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

Mi Ae Lyu, Lawrence H. Cheung, Walter N. Hittelman, John W. Marks, Ricardo C T Aguiar, Michael G. Rosenblum

Research output: Contribution to journalArticle

36 Citations (Scopus)

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 (IC50 = 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 PLyS has the potential to serve as an excellent targeting ligand for the specific delivery of cytotoxic molecules to neoplastic B BLyS fusion toxin may be an excellent candidate for the treatment of B-cell malignancies especially MCL and DLBCL.

Original languageEnglish (US)
Pages (from-to)460-470
Number of pages11
JournalMolecular Cancer Therapeutics
Volume6
Issue number2
DOIs
StatePublished - Feb 2007

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B-Cell Activation Factor Receptor
B-Cell Activating Factor
B-Lymphocytes
Antibodies
Mantle-Cell Lymphoma
Lymphoma, Large B-Cell, Diffuse
Cell Line
Gelonium multiflorum GEL protein
Interleukin-4 Receptors
Cyclophilins
Ligands
Neoplasms
Poly(ADP-ribose) Polymerases
Cell Surface Receptors

ASJC Scopus subject areas

  • Oncology
  • Drug Discovery
  • Pharmacology

Cite this

The rGel/BLyS fusion toxin specifically targets malignant B cells expressing the BLyS receptors BAFF-R, TACI, and BCMA. / Lyu, Mi Ae; Cheung, Lawrence H.; Hittelman, Walter N.; Marks, John W.; Aguiar, Ricardo C T; Rosenblum, Michael G.

In: Molecular Cancer Therapeutics, Vol. 6, No. 2, 02.2007, p. 460-470.

Research output: Contribution to journalArticle

Lyu, Mi Ae ; Cheung, Lawrence H. ; Hittelman, Walter N. ; Marks, John W. ; Aguiar, Ricardo C T ; Rosenblum, Michael G. / The rGel/BLyS fusion toxin specifically targets malignant B cells expressing the BLyS receptors BAFF-R, TACI, and BCMA. In: Molecular Cancer Therapeutics. 2007 ; Vol. 6, No. 2. pp. 460-470.
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T1 - The rGel/BLyS fusion toxin specifically targets malignant B cells expressing the BLyS receptors BAFF-R, TACI, and BCMA

AU - Lyu, Mi Ae

AU - Cheung, Lawrence H.

AU - Hittelman, Walter N.

AU - Marks, John W.

AU - Aguiar, Ricardo C T

AU - Rosenblum, Michael G.

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