Structural Characterization of a Recombinant Fusion Protein by Instrumental Analysis and Molecular Modeling

Wu, Zhigang; Zhou, Peng; Li, Xiaoxin; Wang, Hui; Luo, Delun; Qiao, Huaiyao; Ke, Xiaoyan; Huang, Jian

doi:10.1371/journal.pone.0057642

Cited by 51 publications

(36 citation statements)

References 46 publications

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“…FP3, later named KH902 or conbercept, contains the second Ig-like domain of VEGFR-1 and the third and fourth Ig-like domains of VEGFR-2, was fused to the Fc portion of human IgG1 (shown in Figure 1 ). 32 Conbercept has the highest binding affinity to VEGF-A 165 (Kd =0.5 pM) and binds all isoforms of VEGF-A, VEGF-B, VEGF-C, and PlGF with high affinity. A comparison of anti-VEGF drugs is shown in Table 1 .…”

Section: Introduction To Conberceptmentioning

confidence: 99%

Profile of conbercept in the treatment of neovascular age-related macular degeneration

Lu¹,

Sun²

2015

DDDT

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In developed countries, age-related macular degeneration (AMD) is the leading cause of irreversible blindness in individuals over the age of 65 years. Vascular endothelial growth factor (VEGF) plays a vital role in the formation of neovascular AMD. VEGF regulates angiogenesis, enhances vascular permeability, and drives the formation of choroidal neovascularization. As a result of the introduction of anti-VEGF drugs, the incidence of blindness from neovascular AMD has greatly reduced. Anti-VEGF drugs are used as a first-line treatment for neovascular AMD. The most recent anti-VEGF drug is conbercept, also named KH902, which was approved for the treatment of neovascular AMD by the China Food and Drug Administration in December 2013. In this review, recent clinical information regarding the use of conbercept to treat neovascular AMD is summarized. Conbercept is a soluble receptor decoy that blocks all isoforms of VEGF-A, VEGF-B, VEGF-C, and PlGF, which has a high binding affinity to VEGF and a long half-life in vitreous. Preclinical studies have demonstrated its anti-angiogenesis activity in both ocular neovascular disease models and tumor models. Clinical trials of conbercept have shown its superior efficacy and safety. Patients respond well even with 3-month treatment intervals following loading doses once a month for 3 months. The potential therapeutic effect of conbercept on the treatment of polypoidal choroidal vasculopathy, a special type of neovascular AMD, is also promising. In summary, conbercept is a new treatment option for ophthalmologists and their patients and may help address the limitations of current anti-VEGF drugs.

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Section: Introduction To Conberceptmentioning

confidence: 99%

Profile of conbercept in the treatment of neovascular age-related macular degeneration

Lu¹,

Sun²

2015

DDDT

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“…The structural characterization of conbercept was reported not long ago [14]. It is designed as a receptor decoy with high affinity for all VEGF isoforms and PlGF.…”

Section: Introductionmentioning

confidence: 99%

Novel VEGF Decoy Receptor Fusion Protein Conbercept Targeting Multiple VEGF Isoforms Provide Remarkable Anti-Angiogenesis Effect In Vivo

Wang

Wu³

et al. 2013

PLoS ONE

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VEGF family factors are known to be the principal stimulators of abnormal angiogenesis, which play a fundamental role in tumor and various ocular diseases. Inhibition of VEGF is widely applied in antiangiogenic therapy. Conbercept is a novel decoy receptor protein constructed by fusing VEGF receptor 1 and VEGF receptor 2 extracellular domains with the Fc region of human immunoglobulin. In this study, we systematically evaluated the binding affinity of conbercept with VEGF isoforms and PlGF by using anti-VEGF antibody (Avastin) as reference. BIACORE and ELISA assay results indicated that conbercept could bind different VEGF-A isoforms with higher affinity than reference. Furthermore, conbercept could also bind VEGF-B and PlGF, whereas Avastin showed no binding. Oxygen-induced retinopathy model showed that conbercept could inhibit the formation of neovasularizations. In tumor-bearing nude mice, conbercept could also suppress tumor growth very effectively in vivo. Overall, our study have demonstrated that conbercept could bind with high affinity to multiple VEGF isoforms and consequently provide remarkable anti-angiogenic effect, suggesting the possibility to treat angiogenesis-related diseases such as cancer and wet AMD etc.

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“…the native human GLP-1, the analog part of dulaglutide has three sitedirected mutations (A8G, G22E, and R36G), which can improve solubility and increase protection against proteases [4]. Not only small peptide ligands, but also large domains of native protein receptors can be selected to make another type of Fc fusion drugs such as aflibercept, conbercept, etanercept, and so on [12,29]. Unfortunately, the natural partners for a given drug target, either as proteins or as small peptides, are limited in number.…”

Section: Native Ligandsmentioning

confidence: 99%

Molecular Design of Peptide-Fc Fusion Drugs

Lin

Zhou

et al. 2019

CDM

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Peptide-Fc fusion drugs are a category of biological therapeutics in which the Fc region of an antibody is genetically fused to a peptide of interest. In this review, we summarize the key steps in peptide-Fc fusion technology and stress the main computational resources, tools, and methods that have been used in the rational design of peptide-Fc fusion drugs. Additionally, open questions about the computer-aided molecular design of peptide-Fc are raised. Answers to these questions by future research will certainly help make the transition from peptide leads to drugs on the market quicker and cheaper.

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Structural Characterization of a Recombinant Fusion Protein by Instrumental Analysis and Molecular Modeling

Cited by 51 publications

References 46 publications

Profile of conbercept in the treatment of neovascular age-related macular degeneration

Profile of conbercept in the treatment of neovascular age-related macular degeneration

Novel VEGF Decoy Receptor Fusion Protein Conbercept Targeting Multiple VEGF Isoforms Provide Remarkable Anti-Angiogenesis Effect In Vivo

Molecular Design of Peptide-Fc Fusion Drugs

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Structural Characterization of a Recombinant Fusion Protein by Instrumental Analysis and Molecular Modeling

Cited by 51 publications

References 46 publications

Profile of conbercept in the treatment of&nbsp;neovascular age-related macular degeneration

Profile of conbercept in the treatment of&nbsp;neovascular age-related macular degeneration

Novel VEGF Decoy Receptor Fusion Protein Conbercept Targeting Multiple VEGF Isoforms Provide Remarkable Anti-Angiogenesis Effect In Vivo

Molecular Design of Peptide-Fc Fusion Drugs

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Product

Resources

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Profile of conbercept in the treatment of neovascular age-related macular degeneration

Profile of conbercept in the treatment of neovascular age-related macular degeneration