%0 Journal Article %1 ISI:000257768600004 %A Arcangeli, Caterina %A Cantale, Cristina %A Galeffi, Patrizia %A Gianese, Giulio %A Paparcone, Raffaella %A Rosato, Vittorio %C 2066 CENTRAL AVE, SCHENECTADY, NY 12304 USA %D 2008 %I ADENINE PRESS %J JOURNAL OF BIOMOLECULAR STRUCTURE & DYNAMICS %K analysis antibody cancer chain computational dynamics engineered function immunoconjugates molecular of protein simulation single structure studies therapy %N 1 %P 35-47 %T Understanding structural/functional properties of immunoconjugates for cancer therapy by computational approaches %V 26 %X 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.

@article{ISI:000257768600004, 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.}}, added-at = {2009-01-04T02:15:28.000+0100}, address = {{2066 CENTRAL AVE, SCHENECTADY, NY 12304 USA}}, affiliation = {{Arcangeli, C (Reprint Author), ENEA Casaccia Res Ctr, Comp \& Modeling Unit, Via Anguillarese 301, I-00123 Santa Maria Di Galeria, Italy. {[}Arcangeli, Caterina; Rosato, Vittorio] ENEA Casaccia Res Ctr, Comp \& Modeling Unit, I-00123 Santa Maria Di Galeria, Italy. {[}Cantale, Cristina; Galeffi, Patrizia] ENEA Casaccia Res Ctr, Biotechnol Unit, I-00123 Santa Maria Di Galeria, Italy.}}, author = {Arcangeli, Caterina and Cantale, Cristina and Galeffi, Patrizia and Gianese, Giulio and Paparcone, Raffaella and Rosato, Vittorio}, author-email = {{caterina.arcangeli@casaccia.enea.it}}, biburl = {https://www.bibsonomy.org/bibtex/26332214d75e5d4277abbf04615a7ca11/huiyangsfsu}, cited-references = {{ADAMS GP, 2005, NAT BIOTECHNOL, V23, P1147, DOI 10.1035/nbt1137. 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VANDERSPOEL D, 2005, J COMPUT CHEM, V26, P1701, DOI 10.1002/jcc.20291. VONMINCKWITZ G, 2005, BREAST CANCER RES, V7, R617, DOI 10.1186/bcr1264. VOORDIJK S, 2000, J MOL BIOL, V300, P963. WELS W, 1992, CANCER RES, V52, P6310. WISHART DS, 2005, DRUG METAB REV, V37, P279, DOI 10.1081/DMR-200055225. WU AM, 2005, NAT BIOTECHNOL, V23, P1137, DOI 10.1038/nbt1141.}}, doc-delivery-number = {{328AC}}, interhash = {827348cc66454c4ea928bfe7f2d5d914}, intrahash = {6332214d75e5d4277abbf04615a7ca11}, issn = {{0739-1102}}, journal = {{JOURNAL OF BIOMOLECULAR STRUCTURE \& DYNAMICS}}, journal-iso = {{J. Biomol. Struct. Dyn.}}, keywords = {analysis antibody cancer chain computational dynamics engineered function immunoconjugates molecular of protein simulation single structure studies therapy}, keywords-plus = {{MOLECULAR-DYNAMICS; ANTIBODY-TOXIN; ERBB-2 RECEPTOR; PROTEINS; CHAIN; SIMULATIONS; DOMAIN; THERAPEUTICS; RECOGNITION; ALIGNMENTS}}, language = {{English}}, month = {{AUG}}, number = {{1}}, number-of-cited-references = {{44}}, pages = {{35-47}}, publisher = {{ADENINE PRESS}}, subject-category = {{Biochemistry \& Molecular Biology; Biophysics}}, times-cited = {{0}}, timestamp = {2009-01-04T02:15:28.000+0100}, title = {{Understanding structural/functional properties of immunoconjugates for cancer therapy by computational approaches}}, type = {{Article}}, unique-id = {{ISI:000257768600004}}, volume = {{26}}, year = {{2008}} }