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Technology Overview
Advantages of PBDs as ADC Warheads
ADC CHALLENGES
PBD BENEFITS
Ability to deliver enough drug to kill cancer cell
High Potency
Low antigen number, slow internalisation
Efflux pumps and resistance
Sub-picomolar IC
50
Releasing the drug in the target cell and not systemically
Mechanism of action
Linker stability, conjugation stability (e.g. non-retro Michael)
DAR, site-specific conjugation
Target expression on healthy tissue
Great flexibility to utilise different linker and conjugation chemistry and linker positions
Can enhance activity and improve tolerability
PBD mechanism of action processed by healthy tissue
Spirogen PBDs are Highly Potent with Activity at Sub-picomolar Concentrations
WARHEAD POTENCY FOR ADCs
PBD Dimers Cross Link DNA Strands in the Minor Groove
PBD dimers cross-link DNA in sequence selective fashion & block replication
PBD-DNA adduct non-distortive & avoids nucleotide excision repair
Cross-links persist, allowing killing of cancer stem cells
PBD dimers are not cross-resistant with platinum drugs and nitrogen mustards
Two Sites Available for Linker Conjugation
N10-LINKED
Linker cleaved in traceless fashion to release active drug
PBDs compatible with many different conjugation chemistries
C2-LINKED