Skip to main content

Advertisement

SpringerLink
Log in

Ocular delivery systems for the administration of antibody therapeutics

  • Review
  • Published:
Journal of Pharmaceutical Investigation Aims and scope Submit manuscript

Abstract

Antibodies (Abs) have been extensively used as a powerful tool for targeting proteins based on their immunologic functions such as antigen recognition and pathogen neutralization. In particular, monoclonal Abs (mAbs) and fragments can be promising drugs in clinics owing to their sensitivity and specificity. The controlled release of Ab drugs after local delivery would lead to their prolonged exposure at the disease site, thereby improving the disease condition. In this review, we illustrate the activity of clinically used anti-vascular endothelial growth factor drugs, including aflibercept (Eylea; Regeneron Pharmaceuticals, Bayer Pharma), bevacizumab (Avastin; Genentech, Novartis), and ranibizumab (Lucentis; Genentech, Novartis), in ocular diseases such as wet age-related macular degeneration and myopic choroidal neovascularization. For controlled and prolonged release of the aforementioned drugs after ocular administration, recent approaches using liposomes, hydrogels, and nanoparticles have been introduced. In addition, the evaluation methods to meet the requirements of clinically used Abs are discussed. On the basis of the findings of our review, we can suggest that an ocular delivery system can be a promising platform to overcome the limitations associated with clinically used Abs.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

References

  • Abrishami M, Zarei-Ghanavati S, Soroush D et al (2009) Preparation, characterization, and in vivo evaluation of nanoliposomes-encapsulated bevacizumab (avastin) for intravitreal administration. Retina 29(5):699–703

    Article  PubMed  Google Scholar 

  • Achouri D, Alhanout K, Piccerelle P et al (2013) Recent advances in ocular drug delivery. Drug Dev Ind Pharm 39(11):1599–1617

    Article  CAS  PubMed  Google Scholar 

  • Agrahari V, Agrahari V, Hung WT et al (2016) Composite Nanoformulation therapeutics for long-term ocular delivery of macromolecules. Mol Pharm 13(9):2912–2922

    Article  CAS  PubMed  Google Scholar 

  • Bae JH, Lee SC (2015) Intravitreal liposomal amphotericin B for treatment of endogenous candida endophthalmitis. Jpn J Ophthalmol 59(5):346–352

    Article  CAS  PubMed  Google Scholar 

  • Bakri SJ, Snyder MR, Reid JM et al (2007) Pharmacokinetics of intravitreal bevacizumab (Avastin). Ophthalmology 114(5):855–859

    Article  PubMed  Google Scholar 

  • Baranowski P, Karolewicz B, Gajda M et al (2014) Ophthalmic drug dosage forms: characterisation and research methods. Sci World J 2014:861904

    Article  Google Scholar 

  • Barar J, Aghanejad A, Fathi M et al. (2016) Advanced drug delivery and targeting technologies for the ocular diseases. Bioimpacts 6(1):49–67

    Article  PubMed  PubMed Central  Google Scholar 

  • Bellhorn RW (1981) Permeability of blood-ocular barriers of neonatal and adult cats to fluorescein-labeled dextrans of selected molecular sizes. Invest Ophthalmol Vis Sci 21(2):282–290

    CAS  PubMed  Google Scholar 

  • Bolinger M, Antonetti D (2016) Moving past Anti-VEGF: novel therapies for treating diabetic retinopathy. Int J Mol Sci 17(9):1498

    Article  PubMed Central  Google Scholar 

  • Burt T, Yoshida K, Lappin G et al (2016) Microdosing and other phase 0 clinical trials: facilitating translation in drug development. Clin Transl Sci 9(2):74–88

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Chinen AB, Guan CM, Ferrer JR et al (2015) Nanoparticle probes for the detection of cancer biomarkers, cells, and tissues by fluorescence. Chem Rev 115(19):10530–10574

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Chong V (2016) Ranibizumab for the treatment of wet AMD: a summary of real-world studies. Eye 30(2):270–286

    Article  CAS  PubMed  Google Scholar 

  • Claudio C, Giuseppe A, Elena B et al (2016) Anti-VEGF therapy for retinal vein occlusions. Curr Drug Targets 17(3):328–336

