Preliminary pharmacokinetic and bioanalytical studies of SJG-136 (NSC 694501), a sequence-selective pyrrolobenzodiazepine dimer DNA-cross-linking agent

Wilkinson, Gary; Taylor, James P.; Shnyder, Steve D.; Cooper, Patricia A.; Howard, Phil W.; Thurston, David E.; Jenkins, Terence C.; Loadman, Paul M.

doi:10.1023/b:drug.0000026249.97007.60

Cited by 18 publications

(14 citation statements)

References 15 publications

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“…Recently, there has been significant interest in developing nextgeneration ADCs with increased potency and alternative mechanisms of action. Pyrrolobenzodiazepine dimers (PBDs) are a class of DNA crosslinking warheads that are significantly more potent than the tubulin-inhibiting payloads used in most clinical-phase ADCs (13). Interest in PBD dimers has grown significantly over the past year following the release of promising clinical data from trials with PBD conjugates, rovalpituzumab tesirine (14) and vadastuximab talirine (SGN-CD33A; ref.…”

Section: Introductionmentioning

confidence: 99%

Fractionated Dosing Improves Preclinical Therapeutic Index of Pyrrolobenzodiazepine-Containing Antibody Drug Conjugates

Hinrichs¹,

Ryan²,

Zheng³

et al. 2017

Clinical Cancer Research

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To use preclinical models to identify a dosing schedule that improves tolerability of highly potent pyrrolobenzodiazepine dimers (PBDs) antibody drug conjugates (ADCs) without compromising antitumor activity. A series of dose-fractionation studies were conducted to investigate the pharmacokinetic drivers of safety and efficacy of PBD ADCs in animal models. The exposure-activity relationship was investigated in mouse xenograft models of human prostate cancer, breast cancer, and gastric cancer by comparing antitumor activity after single and fractionated dosing with tumor-targeting ADCs conjugated to SG3249, a potent PBD dimer. The exposure-tolerability relationship was similarly investigated in rat and monkey toxicology studies by comparing tolerability, as assessed by survival, body weight, and organ-specific toxicities, after single and fractionated dosing with ADCs conjugated to SG3249 (rats) or SG3400, a structurally related PBD (monkeys). Observations of similar antitumor activity in mice treated with single or fractionated dosing suggests that antitumor activity of PBD ADCs is more closely related to total exposure (AUC) than peak drug concentrations (). In contrast, improved survival and reduced toxicity in rats and monkeys treated with a fractionated dosing schedule suggests that tolerability of PBD ADCs is more closely associated with than AUC. We provide the first evidence that fractionated dosing can improve preclinical tolerability of at least some PBD ADCs without compromising efficacy. These findings suggest that preclinical exploration of dosing schedule could be an important clinical strategy to improve the therapeutic window of highly potent ADCs and should be investigated further. .

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Section: Introductionmentioning

confidence: 99%

Fractionated Dosing Improves Preclinical Therapeutic Index of Pyrrolobenzodiazepine-Containing Antibody Drug Conjugates

Hinrichs¹,

Ryan²,

Zheng³

et al. 2017

Clinical Cancer Research

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“…In preclinical PK experiments, SJG‐136 was detected in mouse plasma for up to 4 h after administration of the maximum tolerated dose and reached a peak plasma concentration of ca 10‐fold higher than required to achieve LC 50 in the most sensitive human tumor cell lines in vitro. 28, 30 SJG‐136 is currently under phase I clinical investigations in the US and in the UK.…”

Section: Resultsmentioning

confidence: 99%

“…On the basis of its favorable preclinical pharmacokinetic (PK) and pharmacological properties,28–30 SJG‐136 was selected for anticancer phase I clinical trials in both the United Kingdom (Cancer Research UK) and the United States (NCI). Human dose escalation studies were initiated at ∼3 µg/m 2 /day because of the potent biological activity of SJG‐136 at subnanomolar concentrations in vitro (LC 50 ∼25 pM in sensitive cell lines) 28.…”

Section: Introductionmentioning

confidence: 99%

“…To support correlative clinical PK studies, a highly sensitive assay for the determination of SJG‐136 in human plasma was required. Previously published bioanalytical methods based on fluorescence and mass spectral detection were limited by the complex imine/carbinolamine chemical reactivity of the PBD dimer 30–32. This report describes the development of a sensitive HPLC‐MS/MS method for the rapid quantitation of the chemically reduced SJG‐136 amine in human plasma validated over a concentration range of 0.056–56 ng/ml.…”

