title: New high affinity monoclonal antibodies recognize non-overlapping epitopes on mesothelin for monitoring and treating mesothelioma.
abstract: Mesothelin is an emerging cell surface target in mesothelioma and other solid tumors. Most antibody drug candidates recognize highly immunogenic Region I (296-390) on mesothelin. Here, we report a group of high-affinity non-Region I rabbit monoclonal antibodies. These antibodies do not compete for mesothelin binding with the immunotoxin SS1P that binds Region I of mesothelin. One pair of antibodies (YP218 and YP223) is suitable to detect soluble mesothelin in a sandwich ELISA with high sensitivity. The new assay can also be used to measure serum mesothelin concentration in mesothelioma patients, indicating its potential use for monitoring patients treated with current antibody therapies targeting Region I. The antibodies are highly specific and sensitive in immunostaining of mesothelioma. To explore their use in tumor therapy, we have generated the immunotoxins based on the Fv of these antibodies. One immunotoxin (YP218 Fv-PE38) exhibits potent anti-tumor cytotoxicity towards primary mesothelioma cell lines in vitro and an NCI-H226 xenograft tumor in mice. Furthermore, we have engineered a humanized YP218 Fv that retains full binding affinity for mesothelin-expressing cancer cells. In conclusion, with their unique binding properties, these antibodies may be promising candidates for monitoring and treating mesothelioma and other mesothelin-expressing cancers.
authors.affiliation: Laboratory of Molecular Biology, Center for Cancer Research, National Cancer Institute, Bethesda, Bethesda, MD 20892, United States.
authors.forename: Yi-Fan
authors.initials: YF
authors.lastname: Zhang
authors.affiliation: Laboratory of Molecular Biology, Center for Cancer Research, National Cancer Institute, Bethesda, Bethesda, MD 20892, United States.
authors.forename: Yen
authors.initials: Y
authors.lastname: Phung
authors.affiliation: Laboratory of Molecular Biology, Center for Cancer Research, National Cancer Institute, Bethesda, Bethesda, MD 20892, United States.
authors.forename: Wei
authors.initials: W
authors.lastname: Gao
authors.affiliation: Laboratory of Molecular Biology, Center for Cancer Research, National Cancer Institute, Bethesda, Bethesda, MD 20892, United States.
authors.forename: Seiji
authors.initials: S
authors.lastname: Kawa
authors.affiliation: Thoracic and Gastrointestinal Oncology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, United States.
authors.forename: Raffit
authors.initials: R
authors.lastname: Hassan
authors.affiliation: Laboratory of Molecular Biology, Center for Cancer Research, National Cancer Institute, Bethesda, Bethesda, MD 20892, United States.
authors.forename: Ira
authors.initials: I
authors.lastname: Pastan
authors.affiliation: Laboratory of Molecular Biology, Center for Cancer Research, National Cancer Institute, Bethesda, Bethesda, MD 20892, United States.
authors.forename: Mitchell
authors.initials: M
authors.lastname: Ho
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000627:therapeutic use*; D061067:Antibodies, Monoclonal, Humanized / Q000276:immunology / Q000627:therapeutic use; D045744:Cell Line, Tumor; D004797:Enzyme-Linked Immunosorbent Assay; D000939:Epitopes / Q000276:immunology*; D058851:GPI-Linked Proteins / Q000097:blood / Q000378:metabolism*; D006801:Humans; D007150:Immunohistochemistry; D000090204:Mesothelin; D008654:Mesothelioma / Q000175:diagnosis / Q000188:drug therapy*; D051379:Mice; D008819:Mice, Nude; D011817:Rabbits; D057127:Single-Chain Antibodies / Q000235:genetics / Q000378:metabolism; D014183:Transplantation, Heterologous
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000939:Epitopes; D058851:GPI-Linked Proteins; C000715528:Msln protein, mouse; D057127:Single-Chain Antibodies; D000090204:Mesothelin