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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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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.
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.
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).
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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