The novel antisense Bcl-2 inhibitor SPC2996 causes rapid leukemic cell clearance and immune activation in chronic lymphocytic leukemia

Leukemia. 2011 Apr;25(4):638-47. doi: 10.1038/leu.2010.322. Epub 2011 Mar 1.


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.

Publication types

  • Clinical Trial, Phase I
  • Multicenter Study

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • Biomarkers, Tumor / genetics*
  • Biomarkers, Tumor / metabolism
  • Cytokines / metabolism*
  • Female
  • Gene Expression Profiling
  • Gene Expression Regulation, Leukemic / genetics*
  • Humans
  • Leukemia, Lymphocytic, Chronic, B-Cell / genetics*
  • Leukemia, Lymphocytic, Chronic, B-Cell / immunology
  • Leukemia, Lymphocytic, Chronic, B-Cell / therapy*
  • Male
  • Middle Aged
  • Oligonucleotide Array Sequence Analysis
  • Oligoribonucleotides, Antisense / therapeutic use*
  • Proto-Oncogene Proteins c-bcl-2 / antagonists & inhibitors*
  • Proto-Oncogene Proteins c-bcl-2 / genetics
  • RNA, Messenger / genetics
  • Reverse Transcriptase Polymerase Chain Reaction
  • Tumor Cells, Cultured


  • Biomarkers, Tumor
  • Cytokines
  • Oligoribonucleotides, Antisense
  • Proto-Oncogene Proteins c-bcl-2
  • RNA, Messenger