Article Figures & Data
Figures
- Figure 1
Conceptual schematic of HER2 receptor engagement and trafficking by single-epitope and dual-epitope ADCs. In single-epitope HER2 ADCs, (A) monomeric binding is followed by (B) variable internalization, (C) potential receptor recycling, (D) trafficking-dependent payload delivery, and (E) payload-dependent cytotoxic effects. In dual-epitope HER2 ADCs, (A) biparatopic binding may promote (B) receptor clustering, (C) decreased receptor recycling and preferential lysosomal trafficking, (D) enhanced payload delivery, and (E) potential bystander effects. Created with BioRender.com (www.biorender.com). ADC, antibody-drug conjugate; HER2, human epidermal growth factor receptor 2; ECD2, extracellular domain 2; ECD4, extracellular domain 4.
- Figure 2
Proposed biomarker-guided framework for neoadjuvant development of dual-epitope HER2 ADCs. Routine core needle biopsy defines HER2 status by IHC/ISH, whereas baseline biomarker profiling can be used to assess HER2 heterogeneity and immune/spatial features. Patients may be stratified into HER2-homogeneous immune-hot tumors for de-escalation or chemotherapy-sparing strategies; spatially heterogeneous tumors for approaches leveraging the bystander effect; and immune-suppressed or cold tumors for biomarker-guided combinations with ADCs, immune checkpoint inhibitors, anti-VEGF therapy, or metabolic modulators. Surgery and pathological assessment enable response evaluation and provide material for further translational analysis. Created with BioRender.com (www.biorender.com). ADC, antibody-drug conjugate; BC, breast cancer; HER2, human epidermal growth factor receptor 2; IF, immunofluorescence; IHC, immunohistochemistry; ISH, in situ hybridization; TME, tumor microenvironment; PD-1, programmed cell death protein 1; VEGF, vascular endothelial growth factor.
Tables
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 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.
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