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      Effects of a Single Intravitreal Injection of Aflibercept and Ranibizumab on Glomeruli of Monkeys

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          Abstract

          Purpose

          It is known that endothelial cells in the kidney are also strongly VEGF-dependent. Whether intravitreal drugs can be detected within the glomeruli or affect VEGF in glomerular podocytes is not known. Therefore, the aim of this pilot study was to investigate the effects of a single intravitreal injection of aflibercept and ranibizumab on glomeruli of monkeys.

          Methods

          The kidneys of eight cynomolgus monkeys, which were intravitreally injected either with 2 mg of aflibercept or with 0.5 mg of ranibizumab, were investigated one and seven days after injection. Two animals served as controls. The distribution of aflibercept, ranibizumab and VEGF was evaluated using anti-Fc- or anti-F(ab)-fragment and anti-VEGF antibodies respectively. The ratio of stained area/nuclei was calculated using a semi-quantitative computer assisted method. Glomerular endothelial cell fenestration was quantified in electron microscopy using a systematic uniform random sampling protocol and estimating the ratio of fenestrae per µm.

          Results

          Compared to the controls, the anti-VEGF stained area/nuclei ratio of the ranibizumab-treated animals showed no significant changes whereas the stained areas of the aflibercept-treated monkeys showed a significant decrease post-treatment. Immune reactivity (IR) against aflibercept or ranibizumab was detected in aflibercept- or ranibizumab treated animals respectively. The number of fenestrations of the glomerular endothelial cells has shown no significant differences except one day after aflibercept injection in which the number was increased.

          Conclusion

          Surprisingly, both drugs could be detected within the capillaries of the glomeruli. After a single intravitreal injection of aflibercept, VEGF IR in the podocytes was significantly reduced compared to controls. Ranibizumab injection had no significant effect on the glomeruli's VEGF level. Whether this is caused by aflibercept's higher affinity to VEGF or because it is used in a higher stoichiometric concentration compared to ranibizumab remains to be investigated.

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          Most cited references40

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          Ranibizumab versus bevacizumab to treat neovascular age-related macular degeneration: one-year findings from the IVAN randomized trial.

          Usha Chakravarthy, Simon Harding, Chris A Rogers … (2012)
          To compare the efficacy and safety of ranibizumab and bevacizumab intravitreal injections to treat neovascular age-related macular degeneration (nAMD). Multicenter, noninferiority factorial trial with equal allocation to groups. The noninferiority limit was 3.5 letters. This trial is registered (ISRCTN92166560). People >50 years of age with untreated nAMD in the study eye who read ≥ 25 letters on the Early Treatment Diabetic Retinopathy Study chart. We randomized participants to 4 groups: ranibizumab or bevacizumab, given either every month (continuous) or as needed (discontinuous), with monthly review. The primary outcome is at 2 years; this paper reports a prespecified interim analysis at 1 year. The primary efficacy and safety outcome measures are distance visual acuity and arteriothrombotic events or heart failure. Other outcome measures are health-related quality of life, contrast sensitivity, near visual acuity, reading index, lesion morphology, serum vascular endothelial growth factor (VEGF) levels, and costs. Between March 27, 2008 and October 15, 2010, we randomized and treated 610 participants. One year after randomization, the comparison between bevacizumab and ranibizumab was inconclusive (bevacizumab minus ranibizumab -1.99 letters, 95% confidence interval [CI], -4.04 to 0.06). Discontinuous treatment was equivalent to continuous treatment (discontinuous minus continuous -0.35 letters; 95% CI, -2.40 to 1.70). Foveal total thickness did not differ by drug, but was 9% less with continuous treatment (geometric mean ratio [GMR], 0.91; 95% CI, 0.86 to 0.97; P = 0.005). Fewer participants receiving bevacizumab had an arteriothrombotic event or heart failure (odds ratio [OR], 0.23; 95% CI, 0.05 to 1.07; P = 0.03). There was no difference between drugs in the proportion experiencing a serious systemic adverse event (OR, 1.35; 95% CI, 0.80 to 2.27; P = 0.25). Serum VEGF was lower with bevacizumab (GMR, 0.47; 95% CI, 0.41 to 0.54; P<0.0001) and higher with discontinuous treatment (GMR, 1.23; 95% CI, 1.07 to 1.42; P = 0.004). Continuous and discontinuous treatment costs were £9656 and £6398 per patient per year for ranibizumab and £1654 and £1509 for bevacizumab; bevacizumab was less costly for both treatment regimens (P<0.0001). The comparison of visual acuity at 1 year between bevacizumab and ranibizumab was inconclusive. Visual acuities with continuous and discontinuous treatment were equivalent. Other outcomes are consistent with the drugs and treatment regimens having similar efficacy and safety. Proprietary or commercial disclosures may be found after the references. Copyright © 2012 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.
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            Risks of proteinuria and hypertension with bevacizumab, an antibody against vascular endothelial growth factor: systematic review and meta-analysis.

