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

Mol Cancer Ther. 2007 Feb;6(2):460-70. doi: 10.1158/1535-7163.MCT-06-0254. Epub 2007 Jan 31.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Apoptosis / drug effects
  • B-Cell Activating Factor / genetics*
  • B-Cell Activation Factor Receptor / genetics
  • B-Cell Activation Factor Receptor / metabolism*
  • B-Cell Maturation Antigen / genetics
  • B-Cell Maturation Antigen / metabolism*
  • B-Lymphocytes / drug effects*
  • B-Lymphocytes / metabolism
  • Blotting, Western
  • Humans
  • Lymphoma / drug therapy
  • Lymphoma / metabolism
  • Lymphoma / 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
  • Transmembrane Activator and CAML Interactor Protein / metabolism*
  • Tumor Cells, Cultured


  • 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