Ranibizumab and Bevacizumab but Not Aflibercept Inhibit Proliferation of Primary Human Retinal Pigment Epithelium in vitro

Parisi, Lorenzo; Fuhrer, Reto; Zinkernagel, Martin; Enzmann, Volker

doi:10.1159/000490430

Cited by 3 publications

(2 citation statements)

References 22 publications

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“…The research complies with the human research act (HRA) stating that small quantities of bodily substances removed in the course of transplantation may be anonymized for research purposes without consent (HRA chapter 5, paragraph 38, Switzerland). hpRPE were prepared from left and right eyes of 15 anonymized donors ( Table 1 ) as previously described [ 37 , 38 ]. Briefly, hpRPE cells were harvested from the eyecup after enzymatic digestion and centrifuged with 259× g at 4 °C for 5 min.…”

Section: Methodsmentioning

confidence: 99%

Properdin Modulates Complement Component Production in Stressed Human Primary Retinal Pigment Epithelium Cells

et al. 2020

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The retinal pigment epithelium (RPE) maintains visual function and preserves structural integrity of the retina. Chronic dysfunction of the RPE is associated with retinal degeneration, including age-related macular degeneration (AMD). The AMD pathogenesis includes both increased oxidative stress and complement dysregulation. Physiological sources of oxidative stress in the retina are well known, while complement sources and regulation are still under debate. Using human primary RPE (hpRPE) cells, we have established a model to investigate complement component expression on transcript and protein level in AMD-risk and non-risk hpRPE cells. We evaluated the effect of properdin, a complement stabilizer, on the hpRPE cell-dependent complement profile exposed to oxidative stress. hpRPE cells expressed complement components, receptors and regulators. Complement proteins were also stored and secreted by hpRPE cells. We associated AMD-risk single nucleotide polymorphisms with an increased secretion of complement factors D (CFD) and I (CFI). Furthermore, we detected hpRPE cell-associated complement activation products (C3a, C5a) independent of any extracellularly added complement system. Exogenous properdin increased the mRNA expression of CFI and CFD, but decreased levels of complement components (C1Q, C3), receptors (C3AR, C5AR1, CD11B) and inflammation-associated transcripts (NLRP3, IL1B) in hpRPE cells exposed to oxidative stress. This properdin effect was time-dependently counter regulated. In conclusion, our data unveiled a local, genotype-associated complement component production in hpRPE cells, regulated by exogenous properdin. The local complement production and activation via blood-independent mechanisms can be a new therapeutic target for AMD.

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Section: Methodsmentioning

confidence: 99%

Properdin Modulates Complement Component Production in Stressed Human Primary Retinal Pigment Epithelium Cells

et al. 2020

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“…Our data indicate that the HaCaT cells were less affected by the treatment with Aflibercept compared with the effect produced by Bevacizumab. Parisi et al had similar results when they evaluated the effect on healthy cells, on primary human retinal pigment epithelium cells and on scleral fibroblasts [ 18 ]. Their data indicated that Bevacizumab decreased primary human retinal pigment epithelium cells and scleral fibroblasts proliferation more that Aflibercept [ 18 ].…”

Section: ⧉ Discussionmentioning

confidence: 91%

In vitro and in ovo experimental study of two anti-VEGF agents used in ophthalmology

Palfi

Mușat²,

Şeclăman³

et al. 2021

Rom J Morphol Embryol

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Anti-vascular endothelial growth factor (anti-VEGF) monoclonal antibodies can inhibit neovascularization and also to block the growth of several tumor cell lines. Treatment with anti-VEGF drugs like Bevacizumab (Avastin ® ) and Aflibercept has proven optimistic results in various malignant diseases. The present study was aimed to investigate Bevacizumab and Aflibercept in vitro effects on two human melanoma cell lines (A375 and SK-Mel-28), as well as on a healthy cell line (HaCaT human keratinocytes), followed by characterization of the in ovo effects on the chorioallantoic membrane (CAM). Our data indicated that Bevacizumab and Aflibercept decreased human melanoma cells viability in a dose-dependent way, a more significant effect was obtained for Aflibercept. Regarding the safety profile of the active compounds tested, they showed a low-moderate irritation score. In the case of the tested samples, the vascular capillaries were not majorly affected. In both cases, the only notable change was the appearance of a slight vascular coagulation. The viability of the embryos after application was good, they survived more than 24 hours after testing the compounds on the CAM.

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Co-inhibition of PGF and VEGF blocks their expression in mononuclear phagocytes and limits neovascularization and leakage in the murine retina

Balser

Wolf

Herb

et al. 2019

J Neuroinflammation

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BackgroundAge-related macular degeneration (AMD) is a leading cause of visual impairment in the elderly. The neovascular (wet) form of AMD can be treated with intravitreal injections of different anti-vascular endothelial growth factor (VEGF) agents. Placental growth factor (PGF) is another member of the VEGF family of cytokines with pro-angiogenic and pro-inflammatory effects. Here, we aimed to compare single and combined inhibition of VEGF-A and PGF in the laser-induced mouse model of choroidal neovascularization (CNV) with a focus on the effects on retinal mononuclear phagocytes.MethodsCNV was induced in C57BL/6J mice using a YAG-Laser. Immediately after laser damage antibodies against VEGF-A (aVEGF), anti-PGF (aPGF), aVEGF combined with aPGF, aflibercept, or IgG control were injected intravitreally in both eyes. Three and 7 days after laser damage, the vascular leakage was determined by fluorescence angiography. Lectin staining of retinal and RPE/choroidal flat mounts was used to monitor CNV. In situ mRNA co-expression of Iba1, VEGF and PGF were quantified using in situ hybridization. Retinal and RPE/choroidal protein levels of VEGF and PGF as well as the pro-inflammatory cytokines IL-6, IL1-beta, and TNF were determined by ELISA.ResultsEarly (day 3) and intermediate (day 7) vascular leakage and CNV were significantly inhibited by PGF and VEGF-A co-inhibition, most effectively with the trap molecule aflibercept. While VEGF-A blockage alone had no effects, trapping PGF especially with aflibercept prevented the accumulation of reactive microglia and macrophages in laser lesions. The lesion-related mRNA expression and secretion of VEGF-A and PGF by mononuclear phagocytes were potently suppressed by PGF and partially by VEGF-A inhibition. Protein levels of IL-6 and IL1-beta were strongly reduced in all treatment groups.ConclusionsRetinal inhibition of PGF in combination with VEGF-A prevents vascular leakage and CNV possibly via modulating their own expression in mononuclear phagocytes. PGF-related, optimized strategies to target inflammation-mediated angiogenesis may help to increase efficacy and reduce non-responders in the treatment of wet AMD patients.Electronic supplementary materialThe online version of this article (10.1186/s12974-019-1419-2) contains supplementary material, which is available to authorized users.

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Ranibizumab and Bevacizumab but Not Aflibercept Inhibit Proliferation of Primary Human Retinal Pigment Epithelium in vitro

Cited by 3 publications

References 22 publications

Properdin Modulates Complement Component Production in Stressed Human Primary Retinal Pigment Epithelium Cells

Properdin Modulates Complement Component Production in Stressed Human Primary Retinal Pigment Epithelium Cells

In vitro and in ovo experimental study of two anti-VEGF agents used in ophthalmology

Co-inhibition of PGF and VEGF blocks their expression in mononuclear phagocytes and limits neovascularization and leakage in the murine retina

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