June 2020
Volume 61, Issue 7
Free
ARVO Annual Meeting Abstract  |   June 2020
Sex determines the off-target effects of Bevacizumab (Avastin) in mouse models
Author Affiliations & Notes
  • Dionne Argyle
    Experimental Pathology, University of Virginia , Charlottesville, Virginia, United States
  • Felipe Pereira
    Ophthalmology, University of Virginia, Charlottesville, Virginia, United States
  • Ivana Apicella
    Ophthalmology, University of Virginia, Charlottesville, Virginia, United States
  • Nagaraj Kerur
    Ophthalmology, University of Virginia, Charlottesville, Virginia, United States
  • Jayakrishna Ambati
    Ophthalmology, University of Virginia, Charlottesville, Virginia, United States
  • Bradley Gelfand
    Ophthalmology, University of Virginia, Charlottesville, Virginia, United States
  • Footnotes
    Commercial Relationships   Dionne Argyle, None; Felipe Pereira, None; Ivana Apicella, None; Nagaraj Kerur, None; Jayakrishna Ambati, Allergan (C), Allergan (R), Immunovant (C), Inflammasome Therapeutics (I), Inflammasome Therapeutics (S), Inflammasome Therapeutics (P), iVeena Delivery System (S), iVeena Delivery Systems (I), iVenna Holdings (I), iVenna Holdings (S), Olix Phamaceuticals (C), Retinal Solutions (C), Saskin Lifesciences (C), Saskin Lifesciences (R); Bradley Gelfand, None
  • Footnotes
    Support  BTP 5T32 GM008715; NIH grant R01EY028027; American Heart Association (13SDG16770008); NIH DP1GM114862; NIH R01EY022238; NIH R01EY024068; NIH R01EY028027; John Templeton Foundation Grant 60763; NIH K99EY024336; NIH R00EY024336; Beckman Initiative for Macular Research (BIMR); DuPont Guerry, III, Professorship
Investigative Ophthalmology & Visual Science June 2020, Vol.61, 4346. doi:
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      Dionne Argyle, Felipe Pereira, Ivana Apicella, Nagaraj Kerur, Jayakrishna Ambati, Bradley Gelfand; Sex determines the off-target effects of Bevacizumab (Avastin) in mouse models. Invest. Ophthalmol. Vis. Sci. 2020;61(7):4346.

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      © ARVO (1962-2015); The Authors (2016-present)

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Abstract

Purpose : In addition to its ability to neutralize human, but not mouse, vascular endothelial growth factor (VEGF), bevacizumab also suppress angiogenesis via VEGF receptor 1 (Flt-1/VEGFR1) degradation through Fc gamma receptor 1 (FcgR1). Women account for a majority of age-related macular degeneration patients. However, it is unknown whether the FcγR1-dependent angiomodulatory activity of bevacizumab is sexually dimorphic. We sought to investigate this using mouse models in which bevacizumab is unable to neutralize VEGF.

Methods : Bone marrow-derived macrophages were differentiated from 4-6-week-old, age-matched male and female C57BL/6J and Fcγr1 knockout mice. The effect of bevacizumab on macrophage chemotaxis was measured in transwell assays. The ability of bevacizumab to induce VEGFR1 degradation was measured by immunoblotting. Choroidal neovascularization (CNV) was induced by laser photocoagulation in 6-week old C57BL/6J male and female mice (N=6 males and 6 females), followed immediately by intravitreous injection of either PBS or bevacizumab (25 mg/1 mL). Eyes were collected after seven days and the volume of the lesions measured by confocal microscopy.

Results : Bevacizumab reduced macrophage chemotaxis by 67% in C57BL/6J male cells, but only 28% in female cells. Bevacizumab also induced rapid degradation of VEGFR1 in male but not female C57BL/6J macrophages. Bevacizumab had no effect on macrophage chemotaxis or VEGFR1 degradation in FcgR1 knockout cells. CNV lesions of C57BL/6J male mice were inhibited more by bevacizumab than female mice (26%, P=0.024 vs. 9%, P=0.230).

Conclusions : The effects of bevacizumab are different between females and males both in vitro and in vivo, indicating that male mice are more sensitive to the off-target effects of bevacizumab than female mice. Future studies are needed to understand the cause of these differences and whether such sexual dimorphism is also operative in humans.

This is a 2020 ARVO Annual Meeting abstract.

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