    Article  Google Scholar 

  • Davis BM, Normando EM, Guo L et al (2014) Topical delivery of avastin to the posterior segment of the eye in vivo using annexin A5-associated liposomes. Small 10(8):1575–1584

    Article  CAS  PubMed  Google Scholar 

  • de Oliveira Dias JR, de Andrade GC, Novais EA et al (2016) Fusion proteins for treatment of retinal diseases: aflibercept, ziv-aflibercept, and conbercept. Int J Retina Vitreous 2(1):3

    Article  PubMed  PubMed Central  Google Scholar 

  • del Amo EM, Rimpelä A-K, Heikkinen E et al (2017) Pharmacokinetic aspects of retinal drug delivery. Prog Retin Eye Res 57:134–185

    Article  PubMed  Google Scholar 

  • Dickmann L (2016) Ocular therapeutics: drug delivery and pharmacology. Mol Pharm 13(9):2875–2876

    Article  CAS  PubMed  Google Scholar 

  • Diebold Y, Calonge M (2010) Applications of nanoparticles in ophthalmology. Prog Retin Eye Res 29(6):596–609

    Article  CAS  PubMed  Google Scholar 

  • Elgundi Z, Reslan M, Cruz E et al (in press) The state-of-play and future of antibody therapeutics. Adv Drug Deliv Rev. doi:10.1016/j.addr.2016.11.004

  • Fuchs H, Igney F (2017) Binding to ocular albumin as a half-life extension principle for intravitreally injected drugs: evidence from mechanistic rat and rabbit studies. J Ocul Pharmacol Ther. doi:10.1089/jop.2016.0083

    PubMed  Google Scholar 

  • Grossniklaus HE, Kang SJ, Berglin L (2010) Animal models of choroidal and retinal neovascularization. Prog Retin Eye Res 29(6):500–519

    Article  PubMed  PubMed Central  Google Scholar 

  • Hansel TT, Kropshofer H, Singer T et al (2010) The safety and side effects of monoclonal antibodies. Nat Rev Drug Discov 9(4):325–338

    Article  CAS  PubMed  Google Scholar 

  • Hayreh SS (2014) Ocular vascular occlusive disorders: Natural history of visual outcome. Prog Retin Eye Res 41:1–25

    Article  PubMed  Google Scholar 

  • Kang DJJ, Mieler WF (2008) Thermoresponsive hydrogels as a new ocular drug delivery platform to the posterior segment of the eye. Trans Am Ophthalmol Soc 106:206–213

    Google Scholar 

  • Khalili H, Godwin A, Choi JW et al (2013) Fab-PEG-Fab as a potential antibody mimetic. Bioconjug Chem 24(11):1870–1882

    Article  CAS  PubMed  Google Scholar 

  • Kim YC, Chiang B, Wu X et al (2014) Ocular delivery of macromolecules. J Controlled Release 190:172–181

    Article  CAS  Google Scholar 

  • Krohne TU, Liu Z, Holz FG et al (2012) Intraocular Pharmacokinetics of Ranibizumab Following a Single Intravitreal Injection in Humans. Am J Ophthalmol 154(4):682–686.e682

    Article  CAS  PubMed  Google Scholar 

  • Lao YH, Phua KKL, Leong KW (2015) Aptamer nanomedicine for cancer therapeutics: barriers and potential for translation. ACS Nano 9(3):2235–2254

    Article  CAS  PubMed  Google Scholar 

  • Laude A, Tan LE, Wilson CG et al (2010) Intravitreal therapy for neovascular age-related macular degeneration and inter-individual variations in vitreous pharmacokinetics. Prog Retin Eye Res 29(6):466–475

    Article  CAS  PubMed  Google Scholar 

  • Li H, Liu Y, Zhang Y et al (2016) Liposomes as a novel ocular delivery system for brinzolamide: in vitro and in vivo studies. AAPS PharmSciTech 17(3):710–717

    Article  CAS  PubMed  Google Scholar 

  • Lopez-Cortes LF, Pastor-Ramos MT, Ruiz-Valderas R et al (2001) Intravitreal pharmacokinetics and retinal concentrations of ganciclovir and foscarnet after intravitreal administration in rabbits. Invest Ophthalmol Vis Sci 42(5):1024–1028

