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Preclinical evaluation of MORAb-009, a chimeric antibody targeting tumor-associated mesothelin
Raffit Hassan1, Wolfgang Ebel, Eric L Routhier
1Morphotek Inc., 210 Welsh Pool Road, Exton, PA, USA.
Abstract:
Novel therapeutic agents that are safe and effective are needed for the treatment of pancreatic, ovarian, lung adenocarcinomas and mesotheliomas. Mesothelin is a glycosyl-phosphatidyl inositol (GPI)-linked membrane protein of 40 kDa over-expressed in all pancreatic adenocarcinoma and mesothelioma, in >70% of ovarian adenocarcinoma, and in non-small cell lung and colorectal cancers. The biological functions of mesothelin are not known, although it appears to be involved in cell adhesion via its interaction with MUC16. We have recently developed MORAb-009, a mouse-human chimeric IgG1kappa monoclonal antibody with an affinity of 1.5 nM for human mesothelin. Here we provide evidence that MORAb-009 prevents adhesion of mesothelin-bearing tumor cells to MUC16 positive cells and can elicit cell-mediated cytotoxicity on mesothelin-bearing tumor cells. Treatment that included MORAb-009 in combination with chemotherapy led to a marked reduction in tumor growth of mesothelin-expressing tumors in nude mice compared to chemotherapy or MORAb-009 treatment alone. No adverse effects of MORAb-009 were noted during toxicology studies conducted in non-human primates. The preclinical data obtained from our studies warrants pursuing clinical testing of MORAb-009. We have in fact initiated a Phase I clinical study enrolling patients with mesothelin-positive pancreatic, mesothelioma, non-small cell lung and ovarian cancers.
Insights
A new antibody, MORAb-009, targets mesothelin, a protein overexpressed in pancreatic, ovarian, lung cancers, and mesothelioma. MORAb-009 shows promise in reducing tumor growth and is advancing to clinical trials.
Area of Science:
- Oncology
- Immunotherapy
- Molecular Biology
Background:
- Novel therapeutic agents are needed for pancreatic, ovarian, lung adenocarcinomas, and mesotheliomas.
- Mesothelin is a cell surface protein overexpressed in these cancers.
- Mesothelin's role in cell adhesion via MUC16 interaction is being investigated.
Purpose of the Study:
- To evaluate the efficacy and safety of MORAb-009, a monoclonal antibody targeting mesothelin.
- To assess MORAb-009's ability to inhibit tumor cell adhesion and induce cytotoxicity.
- To determine the therapeutic potential of MORAb-009 in combination with chemotherapy.
Main Methods:
- Development of MORAb-009, a mouse-human chimeric IgG1kappa monoclonal antibody against human mesothelin.
- In vitro studies assessing MORAb-009's effect on mesothelin-MUC16 cell adhesion and cell-mediated cytotoxicity.
- In vivo studies in nude mice evaluating tumor growth reduction with MORAb-009 and chemotherapy.
- Toxicology studies in non-human primates.
Main Results:
- MORAb-009 demonstrated an affinity of 1.5 nM for human mesothelin.
- MORAb-009 prevented adhesion of mesothelin-bearing tumor cells to MUC16-positive cells.
- MORAb-009 elicited cell-mediated cytotoxicity against mesothelin-bearing tumor cells.
- Combination treatment of MORAb-009 and chemotherapy significantly reduced tumor growth in vivo.
- No adverse effects were observed in toxicology studies.
Conclusions:
- MORAb-009 is a promising therapeutic agent for mesothelin-expressing cancers.
- Preclinical data support the clinical testing of MORAb-009.
- A Phase I clinical study is underway for patients with mesothelin-positive cancers.
