Novel monoclonal antibodies targeting conformational ERBB2 epitopes

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buir.advisorÖztürk, Mehmet
dc.contributor.authorCeran, Ceyhan
dc.date.accessioned2016-01-08T18:19:25Z
dc.date.available2016-01-08T18:19:25Z
dc.date.issued2012
dc.departmentDepartment of Molecular Biology and Geneticsen_US
dc.descriptionAnkara : The Department of Molecular Biology and Genetics and the Graduate School of Engineering and Science of Bilkent University, 2012.en_US
dc.descriptionThesis (Ph. D.) -- Bilkent University, 2012.en_US
dc.descriptionIncludes bibliographical references leaves 169-198.en_US
dc.description.abstractERBB2 is a tyrosine kinase receptor which can act as homodimers or heterodimers with other members of the ERBB family. Nearly 30% of breast cancers overexpress ERBB2, which can be effectively targeted by anti-ERBB2 monoclonal antibodies. Trastuzumab directed against an epitope on subdomain IV of the extracellular domain (ECD) of ERBB2 is a clinically used therapeutics but the response rate is poor and acquired resistance is frequent. Pertuzumab that binds to subdomain II and inhibits receptor dimerization is another promising therapeutics under clinical trials. Anti-ERBB2 antibodies directed to novel epitopes are potentially useful tools for replacement and combinatorial therapies. We produced five new anti-ERBB2 antibodies, all directed against epitope(s) present only on the native ECD. They performed selective growth inhibitory effects depending on the level of ERBB2 expression and cellular background. When used alone, novel anti-ERBB2 antibodies displayed modest but significant growth inhibition on SK-BR-3, BT-474 and MDA-MB-361 cells with ERBB2 overexpression; while no detectable inhibition was observed on MCF-7 and T47D cells lacking ERBB2 amplification. When the antibodies were tested in combination with TNF-α, they acted synergistically on SK-BR-3 cells, producing upto 80% growth inhibition; but performed antagonistically on BT-474 cells. Detailed investigation of a representative antibody indicated G1-arrest as the main mechanism of the anti-proliferative effects exerted on SK-BR-3 cells. Antibody treatment induced permanent inhibition of DNA synthesis, leading to accumulation of cells at G1-phase; an effect which was accelerated in the presence of TNF-α. In addition, treated SK-BR-3 cells displayed inhibition of Akt and ERK1/2 phosphorylation leading to cyclin D1 accumulation and growth arrest, independently from TNF-α. Novel antibodies against conformational epitopes present on the extracellular domain of ERBB2 receptor may serve as new analytical and diagnostic tools, in addition to being potent anti-cancer bioactive molecules. Cell-dependent synergy and antagonism between anti-ERBB2 antibodies and TNF-α provide evidence for a complex interplay between ERBB2 and TNF-α signaling pathways. Such complexity may drastically affect the outcome of ERBB2-directed therapeutic interventions.en_US
dc.description.degreePh.D.en_US
dc.description.statementofresponsibilityCeran, Ceyhanen_US
dc.format.extentxx, 233 leaves, illustrationsen_US
dc.identifier.urihttp://hdl.handle.net/11693/15494
dc.language.isoEnglishen_US
dc.publisherBilkent Universityen_US
dc.rightsinfo:eu-repo/semantics/openAccessen_US
dc.subject.lccQW575.5.A6 C47 2012en_US
dc.subject.lcshMonoclonal antibodies.en_US
dc.subject.lcshAntibodies, Monoclonal.en_US
dc.subject.lcshImmunoglobulin genes.en_US
dc.subject.lcshGene expression.en_US
dc.subject.lcshAntibodies--genetics.en_US
dc.subject.lcshBreast cancer.en_US
dc.titleNovel monoclonal antibodies targeting conformational ERBB2 epitopesen_US
dc.typeThesisen_US

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