            Chirag Parikh, William Dahut, Xiaolei Zhu … (2007)
            Angiogenesis inhibitors have emerged as an effective targeted therapy in the treatment of patients with many cancers. One of the most widely used angiogenesis inhibitors is bevacizumab, a neutralizing antibody against vascular endothelial growth factor. The overall risk of proteinuria and hypertension in patients with cancer on bevacizumab therapy is unclear. We performed a systematic review and meta-analysis of published clinical trials of bevacizumab to quantify the risk of proteinuria and hypertension. The databases MEDLINE (OVID, 1966 to June 2006) and Web of Science and abstracts presented at the American Society of Clinical Oncology annual meetings from 2004 through 2006 were searched to identify relevant studies. Eligible studies were randomized controlled trials of patients with cancer treated with bevacizumab that described the incidence of proteinuria and hypertension. Relative risk (RR) was calculated by using the fixed-effects model. A total of 1,850 patients were included in the 7 trials identified from the literature. Bevacizumab was associated with a significant increased risk of proteinuria (RR, 1.4 with low-dose bevacizumab; 95% confidence interval [CI], 1.1 to 1.7; RR, 2.2 with high dose; 95% CI, 1.6 to 2.9). Hypertension also was increased significantly among patients receiving bevacizumab (RR, 3.0 for low dose; 95% CI, 2.2 to 4.2; RR, 7.5 for high dose; 95% CI, 4.2 to 13.4). There was a significant dose-dependent increase in risk of proteinuria and hypertension in patients with cancer who received bevacizumab.
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              Vascular endothelial growth factor.

              Napoleone Ferrara (2009)
              Vascular endothelial growth factor (VEGF, VEGF-A) is a major regulator of physiological and pathological angiogenesis. Several VEGF inhibitors have been approved by the FDA for the treatment of advanced cancer and neovascular age-related macular degeneration. This brief review provides a historic account of the challenges associated with the discovery of VEGF and the early steps in elucidating the role of this molecule in the regulation of angiogenesis.
              Article 0 comments Cited 111 times – based on 0 reviews     Review now
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                Author and article information

                Contributors
                Stuart E. Dryer: Role: Editor
                Journal
                Journal ID (nlm-ta): PLoS One
                Journal ID (iso-abbrev): PLoS ONE
                Journal ID (publisher-id): plos
                Journal ID (pmc): plosone
                Title: PLoS ONE
                Publisher: Public Library of Science (San Francisco, USA )
                ISSN (Electronic): 1932-6203
                Publication date Collection: 2014
                Publication date (Electronic): 21 November 2014
                Volume: 9
                Issue: 11
                Electronic Location Identifier: e113701
                Affiliations
                [1 ]Section of Experimental Vitreoretinal Surgery, Centre for Ophthalmology, Tuebingen, Germany
                [2 ]STZ OcuTox Preclinical Drug Assessment, Hechingen, Germany
                [3 ]Division of Nephrology, Charité University Medicine, Charité Campus Benjamin Franklin, Berlin, Germany
                University of Houston, United States of America
                Author notes

                Competing Interests: This study was financially supported by Novartis Pharma AG. Ranibizumab is marketed by Novartis and Ulrich Schraermeyer is a consultant on ocular toxicity to Novartis Pharma AG. SZT Ocutox is a Steinbeis transfer centre. Ulrich Schraermeyer and Sylvie Julien work as freelancers for STZ OcuTox, and Ulrich Schraermeyer is the managing director. The Steinbeis Foundation is an institute headquartered in Stuttgart, Germany dedicated to the transfer of academic findings and knowledge into the field of business. The transfer centres operate as standalone profit centres. There are no further patents, products in development or marketed products to declare. This does not alter the authors' adherence to all the PLOS ONE policies on sharing data and materials, as detailed online in the guide for authors.

                Conceived and designed the experiments: SJ US. Performed the experiments: AT SC. Analyzed the data: AT SC SJ ML MG US. Contributed reagents/materials/analysis tools: US. Wrote the paper: AT SC SJ.

                Article
                Publisher ID: PONE-D-14-27962
                DOI: 10.1371/journal.pone.0113701
                PMC ID: 4240650
                PubMed ID: 25415380
                SO-VID: 4ed6dc6b-e378-49a5-a97b-a63e07dcfdc1
                Copyright statement: Copyright @ 2014
                License:

                This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                Date received : 1 August 2014
                Date accepted : 28 October 2014
                Page count
                Pages: 20
                Funding
                The study was financially supported by Novartis Pharma AG. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. STZ OcuTox Preclinical Drug Assessment provided support in the form of an honorarium for author US, but did not have any additional role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. The specific roles of these authors are articulated in the ‘author contributions’ section.
                Categories
                Subject: Research Article
                Subject: Medicine and Health Sciences
                Subject: Nephrology
                Subject: Renal Failure
                Subject: Ophthalmology
                Subject: Research and Analysis Methods
                Subject: Animal Studies
                Subject: Animal Models of Disease
                Subject: Histochemistry and Cytochemistry Techniques
                Subject: Immunohistochemistry Techniques
                Subject: Microscopy
                Subject: Electron Microscopy
                Subject: Transmission Electron Microscopy
                Subject: Light Microscopy
                Subject: Fluorescence Microscopy
                Custom metadata
                Data Availability The authors confirm that all data underlying the findings are fully available without restriction. All relevant data are within the paper.

                ScienceOpen disciplines: Uncategorized
                Data availability:
                ScienceOpen disciplines: Uncategorized

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