Comparative thermodynamic analysis in solution of a next generation antibody mimetic to VEGF
Article
Khalili, H., Brocchini, Steve, Khaw, Peng Tee and Filippov, Sergey K. 2018. Comparative thermodynamic analysis in solution of a next generation antibody mimetic to VEGF. RSC Advances. 8 (62), pp. 35787-35793. https://doi.org/10.1039/C8RA07059H
Authors | Khalili, H., Brocchini, Steve, Khaw, Peng Tee and Filippov, Sergey K. |
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Abstract | An antibody mimetic known as Fab–PEG–Fab (FpF) is a stable bivalent molecule that may have some potential therapeutic advantages over IgG antibodies due to differences in their binding kinetics as determined by surface plasmon resonance. Here we describe the thermodynamic binding properties to vascular endothelial growth factor (VEGF) of the FpF antibody mimetics derived from bevacizumab and ranibizumab. Bevacizumab is an IgG antibody and ranibizumab is an antibody fragment (Fab). Both are used clinically to target VEGF to inhibit angiogenesis. FpFbeva displayed comparable binding affinity (KD) and binding thermodynamics (ΔH = −25.7 kcal mole−1 and ΔS = 14 kcal mole−1) to bevacizumab (ΔH = −25 kcal mole−1, ΔS = 13.3 kcal mole−1). FpFrani interactions with VEGF were characterised by large favourable enthalpy (ΔH = −42 kcal mole−1) and unfavourable entropy (ΔS = 31 kcal mole−1) changes compared to ranibizumab (ΔH = −18.5 kcal mole−1 and ΔS = 6.7 kcal mole−1), which being a Fab, is mono-valent. A large negative entropy change resulting in binding of bivalent FpF to homodimer VEGF might be due to the conformational change of the flexible regions of the FpF upon ligand binding. Mono-valent Fab (i.e. ranibizumab or the Fab derived from bevacizumab) displayed a larger degree of freedom (smaller unfavourable entropy) upon binding to homodimer VEGF. Our report describes the first comprehensive enthalpy and entropy compensation analysis for FpF antibody mimetics. While the FpFs displayed similar thermodynamics and binding affinity to the full IgG (i.e. bevacizumab), their enhanced protein stability, slower dissociation rate and lack of Fc effector functions could make FpF a potential next-generation therapy for local tissue-targeted indications. |
Journal | RSC Advances |
Journal citation | 8 (62), pp. 35787-35793 |
ISSN | 2046-2069 |
Year | 2018 |
Publisher | Royal Society of Chemistry |
Publisher's version | License |
Digital Object Identifier (DOI) | https://doi.org/10.1039/C8RA07059H |
Web address (URL) | https://doi.org/10.1039/C8RA07059H |
Publication dates | |
Online | 19 Oct 2018 |
Publication process dates | |
Deposited | 22 Oct 2018 |
Accepted | 12 Oct 2018 |
Accepted | 12 Oct 2018 |
Funder | University of East London |
National Institute for Health Research | |
Moorfields Eye Charity | |
Helen Hamlyn Trust in memory of Paul Hamlyn | |
The Michael and Isle Katz Foundation | |
Czech Science Foundation GACR | |
University of East London | |
National Institute for Health Research | |
Moorfields Eye Charity | |
Helen Hamlyn Trust in memory of Paul Hamlyn | |
The Michael and Isle Katz Foundation | |
Czech Science Foundation GACR | |
Copyright information | © 2018 The authors |
License | CC BY 4.0 |
https://repository.uel.ac.uk/item/8462z
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