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

被引：82

作者：

Hartley, John A. ^{[1
,2
]}

Flynn, Michael J. ^{[1
]}

Bingham, John P. ^{[1
]}

Corbett, Simon ^{[1
,2
]}

Reinert, Halla ^{[1
]}

Tiberghien, Arnaud ^{[2
]}

Masterson, Luke A. ^{[2
]}

Antonow, Dyeison ^{[2
]}

Adams, Lauren ^{[2
]}

Chowdhury, Sajidah ^{[2
]}

Williams, David G. ^{[2
]}

Mao, Shenlan ^{[3
]}

Harper, Jay ^{[3
]}

Havenith, Carin E. G. ^{[4
]}

Zammarchi, Francesca ^{[4
]}

Chivers, Simon ^{[4
]}

van Berkel, Patrick H. ^{[4
]}

Howard, Philip W. ^{[2
]}

机构：

[1] UCL Canc Inst, Canc Res UK Drug DNA Interact Res Grp, 72 Huntley St, London WC1E 6BT, England

[2] Spirogen Ltd, QMB Innovat Ctr, 42 New Rd, London E1 2AX, England

[3] MedImmune, One MedImmune Way, Gaithersburg, MD 20878 USA

[4] ADC Therapeut UK Ltd, QMB Innovat Ctr, 42 New Rd, London E1 2AX, England

来源：

SCIENTIFIC REPORTS | 2018年 / 8卷

关键词：

INTERSTRAND CROSS-LINKING; SPECTRUM ANTITUMOR-ACTIVITY; CELLULAR PHARMACOLOGY; SEQUENCE SPECIFICITY; SJG-136; NSC-694501; PHASE-I; DNA; REPAIR; AGENT; ANTHRAMYCIN;

D O I：

10.1038/s41598-018-28533-4

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

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 GI(50) 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.

引用

页数：10

共 12 条

[1] 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 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
[J]. Scientific Reports, 8
[2] Design and Synthesis of Tesirine, a Clinical Antibody-Drug Conjugate Pyrrolobenzodiazepine Dimer Payload
Tiberghien, Arnaud C.
Levy, Jean-Noel
Masterson, Luke A.
Patel, Neki V.
Adams, Lauren R.
Corbett, Simon
Williams, David G.
Hartley, John A.
Howard, Philip W.
[J]. ACS MEDICINAL CHEMISTRY LETTERS, 2016, 7 (11): : 983 - 987
[3] Synthesis and in vitro evaluation of SG3227, a pyrrolobenzodiazepine dimer antibody-drug conjugate payload based on sibiromycin
Kemp, Gary C.
Tiberghien, Arnaud C.
Patel, Neki V.
D'Hooge, Francois
Nilapwar, Sanjay M.
Adams, Lauren R.
Corbett, Simon
Williams, David G.
Hartley, John A.
Howard, Philip W.
[J]. BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 2017, 27 (05) : 1154 - 1158
[4] Pre-clinical characterization of the mechanism of action of a CD25-targeted pyrrolobenzodiazepine dimer-based antibody-drug conjugate targeting regulatory T cells in solid cancers
Zammarchi, Francesca
Chivers, Simon
van Berkel, Patrick
[J]. JOURNAL FOR IMMUNOTHERAPY OF CANCER, 2019, 7
[5] Pre-Clinical Activity of Adct-301, a Novel Pyrrolobenzodiazepine (PBD) Dimer-Containing Antibody Drug Conjugate (ADC) Targeting CD25-Expressing Hematological Malignancies
Flynn, Michael J.
van Berkel, Patrick
Zammarchi, Francesca
Levy, Jean-Noel
Tiberghien, Arnaud
Masterson, Luke A.
D'Hooge, Francois
Adams, Lauren
Williams, David G.
Howard, Philip W.
Hartley, John A.
[J]. BLOOD, 2014, 124 (21)
[6] ADCT-301, a Pyrrolobenzodiazepine (PBD) Dimer-Containing Antibody-Drug Conjugate (ADC) Targeting CD25-Expressing Hematological Malignancies
Flynn, Michael J.
Zammarchi, Francesca
Tyrer, Peter C.
Akarca, Ayse U.
Janghra, Narinder
Britten, Charles E.
Havenith, Carin E. G.
Levy, Jean-Noel
Tiberghien, Arnaud
Masterson, Luke A.
Barry, Conor
D'Hooge, Francois
Marafioti, Teresa
Parren, Paul W. H. I.
Williams, David G.
Howard, Philip W.
van Berkel, Patrick H.
Hartley, John A.
[J]. MOLECULAR CANCER THERAPEUTICS, 2016, 15 (11) : 2709 - 2721
[7] ADCT-701, a novel pyrrolobenzodiazepine (PBD) dimer-based antibody-drug conjugate (ADC) targeting DLK1-expressing tumors
Zammarchi, Francesca
Havenith, Karin
Chivers, Simon
Hogg, Paul W.
Britten, Charlie
Dissanayake, Sandamali
Tyrer, Peter
Bertelli, Francois
Hutchinson, Ian
Masterson, Luke
Howard, Phil
Hartley, John A.
van Berkel, Patrick H.
[J]. CANCER RESEARCH, 2018, 78 (13)
[8] Characterization of the mechanism of action, pharmacodynamics and preclinical safety of ADCT-402, a pyrrolobenzodiazepine (PBD) dimer-containing antibody-drug conjugate (ADC) targeting CD19-expressing hematological malignancies
Zammarchi, Francesca
Corbett, Simon
Havenith, Karin
Janghra, Narinder
Kiakos, Konstantinos
Marafioti, Teresa
Williams, David G.
Chivers, Simon
Howard, Phil W.
Hartley, John A.
van Berkel, Patrick H.
[J]. CANCER RESEARCH, 2017, 77
[9] Preclinical activity of ADCT-601, a novel pyrrolobenzodiazepine (PBD) dimer-based antibody-drug conjugate (ADC) targeting AXL-expressing tumors
Zammarchi, Francesca
Havenith, Karin
Chivers, Simon
Hogg, Paul W.
Britten, Charlie
Dissanayake, Sandamali
Tyrer, Peter
Bertelli, Francois
Hutchinson, Ian
Masterson, Luke
Howard, Phil
Hartley, John A.
van Berkel, Patrick H.
[J]. CANCER RESEARCH, 2018, 78 (13)
[10] Pre-Clinical Development of Adct-402, a Novel Pyrrolobenzodiazepine (PBD)-Based Antibody Drug Conjugate (ADC) Targeting CD19-Expressing B-Cell Malignancies
Zammarchi, Francesca
Williams, David G.
Adams, Lauren
Havenith, Karin
Chivers, Simon
D'Hooge, Francois
Howard, Philip W.
Hartley, John A.
van Berkel, Patrick H.
[J]. BLOOD, 2015, 126 (23)

← 1 2 →