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

作者：Jeffrey Scott C; Burke Patrick J; Lyon Robert P; Meyer David W; Sussman Django; Anderson Martha; Hunter Joshua H; Leiske Chris I; Miyamoto Jamie B; Nicholas Nicole D; Okeley Nicole M; Sanderson Russell J; Stone Ivan J; Zeng Weiping; Gregson Stephen J; Masterson Luke; Tiberghien Arnaud C; Howard Philip W; Thurston David E; Law Che Leung; Senter Peter D

来源：Bioconjugate Chemistry, 2013, 24(7): 1256-1263.

DOI：10.1021/bc400217g

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.

• 出版日期2013-7