Anti-Cd70 Antibody-Drug Conjugates Containing Pyrrolobenzodiazepine Dimers Demonstrate Robust Antitumor Activity

Antibody-drug conjugates (ADCs) represent an important approach for the selective delivery of highly potent small molecules to malignant cells. Recently, we have adapted the highly cytotoxic class of minor groove DNA crosslinking agents, pyrrolobenzodiazepine dimers (PBDs), in order to conjugate them to monoclonal antibodies. These totally synthetic molecules alkylate guanine bases in a sequence-specific manner to cause cell death at pM concentrations. In this report, we describe for the first time a novel PBD that can be stably conjugated to the anti-CD70 monoclonal antibody (mAb) h1F6 via maleimide conjugation to engineered cysteine residues created by the single amino acid substitution S239C on each heavy chain. This results in a uniform loading of two drugs per antibody. The resulting ADC binds selectively to CD70 on renal cell carcinoma cell lines and releases the free drug upon internalization and cleavage of the dipeptide linker in the lysosome. The ADC retains the robust cytotoxicity of the free drug, displaying immunologically selective antitumor activity in xenograft models at well tolerated doses as low as 0.1 mg/kg. The PBDs represent a promising new class of cancer drugs for targeted delivery. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4631. doi:1538-7445.AM2012-4631