June 2021
Volume 62, Issue 8
Open Access
ARVO Annual Meeting Abstract  |   June 2021
VEGF-A/Ang-2 neutralization causes sustained prevention of subretinal macrophage infiltration in a mouse model of spontaneous choroidal neovascularization
Author Affiliations & Notes
  • Jérémie Canonica
    Roche Pharma Research and Early Development, Roche Innovation Center, F Hoffmann-La Roche AG, Basel, Basel-Stadt, Switzerland
  • Sabine Uhles
    Roche Pharma Research and Early Development, Roche Innovation Center, F Hoffmann-La Roche AG, Basel, Basel-Stadt, Switzerland
  • Richard Foxton
    Roche Pharma Research and Early Development, Roche Innovation Center, F Hoffmann-La Roche AG, Basel, Basel-Stadt, Switzerland
  • Nadine Cole
    Roche Pharma Research and Early Development, Roche Innovation Center, F Hoffmann-La Roche AG, Basel, Basel-Stadt, Switzerland
  • Mirjana Lazendic
    Roche Pharma Research and Early Development, Roche Innovation Center, F Hoffmann-La Roche AG, Basel, Basel-Stadt, Switzerland
  • Marina Garcia Garrido
    Roche Pharma Research and Early Development, Roche Innovation Center, F Hoffmann-La Roche AG, Basel, Basel-Stadt, Switzerland
  • Peter Westenskow
    Roche Pharma Research and Early Development, Roche Innovation Center, F Hoffmann-La Roche AG, Basel, Basel-Stadt, Switzerland
  • Footnotes
    Commercial Relationships   Jérémie Canonica, F. Hoffmann-La Roche Ltd. (E); Sabine Uhles, F. Hoffmann-La Roche Ltd. (E); Richard Foxton, F. Hoffmann-La Roche Ltd. (E); Nadine Cole, F. Hoffmann-La Roche Ltd. (E); Mirjana Lazendic, F. Hoffmann-La Roche Ltd. (E); Marina Garcia Garrido, F. Hoffmann-La Roche Ltd. (E); Peter Westenskow, F. Hoffmann-La Roche Ltd. (E)
  • Footnotes
    Support  F. Hoffmann-La Roche Ltd. funded the current study.
Investigative Ophthalmology & Visual Science June 2021, Vol.62, 274. doi:
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      Jérémie Canonica, Sabine Uhles, Richard Foxton, Nadine Cole, Mirjana Lazendic, Marina Garcia Garrido, Peter Westenskow; VEGF-A/Ang-2 neutralization causes sustained prevention of subretinal macrophage infiltration in a mouse model of spontaneous choroidal neovascularization. Invest. Ophthalmol. Vis. Sci. 2021;62(8):274.

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

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Abstract

Purpose : Faricimab, currently in phase 3 trials, is the first bispecific antibody for intraocular use. It independently binds and neutralizes both angiopoietin-2 (Ang-2) and VEGF-A, key drivers of vascular instability (vascular leakage, neovascularization [NV], and inflammation). Faricimab demonstrated sustained efficacy compared with anti-VEGF monotherapy in the phase 2 clinical trial for neovascular AMD. This abstract presents new preclinical data on the anti-inflammatory effect of targeting Ang-2 and supporting the vessel stabilization potential of Ang-2 inhibition in a mouse model of spontaneous choroidal NV (sCNV) in the context of observed phase 2 clinical data.

Methods : 7-week-old JR5558 mice developing bilateral spontaneous neovascular lesions were treated intraperitoneally with mouse cross-reactive tool antibodies against VEGF-A, Ang-2, or both (bispecific anti–VEGF-A/Ang-2 antibody), and IgG as controls. Subretinal macrophage infiltration, detected by Iba1 immunostaining, was evaluated ex vivo by flat-mounted retinal pigment epithelium (RPE)/choroid histology at 1, 3, and 5 weeks post treatment to assess immediate and long-term effects on the number of inflammatory cells around lesions.

Results : Treatment with the bispecific anti–VEGF-A/Ang-2 antibody significantly reduced the number of Iba1-positive macrophages around lesions on flat-mounted RPE/choroid histology by 23% and 38% (P<0.05) vs IgG control at 1 and 3 weeks post treatment, respectively. The effect of VEGF-A or Ang-2 inhibition alone was not significant. At 5 weeks post treatment, only anti–Ang-2– and anti–VEGF-A/Ang-2–treated mice showed significant reduction in the number of Iba1-positive macrophages by 53% and 49% (P<0.0001), respectively, vs IgG control. Anti–VEGF-A treatment alone did not prevent subretinal infiltration of Iba1-positive immune cells.

Conclusions : Preclinical experiments further elucidated the potential role of Ang-2 inhibition alone and in combination with anti-VEGF in reducing inflammation in the retina, and demonstrated that the prolonged anti-inflammatory effect was driven by Ang-2 neutralization. In a mouse model of sCNV, dual Ang-2/VEGF-A inhibition was superior to VEGF-A monotherapy in causing sustained prevention of subretinal macrophage infiltration around lesions on RPE/choroid, supporting the results of the phase 2 clinical trial.

This is a 2021 ARVO Annual Meeting abstract.

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