Format

Send to

Choose Destination
EMBO Mol Med. 2016 Nov 2;8(11):1265-1288. doi: 10.15252/emmm.201505889. Print 2016 Nov.

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

Author information

1
Roche Pharma Research and Early Development, Roche Innovation Center München, Penzberg, Germany.
2
Department of Ocular Biology and Therapeutics, UCL London Institute of Ophthalmology, London, UK.
3
Roche Pharma Research and Early Development, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd, Basel, Switzerland.
4
Translational Pre-Clinical Model Platform, Singapore Eye Research Institute The Academia, Singapore, Singapore.
5
The Ophthalmology & Visual Sciences Academic Clinical Program, DUKE-NUS Graduate Medical School, Singapore, Singapore.
6
Department of Ophthalmology, Goethe University, Frankfurt am Main, Germany.
7
Department of Ophthalmology, Ruprecht Karls University, Heidelberg, Germany.
8
Roche Pharma Research and Early Development, Roche Innovation Center Zürich, F. Hoffmann-La Roche Ltd, Zürich, Switzerland.
9
Roche Pharma Research and Early Development, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd, Basel, Switzerland guido.hartmann@roche.com.

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 FcγR 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.

KEYWORDS:

Fc receptor; age‐related macular degeneration; angiogenesis; angiopoietin‐2; vascular endothelial growth factor

PMID:
27742718
PMCID:
PMC5090659
DOI:
10.15252/emmm.201505889
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for Wiley Icon for PubMed Central
Loading ...
Support Center