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

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 towar...

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Published in:NPJ precision oncology 2023-08, Vol.7 (1), p.74-74, Article 74
Main Authors: Shah, Ashu, Chaudhary, Sanjib, Lakshmanan, Imayavaramban, Aithal, Abhijit, Kisling, Sophia G., Sorrell, Claire, Marimuthu, Saravanakumar, Gautam, Shailendra K., Rauth, Sanchita, Kshirsagar, Prakash, Cox, Jesse L., Natarajan, Gopalakrishnan, Bhatia, Rakesh, Mallya, Kavita, Rachagani, Satyanarayana, Nasser, Mohd Wasim, Ganti, Apar Kishor, Salgia, Ravi, Kumar, Sushil, Jain, Maneesh, Ponnusamy, Moorthy P., Batra, Surinder K.
Format: Article
Language:English
Subjects:
631/67/1059/602
631/67/1504/1713
631/67/1612/1350
Antibodies
Cancer
Cancer Research
Gene Therapy
Human Genetics
Internal Medicine
Lung cancer
Medicine
Medicine & Public Health
Oncology
Pancreatic cancer
Targeted cancer therapy
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Summary: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.
ISSN:2397-768X
2397-768X
DOI:10.1038/s41698-023-00423-7