DAR6 Antibody

In Vitro Cytotoxicity

• DAR6 ADCs show ≥10x greater potency than DAR2 counterparts in low-antigen-expressing tumors (e.g., T47D) .

• Dual-payload DAR6 ADCs (e.g., MMAE + MMAF) overcome resistance in HER2-heterogeneous breast cancer models .

In Vivo Efficacy

• Anti-HER2 DAR6 ADCs induced tumor regression in xenograft models at 3 mg/kg doses, outperforming co-administered DAR2 + DAR4 combinations .

• Homogeneous DAR6 ADCs exhibited longer plasma half-lives (t₁/₂ = 7.2 days) compared to heterogeneous DAR6 formulations (t₁/₂ = 5.1 days) .

Linker Design Innovations

• PEG-spaced linkers: Diethylene glycol units in DAR6 linkers reduce steric hindrance, improving drug release kinetics .

• Cleavable tetrapeptides: GGFG-based linkers enable pH-sensitive payload release in lysosomes .

Analytical Methods

• Hydrophobic interaction chromatography (HIC): Resolves DAR6 species with 1.70 retention time shift vs. DAR4 .

• Rapid deglycosylation: PNGase F treatment coupled with LC-MS enables DAR6 quantification within 15 minutes .

Clinical and Developmental Status

While no DAR6-specific ADC has received FDA approval, key candidates include:

• T-D6-1508: A trastuzumab-based DAR6 ADC with tubulysin payload showing IC₅₀ = 0.15 nM against TNBC .

• ABBV-011: A DAR2 ADC in Phase I trials for SCLC, highlighting the need for higher DAR optimization .

Challenges and Limitations

• Aggregation risk: DAR6 formulations show 12–15% aggregation vs. 5–8% for DAR4 .

• Bystander effect limitations: Unlike DAR8 ADCs (e.g., DS-8201), DAR6 conjugates exhibit reduced payload diffusion to adjacent cells .