Table 1.
Summary of key bispecific Antibody-Drug conjugates (BsADCs) in development for breast cancer therapy
| Target(s) | Example BsADC |
Construction | Key Features/Findings | Development Status/Comment |
|---|---|---|---|---|
| Dual-Epitope HER2(ECD2/ECD4) | ZW49 (based on ZW25) |
Payload: N-acyl sulfonamide auristatin DAR: 2 Linker: cleavable linker |
Biparatopic binding induces HER2 clustering, enhances internalization/CDC; ORR:13% in Phase I; Manageable toxicity (e.g., keratitis). | Phase I ongoing; potent in low- HER2 tumors.(NCT03821233) |
| Dual-Epitope HER2 | MEDI4276 |
Payload: AZ13599185(microtubule inhibitor) DAR:4 Linker: cleavable linker |
Tetravalent biparatopic; robust clustering/lysosomal trafficking. Limited activity due to PK/toxicity issues. | Phase I discon- tinued; high tox- icity (ILD). |
| HER2 (Do- mains II/IV) |
JSKN003 (based on KN026) |
Payload: DXd(Topoisomerase I inhibitor) DAR:4 Linker: cleavable tetrapeptide linker |
Improved stability/homogeneity over T-DXd. Enhanced binding/internalization. | Preclinical/early clinical; reduced ILD risk. |
| HER2/CD63 | bsHER2xCD63 ADC |
Payload: duostatin-3(microtubule inhibitor) DAR: not specified Linker: cleavable VC linker |
Low-affinity CD63 arm pro- motes lysosomal delivery. Po- tent in HER2 + tumors but needs optimization for low- HER2. | Preclinical; ad- dresses internal- ization barriers. |
| HER2/PRLR | HER2xPRLR BsADC |
Payload: DM1(microtubule inhibitor) DAR:3.3 Linker: noncleavable SMCC linker |
Cross-links receptors for enhanced degradation; Improved killing in co- expressing cells. |
Preclinical; targets PRLR- overexpressing subsets (~ 25% breast tumors). |
| HER2/APLP2 | HER2xAPL2P2 BsADC |
Payload: AmPEG6-MMAD DAR:2/4 Linker: cleavable linker |
Redirects to lysosomal degradation; Effective redirection of recycled targets. |
Preclinical; leverages APLP2’s en- docytosis motifs. |
| HER2/HER3 | HER2/HER3 BsADC |
Linker-Payload: MC-vc-PAB-MMAE DAR:2.89 |
Targets heterodimer for re- sistance; inhibits viability in resistant cell lines/xenografts. | Preclinical; com- parable to com- bined monospe- cific ADCs. |
| EGFR/HER3 |
BL-B01D1 (based on SI-B001) |
Payload: TOPIi ED04(topoisomerase I inhibitor) DAR:8 Linker: cleavable AC linker |
Attenuates HER3-induced resistance. Encouraging ef- ficacy in HER2- BC (Phase I/II). | Phase I/II; man- ageable safety in pretreated patients. |
| TROP2/HER3 | JSKN016 |
Payload: Topoisomerase I inhibitor DAR:4 Linker: cleavable linker |
Antitumor activity in TNBC. Manageable safety in FIH study. | Phase I ongoing; breakthrough in TNBC survival. |