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Advancements in Understanding Immunogenicity of Biotherapeutics in the Intraocular Space

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Abstract

Therapeutic breakthroughs in a number of retinal degenerative diseases have come about through the development of biotherapeutics administered directly into the eye. As a consequence of their use, we have gained more insight into the immune privileged status of the eye and the various considerations that development, manufacturing, and use of these drugs require. It has been observed that therapeutic proteins injected into the vitreous can elicit an immune response resulting in the production of anti-drug antibodies (ADAs) which can have clinical consequences. This review includes discussion of the anatomy, physiology, and specific area of the eye that are targeted for drug administration. The various immunologic mechanisms involved in the immune responses to intraocularly administered protein are discussed. This review entails discussion on chemistry, manufacturing, and control (CMC) and formulation-related issues that may influence the risk of immunogenicity. Based on the available immunogenicity profile of the marketed intraocular drugs and their reported adverse events, the animal models and the translational gap from animals to human are discussed. Thus, the objective of this review article is to assess the factors that influence immunogenicity in relation to intraocular administration and the steps taken for mitigating immunogenicity risks.

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References

  1. Medawar PB. Immunity to homologous grafted skin; the fate of skin homografts transplanted to the brain, to subcutaneous tissue, and to the anterior chamber of the eye. Br J Exp Pathol. 1948;29(1):58–69.

    CAS  PubMed  PubMed Central  Google Scholar 

  2. Runkle EA, Antonetti DA. The blood-retinal barrier: structure and functional significance. Methods Mol Biol. 2011;686:133–48.

    Article  CAS  PubMed  Google Scholar 

  3. Cunha-Vaz J. The blood-ocular barriers. Surv Ophthalmol. 1979;23(5):279–96.

    Article  CAS  PubMed  Google Scholar 

  4. Benhar I, London A, Schwartz M. The privileged immunity of immune privileged organs: the case of the eye. Front Immunol. 2012;3:296.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Mochizuki M, Sugita S, Kamoi K. Immunological homeostasis of the eye. Prog Retin Eye Res. 2013;33:10–27.

    Article  CAS  PubMed  Google Scholar 

  6. Stein-Streilein J. Mechanisms of immune privilege in the posterior eye. Int Rev Immunol. 2013;32(1):42–56.

    Article  CAS  PubMed  Google Scholar 

  7. Masli S, Vega JL. Ocular immune privilege sites. Methods Mol Biol. 2011;677:449–58.

    Article  CAS  PubMed  Google Scholar 

  8. McPherson SW, Heuss ND, Gregerson DS. Regulation of CD8(+) T cell responses to retinal antigen by local FoxP3(+) regulatory T cells. Front Immunol. 2012;3:166.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Zhou R, Horai R, Silver PB, Mattapallil MJ, Zarate-Blades CR, Chong WP, et al. The living eye “disarms” uncommitted autoreactive T cells by converting them to Foxp3(+) regulatory cells following local antigen recognition. J Immunol. 2012;188(4):1742–50.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Klaska IP, Forrester JV. Mouse models of autoimmune uveitis. Curr Pharm Des. 2015;21(18):2453–67.

    Article  CAS  PubMed  Google Scholar 

  11. Lightman S, Towler H. Immunopathology and altered immunity in posterior uveitis in man: a review. Curr Eye Res. 1992;11(Suppl):11–5.

    Article  PubMed  Google Scholar 

  12. Kaplan HJ, Streilein JW. Immune response to immunization via the anterior chamber of the eye. I. F. Lymphocyte-induced immune deviation. J Immunol. 1977;118(3):809–14.

    CAS  PubMed  Google Scholar 

  13. Streilein JW. Ocular immune privilege: therapeutic opportunities from an experiment of nature. Nat Rev Immunol. 2003;3(11):879–89.

    Article  CAS  PubMed  Google Scholar 

  14. Taylor AW, Kaplan HJ. Ocular immune privilege in the year 2010: ocular immune privilege and uveitis. Ocul Immunol Inflamm. 2010;18(6):488–92.

    Article  PubMed  PubMed Central  Google Scholar 

  15. Farooq SM, Ashour HM. Eye-mediated induction of specific immune tolerance to encephalitogenic antigens. CNS Neurosci Ther. 2013;19(7):503–10.

