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Understanding structural/functional properties of immunoconjugates for cancer therapy by computational approaches

TitleUnderstanding structural/functional properties of immunoconjugates for cancer therapy by computational approaches
Publication TypeArticolo su Rivista peer-reviewed
Year of Publication2008
AuthorsArcangeli, Caterina, Cantale Cristina, Galeffi Patrizia, Gianese G., Paparcone R., and Rosato V.
JournalJournal of Biomolecular Structure and Dynamics
Volume26
Pagination35-47
ISSN07391102
KeywordsAmino Acid, Amino Acid Sequence, antibody conjugate, article, Bacteria (microorganisms), bacterial toxin, Biology, Cancer therapy, Cancer Vaccines, computer model, Computer simulation, drug carrier, epidermal growth factor receptor 2, erbB-2, Exotoxins, Humans, Hydrogen Bonding, Immunoconjugates, molecular dynamics, Molecular Sequence Data, Neoplasms, physical chemistry, priority journal, Protein Structure, Receptor, Recombinant Fusion Proteins, Secondary, sequence homology, simulation, structure analysis
Abstract

Monoclonal antibodies coupled to highly toxic molecules (immunoconjugates) are currently being developed for cancer therapy. We have used an in silico procedure for evaluating some physicochemical properties of two tumor-targeting anti-HER2 immunoconjugates: (a) the single-chain antibody scFv(FRP5) linked to a bacterial toxin, that has been recently progressed to phase I clinical trial in human cancer; (b) the putative molecule formed by the intrinsically stable scFv(800E6), which has been proposed as toxin carrier to cancer cells in human therapy, joined to the same toxin of (a). Structural models of the immunoconjugates have been built by homology modeling and assessed by molecular dynamics simulations. The trajectories have been analyzed to extract some biochemical properties and to assess the potential effects of the toxin on the structure and dynamics of the anti-HER2 antibodies. The results of the computational approach indicate that the antibodies maintain their correct folding even in presence of the toxin, whereas a certain stiffness in correspondence of some structural regions is observed. Furthermore, the toxin does not seem to affect the antibody solubility, whereas it enhances the structural stability. The proposed computational approach represent a promising tool for analyzing some physicochemical properties of immunoconjugates and for predicting the effects of the linked toxin on structure, dynamics, and functionality of the antibodies. ©Adenine Press (2008).

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URLhttps://www.scopus.com/inward/record.uri?eid=2-s2.0-47849108562&partnerID=40&md5=a4a290de82bbc81ab577b13ade365b9f
Citation KeyArcangeli200835