SPC2996—A Bcl-2 RNA antagonist being studied in chronic lymphocytic leukemia

Abstract

6610 Background: Bcl-2 protein is a critical regulator of programmed cell death and contributes to apoptosis resistance in many cancers, including chronic lymphocytic leukemia (CLL). The novel RNA antagonist, SPC2996, is a 16-mer oligonucleotide incorporating Locked Nucleic Acid (LNA) with unique high-affinity binding to Bcl-2 mRNA and enhanced resistance to nuclease digestion. We report the pharmacological properties of this new investigational drug and are currently evaluating clinical safety and initial efficacy in CLL patients. Methods: In vitro, the effects of SPC2996 on Bcl-2 mRNA and protein levels and phenotypic responses were evaluated in human cancer cell lines by quantitative polymerase chain reaction, Western blotting and biochemical assays. In vivo bio-distribution in rodents was assessed with tritium-labelled SPC2996 given intravenously. Anti-tumour efficacy was assessed in human prostate (PC3) and melanoma (518A2 and 607B) tumour cell line xenografts in immunodeficient mice. Preclinical toxicology and safety pharmacology were evaluated after intravenous treatment in rats and primates and tissue uptake measured by HPLC. Results: In vitro, low nanomolar concentrations of SPC2996 substantially reduced intracellular levels of Bcl-2 mRNA and protein and induced apoptosis in a dose-dependant manner. In vivo, systemically administered SPC2996 accumulated in liver, kidney, bone marrow, and lymph nodes. Repeated dosing at 10mg/kg inhibited growth of human xenografts in mice. Substantial down-regulation of Bcl-2 mRNA was observed in primate tissues after intravenous administration of SPC2996 at 3 and 6mg/kg. No acute toxicity was encountered on systemic bolus dosing of substantially higher doses in primates. An international phase I/II dose-escalating study in 42 patients with relapsed or refractory CLL is currently recruiting in the USA, UK, Denmark and France. Conclusions: SPC2996 is the first member of a new generation of specific RNA antagonising oligonucleotides with enhanced properties derived from LNA. SPC2996 has the potential to lower Bcl-2 levels in CLL cells without significant toxicity and with less frequent dosing than required with previous drugs. [Table: see text]