The potent small molecule integrin antagonist THR-687 is a promising next-generation therapy for retinal vascular disorders

Hu, Tjing-Tjing; Vanhove, Marc; Porcu, Michaël; Hove, Inge Van; Bergen, Tine Van; Jonckx, Bart; Barbeaux, Philippe; Vermassen, Elke; Feyen, Jean H.M.

doi:10.1016/j.exer.2018.11.022

Cited by 31 publications

(20 citation statements)

References 63 publications

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“…Both experimental and clinical evidence demonstrate that integrins play a role in the pathogenic processes of DR and nAMD [72]. In particular, pharmacological inhibition of the integrins αvβ3, αvβ5 and α5β1, which are the main integrins implicated in DR- and nAMD-associated disease processes, has been shown to attenuate VEGF-induced vascular leakage in the mouse retina as well as angiogenesis-induced retinal leakage in the cynomolgus CNV model [73]. Upon activation, αvβ3 integrin initiates a signaling cascade in which an important role is played by rat sarcoma (Ras)-related C3 botulinum toxin substrate 1 (Rac1) that belongs to the Rho proteins, which are a dynamic group of GTPases participating in a multitude of cellular activities and functions.…”

Section: Upar-co-receptor Interactionmentioning

confidence: 99%

“…Results about the role of lateral partners of uPAR are scarce with the exception of major findings about the role of integrins, and αvβ3 integrin in particular, in preclinical studies using animal models of retinal or choroidal neovascularization. In these models, inhibiting the αvβ3 integrin results in reduced ocular angiogenesis and vascular leakage likely by blocking the formation of supramolecular complexes with uPAR thus reducing their downstream intracellular signaling (for Ref., see [73]). Although there are no integrin inhibitors currently available on the market for ophthalmic applications, some clinical trials using ALG-1001, an inhibitor of αvβ3 integrin, have been recently completed and their results demonstrate that the compound may be effective as monotherapy for treatment of either DME or nAMD patients with an efficacy that is not inferior to bevacizumab ( Identifier: NCT01749891; Identifier: NCT02153476; Identifier: NCT02348918).…”

Section: Inhibition Of the Upar Systemmentioning

confidence: 99%

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The uPAR System as a Potential Therapeutic Target in the Diseased Eye

Cammalleri

Monte

Pavone

et al. 2019

Cells

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Dysregulation of vascular networks is characteristic of eye diseases associated with retinal cell degeneration and visual loss. Visual impairment is also the consequence of photoreceptor degeneration in inherited eye diseases with a major inflammatory component, but without angiogenic profile. Among the pathways with high impact on vascular/degenerative diseases of the eye, a central role is played by a system formed by the ligand urokinase-type plasminogen activator (uPA) and its receptor uPAR. The uPAR system, although extensively investigated in tumors, still remains a key issue in vascular diseases of the eye and even less studied in inherited retinal pathologies such as retinitis pigmantosa (RP). Its spectrum of action has been extended far beyond a classical pro-angiogenic function and has emerged as a central actor in inflammation. Preclinical studies in more prevalent eye diseases characterized by neovascular formation, as in retinopathy of prematurity, wet macular degeneration and rubeosis iridis or vasopermeability excess as in diabetic retinopathy, suggest a critical role of increased uPAR signaling indicating the potentiality of its modulation to counteract neovessel formation and microvascular dysfunction. The additional observation that the uPAR system plays a major role in RP by limiting the inflammatory cascade triggered by rod degeneration rises further questions about its role in the diseased eye.

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Section: Upar-co-receptor Interactionmentioning

confidence: 99%

Section: Inhibition Of the Upar Systemmentioning

confidence: 99%

The uPAR System as a Potential Therapeutic Target in the Diseased Eye

Cammalleri

Monte

Pavone

et al. 2019

Cells

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“…***p < 0.001 vs ARPE-19; ###p< 0.001 vs ARPE-19 + Jurkat 24 h (Newman−Keuls test after ANOVA). endothelial cells and thereby neovascularization (Hu et al, 2019) and to counteract choroidal angiogenesis and vascular leakage (Yasukawa et al, 2004). Therefore, antagonists targeting RGD integrins may be valuable in ocular diseases involving neovascularization, as in wet AMD.…”

