A novel human monoclonal antibody that binds with high affinity to mesothelin-expressing cells and kills them by antibody-dependent cell-mediated cytotoxicity.
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.
Feng
Yang
Y
Protein Interactions Group, Center for Cancer Research Nanobiology Program, National Cancer Institute-Frederick, NIH, Frederick, Maryland 21702-1201, USA. yfeng@ncifcrf.gov
Xiao
Xiaodong
X
Zhu
Zhongyu
Z
Streaker
Emily
E
Ho
Mitchell
M
Pastan
Ira
I
Dimitrov
Dimiter S
DS
D000911:Antibodies, Monoclonal / Q000276:immunology* / Q000378:metabolism / Q000494:pharmacology*; D000915:Antibody Affinity / Q000276:immunology*; D000920:Antibody-Dependent Cell Cytotoxicity / Q000276:immunology*; D000951:Antigens, Neoplasm / Q000235:genetics / Q000302:isolation & purification / Q000378:metabolism; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects*; D058851:GPI-Linked Proteins / Q000235:genetics* / Q000302:isolation & purification / Q000378:metabolism*; D057809:HEK293 Cells; D006801:Humans; D007167:Immunotherapy; D000090204:Mesothelin; D009369:Neoplasms / Q000276:immunology; D011485:Protein Binding / Q000276:immunology
D000911:Antibodies, Monoclonal; D000951:Antigens, Neoplasm; D058851:GPI-Linked Proteins; D000090204:Mesothelin