June 2017
Volume 58, Issue 8
Open Access
ARVO Annual Meeting Abstract  |   June 2017
The role of Fc portion in the intravitreous half-life of anti-VEGF drugs
Author Affiliations & Notes
  • Kwangsic Joo
    Department of Ophthalmology, Seoul National University College of Medicine, Seoul National University Bundang Hospital, Seongnam-si, Korea (the Republic of)
  • Sang Jun Park
    Department of Ophthalmology, Seoul National University College of Medicine, Seoul National University Bundang Hospital, Seongnam-si, Korea (the Republic of)
  • Young Mi Na
    Department of Ophthalmology, Seoul National University College of Medicine, Seoul National University Bundang Hospital, Seongnam-si, Korea (the Republic of)
  • Hye kyoung Hong
    Department of Ophthalmology, Seoul National University College of Medicine, Seoul National University Bundang Hospital, Seongnam-si, Korea (the Republic of)
  • Yewon Choi
    Department of Clinical Pharmacology and Therapeutics, Seoul National University College of Medicine and Bundang Hospital, Seongnam-si, Korea (the Republic of)
  • Jung Eun Lee
    Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, Korea (the Republic of)
  • Hyuncheol Kim
    Department of Chemical and Biomolecular Engineering, Sogang University, Seoul, Korea (the Republic of)
  • Kyu Hyung Park
    Department of Ophthalmology, Seoul National University College of Medicine, Seoul National University Bundang Hospital, Seongnam-si, Korea (the Republic of)
  • Ho Min Kim
    Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, Korea (the Republic of)
  • Jae Yong Chung
    Department of Clinical Pharmacology and Therapeutics, Seoul National University College of Medicine and Bundang Hospital, Seongnam-si, Korea (the Republic of)
  • Se Joon Woo
    Department of Ophthalmology, Seoul National University College of Medicine, Seoul National University Bundang Hospital, Seongnam-si, Korea (the Republic of)
  • Footnotes
    Commercial Relationships   Kwangsic Joo, None; Sang Jun Park, None; Young Mi Na, None; Hye kyoung Hong, None; Yewon Choi, None; Jung Eun Lee, None; Hyuncheol Kim, None; Kyu Hyung Park, None; Ho Min Kim, None; Jae Yong Chung, None; Se Joon Woo, None
  • Footnotes
    Support  None
Investigative Ophthalmology & Visual Science June 2017, Vol.58, 1202. doi:
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    • Get Citation

      Kwangsic Joo, Sang Jun Park, Young Mi Na, Hye kyoung Hong, Yewon Choi, Jung Eun Lee, Hyuncheol Kim, Kyu Hyung Park, Ho Min Kim, Jae Yong Chung, Se Joon Woo; The role of Fc portion in the intravitreous half-life of anti-VEGF drugs. Invest. Ophthalmol. Vis. Sci. 2017;58(8):1202.

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      © ARVO (1962-2015); The Authors (2016-present)

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Abstract

Purpose : To identify the role of Fc portion in intraocular pharmacokinetics (PK) of protein drugs using the two identical protein drugs except the Fc portion

Methods : We generated a new VEGF-Trap without Fc portion (small VEGF-Trap, MW=100kDa) by replacing the Fc portion of conventional VEGF-Trap (MW=145kDa) with a dimerized coiled-coil domain. A total of 42 eyes of 42 rabbits were injected intravitreally with VEGF-Trap (n=21) and small VEGF-Trap (n=21). Eyes were harvested at 6 time points (1h and 1, 2, 4, 14 and 30 days after injections). The concentrations of VEGF-Trap and small VEGF-Trap in the vitreous, aqueous humor, and retina/choroid were measured by an indirect enzyme-linked immunosorbent assay, and pharmacokinetic properties of the drugs were analyzed under hypothetical compartment model system. One-compartment model was applied as the final model for the vitreous whereas two-compartment model was applied for aqueous humor and retina/choroid tissue.

Results : In all three tissues, the maximum concentrations of both small VEGF-Trap and VEGF-Trap were observed 1 hour after intravitreal injection. The estimated half-lives of small VEGF-Trap in the vitreous and retina/choroid were 1.4 and 2.3 times longer (145.02 and 102.12 hours, respectively) than those of VEGF-Trap (103.99 and 44.42 hours, respectively). The total exposure of small VEGF-Trap in the aqueous humor and retina/choroid were approximately 13.2% and 39%, respectively, of the vitreous exposure whereas VEGF-Trap concentrations were approximately 25.2% and 26.2%, indicating that small VEGF-Trap show a preference for the posterior excretion.

Conclusions : The vitreous and retina/choroid half-lives of small VEGF-Trap are significantly longer than that of VEGF-Trap in rabbit eyes despite the lower molecular weight of small VEGF-Trap. This suggests that Fc receptors in ocular tissues contribute to the elimination of anti-VEGF drugs. Truncation or mutation of Fc portion can partially prolong the residence time of VEGF-Trap and have the possibility of reducing the number of VEGF-Trap injections.

This is an abstract that was submitted for the 2017 ARVO Annual Meeting, held in Baltimore, MD, May 7-11, 2017.

 

Protein structures of VEGF-Trap and truncated VEGF proteins. (A) Small VEGF-Trap contains a dimerized coiled coil domain instead of Fc domain of VEGF-Trap. (B) A protein 3D structure of small VEGF-Trap was predicted by I-TASSER.

Protein structures of VEGF-Trap and truncated VEGF proteins. (A) Small VEGF-Trap contains a dimerized coiled coil domain instead of Fc domain of VEGF-Trap. (B) A protein 3D structure of small VEGF-Trap was predicted by I-TASSER.

 

Small VEGF-Trap concentration in the eye of rabbit. Points represent observed concentrations and lines represent estimated concentrations by models

Small VEGF-Trap concentration in the eye of rabbit. Points represent observed concentrations and lines represent estimated concentrations by models

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