A novel human monoclonal antibody that binds with high affinity to mesothelin-expressing cells and kills them by antibody-dependent cell-mediated cytotoxicity
- 1 May 2009
- journal article
- Published by American Association for Cancer Research (AACR) in Molecular Cancer Therapeutics
- Vol. 8 (5), 1113-1118
- https://doi.org/10.1158/1535-7163.mct-08-0945
Abstract
Mesothelin is a potential new target for cancer immunotherapy because it is present at relatively low levels only in mesothelial cells of pleura, peritoneum, and pericardium of healthy people, but is significantly elevated in a number of tumors, including mesothelioma, ovarian, pancreatic, and lung cancers. However, all currently available antibodies against mesothelin are either murine or chimeric, which could limit their use because of increased likelihood of immunogenicity compared with fully human antibodies. Here, we report the identification and characterization of a novel fully human monoclonal antibody, m912, which was isolated from a human Fab library by panning against recombinant mesothelin. This antibody in scFv, Fab, and IgG1 formats bound specifically and with high affinity (equilibrium dissociation constant in the nmol/L range) to cell surface-associated human mesothelin and to recombinant mesothelin. It specifically lysed cancer cells engineered to express mesothelin in the presence of peripheral blood mononuclear cells isolated from healthy donors most likely by antibody-dependent cellular cytotoxicity. M912 is the first reported fully human monoclonal antibody to mesothelin, which has potential for cancer treatment and diagnosis. [Mol Cancer Ther 2009;8(5):1113–8]Keywords
This publication has 23 references indexed in Scilit:
- Construction of a Large Naïve Human Phage-Displayed Fab Library Through One-Step CloningPublished by Springer Science and Business Media LLC ,2008
- Localization of Mesothelin in Epithelial Ovarian CancerApplied Immunohistochemistry & Molecular Morphology, 2005
- Mesothelin-specific CD8+ T Cell Responses Provide Evidence of In Vivo Cross-Priming by Antigen-Presenting Cells in Vaccinated Pancreatic Cancer PatientsThe Journal of Experimental Medicine, 2004
- MesothelinClinical Cancer Research, 2004
- Binding of Ovarian Cancer Antigen CA125/MUC16 to Mesothelin Mediates Cell AdhesionPublished by Elsevier BV ,2004
- Mesothelin is overexpressed in the vast majority of ductal adenocarcinomas of the pancreas: Identification of a new pancreatic cancer marker by serial analysis of gene expression (SAGE)2001
- Analysis of cloned Fvs from a phage display library indicates that DNA immunization can mimic antibody response generated by cell immunizationsJournal of Immunological Methods, 1999
- Isolation of a high-affinity stable single-chain Fv specific for mesothelin from DNA-immunized mice by phage display and construction of a recombinant immunotoxin with anti-tumor activityProceedings of the National Academy of Sciences of the United States of America, 1998
- Molecular cloning of mesothelin, a differentiation antigen present on mesothelium, mesotheliomas, and ovarian cancers.Proceedings of the National Academy of Sciences of the United States of America, 1996
- Isolation and characterization of a monoclonal antibody, K1, reactive with ovarian cancers and normal mesotheliumInternational Journal of Cancer, 1992