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Graefe's Archive for Clinical and Experimental Ophthalmology

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17.10.2016 | Basic Science

Effects of intravitreally injected Fc fragment on rat eyes

verfasst von: Tatjana Taubitz, Laura-Pia Steinbrenner, Alexander V. Tschulakow, Antje Biesemeier, Sylvie Julien-Schraermeyer, Ulrich Schraermeyer

Erschienen in: Graefe's Archive for Clinical and Experimental Ophthalmology | Ausgabe 12/2016

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Abstract

Purpose

Anti-vascular endothelial growth factor (VEGF) drugs are used to treat neovascular eye diseases. Some of these drugs contain Fc fragments (Fc), but it is unknown how their mode of action is influenced by Fc. Therefore, this study investigated the effects of Fc on rat eyes after intravitreal injection.

Methods

Eighteen Long–Evans rats were intravitreally injected with sterile, biotin-labeled rat Fc (9.1 μg in 5 μl PBS). For control, 5 μl PBS was injected in another nine rats. Animals were sacrificed between 1 and 3 days (group 1), 7 days (group 2), and 14 days (group 3) after injection. The right eyes were examined by electron microscopy (EM). The left eyes were stained by immunohistochemistry to investigate the distribution of Fc and the presence of macrophages.

Results

After 1 day, Fc had penetrated into the anterior chamber and the retina up to the inner nuclear layer, and was located especially in retinal vessels. High numbers of infiltrating cells were present within the vitreous, around the ciliary body, anterior chamber and inside the retina 1–3 days after Fc injection (p < 0.02 group 1 vs. control). Immunohistochemistry and EM showed that they were macrophages or granulocytes in close association with Fc. Ultrastructurally, there were effects on the blood vessels such as thrombocyte activation and fibrin formation.

Conclusions

Biotin labeling is ideal for investigating the distribution of intravitreally injected proteins in ocular tissue. Fc fragments at a dose corresponding to their concentration in standard AMD treatments induced inflammation, and particularly the attraction of immune-competent cells. This may be associated with the risk of inflammation or endophthalmitis after anti-VEGF treatment, and needs further investigation.

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Ferguson TA, Griffith TS (2006) A vision of cell death: Fas ligand and immune privilege 10 years later. Immunol Rev 213:228–238. doi:10.1111/j.1600-065X.2006.00430.x CrossRefPubMed

Taylor AW (2009) Ocular immune privilege. Eye (Lond) 23:1885–1889. doi:10.1038/eye.2008.382 CrossRef

Agrawal S, Joshi M, Christoforidis JB (2013) Vitreous inflammation associated with intravitreal anti-VEGF pharmacotherapy. Mediators Inflamm 2013:943409. doi:10.1155/2013/943409 CrossRefPubMedPubMedCentral

Hahn P, Yashkin AP, Sloan FA (2016) Effect of prior anti-VEGF injections on the risk of retained lens fragments and endophthalmitis after cataract surgery in the elderly. Ophthalmology 123:309–315. doi:10.1016/j.ophtha.2015.06.040 CrossRefPubMed

Tripathi RC, Borisuth NS, Tripathi BJ (1991) Mapping of Fc gamma receptors in the human and porcine eye. Exp Eye Res 53:647–656CrossRefPubMed

Julien S, Biesemeier A, Schraermeyer U (2012) In vitro induction of protein complexes between bevacizumab, VEGF-A165 and heparin: explanation for deposits observed on endothelial veins in monkey eyes. Br J Ophthalmol. doi:10.1136/bjophthalmol-2012-302308

Julien S, Biesemeier A, Taubitz T, Schraermeyer U (2014) Different effects of intravitreally injected ranibizumab and aflibercept on retinal and choroidal tissues of monkey eyes. Br J Ophthalmol 98:813–825. doi:10.1136/bjophthalmol-2013-304019 CrossRefPubMed

Schraermeyer U, Julien S (2013) Effects of bevacizumab in retina and choroid after intravitreal injection into monkey eyes. Expert Opin Biol Ther 13:157–167. doi:10.1517/14712598.2012.748741 CrossRefPubMed

Schraermeyer U, Julien S (2012) Formation of immune complexes and thrombotic microangiopathy after intravitreal injection of bevacizumab in the primate eye. Graefes Arch Clin Exp Ophthalmol 250:1303–1313. doi:10.1007/s00417-012-2055-z CrossRefPubMed

10.

Lang GE, Lang GK, Deissler HL (2015) Basic in vitro studies on VEGF inhibition with aflibercept: similarities and differences to other VEGF-binding therapeutic proteins. Klin Monbl Augenheilkd 232:295–302. doi:10.1055/s-0034-1383142 PubMed

11.

Deissler HL, Lang GK, Lang GE (2016) Internalization of bevacizumab by retinal endothelial cells and its intracellular fate: evidence for an involvement of the neonatal Fc receptor. Exp Eye Res 143:49–59. doi:10.1016/j.exer.2015.10.007 CrossRefPubMed

12.

Presta LG, Chen H, O’Connor SJ, Chisholm V, Meng YG, Krummen L, Winkler M, Ferrara N (1997) Humanization of an anti-vascular endothelial growth factor monoclonal antibody for the therapy of solid tumors and other disorders. Cancer Res 57:4593–4599PubMed

13.

Papadopoulos N, Martin J, Ruan Q, Rafique A, Rosconi MP, Shi E, Pyles EA, Yancopoulos GD, Stahl N, Wiegand SJ (2012) Binding and neutralization of vascular endothelial growth factor (VEGF) and related ligands by VEGF Trap, ranibizumab and bevacizumab. Angiogenesis 15:171–185. doi:10.1007/s10456-011-9249-6 CrossRefPubMedPubMedCentral

14.

