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Pan chemokine inhibitors : from viral natural solutions to engineered antibodies

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Defense Thèse de doctorat : Univ. Genève, 2011 - Sc. 4308 - 2011/04/08
Abstract Chemokines play a key role in the trafficking of leukocytes both under homeostatic and inflammatory conditions. Due to the complexity of the chemokine signaling system, blocking only one chemokine may be insufficient to antagonize a biological mechanism. Viruses have evolved different strategies in order to efficiently interfere with the chemokine network. They express chemokine-binding proteins such as the soluble secreted vaccinia virus encoded inhibitor (vCCI) that specifically binds with high affinity to a large panel of CC chemokines. We generated a human IgG1 Fc fusion to vCCI and demonstrated that vCCI-Fc was effective in reducing the evolution of the disease score in a Collagen Induced Arthritis animal model. Despite its therapeutic effect, vCCI-Fc was immunogenic thus limiting its use for chronic indications. We therefore explored the possibility of engineering similar cross-reactive molecules using a more suitable antibody format. Using a panel of phage display selection strategies, we isolated cross-reactive antibody fragments (scFv) against both CXC and CC chemokines. In addition, the specificity and neutralizing potential of scFv candidates could be further enhanced by in vitro evolution approaches. It is therefore possible to engineer pan-specific antibodies, challenging the old concept "one antibody, one specificity".
Keywords ChemokineVCCICross-reactive antibodyScFvPhage displayAffinity maturationEpitope mappingChemotaxis
Stable URL http://archive-ouverte.unige.ch/unige:15959
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URN: urn:nbn:ch:unige-159591
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Research group NovImmune

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Deposited on : 2011-05-31

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