Development of conformational antibodies targeting Cripto-1 with neutralizing effects in vitro(651 views) Foca G, Iaccarino E, Foca A, Sanguigno L, Untiveros G, Cuevas-nunez M, Strizzi L, Leonardi A, Ruvo M, Sandomenico A
Institute of Biostructure and Bioimaging, National Research Council (IBB-CNR), Naples, Italy., Department of Molecular Medicine and Medical Biotechnology, University of Naples "Federico II", Naples, Italy., Midwestern University, Colleges of Graduate Studies, Dwners Grove, Chicago, IL, USA., Midwestern University, Colleges of Graduate Studies, Dwners Grove, Chicago, IL, USA; College of Dental Medicine, Dwners Grove, Chicago, IL, USA., Institute of Biostructure and Bioimaging, National Research Council (IBB-CNR), Naples, Italy. Electronic address: menotti.ruvo@unina.it., Institute of Biostructure and Bioimaging, National Research Council (IBB-CNR), Naples, Italy. Electronic address: annamaria.sandomenico@cnr.it.,
Department of Molecular Medicine and Medical Biotechnology, University of Naples "Federico II", Naples, Italy.
Midwestern University, Colleges of Graduate Studies, Dwners Grove, Chicago, IL, USA.
College of Dental Medicine, Dwners Grove, Chicago, IL, USA.
References: Not available.
Development of conformational antibodies targeting Cripto-1 with neutralizing effects in vitro
Human Cripto-1 (Cripto-1), the founding member of the EGF-CFC superfamily, is a key regulator of many processes during embryonic development and oncogenesis. Cripto-1 is barely present or even absent in normal adult tissues while it is aberrantly re-expressed in various tumors. Blockade of the CFC domain-mediated Cripto-1 functions is acknowledged as a promising therapeutic intervention point to inhibit the tumorigenic activity of the protein. In this work, we report the generation and characterization of murine monoclonal antibodies raised against the synthetic folded CFC [112-150] domain of the human protein. Through subtractive ELISA assays clones were screened for the ability to specifically recognize "hot spot" residues on the CFC domain, which are crucial for the interaction with Activin Type I receptor (ALK4) and GRP78. On selected antibodies, SPR and epitope mapping studies have confirmed their specificity and have revealed that recognition occurs only on a conformational epitope. Furthermore, FACS analyses have confirmed the ability of 1B4 antibody to recognize the membrane-anchored and soluble native Cripto-1 protein in a panel of human cancer cells. Finally, we have evaluated its functional effects through in vitro cellular signaling assays and cell cycle analysis. These findings suggest that the selected anti-CFC mAbs have the potential to neutralize the protein oncogenic activity and may be used as theranostic molecules suitable as tumor homing agents for Cripto-1-overexpressing cancer cells and tissues and to overcome drug-resistance in routine cancer therapies.
Development of conformational antibodies targeting Cripto-1 with neutralizing effects in vitro
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Testino G, Leone S, Fagoonee S, Del Bas JM, Rodriguez B, Puiggros F, Marine S, Rodriguez MA, Morina D, Armengol L, Caimari A, Arola L, Cimini FA, Barchetta I, Carotti S, Bertoccini L, Baroni MG, Vespasiani-gentilucci U, Cavallo MG, Morini S, Nelson JE, Roth CL, Wilson LA, Yates KP, Aouizerat B, Morgan-stevenson V, Whalen E, Hoofnagle A, Mason M, Gersuk V, Yeh MM, Kowdley KV, Lee SM, Jun DW, Cho YK, Jang KS, Kucukazman M, Ata N, Dal K, Yeniova AO, Kefeli A, Basyigit S, Aktas B, Akin KO, Agladioglu K, Ure OS, Topal F, Nazligul Y, Beyan E, Ertugrul DT, Catena C, Cosma C, Camozzi V, Plebani M, Ermani M, Sechi LA, Fallo F, Goto Y, Ray MB, Mendenhall CL, French SW, Gartside PS Serum vitamin A deficiency and increased intrahepatic expression of cytokeratin antigen in alcoholic liver disease(707 views) Hepatology (ISSN: 1827-1669electronic, 0026-4806linking), 1988 Sep; 83120693611123109(5): 1019-1026. Impact Factor:0.913 ViewExport to BibTeXExport to EndNote