Human IgG1 antibodies suppress angiogenesis in a target-independent manner(650 views) Bogdanovich S, Kim Y, Mizutani T, Yasuma R, Tudisco L, Cicatiello V, Bastos-carvalho A, Kerur N, Hirano Y, Baffi JZ, Tarallo V, Li S, Yasuma T, Arpitha P, Fowler BJ, Wright CB, Apicella I, Greco A, Brunetti A, Ruvo M, Sandomenico A, Nozaki M, Ijima R, Kaneko H, Ogura Y, Terasaki H, Ambati BK, Leusen JH, Langdon WY, Clark MR, Armour KL, Bruhns P, Verbeek JS, Gelfand BD, De Falco S, Ambati J
Signal Transduct Target Ther (ISSN: 2059-3635print), 2016; 1: N/D-N/D.
Department of Ophthalmology and Visual Sciences, University of Kentucky, Lexington, KY, USA., Department of Ophthalmology and Visual Sciences, University of Kentucky, Lexington, KY, USA; Department of Ophthalmology and Visual Science, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan., Department of Ophthalmology and Visual Sciences, University of Kentucky, Lexington, KY, USA; Department of Ophthalmology, Nagoya University Graduate School of Medicine, Nagoya, Japan., Angiogenesis Lab, Institute of Genetics and Biophysics-CNR, Naples, Italy., Angiogenesis Lab, Institute of Genetics and Biophysics-CNR, Naples, Italy; Bio-Ker, MultiMedica Group, Naples, Italy., Department of Ophthalmology and Visual Sciences, University of Kentucky, Lexington, KY, USA; Angiogenesis Lab, Institute of Genetics and Biophysics-CNR, Naples, Italy., Department of Advanced Biomedical Sciences, University of Naples 'Federico II', Naples, Italy; CEINGE-Biotecnologie Avanzate, s.c.a.r.l., Naples, Italy., Istituto di Biostrutture e Bioimmagini, CNR, Naples, Italy., Department of Ophthalmology and Visual Sciences, Moran Eye Center, University of Utah School of Medicine, Salt Lake City, UT, USA; Department of Ophthalmology, Veterans Affairs Salt Lake City Healthcare System, Salt Lake City, UT, USA., Immunotherapy Laboratory, Laboratory for Translational Immunology, University Medical Center Utrecht, Utrecht, The Netherlands., School of Pathology and Laboratory Medicine, University of Western Australia, Crawley, WA, Australia., Division of Immunology, Department of Pathology, University of Cambridge, Cambridge, UK., Department of Immunology, Unit of Antibodies in Therapy and Pathology, Institut Pasteur, Paris, France; Institut National de la Sante et de la Recherche Medicale (INSERM) U1222, Paris, France., Department of Human Genetics, Leiden University Medical Center, Leiden, The Netherlands., Department of Ophthalmology and Visual Sciences, University of Kentucky, Lexington, KY, USA; Department of Biomedical Engineering
References: Not available.
Human IgG1 antibodies suppress angiogenesis in a target-independent manner
Aberrant angiogenesis is implicated in diseases affecting nearly 10% of the world's population. The most widely used anti-angiogenic drug is bevacizumab, a humanized IgG1 monoclonal antibody that targets human VEGFA. Although bevacizumab does not recognize mouse Vegfa, it inhibits angiogenesis in mice. Here we show bevacizumab suppressed angiogenesis in three mouse models not via Vegfa blockade but rather Fc-mediated signaling through FcγRI (CD64) and c-Cbl, impairing macrophage migration. Other approved humanized or human IgG1 antibodies without mouse targets (adalimumab, alemtuzumab, ofatumumab, omalizumab, palivizumab and tocilizumab), mouse IgG2a, and overexpression of human IgG1-Fc or mouse IgG2a-Fc, also inhibited angiogenesis in wild-type and FcγR humanized mice. This anti-angiogenic effect was abolished by Fcgr1 ablation or knockdown, Fc cleavage, IgG-Fc inhibition, disruption of Fc-FcγR interaction, or elimination of FcRγ-initated signaling. Furthermore, bevacizumab's Fc region potentiated its anti-angiogenic activity in humanized VEGFA mice. Finally, mice deficient in FcγRI exhibited increased developmental and pathological angiogenesis. These findings reveal an unexpected anti-angiogenic function for FcγRI and a potentially concerning off-target effect of hIgG1 therapies.
Human IgG1 antibodies suppress angiogenesis in a target-independent manner
Santulli G, Cipolletta E, Sorriento D, Del Giudice C, Anastasio A, Monaco S, Maione AS, Condorelli G, Puca A, Trimarco B, Illario M, Iaccarino G * CaMK4 gene deletion induces hypertension(409 views) J Am Heart Assoc Journal Of The American Heart Association (ISSN: 2047-9980), 2012; 1(4): N/D-N/D. Impact Factor:2.882 ViewExport to BibTeXExport to EndNote
Ntziachristos V, Cuénod CA, Fournier L, Balvay D, Pradel C, Siauve N, Clement O, Jouannot E, Lucidarme O, Vecchio SD, Salvatore M, Law B, Tung C-H, Jain RK, Fukumura D, Munn LL, Brown EB, Schellenberger E, Montet X, Weissleder R, Clerck ND, Postnov A * Tumor Imaging(449 views) Textbook Of In Vivo Imaging In Vertebrates (ISSN: 9780-4700), 2007 Jul 16; 1: 277-309. Impact Factor:1.148 ViewExport to BibTeXExport to EndNote