A potent anti-CD70 antibody-drug conjugate combining a dimeric pyrrolobenzodiazepine drug with site-specific conjugation technology

  • Bioconjug Chem. 2013 Jul 17;24(7):1256-63. doi: 10.1021/bc400217g.
Scott C Jeffrey  1 ,  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
Affiliations
  • 1. Department of Research & Translational Medicine, Seattle Genetics, Inc., Bothell, WA 98021, USA. [email protected]
PMID: 23808985 DOI: 10.1021/bc400217g
Abstract

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.

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