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مقاله Abstract


Title: Designing msFLT1.0 protein with use of Rational Protein engineering: Improves the potential of VEGF neutralization for inhibiting Neovascular Age-Related Macular Degeneration
Author(s): Edris Rezaei, Mehdi Sadeghi, Zahra-soheila soheili, sepideh taghizadeh
Presentation Type: Poster
Subject: Physiology/Pharmacology
Others:
Presenting Author:
Name: Edris Rezaei
Affiliation :(optional) National Institute of Genetic Engineering and Biotechnology
E mail: edrisrezaei.88@ut.ac.ir
Phone: 021- 66924113
Mobile: 09181707379
Purpose:

Vascular endothelial growth factor performs a critical role in pathological neovascularization, which is a key component of diseases such as the wet form of age-related macular degeneration, proliferative diabetic retinopathy, and cancer. One of the most potent naturally occurring VEGF binders is VEGF receptor Flt-1. The majority of potent new biologics today are IgG-based molecules that have demonstrated tissue-targeting specificity with the favorable clinical response. Several factors determine the efficacy of these products, including target specificity, serum half-life, and effector functions via complement dependent cytotoxicity, antibody-dependent cell-mediated cytotoxicity or drug conjugates. We previously generated chimeric VEGF-binding molecule, sFLT01 by using bioinformatics analysis and molecular methods.

Methods:

To improve the neutralization ability of the anti-VEGF chimeric protein, we used Dezyme and MAESTRO for fast in silico mutagenesis of protein-protein complexes and examined the effects of mutations on half-life and stability msFLT1.0 protein. The free energy differences between the wild type and mutants were evaluated from a thermodynamic stability prediction upon mutation model. Gene splicing by overlap extension (SOEing) was used for variant T221Q/M348L in the sFLT01, then evaluated the pharmacokinetic properties of variant T221Q/M348L with ELISA assay. We demonstrated the anti-angiogenic function of manipulated hRPEs conditioned media by in vitro angiogenesis method.

Results:

Software analysis demonstrated that msFLT1.0 was in an excellent accordance with its natural counterparts based on its tertiary structure.Western blotting data showed expression secretion of msFLT1.0 into the culture medium of hRPE transfected cells. In vitro, angiogenesis assay results showed a decreased potential of tube formation in conditioned medium of treated hRPE cultures. the results of ELISA assay displayed an increases binding affinity to FcRn at pH 6 and negligible binding to FcRn at pH 7.4. , also exhibited an increases exposure and half-life compared with sFLT01 wild type.

Conclusion:

These results suggest that, if proven to be clinically safe and effective, a modified version of msFLT1.0 could potentially provide clinical benefits to patients for its long-lasting effects, anti-VEGF therapy through less-frequent dosing and improved compliance with drug therapy.

Attachment: 79sample.pptx





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