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.
|Journal||Signal Transduction and Targeted Therapy|
|State||Published - 2016|
Bibliographical noteFunding Information:
JA is a co-founder of iVeena Holdings, iVeena Pharmaceuticals, iVeena Delivery Systems and Inflammasome Therapeutics, and has received honoraria from Allergan and research funding from Olix Pharmaceuticals unrelated to this work. JA and SDF are named as inventors on patent applications filed by the University of Kentucky relating to the technology described in this work. MRC is listed as an inventor on patents covering alemtuzumab and MRC and KLA are listed as inventors on patents covering the Fc mutated forms of alemtuzumab.
We thank T.S. Khurana, S. Bondada, K. Ambati, A.M. Rao and G.S. Rao for discussions; L. Toll, G.R. Pattison R. King, L. Xu, M. McConnell, C. Payne, D. Robertson, G. Botzet, A. Uiettenbogaard and the IGB animal house and integrated microscopy facilities, for technical assistance. We thank J.V. Ravetch and N. Ferrara for generously sharing genetically modified mice. JA was supported by NIH grants DP1GM114862, R01EY018350, R01EY018836, R01EY020672, R01EY022238, R01EY024068, R21EY019778 and RC1EY020442, Doris Duke Distinguished Clinical Scientist Award, Burroughs Wellcome Fund Clinical Scientist Award in Translational Research, Ellison Medical Foundation Senior Scholar in Aging Award, Foundation Fighting Blindness Individual Investigator Research Award, Carl Marshall Reeves Foundation, Harrington Discovery Institute Scholar-Innovator Award, John Templeton Foundation, Dr E. Vernon Smith and Eloise C. Smith Macular Degeneration Endowed Chair, and Research to Prevent Blindness departmental unrestricted grant; SDF by Associazione Italiana Ricerca sul Cancro (AIRC) grant no. IG11420 and Italian Ministry for Scientific Research, projects PON01_02342 and PON01_01434; MR and AS by Italian Ministry for Scientific Research, grants FIRB MERIT N° RBNE08NKH7_003 and PON01_01602, PON01_02342. JZB by NIH K08EY021521 and University of Kentucky Physician Scientist Award; BJF and SB by NIH T32HL091812 and UL1RR033173; YH by Alcon Research Award; AB-C by the Program for Advanced Medical Education (sponsored by Fundação Calouste Gulbenkian, Fundação Champalimaud, Ministério da Saúde and Fundação para a Ciência e Tecnologia, Portugal) and Bayer Global Ophthalmology Research Award; YH by Alcon Japan Research award; NK by Beckman Initiative for Macular Research and NIH K99/R00EY024336; TY by Fight for Sight Postdoctoral Award; CBW by International Retinal Research Foundation; BDG by American Heart Association and International Retinal Research Foundation; BKA by NIH R01EY017182 and R01EY017950, VA Merit Award, and Department of Defense.
© 2016 West China Hospital, Sichuan University.
ASJC Scopus subject areas
- Cancer Research