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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
animal experiment
animal model
binding site
cross reaction
drug clearance
drug efficacy
drug potency
drug protein binding
eye disease
priority journal
protein depletion
protein targeting
retina edema
retina vasculitis
subretinal neovascularization
vitreous body
antagonists and inhibitors
disease model
Eye Diseases
isolation and purification
Macaca fascicularis
Neovascularization, Pathologic
preclinical study
treatment outcome
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.
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
ISSN: 17574676
DOI: 10.15252/emmm.201505889
Rights: Attribution 4.0 International
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