2. Academic Validation
  3. Pre-clinical pharmacology and mechanism of action of SG3199, the pyrrolobenzodiazepine (PBD) dimer warhead component of antibody-drug conjugate (ADC) payload tesirine

Pre-clinical pharmacology and mechanism of action of SG3199, the pyrrolobenzodiazepine (PBD) dimer warhead component of antibody-drug conjugate (ADC) payload tesirine

  • Sci Rep. 2018 Jul 11;8(1):10479. doi: 10.1038/s41598-018-28533-4.
John A Hartley 1 2,  Michael J Flynn 3,  John P Bingham 3,  Simon Corbett 3 4,  Halla Reinert 3,  Arnaud Tiberghien 4,  Luke A Masterson 4,  Dyeison Antonow 4,  Lauren Adams 4,  Sajidah Chowdhury 4,  David G Williams 4,  Shenlan Mao 5,  Jay Harper 5,  Carin E G Havenith 6,  Francesca Zammarchi 6,  Simon Chivers 6,  Patrick H van Berkel 6,  Philip W Howard 4
Affiliations

Affiliations

  • 1 Cancer Research UK Drug DNA Interactions Research Group, UCL Cancer Institute, 72 Huntley Street, London, WC1E 6BT, UK. [email protected].
  • 2 Spirogen Ltd, QMB Innovation Centre, 42 New Road, London, E1 2AX, UK. [email protected].
  • 3 Cancer Research UK Drug DNA Interactions Research Group, UCL Cancer Institute, 72 Huntley Street, London, WC1E 6BT, UK.
  • 4 Spirogen Ltd, QMB Innovation Centre, 42 New Road, London, E1 2AX, UK.
  • 5 MedImmune, One MedImmune Way, Gaithersburg, MD, 20878, USA.
  • 6 ADC Therapeutics (UK) Limited, QMB Innovation Centre, 42 New Road, London, E1 2AX, UK.
PMID: 29992976 DOI: 10.1038/s41598-018-28533-4
Abstract

Synthetic pyrrolobenzodiazepine (PBD) dimers, where two PBD monomers are linked through their aromatic A-ring phenolic C8-positions via a flexible propyldioxy tether, are highly efficient DNA minor groove cross-linking agents with potent cytotoxicity. PBD dimer SG3199 is the released warhead component of the antibody-drug conjugate (ADC) payload tesirine (SG3249), currently being evaluated in several ADC clinical trials. SG3199 was potently cytotoxic against a panel of human solid tumour and haematological Cancer cell lines with a mean GI50 of 151.5 pM. Cells defective in DNA repair protein ERCC1 or homologous recombination repair showed increased sensitivity to SG3199 and the drug was only moderately susceptible to multidrug resistance mechanisms. SG3199 was highly efficient at producing DNA interstrand cross-links in naked linear plasmid DNA and dose-dependent cross-linking was observed in cells. Cross-links formed rapidly in cells and persisted over 36 hours. Following intravenous (iv) administration to rats SG3199 showed a very rapid clearance with a half life as short as 8 minutes. These combined properties of cytotoxic potency, rapid formation and persistence of DNA interstrand cross-links and very short half-life contribute to the emerging success of SG3199 as a warhead in clinical stage ADCs.

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