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Targeting key angiogenic pathways with a bispecific CrossMAb optimized for neovascular eye diseases

Regula, JT; von Leithner, PL; Foxton, R; Barathi, VA; Cheung, CMG; Tun, SBB; Wey, YS; ... Hartmann, G; + view all (2016) Targeting key angiogenic pathways with a bispecific CrossMAb optimized for neovascular eye diseases. EMBO Molecular Medicine , 8 (11) pp. 1265-1288. 10.15252/emmm.201505889. Green open access

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Abstract

Anti‐angiogenic therapies using biological molecules that neutralize vascular endothelial growth factor‐A (VEGF‐A) have revolutionized treatment of retinal vascular diseases including age‐related macular degeneration (AMD). This study reports preclinical assessment of a strategy to enhance anti‐VEGF‐A monotherapy efficacy by targeting both VEGF‐A and angiopoietin‐2 (ANG‐2), a factor strongly upregulated in vitreous fluids of patients with retinal vascular disease and exerting some of its activities in concert with VEGF‐A. Simultaneous VEGF‐A and ANG‐2 inhibition was found to reduce vessel lesion number, permeability, retinal edema, and neuron loss more effectively than either agent alone in a spontaneous choroidal neovascularization (CNV) model. We describe the generation of a bispecific domain‐exchanged (crossed) monoclonal antibody (CrossMAb; RG7716) capable of binding, neutralizing, and depleting VEGF‐A and ANG‐2. RG7716 showed greater efficacy than anti‐VEGF‐A alone in a non‐human primate laser‐induced CNV model after intravitreal delivery. Modification of RG7716's FcRn and FcγR binding sites disabled the antibodies' Fc‐mediated effector functions. This resulted in increased systemic, but not ocular, clearance. These properties make RG7716 a potential next‐generation therapy for neovascular indications of the eye.

Type: Article
Title: Targeting key angiogenic pathways with a bispecific CrossMAb optimized for neovascular eye diseases
Open access status: An open access version is available from UCL Discovery
DOI: 10.15252/emmm.201505889
Publisher version: http://dx.doi.org/10.15252/emmm.201505889
Language: English
Additional information: Copyright © 2016 F. Hoffmann‐La Roche Ltd. This is an open access article under the terms of the Creative Commons Attribution 4.0 License (http://creativecommons.org/licenses/by/4.0/), which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
Keywords: Age‐Related Macular Degeneration, Angiogenesis, Angiopoietin‐2Fc Receptor, Vascular Endothelial Growth Factor
UCL classification: UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > Institute of Ophthalmology
URI: https://discovery.ucl.ac.uk/id/eprint/1524825
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