A dual-targeting ADC strategy exploiting exDNA for nuclear payload delivery

Tumor targeting and intracellular payload delivery can limit antibody-drug conjugate (ADC) efficacy, particularly in heterogeneous tumors and challenging anatomical locations.

Read how researchers have developed a novel ADC strategy using V66, a humanized antibody that targets extracellular DNA (exDNA).

Key highlights:

• Novel targeting mechanism: V66 conjugated to topoisomerase 1 (TOP1) inhibitor exatecan binds exDNA in the tumor microenvironment, bypassing the need for a traditional tumor-associated antigen and enabling broader applicability across tumor types
• Nuclear payload delivery: V66-exatecan enters tumor cells via ENT2 transporters (not conventional endocytosis), delivering the payload directly to the nucleus for enhanced cytotoxic effect
• Enhanced potency in BRCA2-deficient tumors: The antibody-drug conjugate V66-exatecan showed enhanced potency against BRCA2-deficient cells
• Radiation priming boosts efficacy: Pre-treatment with radiation increased DNA damage and significantly enhanced V66 tumor accumulation
• Blood-brain barrier penetration: V66 selectively localized to brain tumors in medulloblastoma models, with fluorescence signal correlating with tumor burden
• Favorable safety profile: No significant toxicity to bone marrow, kidney, liver, or muscle at therapeutic doses in preclinical models
• Quantitative in vivo imaging: IVISense™ 680 fluorescent dye and the IVIS™ Spectrum system were used to visualize biodistribution and confirm tumor-specific accumulation across all key experiments.