Antibodies to the MET receptor for cancer therapy
Lead Research Organisation:
University of Cambridge
Department Name: Oncology
Abstract
The most important cause of death in patients with cancer is the migration of cancer cells away from the primary tumour and the emergence of secondary tumours at distance sites in the body, a process called metastasis. At present there are very few effective treatments for metastatic cancer. In this project we aim to develop a therapeutic antibody to MET, a protein critical for initiating the migration of cancer cells. We have made progress in understanding the architecture and the three-dimensional structure of MET and, through the technology available in the laboratories of our Industrial Partner UCB-Celltech, we have a strong prospect of developing an antibody that can block the activity of MET in tumour cells and with potential for the treatment of metastatic cancer.
Technical Summary
The growth of tumours at distant sites (metastasis) is the process responsible for over 90% of cancer deaths. Yet, the therapy of metastatic cancer has witnessed little progress over the last 20-30 years.
This application focuses on MET, the receptor for the cell motility factor HGF/SF and a key target for the therapy of invasive and metastatic cancer. HGF/SF is secreted by cells in the tumour stroma and causes cancer cells expressing MET to dissociate from neighbours, acquire a highly motile phenotype and initiate invasion. The key outcome of MET signalling, therefore, is the migration of cancer cells at a distance from the primary tumour reaching the local lymphatic or blood capillaries where they progress to the later stages of metastasis.
This proposal is for a collaborative project between the Growth Factors Group at the MRC in Cambridge and the Oncology NBE Group at UCB-Celltech with the aim of using MET antibodies to aid in the understanding of the structural interactions involved in the receptor activiation and hence potentially the identification of therapeutic agents with a novel mechanism. The proposal builds on complementary strengths and expertises in the two participating laboratories and has the potential of yielding therapeutic antibodies superior to those currently in development elsewhere. Specifically, the group at the MRC in Cambridge has defined the domain structure of extracellular MET, expressed and characterised the six constituent protein domains and crystallised two such fragments. Several of these recombinant MET fragments will be used at UCB-Celltech for selection of MET-specific mouse antibodies using a proprietary, high-throughput B cell screening technology known as the Selected Lymphocyte Antibody Method (SLAM). Antibodies with blocking activity will be identified using sensitive cell reporter assays developed at the MRC laboratory and used for co-crystallisation experiments with the relevant MET fragments. Finally, knowledge of antibody-MET binding from the co-crystal structure will provide the basis for site-directed mutagenesis and affinity maturation experiments.
This application focuses on MET, the receptor for the cell motility factor HGF/SF and a key target for the therapy of invasive and metastatic cancer. HGF/SF is secreted by cells in the tumour stroma and causes cancer cells expressing MET to dissociate from neighbours, acquire a highly motile phenotype and initiate invasion. The key outcome of MET signalling, therefore, is the migration of cancer cells at a distance from the primary tumour reaching the local lymphatic or blood capillaries where they progress to the later stages of metastasis.
This proposal is for a collaborative project between the Growth Factors Group at the MRC in Cambridge and the Oncology NBE Group at UCB-Celltech with the aim of using MET antibodies to aid in the understanding of the structural interactions involved in the receptor activiation and hence potentially the identification of therapeutic agents with a novel mechanism. The proposal builds on complementary strengths and expertises in the two participating laboratories and has the potential of yielding therapeutic antibodies superior to those currently in development elsewhere. Specifically, the group at the MRC in Cambridge has defined the domain structure of extracellular MET, expressed and characterised the six constituent protein domains and crystallised two such fragments. Several of these recombinant MET fragments will be used at UCB-Celltech for selection of MET-specific mouse antibodies using a proprietary, high-throughput B cell screening technology known as the Selected Lymphocyte Antibody Method (SLAM). Antibodies with blocking activity will be identified using sensitive cell reporter assays developed at the MRC laboratory and used for co-crystallisation experiments with the relevant MET fragments. Finally, knowledge of antibody-MET binding from the co-crystal structure will provide the basis for site-directed mutagenesis and affinity maturation experiments.