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

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Regula JT, Lundh von Leithner P, Foxton R, Barathi VA, Cheung CM, Bo Tun SB, Wey YS, Iwata D, Dostalek M, Moelleken J, Stubenrauch KG, Nogoceke E, Widmer G, Strassburger P, Koss MJ, Klein C, Shima DT, Hartmann G

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

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

PubMed ID

27742718 [ View in PubMed

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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 FcgammaR 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.

DrugBank Data that Cites this Article

Drugs

Faricimab

Drug Targets

Drug	Target	Kind	Organism	Pharmacological Action	Actions
Faricimab	Angiopoietin-2	Protein	Humans	Yes	Antagonist	Details
Faricimab	Vascular endothelial growth factor A	Protein	Humans	Yes	Antagonist	Details