VEGF and beyond: therapeutic targeting in retinal vascular disorders

Modern Retina Digital EditionModern Retina Summer 2021
Volume 1
Issue 1

Promoting Tie2 signaling activity may complement inhibition of VEGF in addressing pathology in disease states characterized by angiogenesis, vascular permeability, and inflammation.

VEGF and beyond: therapeutic targeting in retinal vascular disorders

Understanding the role of the VEGF pathway in various retinal vascular disorders has been instrumental in understanding common pathologic features among them, and, in turn, directing therapeutic strategies. Although diabetic retinopathy (DR) with or without diabetic macular edema (DME), age-related macular degeneration (AMD), and retinal vein occlusion (RVO) with macular edema are distinct clinical entities with differing pathogeneses, they are all characterized by increased vascular permeability, unregulated inflammation, and neovascularization, each of which is mediated, at least in part, by VEGF.

As a result, targeted VEGF inhibition via intravitreal injection of agents designed to halt activity in the pathway has proven to be a largely successful strategy, often leading to a slowing of progression and preservation of vision, and in some cases, anatomic improvement and gain in visual function.

Related: Gene therapy for nAMD maintains vision with single injection

However, mounting evidence suggests that targeting VEGF alone is an incomplete therapeutic strategy. For example, currently approved agents have to be readministered on a frequent basis, as often as every 1 to 3 months.1-3 This creates a significant treatment burden, with many patients ultimately receiving fewer than the recommended number of injections, resulting in suboptimal visual outcomes in real-world studies.

Although less frequent dosing may be effective, patients still require monitoring visits between injections, resulting in a treatment schedule that may be unsustainable for patients and their caregivers. As well, even when administered at recommended intervals, anti-VEGF therapy is insufficient to prevent vision loss in some eyes.4

While incomplete response to VEGF targeting is multifactorial, it is highly plausible that additional signaling pathways complement and work in tandem with VEGF to contribute to pathobiology associated with retinal vascular disorders.

Related: Research focuses on anti-VEGF treatment lapses in retinal vein occlusion

Indeed, recent research has identified the role of additional pathways, such as Tie2 signaling, in DR/DME, AMD, and RVO.5 Under normal healthy conditions, Tie2 is highly functional in maintenance of vascular health,6 suggesting that therapeutic targeting to restore or upregulate activity in this crucial pathway might provide conditions favorable to stopping or reversing pathologic changes associated with retinal vascular diseases.

Novel strategies currently under investigation that offer the prospect of a dual mechanism of action, in which VEGF is inhibited and Tie2 is activated, offer tremendous promise for answering current unmet need in AMD, DR/DME, and RVO.

This article provides a brief overview of Tie2, its relevance to retinal vascular disease, and role as a therapeutic target. Following that is a discussion of the novel agent AXT107 (AsclepiX), focusing on its proposed dual mechanism of action and highlighting features of the peptide that would seem to offer great promise for treatment of retinal vascular disorders.

Role of Tie2 in Retinal Vascular Disorders

Tie2 is a transmembrane protein, expressed primarily on endothelial cells, but also found on some hematopoietic cells. It is primarily associated with two natural ligands: the agonist angiopoietin-1 (Ang1) and the contextual antagonist angiopoietin-2 (Ang2), which is a partial agonist in some situations. Ang1 binding to the Tie2 receptor initiates receptor clustering and activation of a host of provascular activity, including activation of Akt (supports endothelial cell survival and preservation, promotes vascular stability, and suppresses Ang2 production) and the PI3K pathway (promotes endothelial cell migration); suppression of inflammation; and decrease of endothelial cell permeability.

On the other hand, Ang2 destabilizes vessels, allowing for angiogenesis or remodeling of the vasculature. This activity is unregulated in disease states, leading to formation of abnormal vasculature, increased permeability, and inflammation.5

Related: Ang-2/VEGF-A inhibition synergistic effect in DME and AMD (video)

The role of Tie2 in neovascularization is supported by research identifying the antagonistic angiopoietin 2 gene is a susceptibility gene for neovascular AMD7; as well, Ang2 expression is upregulated in highly vascularized regions of surgically excised choroidal neovascular (CNV) membranes.8 Moreover, the Tie2 agonist Ang1 suppresses CNV and vascular leakage.9 The function of Tie2 inactivation leading to increased vascular permeability and inflammation occurs via interactions of Ang2 which cannot cause receptor dimerization and activation.

