Chimeric antibody targeting unique epitope on onco-mucin16 reduces tumor burden in pancreatic and lung malignancies.

Autor: Shah A; Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, 68198-5870, USA., Chaudhary S; Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, 68198-5870, USA., Lakshmanan I; Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, 68198-5870, USA., Aithal A; Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, 68198-5870, USA., Kisling SG; Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, 68198-5870, USA., Sorrell C; Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, 68198-5870, USA., Marimuthu S; Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, 68198-5870, USA., Gautam SK; Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, 68198-5870, USA., Rauth S; Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, 68198-5870, USA., Kshirsagar P; Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, 68198-5870, USA., Cox JL; Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE, USA., Natarajan G; Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, 68198-5870, USA., Bhatia R; Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, 68198-5870, USA., Mallya K; Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, 68198-5870, USA., Rachagani S; Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, 68198-5870, USA., Nasser MW; Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, 68198-5870, USA., Ganti AK; Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, 68198-5870, USA.; Department of Internal Medicine, VA Nebraska Western Iowa Health Care System and University of Nebraska Medical Center, Omaha, NE, USA.; Fred and Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE, 68198-5870, USA., Salgia R; Department of Medical Oncology and Therapeutics, City of Hope, Duarte, CA, 91010, USA., Kumar S; Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, 68198-5870, USA., Jain M; Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, 68198-5870, USA.; Fred and Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE, 68198-5870, USA.; Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE, 68198-5870, USA., Ponnusamy MP; Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, 68198-5870, USA. mpalanim@unmc.edu.; Fred and Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE, 68198-5870, USA. mpalanim@unmc.edu.; Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE, 68198-5870, USA. mpalanim@unmc.edu., Batra SK; Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, 68198-5870, USA. sbatra@unmc.edu.; Fred and Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE, 68198-5870, USA. sbatra@unmc.edu.; Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE, 68198-5870, USA. sbatra@unmc.edu.
Jazyk: angličtina
Zdroj: NPJ precision oncology [NPJ Precis Oncol] 2023 Aug 11; Vol. 7 (1), pp. 74. Date of Electronic Publication: 2023 Aug 11.
DOI: 10.1038/s41698-023-00423-7
Abstrakt: Aberrantly expressed onco-mucin 16 (MUC16) and its post-cleavage generated surface tethered carboxy-terminal (MUC16-Cter) domain are strongly associated with poor prognosis and lethality of pancreatic (PC) and non-small cell lung cancer (NSCLC). To date, most anti-MUC16 antibodies are directed towards the extracellular domain of MUC16 (CA125), which is usually cleaved and shed in the circulation hence obscuring antibody accessibility to the cancer cells. Herein, we establish the utility of targeting a post-cleavage generated, surface-tethered oncogenic MUC16 carboxy-terminal (MUC16-Cter) domain by using a novel chimeric antibody in human IgG1 format, ch5E6, whose epitope expression directly correlates with disease severity in both cancers. ch5E6 binds and interferes with MUC16-associated oncogenesis, suppresses the downstream signaling pFAK(Y397)/p-p70S6K(T389)/N-cadherin axis and exert antiproliferative effects in cancer cells, 3D organoids, and tumor xenografts of both PC and NSCLC. The robust clinical correlations observed between MUC16 and N-cadherin in patient tumors and metastatic samples imply ch5E6 potential in targeting a complex and significantly occurring phenomenon of epithelial to mesenchymal transition (EMT) associated with disease aggressiveness. Our study supports evaluating ch5E6 with standard-of-care drugs, to potentially augment treatment outcomes in malignancies inflicted with MUC16-associated poor prognosis.
(© 2023. Nature Publishing Group UK.)
Databáze: MEDLINE
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