    CAS  PubMed  Google Scholar 

  • Malik D, Tarek M, Caceres del Carpio J et al (2014) Safety profiles of anti-VEGF drugs: bevacizumab, ranibizumab, aflibercept and ziv-aflibercept on human retinal pigment epithelium cells in culture. Br J Ophthalmol 98(Suppl 1):i11–i16

    Article  PubMed  PubMed Central  Google Scholar 

  • Mandal A, Bisht R, Rupenthal ID et al (2017) Polymeric micelles for ocular drug delivery: from structural frameworks to recent preclinical studies. J Controlled Release 248:96–116

    Article  CAS  Google Scholar 

  • Muether PS, Hermann MM, Dröge K et al (2013) Long-term stability of vascular endothelial growth factor suppression time under ranibizumab treatment in age-related macular degeneration. Am J Ophthalmol 156(5):989–993. e982

    Article  CAS  PubMed  Google Scholar 

  • Muller PY, Brennan FR (2009) Safety assessment and dose selection for first-in-human clinical trials with immunomodulatory monoclonal antibodies. Clin Pharmacol Ther 85(3):247–258

    Article  CAS  PubMed  Google Scholar 

  • Nelson AL, Reichert JM (2009) Development trends for therapeutic antibody fragments. Nat Biotech 27(4):331–337

    Article  CAS  Google Scholar 

  • Network TDRCR (2015) Aflibercept, bevacizumab, or ranibizumab for diabetic macular edema. N Engl J Med 372(13):1193–1203

    Article  Google Scholar 

  • Osswald CR, Kang-Mieler JJ (2016) Controlled and extended in vitro release of bioactive anti-vascular endothelial growth factors from a microsphere-hydrogel drug delivery system. Curr Eye Res 41(9):1216–1222

    Article  CAS  PubMed  Google Scholar 

  • Parlevliet KJ, Schellekens PTA (1992) Monoclonal antibodies in renal transplantation: a review. Transpl Int 5(4):234–246

    Article  CAS  PubMed  Google Scholar 

  • Rabinovich-Guilatt L, Couvreur P, Lambert G et al (2004) Cationic vectors in ocular drug delivery. J Drug Target 12(9–10):623–633

    Article  CAS  PubMed  Google Scholar 

  • Radhakrishnan K, Sonali N, Moreno M et al (2017) Protein delivery to the back of the eye: barriers, carriers and stability of anti-VEGF proteins. Drug Discov Today 22:416–423

    Article  CAS  PubMed  Google Scholar 

  • Rauck BM, Friberg TR, Medina Mendez CA et al (2014) Biocompatible reverse thermal gel sustains the release of intravitreal bevacizumab in vivo. Invest Ophthalmol Vis Sci 55(1):469–476

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Reichert JM, Rosensweig CJ, Faden LB et al (2005) Monoclonal antibody successes in the clinic. Nat. Biotech 23(9):1073–1078

    CAS  Google Scholar 

  • Saunders DJ, Muether PS, Fauser S (2015) A model of the ocular pharmacokinetics involved in the therapy of neovascular age-related macular degeneration with ranibizumab. Br J Ophthalmol 99(11):1554–1559

    Article  PubMed  Google Scholar 

  • Schmid MK, Bachmann LM, Fäs L et al (2015) Efficacy and adverse events of aflibercept, ranibizumab and bevacizumab in age-related macular degeneration: a trade-off analysis. Br J Ophthalmol 99(2):141–146

    Article  PubMed  Google Scholar 

  • Schweizer D, Vostiar I, Heier A et al (2013) Pharmacokinetics, biocompatibility and bioavailability of a controlled release monoclonal antibody formulation. J Controlled Release 172(3):975–982

    Article  CAS  Google Scholar 

  • Stefano JE, Bird J, Kyazike J et al (2012) High-affinity VEGF antagonists by oligomerization of a minimal sequence VEGF-binding domain. Bioconjug Chem 23(12):2354–2364

    Article  CAS  PubMed  Google Scholar 

  • Tan G, Yu S, Pan H, et al. (2017) Bioadhesive chitosan-loaded liposomes: a more efficient and higher permeable ocular delivery platform for timolol maleate. Int J Biol Macromol 94(Part A):355–363