For example, the potency of VEGF in inducing permeability is increased in the presence of Ang2,10 and Ang2 sensitizes endothelial cells to TNF-α, thereby playing a key role in induction of inflammation.11

Meanwhile, Ang2 expression is increased in the setting of hypoxia,12 elevated in the vitreous of eyes with diabetic retinopathy,13 and is released from Weibel-Palade bodies in endothelial cells by VEGF activation14 or inflammatory signaling.15 Ang2 has also been identified as a potentially valuable therapeutic target because of its dual functions in promoting angiogenesis and mediating inflammatory processes.16

Dual Mechanism Targeting of AXT107

AXT107 disrupts integrins leading to reduced neovascularization, vascular leakage, and inflammation

Integrin receptors play a key functional role in activation of VEGF and Tie2. VEGF binding to VEGF receptor 2 (VEGFR2) is highly dependent on αvβ3 integrin activation. Furthermore, VEGFR2 activation induces release of Ang2 from retinal vascular cells. The role of AXT107 in mediating activity within the VEGF and Tie2 pathways derive from the molecule’s interactions with integrin proteins.

AXT107 is a peptide derived from collagen IV, which is the substrate for integrin receptors. In the presence of AXT107, α5β1 integrin is disrupted, leading to clustering of Tie2 receptor moieties (activation) at endothelial cell-cell junctions. Notably, this Tie2 clustering is analogous to clustering that occurs under physiologic conditions in response to Ang1 exposure; however, as the activity occurring in the presence of AXT107 does not require previous ligand activation, Tie2 is now available for activation by either Ang1 or Ang2.17

Related: Wet AMD treatment burden eased by nonviral gene therapy

AXT107 inhibits VEGF signaling and thus reduces neovascularization

Such activity is highly consequential for retinal vascular disorders characterized by elevated expression of Ang2, in that the natural antagonist of Tie2 activity is now converted into a strong agonist and promoter of vascular stability. This conversion also has implications for interrupting the synergism between TNF-α and Ang2, which is typically a crucial component in driving inflammatory processes, as well as activating directly anti-inflammatory signaling through Tie2.18

As a second mechanism, AXT107 also disrupts αvβ3 integrin, leaving it unavailable for complex with VEGFR2, thereby blocking downstream signaling activity.

AXT107 is delivered via an intravitreal injection. Post-injection, it self-assembles into a gel depot that settles into the vitreous away from the visual axis and slowly dissipates over several months. Preclinical studies indicate that it may be active for up to a year.19 This unique characteristic suggests the potential to extend the durability of effect and increase the interval between treatment.


The drug’s sponsor (AsclepiX) is expected to initiate phase 1/2 studies of AXT107 in early 2021 based on positive animal models and in vitro evidence demonstrating suppression and regression of CNV and subretinal neovascularization, suppression of VEGF-induced leakage, reduction in inflammation, and good safety.18,20 As with any investigational molecule, additional study is needed to fully understand safety and efficacy in humans.

Related: Subretinal gene therapy for neovascular AMD showing efficacy and safety

Nevertheless, exploring therapeutic targets beyond the VEGF pathway is supported by strong rationale, particularly in light of the growing appreciation of Tie2 activity in promoting healthy vasculature. The ability to supplant or complement currently available therapeutic strategies could, therefore, address unmet treatment need for patients deemed unresponsive or less than ideally responsive to anti-VEGF therapy.

Furthermore, there are limited options to address the role of inflammation in DR/DME, AMD, and RVO. Although intravitreal corticosteroid injections may be used in DR/DME and RVO to address macular edema associated with inflammation, they entail risk of IOP elevation and other complications; there are not additional treatment options for this purpose in AMD.

Related: Faricimab satisfies primary study endpoint in TENAYA and LUCERNE trials

The novelty of AXT107 to form a gel-like depot, and thereby remain available to distribute its active for an extended period of time, represents the potential to reduce treatment burden associated with anti-VEGF injections and monitoring. Additionally, because it mechanistically shuts down VEGF activity while promoting beneficial signaling in Tie2, it is highly likely to be used in a monotherapy approach should it prove safe and effective in human trials. While caution is warranted in interpreting early results, AXT107 potentially represents an important development for improving outcomes for patients with DR/DME, AMD, and RVO.

