The rGel/BLyS fusion toxin specifically targets malignant B cells expressing the BLyS receptors BAFF-R, TACI, and BCMA.
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.
Lyu
Mi-Ae
MA
Immunopharmacology and Targeted Therapy Section, Department of Experimental Therapeutics, The University of Texas M. D. Anderson Cancer Center, Unit 0044, 1515 Holcombe Boulevard, Houston, TX 77030, USA.
Cheung
Lawrence H
LH
Hittelman
Walter N
WN
Marks
John W
JW
Aguiar
Ricardo C T
RC
Rosenblum
Michael G
MG
D017209:Apoptosis / Q000187:drug effects; D053264:B-Cell Activating Factor / Q000235:genetics*; D053265:B-Cell Activation Factor Receptor / Q000235:genetics / Q000378:metabolism*; D053301:B-Cell Maturation Antigen / Q000235:genetics / Q000378:metabolism*; D001402:B-Lymphocytes / Q000187:drug effects* / Q000378:metabolism; D015153:Blotting, Western; D006801:Humans; D008223:Lymphoma / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D010940:Plant Proteins / Q000235:genetics*; D012333:RNA, Messenger / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000494:pharmacology*; D054789:Ribosome Inactivating Proteins, Type 1; D014118:Toxins, Biological / Q000494:pharmacology; D053303:Transmembrane Activator and CAML Interactor Protein / Q000235:genetics / Q000378:metabolism*; D014407:Tumor Cells, Cultured
D053264:B-Cell Activating Factor; D053265:B-Cell Activation Factor Receptor; D053301:B-Cell Maturation Antigen; D010940:Plant Proteins; D012333:RNA, Messenger; D011993:Recombinant Fusion Proteins; D054789:Ribosome Inactivating Proteins, Type 1; C108467:TNFRSF13B protein, human; C435926:TNFRSF13C protein, human; D014118:Toxins, Biological; D053303:Transmembrane Activator and CAML Interactor Protein; C025674:GEL protein, Gelonium multiflorum