Biology:Mesothelin

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Short description: Protein found in humans


A representation of the 3D structure of the protein myoglobin showing turquoise α-helices.
Generic protein structure example


Mesothelin, also known as MSLN, is a protein that in humans is encoded by the MSLN gene.[1][2]

Function

Mesothelin is a 40 kDa protein that is expressed in mesothelial cells.[3] The protein was first identified by its reactivity with monoclonal antibody K1.[4] Subsequent cloning studies showed that the mesothelin gene encodes a precursor protein that is processed to yield mesothelin which is attached to the cell membrane by a glycophosphatidylinositol linkage and a 31-kDa shed fragment named megakaryocyte-potentiating factor (MPF). Although it has been proposed that mesothelin may be involved in cell adhesion, its biological function is not known.[5][6] A knockout mouse line that lacks mesothelin reproduces and develops normally.[7]

Mesothelin is over expressed in several human tumors, including mesothelioma, ovarian cancer, pancreatic adenocarcinoma,[3] lung adenocarcinoma,[8] and cholangiocarcinoma.[9] Mesothelin binds MUC16 (also known as CA125), indicating that the interaction of mesothelin and MUC16 may contribute to the implantation and peritoneal spread of tumors by cell adhesion.[10] The region (residues 296-359) consisting of 64 amino acids at the N-terminus of cell surface mesothelin has been identified as the functional binding domain (named IAB) for MUC16/CA125, suggesting the mechanism of mesothelin acting as a MUC16/CA125 functional partner in cancer development.[11] File:Mesothelin.tif

Medical applications

Mesothelin is a tumor differentiation antigen that is normally present on the mesothelial cells lining the pleura,[13] peritoneum and pericardium.[3] Since mesothelin is overexpressed in several cancers and is immunogenic, the protein could be exploited as tumor marker or as the antigenic target of a therapeutic cancer vaccine.[5][14] A 2016 review indicates that some immunotherapeutic strategies have shown encouraging results in early-phase clinical trials.[15] Elevations of serum mesothelin specific to ovarian and other cancer patients may be measured using ELISA assays.[16] Soluble mesothelin is identified as the extracellular domain of membrane-bound mesothelin shed from tumor cells according to the mass spectrometry analysis of soluble mesothelin purified from cell culture supernatant.[17]

Assays for blood-borne mesothelin and MPF for tumor diagnosis, especially applied to asbestos-related mesothelioma have been developed.[18] Elevated serum mesothelin was found in most patients with mesothelioma (71%) and ovarian cancer (67%).[19] Blood MPF and mesothelin levels were correlated, with modest accuracy for malignant pleural mesothelioma and lung cancer (sensitivity 74% and 59%, specificity 90% and 86%, respectively for MPF and mesothelin assays).[20] Circulating mesothelin is reported in nearly all pancreatic cancers,[21] however the levels in healthy persons often exceed 80 ng/mL (using 40 kD molecular weight as the conversion factor) and to widely overlap the values in the pancreatic cancer patients.[22] It was noted that the cutoff levels for normal could differ as much as 10-fold among publications, depending on the assay used[22][20][19] and thus that normal levels must be determined anew when new assays are introduced. Increase of mesothelin-specific antibodies were also detected in the sera of about 40% of patients with mesothelioma and 42% with ovarian cancer, indicating an antibody response to mesothelin was correlated with high expression of mesothelin on tumor cells.[23]

Human monoclonal antibodies HN1 and SD1 targeting mesothelin have been isolated by phage display.[24][25] Mitchell Ho and Ira Pastan at the U.S. National Institutes of Health (NIH) generated rabbit monoclonal antibodies targeting rare and poorly immunogenic epitopes of mesothelin, including the C terminus recognized by the YP218 antibody.[12] The rabbit antibodies have been "humanized" by Ho and Zhang using human immunoglobulin germline framework sequences for CDR grafting based on computational structure modeling.[26] The CAR-T cells derived from the humanized YP218 antibody (hYP218) effectively inhibit the growth of human xenograft tumors in mice.[27][28]

