TY - JOUR
T1 - Human IgG1 antibodies suppress angiogenesis in a target-independent manner
AU - Bogdanovich, Sasha
AU - Kim, Younghee
AU - Mizutani, Takeshi
AU - Yasuma, Reo
AU - Tudisco, Laura
AU - Cicatiello, Valeria
AU - Bastos-Carvalho, Ana
AU - Kerur, Nagaraj
AU - Hirano, Yoshio
AU - Baffi, Judit Z
AU - Tarallo, Valeria
AU - Li, Shengjian
AU - Yasuma, Tetsuhiro
AU - Arpitha, Parthasarathy
AU - Fowler, Benjamin J
AU - Wright, Charles B
AU - Apicella, Ivana
AU - Greco, Adelaide
AU - Brunetti, Arturo
AU - Ruvo, Menotti
AU - Sandomenico, Annamaria
AU - Nozaki, Miho
AU - Ijima, Ryo
AU - Kaneko, Hiroki
AU - Ogura, Yuichiro
AU - Terasaki, Hiroko
AU - Ambati, Balamurali K
AU - Leusen, Jeanette HW
AU - Langdon, Wallace Y
AU - Clark, Michael R
AU - Armour, Kathryn L
AU - Bruhns, Pierre
AU - Verbeek, J Sjef
AU - Gelfand, Bradley D
AU - De Falco, Sandro
AU - Ambati, Jayakrishna
PY - 2016/2/27
Y1 - 2016/2/27
N2 - 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.
AB - 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.
U2 - 10.1038/sigtrans.2015.1
DO - 10.1038/sigtrans.2015.1
M3 - Article
C2 - 26918197
SN - 2059-3635
VL - 1
JO - Signal transduction and targeted therapy
JF - Signal transduction and targeted therapy
M1 - 15001
ER -