Targeting c-Met for therapy

c-Met is a tyrosine receptor kinase which is activated by its only ligand, the hepatocyte growth factor (HGF). Activation of c-Met leads to a wide spectrum of biological activities such as motility, angiogenesis, morphogenesis, cell survival and cell regeneration. c-Met and HGF knock-out mice are embryonic lethal. During embryogenesis, c-Met is required for liver, kidney and skeletal muscles development. In adult tissues, c-Met is involved in wound healing and hepatocyte regeneration. c-Met is abnormally activated in many tumours types. Aberrant c-Met activation was found to induce tumour development, tumour cell migration and invasion, and the worst and final step in cancer progression, metastasis. In addition, c-Met activation in cells was also shown to confer resistance to apoptosis induced by UV damage or chemotherapeutic drugs. c-Met is thus an attractive target for drug development. This study describes the development of monoclonal antibodies against c-Met as therapeutic molecules in cancer treatment/diagnostics. Antibodies were raised against the a-chain of c-Met. 21 hybridoma clones were single-cell cloned and subjected to preliminary monoclonal antibody characterisation. 11 monoclonal antibodies were finally selected for ascites production and antibody purification. These purified antibodies were characterised by Western blotting, immunofluorescence staining, functional assays (ERK phosphorylation and cell scatter) and for their ability to recognise native c-Met by flow cytometry. Some of the anti-a-chain c-Met antibodies perform better in Western blotting and immunofluorescence staining than the presently-available commercial antibodies. The Mab 2.1 and 13.1 bind strongly to native c-Met in flow cytometry and may be potential candidates for antibody therapy and cancer diagnostics.

Name dc:type.qualificationname

Doctor of Philosophy

Level dc:type.qualificationlevel

Doctoral Thesis

Grantor dc:publisher.institution

University of Dundee

Year dc:date.issued

2011

Author dc:creator

• Wong, Julin

• c-Met
• Antibodies
• HGFR

Language dc:language

eng

Identifier

oai:discovery.dundee.ac.uk:studenttheses/a670d71d-758a-48b2-aa5b-2255b2373d7e

OAI identifier oai:identifier

oai:discovery.dundee.ac.uk:studenttheses/a670d71d-758a-48b2-aa5b-2255b2373d7e