New Therapies of Neovascular AMD beyond Anti-VEGF Injections

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Abstract

Neovascular age-related macular degeneration is a leading cause of vision loss among the aging population. The current standard of care to treat neovascular age-related macular degeneration is inhibiting vascular endothelial growth factor (VEGF) through intravitreal injections. Recent studies have demonstrated that the tyrosine kinase with immunoglobulin-like and epidermal growth factor-like domains 2 (Tie2) pathway also plays a critical role in angiogenesis and vascular stability. Additionally, newly developed treatment delivery systems have been designed to greatly reduce the frequency of injections. In targeting the Tie2 pathway and utilizing a sustained release delivery system, patients may experience improved visual outcomes and a reduced burden of treatment.

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Angiopoietin-2 sensitizes endothelial cells to TNF-alpha and has a crucial role in the induction of inflammation.

Ulrike Fiedler, Yvonne Reiss, Marion Scharpfenecker … (2006)

The angiopoietins Ang-1 and Ang-2 have been identified as ligands of the receptor tyrosine kinase Tie-2 (refs. 1,2). Paracrine Ang-1-mediated activation of Tie-2 acts as a regulator of vessel maturation and vascular quiescence. In turn, the antagonistic ligand Ang-2 acts by an autocrine mechanism and is stored in endothelial Weibel-Palade bodies from where it can be rapidly released upon stimulation. The rapid release of Ang-2 implies functions of the angiopoietin-Tie system beyond its established role during vascular morphogenesis as a regulator of rapid vascular responses. Here we show that mice deficient in Ang-2 (encoded by the gene Angpt2) cannot elicit an inflammatory response in thioglycollate-induced or Staphylococcus aureus-induced peritonitis, or in the dorsal skinfold chamber model. Recombinant Ang-2 restores the inflammation defect in Angpt2(-/-) mice. Intravital microscopy showed normal TNF-alpha-induced leukocyte rolling in the vasculature of Angpt2(-/-)mice, but rolling cells did not firmly adhere to activated endothelium. Cellular experiments showed that Ang-2 promotes adhesion by sensitizing endothelial cells toward TNF-alpha and modulating TNF-alpha-induced expression of endothelial cell adhesion molecules. Together, these findings identify Ang-2 as an autocrine regulator of endothelial cell inflammatory responses. Ang-2 thereby acts as a switch of vascular responsiveness exerting a permissive role for the activities of proinflammatory cytokines.

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The Tie-2 ligand angiopoietin-2 is stored in and rapidly released upon stimulation from endothelial cell Weibel-Palade bodies.

Ulrike Fiedler, Marion Scharpfenecker, Stefanie Koidl … (2004)

The angiopoietins Ang-1 and Ang-2 have been identified as ligands with opposing functions of the receptor tyrosine kinase Tie-2 regulating endothelial cell survival and vascular maturation. Ang-1 acts in a paracrine agonistic manner, whereas Ang-2 appears to act primarily as an autocrine antagonistic regulator. To shed further light on the complexity of autocrine/paracrine agonistic/antagonistic functions of the angiopoietin/Tie-2 system, we have studied Ang-2 synthesis and secretion in different populations of wild-type and retrovirally Ang-2-transduced endothelial cells. Endogenous and overexpressed endothelial cell Ang-2 is expressed in a characteristic granular pattern indicative of a cytoplasmic storage granule. Light and electron microscopic double staining revealed Ang-2 colocalization with von Willebrand factor, identifying Ang-2 as a Weibel-Palade body molecule. Costaining with P-selectin showed that storage of Ang-2 and P-selectin in Weibel-Palade bodies is mutually exclusive. Stored Ang-2 has a long half-life of more than 18 hours and can be secreted within minutes of stimulation (eg, by phorbol 12-myristate 13-acetate [PMA], thrombin, and histamine). Collectively, the identification of Ang-2 as a stored, rapidly available molecule in endothelial cells strongly suggests functions of the angiopoietin/Tie-2 system beyond the established roles during angiogenesis likely to be involved in rapid vascular homeostatic reactions such as inflammation and coagulation.

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

Jörg Regula, Peter Lundh von Leithner, Richard Foxton … (2016)

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.

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Journal ID (nlm-ta): Vision (Basel)

Journal ID (iso-abbrev): Vision (Basel)

Journal ID (publisher-id): vision

Title: Vision

Publisher: MDPI

ISSN (Electronic): 2411-5150

Publication date (Electronic): 19 March 2018

Publication date Collection: March 2018

Volume: 2

Issue: 1

Electronic Location Identifier: 15

Affiliations

[1 ]University of Nevada, Reno School of Medicine, Reno, NV 89557, USA

[2 ]Sierra Eye Associates, Reno, NV 89502, USA

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[* ]Correspondence: arshad.khanani@ 123456gmail.com

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Greggory M. Gahn https://orcid.org/0000-0003-2393-8002

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Publisher ID: vision-02-00015

DOI: 10.3390/vision2010015

PMC ID: 6835944

PubMed ID: 31735879

SO-VID: 91c1c033-6a87-442d-a30e-d603f049c262

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Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/).

New Therapies of Neovascular AMD beyond Anti-VEGF Injections

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Most cited references 17

Angiopoietin-2 sensitizes endothelial cells to TNF-alpha and has a crucial role in the induction of inflammation.

The Tie-2 ligand angiopoietin-2 is stored in and rapidly released upon stimulation from endothelial cell Weibel-Palade bodies.

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

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