Abstract
EMBO Mol Med (2019) 11: e10204[OpenUrl][1][FREE Full Text][2] Currently, anti‐VEGF‐A therapies are the standard of care for a number of retinal neovascular diseases, including neovascular age‐related macular degeneration, and diabetic macular edema (Kim & D'Amore, 2012). However, additional ANG‐2 neutralization (Kienast et al , 2013; Regula et al , 2016) or Tie‐2 activation (Campochiaro et al , 2016) may be a way to enhance efficacy of treatment for these diseases. We aimed to replicate an in vivo study (Regula et al , 2016) with a bispecific anti‐VEGF‐A/ANG‐2 antibody in a spontaneous chronic CNV mouse model using JR5558 mice (Nagai et al , 2014), whose phenotype has been described differently elsewhere (Hasegawa et al , 2014). Our independent study confirms the previously published data. Simultaneous VEGF‐A and ANG‐2 neutralization was found to reduce neovascular leakage, the number of subretinal inflammatory cells, and retinal cell apoptosis more effectively than either agent alone. ### Relative efficacy of anti‐VEGF‐A/ANG‐2 combotherapy and anti‐VEGF‐A monotherapy in a mouse model of ocular neoangiogenesis Prior to starting dosing of antibodies which were adjusted to equimolar binding sites, JR5558 mice were distributed evenly, in terms of lesion number, across treatment groups. Figure 1B shows no significant differences in pre‐treatment lesion numbers between the anti‐VEGF‐A, anti‐ANG‐2, and anti‐VEGF‐A/ANG‐2 groups as determined by fluorescein fundus angiography (FFA). Figure 1. Reduction of vessel leakiness and lesion number by combined neutralization of VEGF‐A and ANG‐2 in the JR5558 mice using FFA (A) Study schematic. Baseline FFA was carried out at P44‐45. Antibody injections were given IP on P46 and P53. Post‐treatment FFA was at P60 and tissue harvest at P61. (B) Bar/scatter graph of baseline lesion numbers. Lesions were counted in all mice prior to study start. Combined total lesions from left and right eyes were calculated, and then, animals were assigned to treatment groups ensuring no statistically significant differences between groups ( P > 0.05). (C, D) Bar/scatter graphs showing numbers of spontaneously occurring lesions (C) and area by fluorescence angiography (D) after two weekly doses of antibody (IgG, anti‐VEGF‐A, anti‐ANG‐2 at 5 mg/kg IP … [1]: {openurl}?query=rft.jtitle%253DEMBO%2BMol%2BMed%26rft_id%253Dinfo%253Adoi%252F10.15252%252Femmm.201810204%26rft_id%253Dinfo%253Apmid%252F31040126%26rft.genre%253Darticle%26rft_val_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Ajournal%26ctx_ver%253DZ39.88-2004%26url_ver%253DZ39.88-2004%26url_ctx_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Actx [2]: /lookup/ijlink?linkType=FULL&journalCode=embomm&resid=11/5/e10204&atom=%2Fembomm%2F11%2F5%2Fe10204.atom
Highlights
C urrently, anti-VEGF-A therapies are the standard of care for a number of retinal neovascular diseases, including neovascular age-related macular degeneration, and diabetic macular edema (Kim & D’Amore, 2012)
Seven days after the second dosing (Fig 1A), lesion numbers identified during fluorescein fundus angiography (FFA) showed strong, significant reductions following treatment with anti-VEGF-A, antiANG-2, and anti-VEGF-A/ANG-2 compared with untreated and IgG controls
There were no significant differences when comparing between anti-VEGF-A, anti-ANG2, and anti-VEGF-A/ANG-2 treatment groups (Fig 1C)
Summary
C urrently, anti-VEGF-A therapies are the standard of care for a number of retinal neovascular diseases, including neovascular age-related macular degeneration, and diabetic macular edema (Kim & D’Amore, 2012). Additional ANG-2 neutralization (Kienast et al, 2013; Regula et al, 2016) or Tie-2 activation (Campochiaro et al, 2016) may be a way to enhance efficacy of treatment for these diseases. We aimed to replicate an in vivo study (Regula et al, 2016) with a bispecific anti-VEGF-A/ ANG-2 antibody in a spontaneous chronic CNV mouse model using JR5558 mice (Nagai et al, 2014), whose phenotype has been described differently elsewhere (Hasegawa et al, 2014). Simultaneous VEGF-A and ANG-2 neutralization was found to reduce neovascular leakage, the number of subretinal inflammatory cells, and retinal cell apoptosis more effectively than either agent alone
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