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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 IC50
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

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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
PBD dimmers cross link2

Two Sites Available for Linker Conjugation

N10-LINKED

N10 Linked2
  • Linker cleaved in traceless fashion to release active drug
  • PBDs compatible with many different conjugation chemistries

C2-LINKED

C2 Linked2