A Potent Anti-CD70 Antibody-Drug Conjugate Combining a Dimeric Pyrrolobenzodiazepine Drug with Site-Specific Conjugation Technology

被引：197

作者：

Jeffrey, Scott C.

Burke, Patrick J. ^{[1
]}

Lyon, Robert P. ^{[1
]}

Meyer, David W. ^{[1
]}

Sussman, Django ^{[1
]}

Anderson, Martha ^{[1
]}

Hunter, Joshua H. ^{[1
]}

Leiske, Chris I. ^{[1
]}

Miyamoto, Jamie B. ^{[1
]}

Nicholas, Nicole D. ^{[1
]}

Okeley, Nicole M. ^{[1
]}

Sanderson, Russell J. ^{[1
]}

Stone, Ivan J. ^{[1
]}

Zeng, Weiping ^{[1
]}

Gregson, Stephen J. ^{[2
]}

Masterson, Luke ^{[2
]}

Tiberghien, Arnaud C. ^{[2
]}

Howard, Philip W. ^{[2
]}

Thurston, David E. ^{[3
]}

Law, Che-Leung ^{[1
]}

Senter, Peter D. ^{[1
]}

机构：

[1] Seattle Genet Inc, Dept Res & Translat Med, Bothell, WA 98021 USA

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

[3] Kings Coll London, Inst Pharmaceut Sci, Dept Pharm, London SE1 1DB, England

来源：

BIOCONJUGATE CHEMISTRY | 2013年 / 24卷 / 07期

关键词：

RENAL-CELL CARCINOMA; IN-VITRO; ANTITUMOR-ACTIVITY; THERAPEUTIC TARGET; CANCER-THERAPY; CD70; DNA; EXPRESSION; RESISTANCE; STABILITY;

D O I：

10.1021/bc400217g

中图分类号：

Q5 [生物化学];

学科分类号：

070307 [化学生物学];

摘要：

A highly cytotoxic DNA cross-linking pyrrolobenzodiazepine (PBD) dimer with a valine-alanine dipeptide linker was conjugated to the anti-CD70 h1F6 mAb either through endogenous interchain cysteines or, site-specifically, through engineered cysteines at position 239 of the heavy chains. The h1F6(239C)-PBD conjugation strategy proved to be superior to interchain cysteine conjugation, affording an antibody-drug conjugate (ADC) with high uniformity in drug-loading and low levels of aggregation. In vitro cytotoxicity experiments demonstrated that the h1F6(239C)-PBD was potent and immunologically specific on CD70-positive renal cell carcinoma (RCC) and non-Hodgkin lymphoma (NHL) cell lines. The conjugate was resistant to drug loss in plasma and in circulation, and had a pharmacokinetic profile closely matching that of the parental h1F6(239C) antibody capped with N-ethylmaleimide (NEM). Evaluation in CD70-positive RCC and NHL mouse xenograft models showed pronounced antitumor activities at single or weekly doses as low as 0.1 mg/kg of ADC. The ADC was tolerated at 2.5 mg/kg. These results demonstrate that PBDs can be effectively used for antibody-targeted therapy.

引用

页码：1256 / 1263

页数：8

共 41 条

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