title: Targeted delivery of immunotoxin by antibody to ganglioside GD3: a novel drug delivery route for tumor cells.
abstract: Gangliosides are sialic acid-containing glycolipids expressed on plasma membranes from nearly all vertebrate cells. The expression of ganglioside GD3, which plays essential roles in normal brain development, decreases in adults but is up regulated in neuroectodermal and epithelial derived cancers. R24 antibody, directed against ganglioside GD3, is a validated tumor target which is specifically endocytosed and accumulated in endosomes. Here, we exploit the internalization feature of the R24 antibody for the selective delivery of saporin, a ribosome-inactivating protein, to GD3-expressing cells [human (SK-Mel-28) and mouse (B16) melanoma cells and Chinese hamster ovary (CHO)-K1 cells]. This immunotoxin showed a specific cytotoxicity on tumor cells grew on 2D monolayers, which was further evident by the lack of any effect on GD3-negative cells. To estimate the potential antitumor activity of R24-saporin complex, we also evaluated the effect of the immunotoxin on the clonogenic growth of SK-Mel-28 and CHO-K1(GD3+) cells cultured in attachment-free conditions. A drastic growth inhibition (>80-90%) of the cell colonies was reached after 3 days of immunotoxin treatment. By the contrary, colonies continue to growth at the same concentration of the immuntoxin, but in the absence of R24 antibody, or in the absence of both immunotoxin and R24, undoubtedly indicating the specificity of the effect observed. Thus, the ganglioside GD3 emerge as a novel and attractive class of cell surface molecule for targeted delivery of cytotoxic agents and, therefore, provides a rationale for future therapeutic intervention in cancer.
authors: Centro de Investigaciones en Química Biológica de Córdoba-CIQUIBIC, UNC-CONICET, Departamento de Química Biológica, Facultad de Ciencias Químicas, Universidad Nacional de Córdoba, Córdoba, Argentina.
authors: Vanina
authors: V
authors: Torres Demichelis
authors: Aldo A
authors: AA
authors: Vilcaes
authors: Ramiro
authors: R
authors: Iglesias-Bartolomé
authors: Fernando M
authors: FM
authors: Ruggiero
authors: Jose L
authors: JL
authors: Daniotti
mesh_terms: D000818:Animals; D000906:Antibodies / Q000378:metabolism*; D016466:CHO Cells; D049109:Cell Proliferation; D006224:Cricetinae; D003412:Cricetulus; D016503:Drug Delivery Systems / Q000379:methods*; D011992:Endosomes / Q000378:metabolism; D005732:Gangliosides / Q000276:immunology / Q000378:metabolism*; D006801:Humans; D000922:Immunotoxins / Q000378:metabolism* / Q000493:pharmacokinetics; D051379:Mice; D018613:Microscopy, Confocal; D008856:Microscopy, Fluorescence; D054789:Ribosome Inactivating Proteins, Type 1 / Q000378:metabolism* / Q000493:pharmacokinetics; D000076985:Saporins; D013778:Tetrazolium Salts; D013844:Thiazoles
chemical_list: D000906:Antibodies; D005732:Gangliosides; D000922:Immunotoxins; D054789:Ribosome Inactivating Proteins, Type 1; D013778:Tetrazolium Salts; D013844:Thiazoles; C026226:ganglioside, GD3; D000076985:Saporins; C022616:thiazolyl blue
references: Nat Rev Cancer. 2002 Oct;2(10):750-63
references: 12360278
references: Biotechnology (N Y). 1992 Apr;10(4):405-12
references: 1368484
references: J Neurochem. 2000 Apr;74(4):1711-20
references: 10737630
references: Melanoma Res. 1997 Aug;7 Suppl 2:S155-62
references: 9578432
references: Int Rev Immunol. 1991;7(4):303-29
references: 1779175
references: J Pediatr Surg. 2002 Mar;37(3):539-44
references: 11877684
references: Proc Natl Acad Sci U S A. 2002 Aug 6;99(16):10231-3
references: 12149519
references: Leukemia. 2004 Jul;18(7):1215-22
references: 15103391
references: Neurochem Res. 2002 Nov;27(11):1421-9
references: 12512945
references: J Neurochem. 1989 Mar;52(3):768-76
references: 2645382
references: FEBS J. 2006 Apr;273(8):1744-58
references: 16623710
references: J Biol Chem. 2002 Nov 22;277(47):44731-9
references: 12237294
references: Neurochem Pathol. 1988 Jun;8(3):189-202
references: 3075728
references: Cancer Res. 2001 Jun 1;61(11):4474-82
references: 11389078
references: Clin Cancer Res. 2010 May 15;16(10):2769-80
references: 20460472
references: Oncogene. 2004 Apr 29;23(20):3613-21
references: 15034547
references: IUBMB Life. 2011 Jul;63(7):513-20
references: 21698755
references: Cancer Res. 2001 Jan 15;61(2):694-9
references: 11212270
references: J Exp Med. 1982 Apr 1;155(4):1133-47
references: 7061953
references: Int J Dev Neurosci. 1997 Oct;15(6):767-76
references: 9402227
references: Curr Opin Chem Biol. 2010 Aug;14(4):529-37
references: 20643572