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Anti-CD160, Alone Or in Combination with Bevacizumab, Is a Potent Inhibitor of Ocular Neovascularization in Rabbit and Monkey Models

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Anti-CD160, Alone Or in Combination with Bevacizumab, Is a Potent Inhibitor of Ocular Neovascularization in Rabbit and Monkey Models Retinal Cell Biology Anti-CD160, Alone or in Combination With Bevacizumab, Is a Potent Inhibitor of Ocular Neovascularization in Rabbit and Monkey Models Thierry Menguy,1 Anne Briaux,2 Elisabeth Jeunesse,3 Jer´ omeˆ Giustiniani,4–7 Alexandre Calcei,1 Thierry Guyon,8 Jacques Mizrahi,1 Hel´ ene` Haegel,1 Vanessa Duong,1 Vincent Soler,9–11 Pierre Brousset,12 Armand Bensussan,4 Isabelle Raymond Letron,3 and Philippe Le Bouteiller2,4 1Elsalys Biotech, Lyon, France 2Centre de Physiopathologie de Toulouse Purpan, INSERM UMR 1043, CNRS UMR 5282, Universite´ Toulouse III, Toulouse, France 3STROMALab, Universite´ de Toulouse, EFS, ENVT, INSERM U1031, Toulouse, France et LabHPEC, Ecole Nationale Vet´ erinaire,´ Toulouse, France 4INSERM UMR 976, Hopitalˆ Saint-Louis, Paris, France 5Universite´ Paris Diderot-Paris 7, Paris, France 6Institut Jean Godinot, Unicancer, F-51726 Reims, France 7Universite´ Reims-Champagne-Ardenne, DERM-I-C, EA7319, Reims, France 8Mabsolys, Evry, France 9UnitedeR´ etine,´ Ophthalmology Department, Hopitalˆ Pierre-Paul Riquet, Toulouse University Hospital, Place Baylac, Toulouse, France 10Unite´ Differenciation´ Epitheliale´ et Autoimmunite´ Rhumato¨ıde UMR 1056 Inserm - Universite´ Toulouse III, Toulouse, France 11Universite´ Toulouse III, Toulouse, France 12Centre de Recherche en Cancerologie´ de Toulouse, INSERM UMR1037, Toulouse, France Correspondence: Thierry Menguy, PURPOSE. To assess the efficacy of the murine first-in-class CL1-R2 monoclonal antibody (mAb) Elsalys Biotech 317 avenue Jean targeting human CD160 (alone or in combination with bevacizumab) by using the rabbit Jaures,` 69007 Lyon, France; corneal neovascularization (CNV) model, and determine the safety and efficacy of ELB01101, [email protected]. a novel CL1-R2–derived humanized IgG4 mAb, in a monkey model of choroidal neovascu- AB, IRL, and PLB contributed equally larization (ChNV). to the work presented here and should therefore be regarded as METHODS. Comparison of effect of CL1-R2, bevacizumab, or aflibercept or IgG1 (control) equivalent senior authors. injections in early and late treatment schemes on evolution of VEGF- or FGF2-induced rabbit CNV was performed. In the combination setting, bevacizumab was coinjected with different Submitted: February 3, 2018 doses of CL1-R2. ELB01101 or vehicle was administered intravitreally in monkeys after laser- Accepted: April 24, 2018 induced ChNV. Individual laser-induced lesions were semiquantitatively graduated by using Citation: Menguy T, Briaux A, Jeunesse fluorescein angiography to determine leakage. E, et al. Anti-CD160, alone or in combination with bevacizumab, is a RESULTS. In the rabbit model, early and late treatments with CL1-R2 significantly decreased potent inhibitor of ocular neovascu- both area and length of CNV neovessels. The effect was as potent as produced with anti-VEGF larization in rabbit and monkey mod- comparators. When combined with bevacizumab, an additive effect of CL1-R2 was measured els. Invest Ophthalmol Vis Sci. at all doses tested. In the ChNV model, on day 29, eyes treated with ELB01101 showed a 2018;59:2687–2698. https://doi.org/ statistically significant reduction in clinically relevant lesions compared to vehicle-treated eyes 10.1167/iovs.18-24024 (~50%; v2 test, P ¼ 0.032001). CONCLUSIONS. The additive effects of anti-CD160 and bevacizumab in the CNV model suggest that these compounds could act via different pathways, opening new therapeutic pathways for cotargeted or combination therapies. In the ChNV model, ELB01101 was well tolerated and prevented approximately 50% of clinically relevant lesions, validating CD160 targeting as a safe approach for treatment of retinal diseases in the most relevant animal model of wet AMD. Keywords: CD160, monoclonal antibody, anti VEGF, neovascularization, combotherapy ngiogenesis, the formation of new blood vessels from Increasing knowledge of angiogenesis and its etiology in 1 A preexisting vasculature, is a physiological process. How- wAMD and IRs has led to the development of drugs targeting ever, it also plays a role in a number of diseases, including the VEGF (vascular endothelial growth factor) pathway. corneal/retinal neovascular diseases—mainly ischemic retinop- Intravitreal (IVT) injections of anti-VEGF therapeutic agents athies (IRs) or choroidal retinopathies such as exudative or ‘‘wet’’ age-related macular degeneration (wAMD).2 Together, have been used over the past decade as the first line of 5 these diseases constitute the primary cause of moderate and treatment for wAMD, retinal vein occlusion, and macular severe vision loss in