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

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BlankThe novel antisense Bcl-2 inhibitor SPC2996 causes rapid leukemic cell

clearance and immune activation in chronic lymphocytic leukemia.

J Durig, U Duhrsen, L Klein-Hitpass, J Worm, JB Hansen, H Orum, and M Wissenbach

Leukemia, March 1, 2011;

Department of Hematology, University Hospital, University of Duisburg-Essen,

Essen, Germany.

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 1?) and tumor necrosis factor-?, 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.Leukemia advance online publication, 1 March 2011;

doi:10.1038/leu.2010.322.

PMID: 21358717