Section: Introductionmentioning

confidence: 99%

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Determination of chemically reduced pyrrolobenzodiazepine SJG‐136 in human plasma by HPLC‐MS/MS: application to an anticancer phase I dose escalation study

et al. 2007

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SJG-136 1,1'-[[(propane-1,3-diyl)dioxy]bis[(11aS)-7-methoxy-2-methylidene-1,2,3,11a-tetrahydro-5H-pyr- rolo[2,1-c][1,4]benzodiazepin-5-one]] (NSC 694501), is a bifunctional pyrrolobenzodiazepine (PBD) dimer that forms selective, irreversible, interstrand DNA cross-links via exocyclic N2 atoms of two guanine bases, with a preference for 5'PuGATCPy binding sites. SJG-136 is highly cytotoxic in human tumor cells in vitro and in human tumor xenograft models in vivo at subnanomolar concentrations and is currently in anticancer phase I clinical trials in the United Kingdom and United States. To support correlative pharmacokinetics studies, a highly sensitive HPLC-MS/MS assay was developed and validated for the reliable quantitation of SJG-136 in human plasma, using the structurally similar PBD dimer DSB-120 as an internal standard. Chemical reduction of SJG-136 to its corresponding amine (SJG-136-H(4), [M + H](+)m/z 561) improved HPLC peak resolution and sensitivity by minimizing complications that arose from the reactivity of the labile imine moieties. Plasma samples were processed by protein precipitation and centrifugal membrane dialysis; components were separated by HPLC using an Agilent Rapid Resolution HT 1.8 mm (2.1 mm x 50 mm) analytical column. The total analysis time from injection to injection was 11 min. Electrospray MS/MS detection of SJG-136-H(4) was based on the selected reaction monitoring (SRM) transition [M + H](+)m/z 561 --> 301. The analytical response ratio was linearly proportional to the plasma concentration of SJG-136 over the nominal concentration range of 25 pg/ml to 250 ng/ml, with a coefficient of determination of r > or = 0.999. The intrarun absolute %RE was < or =19.6, 14.2, and 14.0% at 0.056, 2.83, and 56.3 ng/ml, respectively. The corresponding %RSD was < or =14.9%, 9.01, and 4.59%. The interday %RSD was < or =2.72, 3.46, and 5.20%. The lower and upper limits of quantitation were 0.056 and 56 ng/ml, respectively; recovery of SJG-136 from plasma was > or = 62% across the validated concentration range. The sensitivity of the validated assay was sufficient to detect SJG-136 in human subjects for up to 6 h after intravenous administration of 6 microg/m(2), the starting dose of an NCI-sponsored dose escalation study.

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“…[84] [20] Nach einer Verabreichung von 25 mg kg À1 Tag À1 an fünf Tagen wurde keine Anreicherung im Plasma beobachtet. Ein alternativer HPLCAssay wurde zur Quantifizierung der reaktiven Iminform von SJG-136 entwickelt und erwies sich als akkurat, reproduzierbar und linear.…”

Section: Die Präklinische Evaluierung Von Sjg-136unclassified

Entwicklung Pyrrolobenzodiazepin(PBD)‐haltiger Antikörper‐Wirkstoff‐Konjugate (ADCs) ausgehend von Anthramycin

et al. 2016

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Die Pyrrolo[2,1‐c][1,4]benzodiazepine (PBDs) sind eine Familie sequenzselektiver Wirkstoffe, die an die kleine Furche der DNA binden und eine kovalente Aminalbindung zwischen der C11‐Position und den C2‐NH2‐Gruppen der Guaninbasen bilden. Anthramycin ist das erste Beispiel eines PBD‐Monomers und wurde in den 1960er Jahren entdeckt. In den 1990er Jahren wurde das bekannteste PBD‐Dimer SJG‐136 entwickelt und hat jetzt bereits die klinischen Studien der Phase II in Patienten mit Leukämie und Eierstockkrebs durchlaufen. Seit kurzem werden aus PBD‐Dimeranaloga und spezifisch an Tumorzellen bindenden Antikörpern Antikörper‐Wirkstoff‐Konjugate (ADCs) hergestellt. Von diesen befinden sich derzeit mehrere in klinischen Studien und viele andere in der präklinischen Entwicklung. Dieser Aufsatz zeigt die Entwicklung der PBDs ausgehend von Anthramycin über die ersten PBD‐Dimere bis hin zu PBD‐haltigen ADCs und behandelt sowohl die Struktur‐Wirkungs‐Beziehungen und die Biologie der PBDs als auch die Strategien für ihre Verwendung als Wirkstoffkomponente in ADCs.

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Preliminary pharmacokinetic and bioanalytical studies of SJG-136 (NSC 694501), a sequence-selective pyrrolobenzodiazepine dimer DNA-cross-linking agent

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Cited by 18 publications

References 15 publications

Fractionated Dosing Improves Preclinical Therapeutic Index of Pyrrolobenzodiazepine-Containing Antibody Drug Conjugates

Fractionated Dosing Improves Preclinical Therapeutic Index of Pyrrolobenzodiazepine-Containing Antibody Drug Conjugates

Determination of chemically reduced pyrrolobenzodiazepine SJG‐136 in human plasma by HPLC‐MS/MS: application to an anticancer phase I dose escalation study

Entwicklung Pyrrolobenzodiazepin(PBD)‐haltiger Antikörper‐Wirkstoff‐Konjugate (ADCs) ausgehend von Anthramycin

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