Ohr M, Kaiser PK (2012) Aflibercept in wet age-related macular degeneration: a perspective review. Ther Adv Chronic Dis 3:153–161. doi:10.1177/2040622312446007 CrossRefPubMedPubMedCentral

15.

Ferrara N, Damico L, Shams N, Lowman H, Kim R (2006) Development of ranibizumab, an anti-vascular endothelial growth factor antigen binding fragment, as therapy for neovascular age-related macular degeneration. Retina 26:859–870. doi:10.1097/01.iae.0000242842.14624.e7 CrossRefPubMed

16.

Nomura Y, Kaneko M, Miyata K, Yatomi Y, Yanagi Y (2015) Bevacizumab and Aflibercept activate platelets via FcγRIIa. Invest Ophthalmol Vis Sci 56:8075–8082. doi:10.1167/iovs.15-17814 CrossRefPubMed

17.

Meyer T, Robles-Carrillo L, Robson T, Langer F, Desai H, Davila M, Amaya M, Francis JL, Amirkhosravi A (2009) Bevacizumab immune complexes activate platelets and induce thrombosis in FCGR2A transgenic mice. J Thromb Haemost 7:171–181. doi:10.1111/j.1538-7836.2008.03212.x CrossRefPubMed

18.

Klettner AK, Kruse ML, Meyer T, Wesch D, Kabelitz D, Roider J (2009) Different properties of VEGF-antagonists: Bevacizumab but not Ranibizumab accumulates in RPE cells. Graefes Arch Clin Exp Ophthalmol 247:1601–1608. doi:10.1007/s00417-009-1136-0 CrossRefPubMed

19.

Kim H, Robinson SB, Csaky KG (2009) FcRn receptor-mediated pharmacokinetics of therapeutic IgG in the eye. Mol Vis 15:2803–2812PubMedPubMedCentral

20.

Dithmer M, Hattermann K, Pomarius P, Aboul Naga SH, Meyer T, Mentlein R, Roider J, Klettner A (2016) The role of Fc-receptors in the uptake and transport of therapeutic antibodies in the retinal pigment epithelium. Exp Eye Res 145:187–205. doi:10.1016/j.exer.2015.12.013 CrossRefPubMed

21.

Tolentino M (2011) Systemic and ocular safety of intravitreal anti-VEGF therapies for ocular neovascular disease. Surv Ophthalmol 56:95–113. doi:10.1016/j.survophthal.2010.08.006 CrossRefPubMed

22.

Schmucker C, Ehlken C, Agostini HT, Antes G, Ruecker G, Lelgemann M, Loke YK (2012) A safety review and meta-analyses of bevacizumab and ranibizumab: off-label versus goldstandard. PLoS One 7, e42701. doi:10.1371/journal.pone.0042701 CrossRefPubMedPubMedCentral

23.

van der Reis MI, La Heij EC, De Jong-Hesse Y, Ringens PJ, Hendrikse F, Schouten JS (2011) A systematic review of the adverse events of intravitreal anti-vascular endothelial growth factor injections. Retina 31:1449–1469. doi:10.1097/IAE.0b013e3182278ab4 CrossRefPubMed

24.

Modi YS, Tanchon C, Ehlers JP (2015) Comparative safety and tolerability of anti-VEGF therapy in age-related macular degeneration. Drug Saf 38:279–293. doi:10.1007/s40264-015-0273-0 CrossRefPubMedPubMedCentral

25.

Schraermeyer U, Julien S, Biesemeier A, Bartz-Schmidt KU, Wolburg H (2015) A new kind of labyrinth-like capillary is responsible for leakage from human choroidal neovascular endothelium, as investigated by high-resolution electron microscopy. Graefes Arch Clin Exp Ophthalmol 253:681–689. doi:10.1007/s00417-014-2733-0 CrossRefPubMed

26.

Sorensen KK, McCourt P, Berg T, Crossley C, Le Couteur D, Wake K, Smedsrod B (2012) The scavenger endothelial cell: a new player in homeostasis and immunity. Am J Physiol Regul Integr Comp Physiol 303:R1217–R1230. doi:10.1152/ajpregu.00686.2011 CrossRefPubMed

27.

Niu N, Zhang J, Sun Y, Wang S, Sun Y, Korteweg C, Gao W, Gu J (2011) Expression and distribution of immunoglobulin G and its receptors in an immune privileged site: the eye. Cell Mol Life Sci 68:2481–2492. doi:10.1007/s00018-010-0572-7 CrossRefPubMed

28.

Joshi T, Butchar JP, Tridandapani S (2006) Fcgamma receptor signaling in phagocytes. Int J Hematol 84:210–216. doi:10.1532/IJH97.06140 CrossRefPubMed

29.

Nomura S, Shimizu M (2015) Clinical significance of procoagulant microparticles. J Intensive Care 3:2. doi:10.1186/s40560-014-0066-z CrossRefPubMedPubMedCentral

Titel: Effects of intravitreally injected Fc fragment on rat eyes
verfasst von: Tatjana Taubitz
Laura-Pia Steinbrenner
Alexander V. Tschulakow
Antje Biesemeier
Sylvie Julien-Schraermeyer
Ulrich Schraermeyer
Publikationsdatum: 17.10.2016
Verlag: Springer Berlin Heidelberg
Erschienen in: Graefe's Archive for Clinical and Experimental Ophthalmology / Ausgabe 12/2016
Print ISSN: 0721-832X
Elektronische ISSN: 1435-702X
DOI: https://doi.org/10.1007/s00417-016-3511-y

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