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

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 (AM
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 FccR binding sites disabled the antibodies’ Fc-mediated effector functions. This resulted in increased systemic, but not ocular, clearance. These properties make RG7716 a potential nextgeneration therapy for neovascular indications of the eye.
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Metadaten
Author:Jörg Thomas Regula, Peter Lundh von Leithner, Richard Foxton, Veluchamy A. Barathi, Chui Ming Gemmy Cheung, Sai Bo Bo Tun, Yeo Sia Wey, Daiju Iwata, Miroslav Dostalek, Jörg Moelleken, Kay-Gunnar Stubenrauch, Everson Nogoceke, Gabriella Widmer, Pamela Strassburger, Michael Janusz Koss, Christian Klein, David T. Shima, Guido Hartmann
URN:urn:nbn:de:hebis:30:3-444560
DOI:http://dx.doi.org/10.15252/emmm.201505889
Pubmed Id:http://www.ncbi.nlm.nih.gov/pubmed?term=27742718
Parent Title (English):EMBO Molecular Medicine
Document Type:Article
Language:English
Date of Publication (online):2016/10/14
Year of first Publication:2016
Publishing Institution:Universitätsbibliothek Johann Christian Senckenberg
Release Date:2017/09/18
Tag:Fc receptor; age-related macular degeneration; angiogenesis; angiopoietin-2; vascular endothelial growth factor
Volume:8
Issue:11
Pagenumber:24
First Page:1265
Last Page:1288
Note:
Published under the terms of the CC BY 4.0 license
HeBIS PPN:425293149
Institutes:Medizin
Dewey Decimal Classification:610 Medizin und Gesundheit
Sammlungen:Universitätspublikationen
Licence (German):License LogoCreative Commons - Namensnennung 4.0

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