    Article  CAS  PubMed  Google Scholar 

  16. Ashour HM, Niederkorn JY. Expansion of B cells is necessary for the induction of T-cell tolerance elicited through the anterior chamber of the eye. Int Arch Allergy Immunol. 2007;144(4):343–6.

    Article  PubMed  Google Scholar 

  17. D'Orazio TJ, Niederkorn JY. Splenic B cells are required for tolerogenic antigen presentation in the induction of anterior chamber-associated immune deviation (ACAID). Immunology. 1998;95(1):47–55.

    Article  PubMed  PubMed Central  Google Scholar 

  18. Niederkorn JY, Mayhew E. Role of splenic B cells in the immune privilege of the anterior chamber of the eye. Eur J Immunol. 1995;25(10):2783–7.

    Article  CAS  PubMed  Google Scholar 

  19. Wilbanks GA, Streilein JW. Distinctive humoral immune responses following anterior chamber and intravenous administration of soluble antigen. Evidence for active suppression of IgG2-secreting B lymphocytes. Immunology. 1990;71(4):566–72.

    CAS  PubMed  PubMed Central  Google Scholar 

  20. Del Amo EM, Rimpela AK, Heikkinen E, Kari OK, Ramsay E, Lajunen T, et al. Pharmacokinetic aspects of retinal drug delivery. Prog Retin Eye Res. 2017;57:134–85.

    Article  PubMed  Google Scholar 

  21. LUCENTIS. R ranibizumab injection US package insert Genentech Inc., South San Francisco, CA. 2006. Available from: http://www.accessdata.fda.gov/drugsatfda_docs/label/2014/125156s105lbl.pdf.

  22. EYLEA™ (aflibercept) Injection, 2011 US package insert, Regeneron Pharmaceuticals Inc., New York. Available from: https://www.regeneron.com/sites/default/files/EYLEA_FPI.pdf.

  23. Mo JS, Streilein JW. Immune privilege persists in eyes with extreme inflammation induced by intravitreal LPS 2001. Ocul Immunol Inflamm. 2007;15(3):249–59.

    Article  CAS  PubMed  Google Scholar 

  24. Ohta K, Yamagami S, Taylor AW, Streilein JW. IL-6 antagonizes TGF-beta and abolishes immune privilege in eyes with endotoxin-induced uveitis. Invest Ophthalmol Vis Sci. 2000;41(9):2591–9.

    CAS  PubMed  Google Scholar 

  25. Okamoto S, Streilein JW. Role of inflammatory cytokines in induction of anterior chamber-associated immune deviation. Ocul Immunol Inflamm. 1998;6(1):1–11.

    Article  CAS  PubMed  Google Scholar 

  26. Zamiri P, Masli S, Kitaichi N, Taylor AW, Streilein JW. Thrombospondin plays a vital role in the immune privilege of the eye. Invest Ophthalmol Vis Sci. 2005;46(3):908–19.

    Article  PubMed  Google Scholar 

  27. Contreras-Ruiz L, Ryan DS, Sia RK, Bower KS, Dartt DA, Masli S. Polymorphism in THBS1 gene is associated with post-refractive surgery chronic ocular surface inflammation. Ophthalmology. 2014;121(7):1389–97.

    Article  PubMed  PubMed Central  Google Scholar 

  28. Hashemi H, Khabazkhoob M, Miraftab M, Emamian MH, Shariati M, Abdolahinia T, et al. The distribution of axial length, anterior chamber depth, lens thickness, and vitreous chamber depth in an adult population of Shahroud, Iran. BMC Ophthalmol. 2012;12:50.

    Article  PubMed  PubMed Central  Google Scholar 

  29. Meyer CH, Krohne TU, Charbel Issa P, Liu Z, Holz FG. Routes for drug delivery to the eye and retina: intravitreal injections. Dev Ophthalmol. 2016;55:63–70.

    Article  PubMed  Google Scholar 

  30. Amsden BG, Marecak D. Long-term sustained release from a biodegradable photo-cross-linked network for intraocular corticosteroid delivery. Mol Pharm. 2016;13(9):3004–12.

    Article  CAS  PubMed  Google Scholar 

  31. Johnson MW, Olsen KR, Hernandez E, Irvine WD, Johnson RN. Retinal toxicity of recombinant tissue plasminogen activator in the rabbit. Arch Ophthalmol. 1990;108(2):259–63.

