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

John A Hartley; Michael J. Flynn; John P. Bingham; Simon Corbett; Halla Weihe Reinert; Arnaud Tiberghien; Luke A. Masterson; Dyeison Antonow; Lauren Adams; Sajidah Chowdhury; David G. Williams; Shenlan Mao; Jay Harper; Carin E.G. Havenith; Francesca Zammarchi; Simon Chivers; Patrick H van Berkel; Philip W. Howard

doi:10.1038/s41598-018-28533-4

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

John A Hartley, Michael J. Flynn, John P. Bingham, Simon Corbett, Halla Weihe Reinert, Arnaud Tiberghien, Luke A. Masterson, Dyeison Antonow, Lauren Adams, Sajidah Chowdhury, David G. Williams, Shenlan Mao, Jay Harper, Carin E.G. Havenith, Francesca Zammarchi, Simon Chivers, Patrick H van Berkel, Philip W. Howard

Umhvørvisstovan - The Faroese Environment Agency

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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.

Original language	English
Article number	10479
Number of pages	10
Journal	SCIENTIFIC REPORTS
Volume	8
DOIs	https://doi.org/10.1038/s41598-018-28533-4
Publication status	Published - 11 Jul 2018

Keywords

Targeted therapies
Pharmacology
ADC

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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Pre-clinical pharmacology and mechanism of action of SG3199, the pyrrolobenzodiazepine (PBD) dimer warhead component of antibody-drug conjugate (ADC) payload tesirineFinal published version, 1.31 MBLicence: CC BY

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Hartley, J. A., Flynn, M. J., Bingham, J. P., Corbett, S., Weihe Reinert, H., Tiberghien, A., Masterson, L. A., Antonow, D., Adams, L., Chowdhury, S., Williams, D. G., Mao, S., Harper, J., Havenith, C. E. G., Zammarchi, F., Chivers, S., van Berkel, P. H., & Howard, P. W. (2018). Pre-clinical pharmacology and mechanism of action of SG3199, the pyrrolobenzodiazepine (PBD) dimer warhead component of antibody-drug conjugate (ADC) payload tesirine. SCIENTIFIC REPORTS, 8, Article 10479. https://doi.org/10.1038/s41598-018-28533-4

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

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.",

keywords = "Targeted therapies, Pharmacology, ADC",

author = "Hartley, {John A} and Flynn, {Michael J.} and Bingham, {John P.} and Simon Corbett and {Weihe Reinert}, Halla and Arnaud Tiberghien and Masterson, {Luke A.} and Dyeison Antonow and Lauren Adams and Sajidah Chowdhury and Williams, {David G.} and Shenlan Mao and Jay Harper and Havenith, {Carin E.G.} and Francesca Zammarchi and Simon Chivers and {van Berkel}, {Patrick H} and Howard, {Philip W.}",

year = "2018",

month = jul,

day = "11",

doi = "10.1038/s41598-018-28533-4",

language = "English",

volume = "8",

journal = "SCIENTIFIC REPORTS",

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Hartley, JA, Flynn, MJ, Bingham, JP, Corbett, S, Weihe Reinert, H, Tiberghien, A, Masterson, LA, Antonow, D, Adams, L, Chowdhury, S, Williams, DG, Mao, S, Harper, J, Havenith, CEG, Zammarchi, F, Chivers, S, van Berkel, PH & Howard, PW 2018, 'Pre-clinical pharmacology and mechanism of action of SG3199, the pyrrolobenzodiazepine (PBD) dimer warhead component of antibody-drug conjugate (ADC) payload tesirine', SCIENTIFIC REPORTS, vol. 8, 10479. https://doi.org/10.1038/s41598-018-28533-4

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T1 - Pre-clinical pharmacology and mechanism of action of SG3199, the pyrrolobenzodiazepine (PBD) dimer warhead component of antibody-drug conjugate (ADC) payload tesirine

AU - Hartley, John A

AU - Flynn, Michael J.

AU - Bingham, John P.

AU - Corbett, Simon

AU - Weihe Reinert, Halla

AU - Tiberghien, Arnaud

AU - Masterson, Luke A.

AU - Antonow, Dyeison

AU - Adams, Lauren

AU - Chowdhury, Sajidah

AU - Williams, David G.

AU - Mao, Shenlan

AU - Harper, Jay

AU - Havenith, Carin E.G.

AU - Zammarchi, Francesca

AU - Chivers, Simon

AU - van Berkel, Patrick H

AU - Howard, Philip W.

PY - 2018/7/11

Y1 - 2018/7/11

N2 - 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.

AB - 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.

KW - Targeted therapies

KW - Pharmacology

KW - ADC

UR - http://dx.doi.org/10.1038/s41598-018-28533-4

U2 - 10.1038/s41598-018-28533-4

DO - 10.1038/s41598-018-28533-4

M3 - Article

SN - 2045-2322

VL - 8

JO - SCIENTIFIC REPORTS

JF - SCIENTIFIC REPORTS

M1 - 10479

ER -

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

Abstract

Keywords

UN SDGs

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