Journal
SIGNAL TRANSDUCTION AND TARGETED THERAPY
Volume 1, Issue -, Pages -Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/sigtrans.2015.1
Keywords
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Funding
- NIH [R01EY017182, R01EY017950, DP1GM114862, R01EY018350, R01EY018836, R01EY020672, R01EY022238, R01EY024068, R21EY019778, RC1EY020442, K08EY021521, T32HL091812, UL1RR033173, K99/R00EY024336]
- 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
- Research to Prevent Blindness
- Associazione Italiana Ricerca sul Cancro (AIRC) [IG11420]
- Italian Ministry for Scientific Research [RBNE08NKH7_003, PON01_01602, PON01_02342, PON01_01434]
- University of Kentucky Physician Scientist Award
- Alcon Research Award
- Program for Advanced Medical Education - Fundacao Calouste Gulbenkian, Portugal
- Program for Advanced Medical Education - Fundacao Champalimaud, Portugal
- Program for Advanced Medical Education - Ministerio da Saude, Portugal
- Program for Advanced Medical Education - Fundacao para a Ciencia e Tecnologia, Portugal
- Bayer Global Ophthalmology Research Award
- Alcon Japan Research award
- Beckman Initiative for Macular Research
- Fight for Sight Postdoctoral Award
- International Retinal Research Foundation
- American Heart Association
- VA Merit Award
- Department of Defense
- NATIONAL EYE INSTITUTE [R00EY024336] Funding Source: NIH RePORTER
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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.
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