Human IgG1 antibodies suppress angiogenesis in a target-independent manner

被引：30

作者：

Bogdanovich, Sasha ^{[1
]}

Kim, Younghee ^{[1
]}

Mizutani, Takeshi ^{[1
,2
]}

Yasuma, Reo ^{[1
,3
]}

Tudisco, Laura ^{[4
]}

Cicatiello, Valeria ^{[4
,5
]}

Bastos-Carvalho, Ana ^{[1
]}

Kerur, Nagaraj ^{[1
]}

Hirano, Yoshio ^{[1
]}

Baffi, Judit Z. ^{[1
]}

Tarallo, Valeria ^{[1
,4
]}

Li, Shengjian ^{[1
]}

Yasuma, Tetsuhiro ^{[1
]}

Arpitha, Parthasarathy ^{[1
]}

Fowler, Benjamin J. ^{[1
]}

Wright, Charles B. ^{[1
]}

Apicella, Ivana ^{[4
]}

Greco, Adelaide ^{[6
,7
]}

Brunetti, Arturo ^{[6
,7
]}

Ruvo, Menotti ^{[8
]}

Sandomenico, Annamaria ^{[8
]}

Nozaki, Miho ^{[2
]}

Ijima, Ryo ^{[3
]}

Kaneko, Hiroki ^{[6
]}

Ogura, Yuichiro ^{[2
]}

Terasaki, Hiroko ^{[3
]}

Ambati, Balamurali K. ^{[9
,10
]}

Leusen, Jeanette H. W. ^{[11
]}

Langdon, Wallace Y. ^{[12
]}

Clark, Michael R. ^{[13
]}

Armour, Kathryn L. ^{[13
]}

Bruhns, Pierre ^{[14
,15
]}

Verbeek, J. Sjef ^{[16
]}

Gelfand, Bradley D. ^{[1
,17
,18
]}

De Falco, Sandro ^{[4
,19
]}

Ambati, Jayakrishna ^{[1
,20
]}

机构：

[1] Univ Kentucky, Dept Ophthalmol & Visual Sci, Lexington, KY 40506 USA

[2] Nagoya City Univ, Grad Sch Med Sci, Dept Ophthalmol & Visual Sci, Nagoya, Aichi, Japan

[3] Nagoya Univ, Dept Ophthalmol, Grad Sch Med, Nagoya, Aichi, Japan

[4] CNR, Inst Genet & Biophys, Angiogenesis Lab, Naples, Italy

[5] MultiMed Grp, Bioker, Naples, Italy

[6] Univ Naples Federico II, Dept Adv Biomed Sci, Naples, Italy

[7] CEINGE Biotecnol Avanzate, Scarl, Naples, Italy

[8] CNR, Ist Biostrutture & Bioimmagini, Naples, Italy

[9] Univ Utah, Sch Med, Dept Ophthalmol & Visual Sci, Moran Eye Ctr, Salt Lake City, UT USA

[10] Vet Affairs Salt Lake City Healthcare Syst, Dept Ophthalmol, Salt Lake City, UT USA

[11] Univ Med Ctr Utrecht, Lab Translat Immunol, Immunotherapy Lab, Utrecht, Netherlands

[12] Univ Western Australia, Sch Pathol & Lab Med, Crawley, WA, Australia

[13] Univ Cambridge, Dept Pathol, Div Immunol, Cambridge, England

[14] Inst Pasteur, Unit Antibodies Therapy & Pathol, Dept Immunol, Paris, France

[15] INSERM U1222, Paris, France

[16] Leiden Univ, Dept Human Genet, Med Ctr, Leiden, Netherlands

[17] Univ Kentucky, Dept Biomed Engn, Lexington, KY USA

[18] Univ Kentucky, Dept Microbiol Immunol & Mol Genet, Lexington, KY USA

[19] IRCCS MultiMed, Milan, Italy

[20] Univ Kentucky, Dept Physiol, Lexington, KY 40506 USA

来源：

SIGNAL TRANSDUCTION AND TARGETED THERAPY | 2016年 / 1卷

关键词：

FC-GAMMA-RI; HIGH-AFFINITY IGG; ANTI-VEGF ANTIBODY; GROWTH-FACTOR; CHOROIDAL NEOVASCULARIZATION; MONOCLONAL-ANTIBODY; CORNEAL NEOVASCULARIZATION; MACULAR DEGENERATION; BINDING-SITE; MOUSE MODEL;

D O I：

10.1038/sigtrans.2015.1

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

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 Fc gamma RI (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 Fc gamma R humanized mice. This anti-angiogenic effect was abolished by Fcgr1 ablation or knockdown, Fc cleavage, IgG-Fc inhibition, disruption of Fc-Fc gamma R interaction, or elimination of FcR gamma-initated signaling. Furthermore, bevacizumab's Fc region potentiated its anti-angiogenic activity in humanized VEGFA mice. Finally, mice deficient in Fc gamma RI exhibited increased developmental and pathological angiogenesis. These findings reveal an unexpected anti-angiogenic function for Fc gamma RI and a potentially concerning off-target effect of hIgG1 therapies.