    Article  CAS  PubMed  Google Scholar 

  32. Loewenstein A, Zemel E, Lazar M, Perlman I. Drug-induced retinal toxicity in albino rabbits: the effects of imipenem and aztreonam. Invest Ophthalmol Vis Sci. 1993;34(12):3466–76.

    CAS  PubMed  Google Scholar 

  33. Oku H, Yamaguchi H, Sugiyama T, Kojima S, Ota M, Azuma I. Retinal toxicity of nitric oxide released by administration of a nitric oxide donor in the albino rabbit. Invest Ophthalmol Vis Sci. 1997;38(12):2540–4.

    CAS  PubMed  Google Scholar 

  34. Sakimoto A, Sawa M, Oshida T, Sugaya S, Hirono T, Ishimori A. Minimum endotoxin concentration causing inflammation in the anterior segment of rabbit eyes. Jpn J Ophthalmol. 2009;53(4):425–32.

    Article  CAS  PubMed  Google Scholar 

  35. Buchen SY, Calogero D, Hilmantel G, Eydelman MB. Rabbit ocular reactivity to bacterial endotoxin contained in aqueous solution and ophthalmic viscosurgical devices. Ophthalmology. 2012;119(7):e4–e10.

    Article  PubMed  Google Scholar 

  36. Food Drug Administration Center for Devices and Radiological Health. Guidance for Industry: Endotoxin Testing Recommendations for Single-Use Intraocular Ophthalmic Devices. Maryland: FDA; 2015.

  37. Bantseev V, Miller PE, Bentley E, Schuetz C, Streit TM, Christian BJ, et al. Determination of a no-observable effect level for endotoxin following a single intravitreal administration to Dutch belted rabbits. Invest Ophthalmol Vis Sci. 2017;58(3):1545–52.

    Article  PubMed  Google Scholar 

  38. Mahler HC, Friess W, Grauschopf U, Kiese S. Protein aggregation: pathways, induction factors and analysis. J Pharm Sci. 2009;98(9):2909–34.

    Article  CAS  PubMed  Google Scholar 

  39. Rosenberg AS. Effects of protein aggregates: an immunologic perspective. AAPS J. 2006;8(3):E501–7.

    Article  PubMed  PubMed Central  Google Scholar 

  40. Holz FG, Tadayoni R, Beatty S, Berger A, Cereda MG, Cortez R, et al. Multi-country real-life experience of anti-vascular endothelial growth factor therapy for wet age-related macular degeneration. Br J Ophthalmol. 2015;99(2):220–6.

    Article  PubMed  Google Scholar 

  41. Schwendeman SP, Shah RB, Bailey BA, Schwendeman AS. Injectable controlled release depots for large molecules. J Control Release. 2014;190:240–53.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Schwendeman SP. Recent advances in the stabilization of proteins encapsulated in injectable PLGA delivery systems. Crit Rev Ther Drug Carrier Syst. 2002;19(1):73–98.

    Article  CAS  PubMed  Google Scholar 

  43. Houée-Levin C, Sicard-Roselli C. Radiation chemistry of proteins. In: Jonah CD, Madhav Rao BS, editors. Studies in Physical and Theoretical Chemistry, vol. 87. Amsterdam: Elsevier; 2001. p. 553–84.

    Google Scholar 

  44. Li F, Hurley B, Liu Y, Leonard B, Griffith M. Controlled release of bevacizumab through nanospheres for extended treatment of age-related macular degeneration. Open Ophthalmol J. 2012;6:54–8.

    Article  PubMed  PubMed Central  Google Scholar 

  45. Mordenti J, Thomsen K, Licko V, Berleau L, Kahn JW, Cuthbertson RA, et al. Intraocular pharmacokinetics and safety of a humanized monoclonal antibody in rabbits after intravitreal administration of a solution or a PLGA microsphere formulation. Toxicol Sci. 1999;52(1):101–6.

    Article  CAS  PubMed  Google Scholar 

  46. Pan CK, Durairaj C, Kompella UB, Agwu O, Oliver SC, Quiroz-Mercado H, et al. Comparison of long-acting bevacizumab formulations in the treatment of choroidal neovascularization in a rat model. J Ocul Pharmacol Ther. 2011;27(3):219–24.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Abrishami M, Zarei-Ghanavati S, Soroush D, Rouhbakhsh M, Jaafari MR, Malaekeh-Nikouei B. Preparation, characterization, and in vivo evaluation of nanoliposomes-encapsulated bevacizumab (avastin) for intravitreal administration. Retina. 2009;29(5):699–703.