Section: Discussionmentioning

confidence: 99%

Leukocyte Integrin Antagonists as a Novel Option to Treat Dry Age-Related Macular Degeneration

et al. 2021

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Age-related macular degeneration (AMD) is a complex multifactorial degenerative disease that leads to irreversible blindness. AMD affects the macula, the central part of the retina responsible for sharp central vision. Retinal pigment epithelium (RPE) is the main cellular type affected in dry AMD. RPE cells form a monolayer between the choroid and the neuroretina and are in close functional relationship with photoreceptors; moreover, RPE cells are part of the blood retina barrier that is disrupted in ocular diseases such as AMD. During ocular inflammation lymphocytes and macrophages are recruited, contact RPE and produce pro-inflammatory cytokines, which play an important role in AMD pathogenesis. The interaction between RPE and immune cells is mediated by leukocyte integrins, heterodimeric transmembrane receptors, and adhesion molecules, including VCAM-1 and ICAM-1. Within this frame, this study aimed to characterize RPE-leukocytes interaction and to investigate any potentially beneficial effects induced by integrin antagonists (DS-70, MN27 and SR714), developed in previous studies. ARPE-19 cells were co-cultured for different incubation times with Jurkat cells and apoptosis and necrosis levels were analyzed by flow cytometry. Moreover, we measured the mRNA levels of the pro-inflammatory cytokine IL-1β and the expression of adhesion molecules VCAM-1 and ICAM-1. We found that RPE-lymphocyte interaction increased apoptosis and necrosis levels in RPE cells and the expression of IL-1β. This interaction was mediated by the binding of α4β1 and αLβ2 integrins to VCAM-1 and ICAM-1, respectively. The blockade of RPE-lymphocyte interaction with blocking antibodies highlighted the pivotal role played by integrins. Therefore, α4β1 and αLβ2 integrin antagonists were employed to disrupt RPE-lymphocyte crosstalk. Small molecule integrin antagonists proved to be effective in reducing RPE cell death and expression of IL-1β, demonstrating that integrin antagonists could protect RPE cells from detrimental effects induced by the interaction with immune cells recruited to the retina. Overall, the leukocyte integrin antagonists employed in the present study may represent a novel opportunity to develop new drugs to fight dry AMD.

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“…Intravitreal pharmacokinetics following bilateral administration of 3 mg per eye of THR-687 in New-Zealand White (NZW) rabbits was reported previously [16]. Experimental data (THR-687 concentration vs. time) were analyzed based on a mono-compartmental model (Eq.…”

Section: Intravitreal Pharmacokineticsmentioning

confidence: 99%

“…https:// doi.org/10.1007/s10928-021-09773-w), we attempted to model circulating levels following IVT administration of THR-149, a plasma kallikrein bicyclic peptide inhibitor currently being developed by Oxurion N.V. (Belgium) for the treatment of DME patients who are sub-optimal responders to anti-VEGFs. In this paper, we report the pharmacokinetic properties in rabbit and minipig of THR-687, a pan RGD integrin small molecule antagonist [16] also being developed by Oxurion N.V. for the treatment of DME (source: www.clinicaltrials.gov). Circulating THR-687 levels following injection in the eye were interpreted based on a novel multi-compartmental pharmacokinetic model which shares similarities with the one used to model circulating levels of THR-149 but specifically applies to drugs which intravenous pharmacokinetics are described by a standard bi-compartmental model.…”

Section: Introductionmentioning

confidence: 99%

Systemic exposure following intravitreal administration of therapeutic agents: an integrated pharmacokinetic approach. 2. THR-687

Vanhove

Wagner

Noppen

et al. 2021

J Pharmacokinet Pharmacodyn

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Intravitreal (IVT) injection remains the preferred administration route of pharmacological agents intended for the treatment of back of the eye diseases such as diabetic macular edema (DME) and neovascular age-related macular degeneration (nvAMD). The procedure enables drugs to be delivered locally at high concentrations whilst limiting whole body exposure and associated risk of systemic adverse events. Nevertheless, intravitreally-delivered drugs do enter the general circulation and achieving an accurate understanding of systemic exposure is pivotal for the evaluation and development of drugs administered in the eye. We report here the full pharmacokinetic properties of THR-687, a pan RGD integrin antagonist currently in clinical development for the treatment of DME, in both rabbit and minipig. Pharmacokinetic characterization included description of vitreal elimination, of systemic pharmacokinetics, and of systemic exposure following IVT administration. For the latter, we present a novel pharmacokinetic model that assumes clear partition between the vitreous humor compartment itself where the drug is administered and the central systemic compartment. We also propose an analytical solution to the system of differential equations that represent the pharmacokinetic model, thereby allowing data analysis with standard nonlinear regression analysis. The model accurately describes circulating levels of THR-687 following IVT administration in relevant animal models, and we suggest that this approach is relevant to a range of drugs and analysis of subsequent systemic exposure.

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The potent small molecule integrin antagonist THR-687 is a promising next-generation therapy for retinal vascular disorders

Cited by 31 publications

References 63 publications

The uPAR System as a Potential Therapeutic Target in the Diseased Eye

The uPAR System as a Potential Therapeutic Target in the Diseased Eye

Leukocyte Integrin Antagonists as a Novel Option to Treat Dry Age-Related Macular Degeneration

Systemic exposure following intravitreal administration of therapeutic agents: an integrated pharmacokinetic approach. 2. THR-687

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