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New high affinity monoclonal antibodies recognize non-overlapping epitopes on mesothelin for monitoring and treating mesothelioma.

Zhang YF, Phung Y, Gao W, Kawa S, Hassan R, Pastan I, Ho M - Sci Rep (2015)

Bottom Line: These antibodies do not compete for mesothelin binding with the immunotoxin SS1P that binds Region I of mesothelin.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.

View Article: PubMed Central - PubMed

Affiliation: Laboratory of Molecular Biology, Center for Cancer Research, National Cancer Institute, Bethesda, Bethesda, MD 20892, United States.

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.

No MeSH data available.


Related in: MedlinePlus

Immunohistochemistry with patient mesothelioma tissue sections stained with either an isotype control antibody or the anti-mesothelin antibody as indicated.
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f3: Immunohistochemistry with patient mesothelioma tissue sections stained with either an isotype control antibody or the anti-mesothelin antibody as indicated.

Mentions: Mesothelin has been used as a tissue marker for mesothelioma and other cancers7. To evaluate potential use of the new mAbs in immunohistochemistry, fixed patient mesothelioma tissue was stained with YP187, YP223, YP218 and YP3 at an antibody concentration of 0.1 μg ml−1 or less (Fig. 3). The staining of tumor tissues was very strong and highly specific. The tumor cell membranes stained more strongly than the cytoplasm and there was no obvious staining in the nucleus. Collectively, these new antibodies are highly specific for tumor tissues, indicating that they are suitable for immunodiagnostics.


New high affinity monoclonal antibodies recognize non-overlapping epitopes on mesothelin for monitoring and treating mesothelioma.

Zhang YF, Phung Y, Gao W, Kawa S, Hassan R, Pastan I, Ho M - Sci Rep (2015)

Immunohistochemistry with patient mesothelioma tissue sections stained with either an isotype control antibody or the anti-mesothelin antibody as indicated.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4440525&req=5

f3: Immunohistochemistry with patient mesothelioma tissue sections stained with either an isotype control antibody or the anti-mesothelin antibody as indicated.
Mentions: Mesothelin has been used as a tissue marker for mesothelioma and other cancers7. To evaluate potential use of the new mAbs in immunohistochemistry, fixed patient mesothelioma tissue was stained with YP187, YP223, YP218 and YP3 at an antibody concentration of 0.1 μg ml−1 or less (Fig. 3). The staining of tumor tissues was very strong and highly specific. The tumor cell membranes stained more strongly than the cytoplasm and there was no obvious staining in the nucleus. Collectively, these new antibodies are highly specific for tumor tissues, indicating that they are suitable for immunodiagnostics.

Bottom Line: These antibodies do not compete for mesothelin binding with the immunotoxin SS1P that binds Region I of mesothelin.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.

View Article: PubMed Central - PubMed

Affiliation: Laboratory of Molecular Biology, Center for Cancer Research, National Cancer Institute, Bethesda, Bethesda, MD 20892, United States.

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.

No MeSH data available.


Related in: MedlinePlus