    Article  PubMed  Google Scholar 

  48. Ratanji KD, Derrick JP, Dearman RJ, Kimber I. Immunogenicity of therapeutic proteins: influence of aggregation. J Immunotoxicol. 2014;11(2):99–109.

    Article  CAS  PubMed  Google Scholar 

  49. Narhi LO, Schmit J, Bechtold-Peters K, Sharma D. Classification of protein aggregates. J Pharm Sci. 2012;101(2):493–8.

    Article  CAS  PubMed  Google Scholar 

  50. ICH harmonized tripartite guideline. Quality of Biotechnological Products: Stability testing of biotechnological/biological products Q5C. 1995.

  51. Patel S, Muller G, Stracke JO, Altenburger U, Mahler HC, Jere D. Evaluation of protein drug stability with vitreous humor in a novel ex-vivo intraocular model. Eur J Pharm Biopharm. 2015;95(Pt B):407–17.

    Article  CAS  PubMed  Google Scholar 

  52. Patel S, Stracke JO, Altenburger U, Mahler HC, Metzger P, Shende P, et al. Prediction of intraocular antibody drug stability using ex-vivo ocular model. Eur J Pharm Biopharm. 2017;112:177–86.

    Article  CAS  PubMed  Google Scholar 

  53. Ponce R, Abad L, Amaravadi L, Gelzleichter T, Gore E, Green J, et al. Immunogenicity of biologically-derived therapeutics: assessment and interpretation of nonclinical safety studies. Regul Toxicol Pharmacol. 2009;54(2):164–82.

    Article  CAS  PubMed  Google Scholar 

  54. Nussenblatt RB, Calogero D, Buchen SY, Leder HA, Goodkin M, Eydelman MB. Rabbit intraocular reactivity to endotoxin measured by slit-lamp biomicroscopy and laser flare photometry. Ophthalmology. 2012;119(7):e19–23.

    Article  PubMed  Google Scholar 

  55. Streit T, Miller P, Bentley E, Thackaberry E, Schuetz C, Sonnentag P, et al. Determination of a No-Observable Effect Level for Endotoxin Following a Single Intravitreal Administration to Dutch Belted Rabbits. Invest Ophthal Vis Sci. 2017;58:1545-52.

  56. Verthelyi D, Wang V. Trace levels of innate immune response modulating impurities (IIRMIs) synergize to break tolerance to therapeutic proteins. PLoS One. 2010;5(12):e15252.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Caspi RR. Understanding autoimmunity in the eye: from animal models to novel therapies. Discov Med. 2014;17(93):155–62.

    PubMed  PubMed Central  Google Scholar 

  58. de Zafra CLZ, Sasseville VG, Matsumoto S, Freichel C, Milton M, Mac Lachlan TK, et al. Inflammation and immunogenicity limit the utility of the rabbit as a nonclinical species for ocular biologic therapeutics. Regul Toxicol Pharmacol. 2017;86:221–30.

    Article  PubMed  Google Scholar 

  59. Short BG. Safety evaluation of ocular drug delivery formulations: techniques and practical considerations. Toxicol Pathol. 2008;36(1):49–62.

    Article  CAS  PubMed  Google Scholar 

  60. Frazier KS, Engelhardt JA, Fant P, Guionaud S, Henry SP, Leach MW, et al. Scientific and regulatory policy committee points-to-consider paper*: drug-induced vascular injury associated with nonsmall molecule therapeutics in preclinical development: part I. Biotherapeutics Toxicol Pathol. 2015;43(7):915–34.

    Article  CAS  PubMed  Google Scholar 

  61. Leach MW, Rottman JB, Hock MB, Finco D, Rojko JL, Beyer JC. Immunogenicity/hypersensitivity of biologics. Toxicol Pathol. 2014;42(1):293–300.

    Article  CAS  PubMed  Google Scholar 

  62. Rojko JL, Evans MG, Price SA, Han B, Waine G, DeWitte M, et al. Formation, clearance, deposition, pathogenicity, and identification of biopharmaceutical-related immune complexes: review and case studies. Toxicol Pathol. 2014;42(4):725–64.

    Article  CAS  PubMed  Google Scholar 

  63. Leach MW. Regulatory forum opinion piece: differences between protein-based biologic products (biotherapeutics) and chemical entities (small molecules) of relevance to the toxicologic pathologist. Toxicol Pathol. 2013;41(1):128–36.