    Article  CAS  PubMed  Google Scholar 

  • Teo KYC, Ng WY, Lee SY et al (2016) Management of myopic choroidal neovascularization: focus on Anti-VEGF therapy. Drugs 76(11):1119–1133

    Article  PubMed  Google Scholar 

  • Tyagi P, Barros M, Stansbury JW et al (2013) Light-activated, in situ forming gel for sustained suprachoroidal delivery of bevacizumab. Mol Pharm 10(8):2858–2867

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Vaquer G, Dannerstedt FR, Mavris M et al (2013) Animal models for metabolic, neuromuscular and ophthalmological rare diseases. Nat Rev Drug Discov 12(4):287–305

    Article  CAS  PubMed  Google Scholar 

  • Varshochian R, Jeddi-Tehrani M, Mahmoudi AR et al (2013) The protective effect of albumin on bevacizumab activity and stability in PLGA nanoparticles intended for retinal and choroidal neovascularization treatments. Eur J Pharm Sci 50(3–4):341–352

    Article  CAS  PubMed  Google Scholar 

  • Varshochian R, Riazi-Esfahani M, Jeddi-Tehrani M et al (2015) Albuminated PLGA nanoparticles containing bevacizumab intended for ocular neovascularization treatment. J Biomed Mater Res A 103(10):3148–3156

    Article  CAS  PubMed  Google Scholar 

  • Volz C and Pauly D (2015) Antibody therapies and their challenges in the treatment of age-related macular degeneration. Eur J Pharm Biopharm 95(Part B):158–172

    Article  CAS  PubMed  Google Scholar 

  • Wang CH, Hwang YS, Chiang PR et al (2012) Extended Release of Bevacizumab by Thermosensitive Biodegradable and Biocompatible Hydrogel. Biomacromolecules 13(1):40–48

    Article  CAS  PubMed  Google Scholar 

  • Weiner GJ (2015) Building better monoclonal antibody-based therapeutics. Nat Rev Cancer 15(6):361–370

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wong TY, Ohno-Matsui K, Leveziel N et al (2015) Myopic choroidal neovascularisation: current concepts and update on clinical management. Br J Ophthalmol 99(3):289–296

    Article  PubMed  Google Scholar 

  • Xie B, Jin L, Luo Z et al (2015) An injectable thermosensitive polymeric hydrogel for sustained release of Avastin® to treat posterior segment disease. Int J Pharm 490(1–2):375–383

    Article  CAS  PubMed  Google Scholar 

  • Yu S, Wang QM, Wang X et al (2015) Liposome incorporated ion sensitive in situ gels for opthalmic delivery of timolol maleate. Int J Pharm 480(1–2):128–136

    Article  CAS  PubMed  Google Scholar 

  • Zelikin AN, Ehrhardt C, Healy AM (2016) Materials and methods for delivery of biological drugs. Nat Chem 8(11):997–1007

    Article  CAS  PubMed  Google Scholar 

  • Zhang K, Zhang L, Weinreb RN (2012) Ophthalmic drug discovery: novel targets and mechanisms for retinal diseases and glaucoma. Nat Rev Drug Discov 11(7):541–559

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

This work was supported by the National Research Foundation of Korea (NRF) grant funded by the Korea government (MSIP) (NRF-2014R1A2A2A01005059).

Author information

Authors and Affiliations

  1. College of Pharmacy, Yonsei University, 85 Songdogwahak-ro Yeonsu-gu, Incheon, 21983, South Korea

    Su-Eon Jin & Sung-Joo Hwang

  2. Research Institute for Medical Sciences, College of Medicine, Inha University, Incheon, 22332, South Korea

    Su-Eon Jin

  3. Yonsei Institute of Pharmaceutical Sciences, College of Pharmacy, Yonsei University, Incheon, 21983, South Korea

    Sung-Joo Hwang

Authors
  1. Su-Eon Jin
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Sung-Joo Hwang
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Sung-Joo Hwang.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Statement of human and animal rights

This article does not contain any studies with human and animal subjects performed by any of the authors.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Jin, SE., Hwang, SJ. Ocular delivery systems for the administration of antibody therapeutics. Journal of Pharmaceutical Investigation 47, 373–382 (2017). https://doi.org/10.1007/s40005-017-0336-6

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s40005-017-0336-6

Keywords

Search

Navigation