New High Affinity Monoclonal Antibodies Recognize Non-Overlapping Epitopes On Mesothelin For Monitoring And Treating Mesothelioma

By Yi-Fan Zhang, Yen Phung, Wei Gao, S. Kawa, R. Hassan, I. Pastan, Mitchell Ho. 2015

56 citations recorded by the source corpus.

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.

Subfields: Artificial Intelligence

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Citations in the corpus

• Hitting the Bull’s-Eye: Mesothelin’s Role as a Biomarker and Therapeutic Target for Malignant Pleural Mesothelioma (2021, background): “The extracellular domain of MSLN comprises region I (N-terminal region; residues 296–390), II (residues 391–486), and III (C-terminal region; residues 487–598) [87].”
• Targeting a membrane-proximal epitope on mesothelin increases the tumoricidal activity of a bispecific antibody blocking CD47 on mesothelin-positive tumors (2020, background): “AMSLNmembrane proximal targeted immunotoxin (YP218) has been reported to have potent tumoricidal activities in solid tumors.(39) In addition, by comparing two types of CAR-T cells targeting either the region-I or the region-III ofMSLN, Qian and colleagues demonstrated recently that the membrane-prox”