{"entity":{"id":"ak146d1","kind":"drug","name":"AK146D1","aka":[],"tldr":"AK146D1 is Akeso's Nectin-4 × TROP2 bispecific ADC, combining the two most validated ADC addresses in one molecule.","summary":"AK146D1 is Akeso's bispecific antibody-drug conjugate that binds both Nectin-4 and TROP2, the two most clinically validated ADC targets, and delivers a topoisomerase I inhibitor through a cleavable linker. The rationale is complementary expression across urothelial, breast and lung cancers and potentially higher internalisation when two receptors are engaged on the same cell. It entered the clinic in 2025 in a first-in-human phase 1 dose-escalation study after IND clearance in China, alongside Avenzo's AVZO-103 in the same target pair. No efficacy or toxicity data have yet been reported, so the programme is very early. Whether dual targeting improves on single-target ADCs such as enfortumab vedotin and sacituzumab govitecan, or simply adds toxicity, is the central question. For a newcomer: it combines two proven ADC addresses in one molecule, and the clinic has yet to show if that helps.","status":"phase-1","asOf":"2026-09-04","links":[{"label":"ClinicalTrials.gov NCT06929663: AK146D1 in advanced solid tumours (phase 1)","url":"https://clinicaltrials.gov/study/NCT06929663"},{"label":"Akeso","url":"https://www.akesobio.com/en/"}],"tags":[],"related":[],"cancers":["urothelial","tnbc","nsclc"],"sections":[],"technologies":["bispecific-adc"],"targets":["nectin4","trop2"],"drugs":[],"companies":["akeso"],"institutions":[],"pathways":[],"terms":[],"trials":["nct07669779","nct07591090"],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"modality":"Bispecific ADC","payload":"TOP1 inhibitor","linker":"Cleavable","mechanism":"Bispecific Nectin-4/TROP2 antibody with TOP1 payload.","approvals":[],"mechanismSteps":["Antibody binds Nectin-4 and TROP2 (bispecific) on the tumour cell surface","Receptor-ADC complex is internalised by endocytosis","Trafficked to the lysosome; linker is cleaved or antibody degraded","TOP1 inhibitor is released inside the cell","Topoisomerase-I is trapped on DNA; replication forks collapse into double-strand breaks","Tumour cell dies by apoptosis","Membrane-permeable payload diffuses to kill neighbouring antigen-negative cells (bystander effect)"],"dosing":{"route":"IV infusion","schedule":"Phase 1 dose escalation","source":"https://clinicaltrials.gov"},"toxicity":[],"access":[{"country":"CN","reimbursement":"Investigational","asOf":"2026-09-06"}],"regulatoryEvents":[{"date":"2025-03","type":"filing","region":"China","note":"IND cleared; first-in-human phase 1 started","source":"https://www.fda.gov/drugs/resources-information-approved-drugs/oncology-cancer-hematologic-malignancies-approval-notifications"}]},"route":"/drugs/ak146d1/","neighbours":{"cancer":[{"id":"urothelial","kind":"cancer","name":"Bladder & urothelial cancer","route":"/cancers/urothelial/"},{"id":"nsclc","kind":"cancer","name":"Non-small-cell lung cancer","route":"/cancers/nsclc/"},{"id":"tnbc","kind":"cancer","name":"Triple-negative breast cancer (TNBC)","route":"/cancers/tnbc/"}],"technology":[{"id":"bispecific-adc","kind":"technology","name":"Bispecific ADC","route":"/technologies/bispecific-adc/"}],"target":[{"id":"nectin4","kind":"target","name":"Nectin-4","route":"/targets/nectin4/"},{"id":"trop2","kind":"target","name":"TROP2","route":"/targets/trop2/"}],"company":[{"id":"akeso","kind":"company","name":"Akeso","route":"/companies/akeso/"}],"trial":[{"id":"nct07591090","kind":"trial","name":"A Phase II Study of AK146D1 Combined With AK112 in Advanced Breast Cancer","route":"/trials/nct07591090/"},{"id":"nct07669779","kind":"trial","name":"A Phase II Study of AK146D1 in Combination With AK112 in Advanced Non-Small Cell Lung Cancer","route":"/trials/nct07669779/"}],"roadmap":[{"id":"adc-generations","kind":"roadmap","name":"ADC roadmap: from Mylotarg to bispecific and dual-payload ADCs","route":"/roadmaps/adc-generations/"},{"id":"trop2-adc-roadmap","kind":"roadmap","name":"TROP2 ADC roadmap: sacituzumab govitecan → Dato-DXd → sac-TMT → bispecifics and PET","route":"/roadmaps/trop2-adc-roadmap/"}],"term":[{"id":"exatecan","kind":"term","name":"Exatecan (and derivatives)","route":"/terms/exatecan/"},{"id":"topoisomerase-i-payloads","kind":"term","name":"Topoisomerase-I inhibitor payloads","route":"/terms/topoisomerase-i-payloads/"}]}}