    Article  PubMed  Google Scholar 

  64. Anderson JM. Host response to long acting injections and implants. In: Wright JC, Burgess DJ, editors. Long acting injections and implants. Boston: Springer US; 2012. p. 25–55.

    Chapter  Google Scholar 

  65. Acland GM, Aguirre GD, Ray J, Zhang Q, Aleman TS, Cideciyan AV, et al. Gene therapy restores vision in a canine model of childhood blindness. Nat Genet. 2001;28(1):92–5.

    CAS  PubMed  Google Scholar 

  66. Bennicelli J, Wright JF, Komaromy A, Jacobs JB, Hauck B, Zelenaia O, et al. Reversal of blindness in animal models of leber congenital amaurosis using optimized AAV2-mediated gene transfer. Mol Ther. 2008;16(3):458–65.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Drolet DW, Nelson J, Tucker CE, Zack PM, Nixon K, Bolin R, et al. Pharmacokinetics and safety of an anti-vascular endothelial growth factor aptamer (NX1838) following injection into the vitreous humor of rhesus monkeys. Pharm Res. 2000;17(12):1503–10.

    Article  CAS  PubMed  Google Scholar 

  68. Gao H, Pennesi ME, Qiao X, Iyer MN, Wu SM, Holz ER, et al. Intravitreal moxifloxacin: retinal safety study with electroretinography and histopathology in animal models. Invest Ophthalmol Vis Sci. 2006;47(4):1606–11.

    Article  PubMed  Google Scholar 

  69. Gaudreault J, Fei D, Rusit J, Suboc P, Shiu V. Preclinical pharmacokinetics of ranibizumab (rhu Fab V2) after a single intravitreal administration. Invest Ophthalmol Vis Sci. 2005;46(2):726–33.

    Article  PubMed  Google Scholar 

  70. Kim SJ, Kim J, Lee J, Cho SY, Kang HJ, Kim KY, et al. Intravitreal human complement factor H in a rat model of laser-induced choroidal neovascularisation. Br J Ophthalmol. 2013;97(3):367–70.

    Article  PubMed  Google Scholar 

  71. Krzystolik MG, Afshari MA, Adamis AP, Gaudreault J, Gragoudas ES, Michaud NA, et al. Prevention of experimental choroidal neovascularization with intravitreal anti-vascular endothelial growth factor antibody fragment. Arch Ophthalmol. 2002;120(3):338–46.

    Article  CAS  PubMed  Google Scholar 

  72. Mudumba S, Bezwada P, Takanaga H, Hosoi K, Tsuboi T, Ueda K, et al. Tolerability and pharmacokinetics of intravitreal sirolimus. J Ocul Pharmacol Ther. 2012;28(5):507–14.

    Article  CAS  PubMed  Google Scholar 

  73. Nork TM, Dubielzig RR, Christian BJ, Miller PE, Miller JM, Cao J, et al. Prevention of experimental choroidal neovascularization and resolution of active lesions by VEGF trap in nonhuman primates. Arch Ophthalmol. 2011;129(8):1042–52.

    Article  CAS  PubMed  Google Scholar 

  74. Penn JS, Rajaratnam VS. Inhibition of retinal neovascularization by intravitreal injection of human rPAI-1 in a rat model of retinopathy of prematurity. Invest Ophthalmol Vis Sci. 2003;44(12):5423–9.

    Article  PubMed  Google Scholar 

  75. Yin L, Greenberg K, Hunter JJ, Dalkara D, Kolstad KD, Masella BD, et al. Intravitreal injection of AAV2 transduces macaque inner retina. Invest Ophthalmol Vis Sci. 2011;52(5):2775–83.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Rowe-Rendleman CL, Durazo SA, Kompella UB, Rittenhouse KD, Di Polo A, Weiner AL, et al. Drug and gene delivery to the back of the eye: from bench to bedside. Invest Ophthalmol Vis Sci. 2014;55(4):2714–30.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Bode G, Clausing P, Gervais F, Loegsted J, Luft J, Nogues V, et al. The utility of the minipig as an animal model in regulatory toxicology. J Pharmacol Toxicol Methods. 2010;62(3):196–220.

    Article  CAS  PubMed  Google Scholar 

  78. Guideline on Immunogenicity assessment of biotechnology-derived therapeutic proteins. In: CHMP, editor. London: European Medicines Agency; 2015.