developed countries.3,4 edema.6,7 Copyright 2018 The Authors iovs.arvojournals.org j ISSN: 1552-5783 2687 This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License. Downloaded from iovs.arvojournals.org on 09/27/2021 Targeting CD160 Inhibits Ocular Neovascularization IOVS j June 2018 j Vol. 59 j No. 7 j 2688 Even though anti-VEGF therapy appears safe in the general translational predictability for human clinical studies of population, several practical limitations related to its efficacy treatments for retinal diseases. have emerged, including the high cost of some agents and the In this study, the efficacy of the parental CL1-R2 anti-CD160 need for frequent IVT injections in many cases to reach full mAb delivered as subconjunctival injections early and late in efficacy. Indeed, even with regularly repeated anti-VEGF the rabbit CNV model was assessed. The results provide therapy over 1 year, approximately a third of wAMD patients additional qualitative and quantitative information on the respond poorly or not at all to anti-VEGF agents with standard efficacy and potency of CL1-R2 for the inhibition of CNV in treatment, or they present reduced long-term efficacy.8 the rabbit experimental model. CL1-R2 was used as a stand- Approximately 20% of patients lose vision, around 50% fail to alone treatment and compared to bevacizumab (mAb) or achieve 20/40 visual acuity (VA), and two-thirds achieve a VA aflibercept (fusion protein, reference treatment for wAMD) gain of fewer than three ETDRS lines.9,10 Consequently, up to anti-VEGF agents, as well as in combination with bevacizumab. 30% of patients treated with anti-VEGF therapies are consid- We also assessed the efficacy and tolerance of ELB01101, a ered resistant to the treatment or to have refractory novel CL1-R2–derived humanized therapeutic anti-CD160 neovascular AMD, as defined in the study of Yang et al.11 A IgG4, in the nonhuman primate (NHP) experimental model number of causes have been suggested for this disappointing of laser-induced ChNV. The results from this relevant outcome, such as misdiagnosis, redundancy of proangiogenic preclinical model demonstrated that anti-CD160 therapy could pathways, genetic AMD risk variants, tachyphylaxis, or be used as a main player in future treatment of neovascular tolerance to current anti-VEGF therapies.11–14 ocular diseases. These limitations underline the need to improve sustained delivery approaches for anti-VEGFs without increasing the induction of tolerance or raising safety issues while also MATERIALS AND METHODS reducing the number of injections required. For patients responding incompletely to anti-VEGF therapy, it would be Antiangiogenic Agents Used in Animal Models beneficial to be able to target other molecules involved in The murine IgG1 CL1-R2 mAb targeting human CD160 was as angiogenesis and/or inflammation; thus there is a pressing described.15,16 CL1-R2 is defined by the sequences reported in need to develop VEGF-independent complementary and patent EP1776387B1 and was produced from the I-3204 synergistic therapies that inhibit pathologic neovascularization hybridoma (available from the Collection Nationale de Cultures while having little or no effect on normal mature tissue de Microorganismes [CNCM] depository). CL1-R2 was purified vasculature. by passage on protein G Sepharose 4 Fast Flow (17-0618-01; GE Our previous results indicate that, in vitro, specific Healthcare, Pittsburgh, PA, USA) followed by gel filtration engagement of the hCD160 receptor on activated endothelial (HiLoad 26/60 Superdex prep grade; GE Healthcare). Endo- cells by the CL1-R2 agonist, a murine mAb, inhibits fibroblast toxin-free, 0.22-lm–filtered CL1-R2 batches, suitable for growth factor 2 (FGF2)–mediated tubule vessel growth from subconjunctival injection in rabbits, were formulated at 10 HUVECs (human umbilical vein endothelial cells) expressing mg/mL in Dulbecco’s phosphate-buffered (D-PBS) solution (pH 15 CD160. Antiangiogenic therapeutic efficacy of CL1-R2 has 7.2) (154 mM NaCl, 10 mM NaPO4, 2 mM KCl). The solution been shown in vivo in a number of animal models of ocular and was stable at À808C for more than 2 years or at 48C for up to 6 tumor neovascularization, results that support the relevance of months. To assess the impact of the crystalizable fragment (Fc) this mechanism of action for ocular diseases. Indeed, CL1-R2 on CNV prevention, Fab’2 was prepared by digesting 10 mg inhibits retinal neovascularization in a mouse model of oxygen- purified CL1-R2 by using immobilized ficin from the Mouse induced proliferative retinopathy (ROP model), choroidal IgG1 F(ab’)2 Preparation Kit (No. 44980; Pierce, ThermoFisher neovascularization (ChNV) in a murine model of wAMD, and Scientific, Waltham, MA, USA). FGF2-induced ocular neovascularization in a rabbit corneal ELB01101 anti-hCD160 mAb was generated by humaniza- 16 neovascularization (CNV) model. Furthermore, CL1-R2
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