A Potent Anti-CD70 Antibody鈥揇rug Conjugate Combining a Dimeric Pyrrolobenzodiazepine Drug with Site-Specific Conjugation Technology
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- 作者：Scott C. Jeffrey ; Patrick J. Burke ; Robert P. Lyon ; David W. Meyer ; Django Sussman ; Martha Anderson ; Joshua H. Hunter ; Chris I. Leiske ; Jamie B. Miyamoto ; Nicole D. Nicholas ; Nicole M. Okeley ; Russell J. Sanderson ; Ivan J. Stone ; Weiping Zeng ; Stephen J. Gregson ; Luke Masterson ; Arnaud C. Tiberghien ; Philip W. Howard ; David E. Thurston ; Che-Leung Law ; Peter D. Senter
- 刊名：Bioconjugate Chemistry
- 出版年：2013
- 出版时间：July 17, 2013
- 年：2013
- 卷：24
- 期：7
- 页码：1256-1263
- 全文大小：397K
- 年卷期：v.24,no.7(July 17, 2013)
- ISSN：1520-4812
文摘
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 h1F6239C-PBD conjugation strategy proved to be superior to interchain cysteine conjugation, affording an antibody鈥揹rug conjugate (ADC) with high uniformity in drug-loading and low levels of aggregation. In vitro cytotoxicity experiments demonstrated that the h1F6239C-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 h1F6239C 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.