    Google Scholar 

  79. Antoszyk AN, Tuomi L, Chung CY, Singh A. Ranibizumab combined with verteporfin photodynamic therapy in neovascular age-related macular degeneration (FOCUS): year 2 results. Am J Ophthalmol. 2008;145(5):862–74.

    Article  CAS  PubMed  Google Scholar 

  80. Heier JS, Antoszyk AN, Pavan PR, Leff SR, Rosenfeld PJ, Ciulla TA, et al. Ranibizumab for treatment of neovascular age-related macular degeneration: a phase I/II multicenter, controlled, multidose study. Ophthalmology. 2006;113(4):633–e1-4.

    Article  PubMed  Google Scholar 

  81. Guideline on Immunogenicity Assessment of Biotechnology Derived Therapeutic Proteins. London: European Medical Agency;2007.

  82. Rosenfeld PJ, Schwartz SD, Blumenkranz MS, Miller JW, Haller JA, Reimann JD, et al. Maximum tolerated dose of a humanized anti-vascular endothelial growth factor antibody fragment for treating neovascular age-related macular degeneration. Ophthalmology. 2005;112(6):1048–53.

    Article  PubMed  Google Scholar 

  83. Rosenfeld PJ, Heier JS, Hantsbarger G, Shams N. Tolerability and efficacy of multiple escalating doses of ranibizumab (Lucentis) for neovascular age-related macular degeneration. Ophthalmology. 2006;113(4):623 e1.

    Article  PubMed  Google Scholar 

  84. Sinha DP, Cartwright ME, Johnson RC. Incidental mononuclear cell infiltrate in the uvea of cynomolgus monkeys. Toxicol Pathol. 2006;34(2):148–51.

    Article  PubMed  Google Scholar 

  85. Gupta S, Indelicato SR, Jethwa V, Kawabata T, Kelley M, Mire-Sluis AR, et al. Recommendations for the design, optimization, and qualification of cell-based assays used for the detection of neutralizing antibody responses elicited to biological therapeutics. J Immunol Methods. 2007;321(1–2):1–18.

    Article  CAS  PubMed  Google Scholar 

  86. Koren E, Smith HW, Shores E, Shankar G, Finco-Kent D, Rup B, et al. Recommendations on risk-based strategies for detection and characterization of antibodies against biotechnology products. J Immunol Methods. 2008;333(1–2):1–9.

    Article  CAS  PubMed  Google Scholar 

  87. Mire-Sluis AR, Barrett YC, Devanarayan V, Koren E, Liu H, Maia M, et al. Recommendations for the design and optimization of immunoassays used in the detection of host antibodies against biotechnology products. J Immunol Methods. 2004;289(1–2):1–16.

    Article  CAS  PubMed  Google Scholar 

  88. Shankar G, Devanarayan V, Amaravadi L, Barrett YC, Bowsher R, Finco-Kent D, et al. Recommendations for the validation of immunoassays used for detection of host antibodies against biotechnology products. J Pharm Biomed Anal. 2008;48(5):1267–81.

    Article  CAS  PubMed  Google Scholar 

  89. Guideline immunogenicity assessment of monoclonal antibodies intended for in vivo clinical use. In: CHMP, editor. London: European Medical Agency; 2012.

  90. European Medical Agency. Immunogenicity assessment of monoclonal antibodies intended for in vivo clinical use. London: EMA; 2012.

  91. Singh SK. Impact of product-related factors on immunogenicity of biotherapeutics. J Pharm Sci. 2011;100(2):354–87.

    Article  CAS  PubMed  Google Scholar 

  92. Pandey GS, Sauna ZE. Pharmacogenetics and the immunogenicity of protein therapeutics. J Interf Cytokine Res. 2014;34(12):931–7.

    Article  CAS  Google Scholar 

  93. FDA. In: CDER, CBER, CDRH, editors. Assay development and validation for immunogenicity testing of therapeutic protein products. Rockville: FDA; 2016.

    Google Scholar 

  94. Volz C, Pauly D. Antibody therapies and their challenges in the treatment of age-related macular degeneration. Eur J Pharm Biopharm. 2015;95(Pt B):158–72.

