design.","caveat":"Poor internalisation of a glycolipid antigen and on-nerve expression are two serious objections; preclinical proof that payload reaches tumour without nerve toxicity is needed before any child is dosed.","status":"no public evidence","statusLabel":"No public evidence","score":{"total":60,"burden":18,"worldDeaths":58667,"validationA":15,"validationB":15,"plausibility":12},"evidence":[],"refs":["dinutuximab","naxitamab","trastuzumab-deruxtecan"],"cancers":["neuroblastoma","neuroblastoma-high-risk","osteosarcoma","melanoma"],"proposedBy":"OnCo open pipeline","on":"2026-09-23"}],"note":"Every state is derived from the records named in evidence; untried means no medicine in this corpus combines the two parts. Proposed cells are hypotheses from the open pipeline (docs/OPEN-PIPELINE.md), not records of a medicine. CC BY-NC 4.0, attribute Data from OnCo (onco.cc). Not medical advice."}