Table 1

Overview of representative dual-epitope HER2 ADCs

Agent	Target	Linker	Payload	DAR	Clinical trial	Efficacy	Safety	Status	Limitation	Reference
ZW49	Dual-epitope HER2 ADC targeting ECD2/ECD4	Protease-cleavable linker; site-specific conjugation	N-acyl sulfonamide auristatin	2	HER2-positive advanced solid tumors; phase I, NCT03821233	ORR 31%, DCR 72% at 2.5 mg/kg recommended dose cohort	No ILD or treatment-related deaths; grade ≥2 keratitis/blurred vision	Discontinued	Ocular toxicity, low DAR, unfavorable benefit–risk profile	¹²
MEDI4276	Dual-epitope HER2 ADC targeting ECD2/ECD4	Maleimidocaproyl linker; site-specific conjugation	Tubulysin	4	HER2-positive advanced breast/gastric cancer; phase I, NCT02576548	ORR 9.4% among patients with breast cancer	Grade 3 AST elevation; dose-limiting hepatotoxicity	Discontinued	Narrow therapeutic window, low MTD, high clearance/short half-life	¹³
JSKN003	Dual-epitope HER2 ADC targeting ECD2/ECD4	Site-specific glycan conjugation; DBCO tetrapeptide linker	TOP1i	4	Pretreated advanced solid tumors; phase I, NCT05494918	Overall ORR 50.0%; HER2-positive breast cancer ORR 80.0%; HER2-low ORR 40.0%	One case grade 2 ILD; grade 3 TRAEs in 6.3% of patients	Phase III: NCT06846437; NCT06079983	Early-phase data; limited breast cancer sample; rare toxicities need larger datasets	¹⁴
TQB2102	Dual-epitope HER2 ADC targeting ECD2/ECD4	Enzyme-cleavable linker	TOP1i	6	Advanced solid tumors; phase 1, NCT05735496	ORR 41.2% among 165 previously treated patients	One case grade 2 ILD; no DLTs; main grade ≥3 TRAEs were hematologic	Phase III: NCT06561607 (HER2-low advanced breast cancer)	Direct neoadjuvant evidence mainly phase II; no head-to-head comparison; EFS/OS immature	¹⁵
					Advanced solid tumors; phase 1, NCT05735496	ORR 41.2% among 165 previously treated patients
					HER2-low breast cancer; phase 1b, NCT06115902	ORR 53.4%, with 44.4% in patients previously treated with other ADCs	No ILD events; grade ≥3 TRAEs in 41.1% of patients			¹⁶
					HER2-positive neoadjuvant therapy; phase 2, NCT06198751	tpCR 57.7%–76.9% across dose-cycle cohorts	Grade ≥3 TRAEs 23.1%–30.8%; no treatment-related deaths; low ILD incidence			¹⁷

ADC, antibody-drug conjugate; DAR, drug-to-antibody ratio; DCR, disease control rate; DLT, dose-limiting toxicity; EFS, event-free survival; ILD, interstitial lung disease; ORR, objective response rate; OS, overall survival; pCR, pathologic complete response; tpCR, total pathologic complete response; TRAE, treatment-related adverse event; TOP1i, topoisomerase I inhibitor; DBCO, dibenzocyclooctyne (site-specific conjugation chemistry). ECD2, extracellular domain 2; ECD4, extracellular domain 4; MTD, maximum tolerated dose. Clinical efficacy and safety data are derived from early-phase studies, selected cohorts, or conference-reported datasets where indicated; cross-trial comparisons should be interpreted cautiously.