The rGel/BLyS fusion toxin specifically targets malignant B cells expressing the BLyS receptors BAFF-R, TACI, and BCMA.

Abstract

B lymphocyte stimulator (BLyS) is crucial for B-cell survival, and the biological effects of BLyS are mediated by three cell surface receptors designated B cell-activating factor receptor (BAFF-R), transmembrane activator and calcium modulator and cyclophilin ligand interactor (TACI), and B-cell maturation antibody (BCMA). Increased expression of BLyS and its receptors has been identified in numerous B-cell malignancies. We generated a fusion toxin designated rGel/BLyS for receptor-mediated delivery of the recombinant gelonin (rGel) toxin to neoplastic B cells, and we characterized its activity against various B-cell tumor lines. Three mantle cell lymphoma (MCL) cell lines (JeKo-1, Mino, and SP53) and two diffuse large B-cell lymphoma (DLBCL) cell lines (SUDHL-6 and OCI-Ly3) expressing all three distinct BLyS receptors were found to be the most sensitive to the fusion toxin (IC(50) = 2-5 pmol/L and 0.001-5 nmol/L for MCL and DLBCL, respectively). The rGel/BLyS fusion toxin showed specific binding to cells expressing BLyS receptors and rapid internalization of the rGel component into target cells. The cytotoxic effects of rGel/BLyS were inhibited by pretreatment with free BLyS or with soluble BAFF-R, TACI, and BCMA decoy receptors. This suggests that the cytotoxic effects of the fusion toxin are mediated through BLyS receptors. The rGel/BLyS fusion toxin inhibited MCL cell growth through induction of apoptosis associated with caspase-3 activation and poly (ADP-ribose) polymerase cleavage. Our results suggest that BLyS has the potential to serve as an excellent targeting ligand for the specific delivery of cytotoxic molecules to neoplastic B cells expressing the BLyS receptors, and that the rGel/BLyS fusion toxin may be an excellent candidate for the treatment of B-cell malignancies especially MCL and DLBCL.

• Authors: Mi-Ae Lyu, Lawrence H Cheung, Walter N Hittelman, John W Marks, Ricardo C T Aguiar, Michael G Rosenblum
• Journal: Molecular cancer therapeutics (Mol Cancer Ther) Vol. 6 Issue 2 Pg. 460-70 (Feb 2007) ISSN: 1535-7163 [Print] United States
• PMID: 17267661 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• B-Cell Activating Factor
• B-Cell Activation Factor Receptor
• B-Cell Maturation Antigen
• Plant Proteins
• RNA, Messenger
• Recombinant Fusion Proteins
• Ribosome Inactivating Proteins, Type 1
• TNFRSF13B protein, human
• TNFRSF13C protein, human
• Toxins, Biological
• Transmembrane Activator and CAML Interactor Protein
• GEL protein, Gelonium multiflorum

Topics

• Apoptosis (drug effects)
• B-Cell Activating Factor (genetics)
• B-Cell Activation Factor Receptor (genetics, metabolism)
• B-Cell Maturation Antigen (genetics, metabolism)
• B-Lymphocytes (drug effects, metabolism)
• Blotting, Western
• Humans
• Lymphoma (drug therapy, metabolism, pathology)
• Plant Proteins (genetics)
• RNA, Messenger (metabolism)
• Recombinant Fusion Proteins (pharmacology)
• Ribosome Inactivating Proteins, Type 1
• Toxins, Biological (pharmacology)
• Transmembrane Activator and CAML Interactor Protein (genetics, metabolism)
• Tumor Cells, Cultured