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https://doi.org/10.15252/emmm.201505889
Title: | Targeting key angiogenic pathways with a bispecific CrossMAb optimized for neovascular eye diseases | Authors: | Regula, J.T Lundh von Leithner, P Foxton, R Barathi, V.A Cheung, C.M.G Bo Tun, S.B Wey, Y.S Iwata, D Dostalek, M Moelleken, J Stubenrauch, K.G Nogoceke, E Widmer, G Strassburger, P Koss, M.J Klein, C Shima, D.T Hartmann, G |
Keywords: | angiopoietin 2 CD16 antigen monoclonal antibody rg 7716 unclassified drug vasculotropin A vasculotropin A antibody vasculotropin antibody angiopoietin 2 immunologic factor monoclonal antibody vasculotropin A angiogenesis animal experiment animal model Article binding site cross reaction drug clearance drug efficacy drug potency drug protein binding eye disease human monotherapy mouse nonhuman priority journal protein depletion protein targeting retina edema retina vasculitis subretinal neovascularization upregulation vitreous body animal antagonists and inhibitors disease model Eye Diseases isolation and purification Macaca fascicularis Neovascularization, Pathologic pathology preclinical study treatment outcome Angiopoietin-2 Animals Antibodies, Monoclonal Disease Models, Animal Drug Evaluation, Preclinical Eye Diseases Immunologic Factors Macaca fascicularis Neovascularization, Pathologic Treatment Outcome Vascular Endothelial Growth Factor A |
Issue Date: | 2016 | Citation: | Regula, J.T, Lundh von Leithner, P, Foxton, R, Barathi, V.A, Cheung, C.M.G, Bo Tun, S.B, Wey, Y.S, Iwata, D, Dostalek, M, Moelleken, J, Stubenrauch, K.G, Nogoceke, E, Widmer, G, Strassburger, P, Koss, M.J, Klein, C, Shima, D.T, Hartmann, G (2016). Targeting key angiogenic pathways with a bispecific CrossMAb optimized for neovascular eye diseases. EMBO Molecular Medicine 8 (11) : 1265-1288. ScholarBank@NUS Repository. https://doi.org/10.15252/emmm.201505889 | Rights: | Attribution 4.0 International | 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 Fc?R 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. © 2016 F. Hoffmann-La Roche Ltd. Published under the terms of the CC BY 4.0 license | Source Title: | EMBO Molecular Medicine | URI: | https://scholarbank.nus.edu.sg/handle/10635/179906 | ISSN: | 17574676 | DOI: | 10.15252/emmm.201505889 | Rights: | Attribution 4.0 International |
Appears in Collections: | Staff Publications Elements |
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