References

  1. ↑ "Molecular cloning and expression of megakaryocyte potentiating factor cDNA". The Journal of Biological Chemistry 270 (37): 21984–21990. September 1995. doi:10.1074/jbc.270.37.21984. PMID 7665620. 
  2. ↑ "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 93 (1): 136–140. January 1996. doi:10.1073/pnas.93.1.136. PMID 8552591. Bibcode: 1996PNAS...93..136C. 
  3. ↑ 3.0 3.1 3.2 "Mesothelin targeted cancer immunotherapy". European Journal of Cancer 44 (1): 46–53. January 2008. doi:10.1016/j.ejca.2007.08.028. PMID 17945478. 
  4. ↑ "Characterization of the antigen (CAK1) recognized by monoclonal antibody K1 present on ovarian cancers and normal mesothelium". Cancer Research 52 (1): 181–186. January 1992. PMID 1727378. 
  5. ↑ 5.0 5.1 "Mesothelin: a new target for immunotherapy". Clinical Cancer Research 10 (12 Pt 1): 3937–3942. June 2004. doi:10.1158/1078-0432.CCR-03-0801. PMID 15217923. 
  6. ↑ "Advances in liver cancer antibody therapies: a focus on glypican-3 and mesothelin". BioDrugs 25 (5): 275–284. October 2011. doi:10.2165/11595360-000000000-00000. PMID 21942912. 
  7. ↑ "Mesothelin is not required for normal mouse development or reproduction". Molecular and Cellular Biology 20 (8): 2902–2906. April 2000. doi:10.1128/MCB.20.8.2902-2906.2000. PMID 10733593. 
  8. ↑ "Mesothelin expression in human lung cancer". Clinical Cancer Research 13 (5): 1571–1575. March 2007. doi:10.1158/1078-0432.CCR-06-2161. PMID 17332303. 
  9. ↑ "Mesothelin as a potential therapeutic target in human cholangiocarcinoma". Journal of Cancer 1: 141–149. October 2010. doi:10.7150/jca.1.141. PMID 20922056. 
  10. ↑ "Binding of ovarian cancer antigen CA125/MUC16 to mesothelin mediates cell adhesion". The Journal of Biological Chemistry 279 (10): 9190–9198. March 2004. doi:10.1074/jbc.M312372200. PMID 14676194. 
  11. ↑ "A binding domain on mesothelin for CA125/MUC16". The Journal of Biological Chemistry 284 (6): 3739–3749. February 2009. doi:10.1074/jbc.M806776200. PMID 19075018. 
  12. ↑ 12.0 12.1 "New high affinity monoclonal antibodies recognize non-overlapping epitopes on mesothelin for monitoring and treating mesothelioma". Scientific Reports 5: 9928. May 2015. doi:10.1038/srep09928. PMID 25996440. Bibcode: 2015NatSR...5E9928Z. 
  13. ↑ "Pilot Study to Evaluate Serum Soluble Mesothelin-Related Peptide (SMRP) as Marker for Clinical Monitoring of Pleural Mesothelioma (PM): Correlation with Modified RECIST Score". Diagnostics 11 (11): 2015. October 2021. doi:10.3390/diagnostics11112015. PMID 34829362. 
  14. ↑ "Mesothelin targeted cancer immunotherapy". European Journal of Cancer 44 (1): 46–53. January 2008. doi:10.1016/j.ejca.2007.08.028. PMID 17945478. 
  15. ↑ "Mesothelin-Targeted CARs: Driving T Cells to Solid Tumors". Cancer Discovery 6 (2): 133–146. February 2016. doi:10.1158/2159-8290.CD-15-0583. PMID 26503962. 
  16. ↑ "Soluble member(s) of the mesothelin/megakaryocyte potentiating factor family are detectable in sera from patients with ovarian carcinoma". Proceedings of the National Academy of Sciences of the United States of America 96 (20): 11531–11536. September 1999. doi:10.1073/pnas.96.20.11531. PMID 10500211. Bibcode: 1999PNAS...9611531S. 
  17. ↑ "Mesothelin is shed from tumor cells". Cancer Epidemiology, Biomarkers & Prevention 15 (9): 1751. September 2006. doi:10.1158/1055-9965.EPI-06-0479. PMID 16985043. 
  18. ↑ "Blood tests for asbestos-related mesothelioma". Oncology 71 (1–2): 26–31. 2006. doi:10.1159/000100446. PMID 17344668. 
  19. ↑ 19.0 19.1 "Detection and quantitation of serum mesothelin, a tumor marker for patients with mesothelioma and ovarian cancer". Clinical Cancer Research 12 (2): 447–453. January 2006. doi:10.1158/1078-0432.CCR-05-1477. PMID 16428485. 
  20. ↑ 20.0 20.1 "Megakaryocyte potentiating factor as a tumor marker of malignant pleural mesothelioma: evaluation in comparison with mesothelin". Lung Cancer 62 (1): 45–54. October 2008. doi:10.1016/j.lungcan.2008.02.012. PMID 18394747. 
  21. ↑ "Circulating mesothelin protein and cellular antimesothelin immunity in patients with pancreatic cancer". Clinical Cancer Research 15 (21): 6511–6518. November 2009. doi:10.1158/1078-0432.CCR-09-0565. PMID 19843662. 
  22. ↑ 22.0 22.1 "Serum mesothelin and megakaryocyte potentiating factor in pancreatic and biliary cancers". Clinical Chemistry and Laboratory Medicine 50 (4): 721–725. April 2012. doi:10.1515/CCLM.2011.816. PMID 22149739. 
  23. ↑ "Humoral immune response to mesothelin in mesothelioma and ovarian cancer patients". Clinical Cancer Research 11 (10): 3814–3820. May 2005. doi:10.1158/1078-0432.CCR-04-2304. PMID 15897581. 
  24. ↑ "A novel high-affinity human monoclonal antibody to mesothelin". International Journal of Cancer 128 (9): 2020–2030. May 2011. doi:10.1002/ijc.25557. PMID 20635390. 
  25. ↑ "A human single-domain antibody elicits potent antitumor activity by targeting an epitope in mesothelin close to the cancer cell surface". Molecular Cancer Therapeutics 12 (4): 416–426. April 2013. doi:10.1158/1535-7163.MCT-12-0731. PMID 23371858. 
  26. ↑ "Humanization of rabbit monoclonal antibodies via grafting combined Kabat/IMGT/Paratome complementarity-determining regions: Rationale and examples". mAbs 9 (3): 419–429. April 2017. doi:10.1080/19420862.2017.1289302. PMID 28165915. 
  27. ↑ "Modified CAR T cells targeting membrane-proximal epitope of mesothelin enhances the antitumor function against large solid tumor". Cell Death & Disease 10 (7): 476. June 2019. doi:10.1038/s41419-019-1711-1. PMID 31209210. 
  28. ↑ "Development of Highly Effective Anti-Mesothelin hYP218 Chimeric Antigen Receptor T Cells With Increased Tumor Infiltration and Persistence for Treating Solid Tumors". Molecular Cancer Therapeutics 21 (7): 1195–1206. July 2022. doi:10.1158/1535-7163.MCT-22-0073. PMID 35499461. 

Further reading

External links



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