TY  - JOUR
A1  - Regula, Jörg Thomas
A1  - Lundh von Leithner, Peter
A1  - Foxton, Richard
A1  - Barathi, Veluchamy A.
A1  - Gemmy Cheung, Chui Ming
A1  - Tun, Sai Bo Bo
A1  - Wey, Yeo Sia
A1  - Iwata, Daiju
A1  - Dostalek, Miroslav
A1  - Moelleken, Jörg
A1  - Stubenrauch, Kay-Gunnar
A1  - Nogoceke, Everson
A1  - Widmer, Gabriella
A1  - Strassburger, Pamela
A1  - Koss, Michael Janusz
A1  - Klein, Christian
A1  - Shima, David T.
A1  - Hartmann, Guido
T1  - Targeting key angiogenic pathways with a bispecific CrossMAb optimized for neovascular eye diseases
T2  - EMBO Molecular Medicine
N2  - 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.
KW  - age-related macular degeneration
KW  - angiogenesis
KW  - angiopoietin-2
KW  - Fc receptor
KW  - vascular endothelial growth factor
Y1  - 2016
UR  - http://publikationen.ub.uni-frankfurt.de/frontdoor/index/index/docId/44456
UR  - https://nbn-resolving.org/urn:nbn:de:hebis:30:3-444560
N1  - Published under the terms of the CC BY 4.0 license
VL  - 8
IS  - 11
SP  - 1265
EP  - 1288
ER  -