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
- 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.
MetadatenAuthor: | 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 KossORCiDGND, Christian Klein, David T. Shima, Guido Hartmann |
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URN: | urn:nbn:de:hebis:30:3-444560 |
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DOI: | https://doi.org/10.15252/emmm.201505889 |
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Pubmed Id: | https://pubmed.ncbi.nlm.nih.gov/27742718 |
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Parent Title (English): | EMBO Molecular Medicine |
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Document Type: | Article |
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Language: | English |
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Date of Publication (online): | 2016/10/14 |
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Year of first Publication: | 2016 |
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Publishing Institution: | Universitätsbibliothek Johann Christian Senckenberg |
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Release Date: | 2017/09/18 |
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Tag: | Fc receptor; age-related macular degeneration; angiogenesis; angiopoietin-2; vascular endothelial growth factor |
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Volume: | 8 |
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Issue: | 11 |
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Page Number: | 24 |
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First Page: | 1265 |
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Last Page: | 1288 |
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Note: | Published under the terms of the CC BY 4.0 license |
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HeBIS-PPN: | 425293149 |
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Institutes: | Medizin / Medizin |
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Dewey Decimal Classification: | 6 Technik, Medizin, angewandte Wissenschaften / 61 Medizin und Gesundheit / 610 Medizin und Gesundheit |
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Sammlungen: | Universitätspublikationen |
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Licence (German): | Creative Commons - Namensnennung 4.0 |
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