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Human IgG1 antibodies suppress angiogenesis in a target-independent manner

Signal Transduction and Targeted Therapy 2016年第1期1卷 158-171页

作者： Sasha Bogdanovich Younghee Kim Takeshi Mizutani Reo Yasuma laura Tudisco Valeria Cicatiello Ana Bastos-Carvalho Nagaraj Kerur Yoshio Hirano Judit Z Baffi Valeria Tarallo Shengjian li Tetsuhiro Yasuma Parthasarathy Arpitha Benjamin J Fowler Charles B Wright Ivana Apicella Adelaide Greco Arturo Brunetti Menotti Ruvo Annamaria Sandomenico Miho Nozaki Ryo Ijima Hiroki Kaneko Yuichiro Ogura Hiroko Terasaki Balamurali K Ambati Jeanette HW leusen Wallace Y langdon Michael R Clark kathryn l armour Pierre Bruhns J Sjef Verbeek Bradley D Gelfand Sandro De Falco Jayakrishna Ambati Department of Ophthalmology and Visual Sciences University of KentuckyLexingtonKYUSA Department of Ophthalmology and Visual Science Nagoya City University Graduate School of Medical SciencesNagoyaJapan Department of Ophthalmology Nagoya University Graduate School of MedicineNagoyaJapan Angiogenesis lab Institute of Genetics and Biophysics—CNRNaplesItaly Bio-Ker MultiMedica GroupNaplesItaly Department of Advanced Biomedical Sciences University of Naples‘Federico II’NaplesItaly CEINGE—Biotecnologie Avanzate s.c.a.r.l.NaplesItaly Istituto di Biostrutture e Bioimmagini CNRNaplesItaly Department of Ophthalmology and Visual Sciences Moran Eye CenterUniversity of Utah School of MedicineSalt Lake CityUTUSA Department of Ophthalmology Veterans Affairs Salt Lake City Healthcare SystemSalt Lake CityUTUSA Immunotherapy laboratory Laboratory for Translational ImmunologyUniversity Medical Center UtrechtUtrechtThe Netherlands School of Pathology and laboratory Medicine University of Western AustraliaCrawleyWAAustralia Division of Immunology Department of PathologyUniversity of CambridgeCambridgeUK Department of Immunology Unit of Antibodies in Therapy and PathologyInstitut PasteurParisFrance Institut National de la Santéet de la Recherche Médicale(INSERM)U1222 ParisFrance Department of Human Genetics Leiden University Medical CenterLeidenThe Netherlands Department of Biomedical Engineering University of KentuckyLexingtonKYUSA Department of Microbiology Immunologyand Molecular GeneticsUniversity of KentuckyLexingtonKYUSA IRCCS MultiMedica MilanoItaly Department of Physiology University of KentuckyLexingtonKYUSA.

Aberrant angiogenesis is implicated in diseases affecting nearly 10%of the world’s *** most widely used antiangiogenic drug is bevacizumab,a humanized IgG1 monoclonal antibody that targets human *** bevacizumab does not recognize mouse Vegfa,it inhibits angiogenesis in *** 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 *** 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 *** 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 ***,bevacizumab’s Fc region potentiated its anti-angiogenic activity in humanized VEGFA ***,mice deficient in FcγRI exhibited increased developmental and pathological *** findings reveal an unexpected anti-angiogenic function for FcγRI and a potentially concerning off-target effect of hIgG1 therapies.

关键词： CD64 angiogenesis antibodies

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