The novel antisense Bcl-2 inhibitor SPC2996 causes rapid leukemic cell clearance and immune activation in chronic lymphocytic leukemia.
- Resource Type
- Article
- Authors
- Dürig, J.; Dührsen, U.; Klein-Hitpass, L.; Worm, J.; Hansen, J. B. Rode; Ørum, H.; Wissenbach, M.
- Source
- Leukemia (08876924). Apr2011, Vol. 25 Issue 4, p638-647. 10p. 2 Diagrams, 2 Charts, 3 Graphs.
- Subject
- *LYMPHOCYTIC leukemia
*NUCLEIC acids
*MESSENGER RNA
*IMMUNE response
*LYMPHOCYTES
- Language
- ISSN
- 0887-6924
SPC2996 is a novel locked nucleic acid phosphorothioate antisense molecule targeting the mRNA of the Bcl-2 oncoprotein. We investigated the mechanism of action of SPC2996 and the basis for its clinically observed immunostimulatory effects in chronic lymphocytic leukemia (CLL). Patients with relapsed CLL were treated with a maximum of six doses of SPC2996 (0.2-6 mg/kg) in a multicenter phase I trial. Microarray-based transcriptional profiling of circulating CLL cells was carried out before and after the first infusion of SPC2996 in 18 patients. Statistically significant transcriptomic changes were observed at doses 4 mg/kg and occurred as early as 24 h after the first infusion of the oligonucleotide. SPC2996 induced the upregulation of 466 genes including a large number of immune response and apoptotic regulator molecules, which were enriched for Toll-like receptor response genes. Serum measurements confirmed the release of pro-inflammatory cytokines including chemokine (C-C motif) ligand 3 (macrophage inflammatory protein 1α) and tumor necrosis factor-α, thereby validating the in vivo transcriptomic data at the protein level. SPC2996 caused a 50% reduction of circulating lymphocytes in five of 18 (28%) patients, which was found to be independent of its immunostimulatory and anti-Bcl-2 effects. [ABSTRACT FROM AUTHOR]