bc400217g_si_001.pdf (316.61 kB)

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

Download (316.61 kB)
journal contribution
posted on 17.07.2013, 00:00 by 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
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–drug 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.

History

Exports