Role of the Fc Region in the Vitreous Half-Life of Anti-VEGF Drugs

Joo, Kwangsic; Park, Sang Jun; Choi, Yewon; Lee, Jung Eun; Na, Young Mi; Hong, Hye Kyoung; Park, Kyu Hyung; Kim, Ho Min; Chung, Jae Yong; Woo, Se Joon

doi:10.1167/iovs.17-21813

Cited by 16 publications

(17 citation statements)

References 30 publications

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“…In conclusion, our re-analysis of the concentration data presented by Joo et al 1 does not substantiate a difference in ocular elimination associated with the Fc region, consistent with what has been reported previously by Gadkar et al 2 …”

supporting

confidence: 89%

“…We have read with interest the article by Joo et al 1 entitled "Role of the Fc region in the vitreous half-life of anti-VEGF drugs," which concludes that the fragment crystallizable (Fc) region is a determinant of ocular pharmacokinetics (PK) following intravitreal injection. In this correspondence, we show that the experimental data presented in the article suggests the contrary.…”

mentioning

confidence: 99%

“…Joo et al 1 tested two molecules, a conventional VEGF-Trap and a Fc region-deficient VEGF-Trap (Fcf VEGF-Trap), in a New Zealand white rabbit model of ocular PK. Based on their analysis of the vitreous and retina/choroid concentrations, the authors found longer half-lives for Fcf VEGF-Trap.…”

mentioning

confidence: 99%

“… Semi-logarithmic plots of the concentration-time course for VEGF-Trap and Fcf VEGF-Trap in rabbit eyes. Symbols: experimental data by Joo et al 1 Lines: linear regression of the terminal elimination phase. The exponential function equation reports the estimated decay rate constant, from which the half-life value is calculated.…”

mentioning

confidence: 99%

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Does the Fc Region Have a Role in the Ocular Half-life After Intravitreal Injection?

Caruso

Mazer

2020

Invest. Ophthalmol. Vis. Sci.

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supporting

confidence: 89%

mentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Does the Fc Region Have a Role in the Ocular Half-life After Intravitreal Injection?

Caruso

Mazer

2020

Invest. Ophthalmol. Vis. Sci.

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“…This was demonstrated for aflibercept, bevacizumab and Fc fragments, detected in retinal vessels 1 to 2 days after their intravitreal injection into the eyes of rodents and monkeys [ 3 , 38 – 41 ]. The role of the Fc domain has been emphasized by showing that a VEGF trap derivative, which instead of the Fc terminus contains a dimerized coiled-coil domain, has an increased half-life after intravitreal injection into the rabbit eye compared with the normal VEGF trap with an Fc region [ 4 ]. Together with the observation that after intravitreal injection bevacizumab was present in REC of wild-type mice but not in those of FcRn −/− mice, these findings strongly support the hypothesis that the Fc domain primarily destines the fate of an intravitreally injected protein and that the FcRn plays a crucial role in this process [ 39 ].…”

Section: Discussionmentioning

confidence: 99%

Fate of the Fc fusion protein aflibercept in retinal endothelial cells: competition of recycling and degradation

Deissler

Lang

2018

Graefes Arch Clin Exp Ophthalmol

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PurposeIntravitreal injection of the VEGF-binding protein aflibercept is widely used to treat various ocular diseases. In vitro, immortalized bovine retinal endothelial cells (iBREC) take up and transport aflibercept through the cell layer in a serum-dependent manner, likely mediated through the neonatal Fc receptor (FcRn), but degradation of the Fc domain-containing protein might be a competing intracellular process. Therefore, aflibercept’s associations with proteins either involved in FcRn-mediated transport or in the lysosomal pathway were studied.MethodsConfluent iBREC pre-cultivated with or without FBS were exposed for 4 h to in vivo achievable 250 μg/ml aflibercept, before cells were harvested for immunofluorescence staining or preparation of protein extracts. Intracellular localization of aflibercept and putative co-localizations with proteins involved in transport of IgG/FcRn complexes, i.e., endosomal Rab4 and Rab11, components of the cytoskeleton, motor proteins, or with marker proteins characteristic of multivesicular bodies or lysosomes were assessed by co-immunofluorescence stainings. Amounts of expressed endogenous proteins and of internalized aflibercept were determined by Western blot analyses.ResultsAflibercept-specific perinuclear staining overlapped with that of the motor protein dynein whereas double staining with an anti-kinesin antibody resulted in a patchy pattern. In addition, aflibercept was typically present close to microtubules and often co-localized with α-tubulin. Rab4 and Rab11 stainings partly overlapped with the perinuclear staining of aflibercept whereas co-localization with Rab7 (in late endosomes/lysosomes) was only rarely seen. Interestingly, aflibercept but not the IgG bevacizumab broadly co-localized with the cation-independent mannose 6-phosphate receptor characteristic of multivesicular endosomes. In accordance with partial degradation beside transcytosis, the amount of intracellular aflibercept increased when cells were treated with protease inhibitors MG-132 or MG-101. Serum-deprived iBREC expressed less Rab11 and dynein but slightly more Rab4.ConclusionAfter uptake by iBREC, aflibercept is present in organelles associated with FcRn-mediated transport, but part of the protein is subject to degradation. Transport inhibition of aflibercept during cultivation without FBS is likely a consequence of an attenuated exocytosis due to decreased expression of Rab11.

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A bioengineered anti‐VEGF protein with high affinity and high concentration for intravitreal treatment of wet age‐related macular degeneration

Huang,

Wang,

Huang

et al. 2023

Bioengineering & Transla Med

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Intravitreal (IVT) injection of anti‐vascular endothelial growth factor (anti‐VEGF) has greatly improved the treatment of many retinal disorders, including wet age‐related macular degeneration (wAMD), which is the third leading cause of blindness. However, frequent injections can be difficult for patients and may lead to various risks such as elevated intraocular pressure, infection, and retinal detachment. To address this issue, researchers have found that IVT injection of anti‐VEGF proteins at their maximally viable concentration and dose can be an effective strategy. However, the intrinsic protein structure can limit the maximum concentration due to stability and solution viscosity. To overcome this challenge, we developed a novel anti‐VEGF protein called nanoFc by fusing anti‐VEGF nanobodies with a crystallizable fragment (Fc). NanoFc has demonstrated high binding affinity to VEGF165 through multivalency and potent bioactivity in various bioassays. Furthermore, nanoFc maintains satisfactory chemical and physical stability at 4°C over 1 month and is easily injectable at concentrations up to 200 mg/mL due to its unique architecture that yields a smaller shape factor. The design of nanoFc offers a bioengineering strategy to ensure both strong anti‐VEGF binding affinity and high protein concentration, with the goal of reducing the frequency of IV injections.

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Role of the Fc Region in the Vitreous Half-Life of Anti-VEGF Drugs

Cited by 16 publications

References 30 publications

Does the Fc Region Have a Role in the Ocular Half-life After Intravitreal Injection?

Does the Fc Region Have a Role in the Ocular Half-life After Intravitreal Injection?

Fate of the Fc fusion protein aflibercept in retinal endothelial cells: competition of recycling and degradation

A bioengineered anti‐VEGF protein with high affinity and high concentration for intravitreal treatment of wet age‐related macular degeneration

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