    Article  CAS  PubMed  Google Scholar 

  95. Xue L, Rup B. Evaluation of pre-existing antibody presence as a risk factor for posttreatment anti-drug antibody induction: analysis of human clinical study data for multiple biotherapeutics. AAPS J. 2013;15(3):893–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Garay RP, El-Gewely R, Armstrong JK, Garratty G, Richette P. Antibodies against polyethylene glycol in healthy subjects and in patients treated with PEG-conjugated agents. Expert Opin Drug Deliv. 2012;9(11):1319–23.

    Article  CAS  PubMed  Google Scholar 

  97. Basile AS, Hutmacher M, Nickens D, Nielsen J, Kowalski K, Whitfield L, et al. Population pharmacokinetics of pegaptanib in patients with neovascular, age-related macular degeneration. J Clin Pharmacol. 2012;52(8):1186–99.

    Article  CAS  PubMed  Google Scholar 

  98. Gragoudas ES, Adamis AP, Cunningham ET Jr, Feinsod M, Guyer DR. Pegaptanib for neovascular age-related macular degeneration. N Engl J Med. 2004;351(27):2805–16.

    Article  CAS  PubMed  Google Scholar 

  99. Steffensmeier AC, Azar AE, Fuller JJ, Muller BA, Russell SR. Vitreous injections of pegaptanib sodium triggering allergic reactions. Am J Ophthalmol. 2007;143(3):512–3.

    Article  CAS  PubMed  Google Scholar 

  100. Heier JS, Brown DM, Chong V, Korobelnik JF, Kaiser PK, Nguyen QD, et al. Intravitreal aflibercept (VEGF trap-eye) in wet age-related macular degeneration. Ophthalmology. 2012;119(12):2537–48.

    Article  PubMed  Google Scholar 

  101. Busbee BG, Ho AC, Brown DM, Heier JS, Suner IJ, Li Z, et al. Twelve-month efficacy and safety of 0.5 mg or 2.0 mg ranibizumab in patients with subfoveal neovascular age-related macular degeneration. Ophthalmology. 2013;120(5):1046–56.

    Article  PubMed  Google Scholar 

  102. Heier JS, Boyer D, Nguyen QD, Marcus D, Roth DB, Yancopoulos G, et al. The 1-year results of CLEAR-IT 2, a phase 2 study of vascular endothelial growth factor trap-eye dosed as-needed after 12-week fixed dosing. Ophthalmology. 2011;118(6):1098–106.

    Article  PubMed  Google Scholar 

  103. Apte RS, Modi M, Masonson H, Patel M, Whitfield L, Adamis AP, et al. Study group. Pegaptanib 1-year systemic safety results from a safety-pharmacokinetic trial in patients with neovascular age-related macular degeneration. Ophthalmology. 2007;114(9):1702–12.

    Article  PubMed  Google Scholar 

  104. Withdrawal assessment report for Macugen. http://www.ema.europa.eu/docs/en_GB/document_library/Application_withdrawal_assessment_report/2011/09/WC500115280.pdf. In: CHMP, editor. London: European Medical Agency; 2011.

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Acknowledgments

The authors would like to thank Allison Bruce (Genentech) for creating Figs. 1 and 2. All trademarks belong to their respective owners and are only used for informational purposes. We would like to thank all TPIFG steering committee members for reviewing the manuscript and providing constructive suggestions.

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Authors and Affiliations

  1. BioAnalytical Sciences Genentech, South San Francisco, California, USA

    Eric Wakshull & Valerie Quarmby

  2. Lonza, Drug Product Services, Basel, Switzerland

    Hanns-Christian Mahler & Dhananjay Jere

  3. Drug Delivery, Allergan, Irvine, California, USA

    Hongwen Rivers

  4. AbbVie, Preclinical Safety, North Chicago, Illinois, USA

    Meg Ramos

  5. PDS-Lead, F. Hoffmann-La Roche AG, Basel, Switzerland

    Piotr Szczesny

  6. Novartis Pharma AG, Basel, Switzerland

    Karoline Bechtold-Peters

  7. Boston University, Boston, Massachusetts, USA

    Sharmila Masli

  8. Nonclinical and Translational Sciences, Allergan, Irvine, California, USA

    Swati Gupta

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  8. Karoline Bechtold-Peters
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Correspondence to Swati Gupta.

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Wakshull, E., Quarmby, V., Mahler, HC. et al. Advancements in Understanding Immunogenicity of Biotherapeutics in the Intraocular Space. AAPS J 19, 1656–1668 (2017). https://doi.org/10.1208/s12248-017-0128-y

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