1. Genentech. Lucentis Prescribing Information. 2017.
2. Aflibercept Prescribing Information.
3. Novartis. Beovu Prescribing Information. . 2019.
4. Broadhead GK, Hong T, Chang AA. Treating the untreatable patient: current options for the management of treatment-resistant neovascular age-related macular degeneration. Acta Ophthalmol. 2014 Dec;92(8):713-23.
5. Nguyen QD, Heier JS, Do DV, et al. The Tie2 signaling pathway in retinal vascular diseases: a novel therapeutic target in the eye. Int J Retin Vitr 6, 48 (2020).
6. Thurston G, Daly C. The complex role of angiopoietin-2 in the angiopoietin-tie signaling pathway. Cold Spring Harb Perspect Med. 2012 Sep 1;2(9):a006550.
7. Ma L, Brelen ME, Tsujikawa M, et al. Identification of ANGPT2 as a New Gene for Neovascular Age-Related Macular Degeneration and Polypoidal Choroidal Vasculopathy in the Chinese and Japanese Populations. Invest Ophthalmol Vis Sci. 2017 Feb 1;58(2):1076-1083.
8. Otani A, Takagi H, Oh H, et al. Expressions of angiopoietins and Tie2 in human choroidal neovascular membranes. Invest Ophthalmol Vis Sci. 1999 Aug;40(9):1912-20.
9. Lee J, Park DY, Park DY, et al. Angiopoietin-1 suppresses choroidal neovascularization and vascular leakage. Invest Ophthalmol Vis Sci. 2014 Apr 7;55(4):2191-9.
10. Peters S, Cree IA, Alexander R, et al. Angiopoietin modulation of vascular endothelial growth factor: Effects on retinal endothelial cell permeability. Cytokine. 2007 Nov;40(2):144-50.
11. Fiedler U, Reiss Y, Scharpfenecker M, et al. Angiopoietin-2 sensitizes endothelial cells to TNF-alpha and has a crucial role in the induction of inflammation. Nat Med. 2006 Feb;12(2):235-9.
12. Oh H, Takagi H, Suzuma K, et al. Hypoxia and Vascular Endothelial Growth Factor Selectively up-Regulate Angiopoietin-2 in Bovine Microvascular Endothelial Cells. J Biol Chem 1999;274:15732-9
13. Khalaf N, Helmy H, Labib H, et al. Role of Angiopoietins and Tie-2 in Diabetic Retinopathy. Electron Physician. 2017 Aug 25;9(8):5031-5035.
14. Cossutta M, Darche M, Carpentier G, et aI. Weibel-Palade bodies orchestrate pericytes during angiogenesis. Arterioscler Thromb Vasc Biol. 2019 Sep;39(9):1843-1858.
15. Jang C, Koh YJ, Lim NK, et al. Angiopoietin-2 exocytosis is stimulated by sphingosine-1-phosphate in human blood and lymphatic endothelial cells. Arterioscler Thromb Vasc Biol. 2009 Mar;29(3):401-7.
16. Scholz A, Plate KH, Reiss Y. Angiopoietin-2: a multifaceted cytokine that functions in both angiogenesis and inflammation. Ann N Y Acad Sci. 2015 Jul;1347:45-51.
17. Mirando AC, Shen J, Silva RLE, Chu Z, Sass NC, Lorenc VE, Green JJ, Campochiaro PA, Popel AS, Pandey NB. A collagen IV-derived peptide disrupts α5β1 integrin and potentiates Ang2/Tie2 signaling. JCI Insight. 2019 Feb 21;4(4):e122043.
18. Mirando AC, Lima E Silva R, Chu Z, Campochiaro PA, Pandey NB, Popel AS. Suppression of Ocular Vascular Inflammation through Peptide-Mediated Activation of Angiopoietin-Tie2 Signaling. Int J Mol Sci. 2020 Jul 21;21(14):5142.
19. AsclepiX. Data on file.
20. Silva RLE, Kanan Y, Mirando AC, et al. Tyrosine kinase blocking collagen iv-derived peptide suppresses ocular neovascularization and vascular leakage. Sci Transl Med. 2017;9.

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