引用

页数：14

共 92 条

[1] Structural consequences after intravitreal bevacizumab injection without increasing apoptotic cell death in a retinopathy of prematurity mouse model [J].

Akkoyun, Imren ;

Karabay, Gulten ;

Haberal, Nihan ;

Dagdeviren, Attila ;

Yilmaz, Gursel ;

Oto, Sibel ;

Erkanli, Leyla ;

Akova, Yonca A. .

ACTA OPHTHALMOLOGICA, 2012, 90 (06) :564-570

[2] Alternatively spliced vascular endothelial growth factor receptor-2 is an essential endogenous inhibitor of lymphatic vessel growth [J].

Albuquerque, Romulo J. C. ;

Hayashi, Takahiko ;

Cho, Won Gil ;

Kleinman, Mark E. ;

Dridi, Sami ;

Takeda, Atsunobu ;

Baffi, Judit Z. ;

Yamada, Kiyoshi ;

Kaneko, Hiroki ;

Green, Martha G. ;

Chappell, Joe ;

Wilting, Joerg ;

Weich, Herbert A. ;

Yamagami, Satoru ;

Amano, Shiro ;

Mizuki, Nobuhisa ;

Alexander, Jonathan S. ;

Peterson, Martha L. ;

Brekken, Rolf A. ;

Hirashima, Masanori ;

Capoor, Seema ;

Usui, Tomohiko ;

Ambati, Balamurali K. ;

Ambati, Jayakrishna .

NATURE MEDICINE, 2009, 15 (09) :1023-U74

[3] IgG1 and IVIg induce inhibitory ITAM signaling through FcγRIII controlling inflammatory responses [J].

Aloulou, Meryem ;

Ben Mkaddem, Sanae ;

Biarnes-Pelicot, Martine ;

Boussetta, Tarek ;

Souchet, Herve ;

Rossato, Elisabetta ;

Benhamou, Marc ;

Crestani, Bruno ;

Zhu, Zhou ;

Blank, Ulrich ;

Launay, Pierre ;

Monteiro, Renato C. .

BLOOD, 2012, 119 (13) :3084-3096

[4] Differential binding to human FcγRIIa and FcγRIIb receptors by human IgG wildtype and mutant antibodies [J].

Armour, KL ;

van de Winkel, JGJ ;

Williamson, LM ;

Clark, MR .

MOLECULAR IMMUNOLOGY, 2003, 40 (09) :585-593

[5] Effect of Subconjunctival and Intraocular Bevacizumab Injections on Corneal Neovascularization in a Mouse Model [J].

Avisar, Inbal ;

Weinberger, Dov ;

Kremer, Israel .

CURRENT EYE RESEARCH, 2010, 35 (02) :108-115

[6] Migration of human monocytes in response to vascular endothelial growth factor (VEGF) is mediated via the VEGF receptor flt-1 [J].

Barleon, B ;

Sozzani, S ;

Zhou, D ;

Weich, HA ;

Mantovani, A ;

Marme, D .

BLOOD, 1996, 87 (08) :3336-3343

[7] Fc-γRI-deficient mice show multiple alterations to inflammatory and immune responses [J].

Barnes, N ;

Gavin, AL ;

Tan, PS ;

Mottram, P ;

Koentgen, F ;

Hogarth, PM .

IMMUNITY, 2002, 16 (03) :379-389

[8] Crucial Role of Aspartic Acid at Position 265 in the CH2 Domain for Murine IgG2a and IgG2b Fc-Associated Effector Functions [J].

Baudino, Lucie ;

Shinohara, Yasuro ;

Nimmerjahn, Falk ;

Furukawa, Jun-Ichi ;

Nakata, Munehiro ;

Martinez-Soria, Eduardo ;

Petry, Franz ;

Ravetch, Jeffery V. ;

Nishimura, Shin-Ichiro ;

Izui, Shozo .

JOURNAL OF IMMUNOLOGY, 2008, 181 (09) :6664-6669

[9] Impact of a three amino acid deletion in the CH2 domain of murine IgG1 on Fc-associated effector functions [J].

Baudino, Lucie ;

Nimmerjahn, Falk ;

Shinohara, Yasuro ;

Furukawa, Jun-Ichi ;

Petry, Franz ;

Verbeek, J. Sjef ;

Nishimura, Shin-Ichiro ;

Ravetch, Jeffery V. ;

Izui, Shozo .

JOURNAL OF IMMUNOLOGY, 2008, 181 (06) :4107-4112

[10] Differential contribution of three activating IgG Fc receptors (FcγRI, FcyRIII, and FcγRIV) to IgG2a- and IgG2b-induced autoimmune hemolytic anemia in mice [J].

Baudino, Lucie ;

Nimmerjahn, Falk ;

da Silveira, Samareh Azeredo ;

Martinez-Soria, Eduardo ;

Saito, Takashi ;

Carroll, Michael ;

Ravetch, Jeffrey V. ;

Verbeek, J. Sjef ;

Izui, Shozo .

JOURNAL OF IMMUNOLOGY, 2008, 180 (03) :1948-1953

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