Chimeric antibody targeting unique epitope on onco-mucin16 reduces tumor burden in pancreatic and lung malignancies
Year: 2023
Type: article
Abstract: 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.
Source: npj Precision Oncology
Authors: Ashu Shah, Sanjib Chaudhary, Imayavaramban Lakshmanan, Abhijit Aithal, Sophia G. Kisling, Claire Sorrell, Saravanakumar Marimuthu, Shailendra K. Gautam, Sanchita Rauth, Prakash Kshirsagar, Jesse L. Cox, Gopalakrishnan Natarajan, Rakesh Bhatia, Kavita Mallya, Satyanarayana Rachagani, Mohd Wasim Nasser, Apar Kishor Ganti, Ravi Salgia, Sushil Kumar, Maneesh Jain, Moorthy P. Ponnusamy, Surinder K. Batra
Language: English
Subfield: Radiology, Nuclear Medicine and Imaging
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $3,490
Awards: G1199706347, G1250340004, G1584088213, G1864672129, Role of PD2/Paf1 in Pancreatic Acinar to Ductal Metaplasia, G3276303307, G342133952, G377846833, G3869955002, G3974535400, G4863590166, G5342389596, G5675619324, G5862201136, Rac1 GTPase in tumorigenesis and progression of pancreatic cancer, G6147624802, Pancreatic Cancer Metastasis, G6352617373, G6354342422, G6636999038, G7302086222, G7373015005, G7411945132, Targeting CXCR2 axis in Pancreatic Cancer, Molecular Imaging Probe(s) for Optical Surgical Navigation of Pancreatic Cancer, G7840294326, Modulation of Tumor Microenvironment for Improved Therapy of Pancreatic Cancer, G8742885702, G877420635, G9000013096, G9000032122, G9000046311, G9000077642, G9000099995, G9000168929, G9000171213, G9000191884, G9000217643, G9000258331, G9000295445, G9000341061, G9000347168, Connectivity mapping identified novel combination therapy for glioblastoma, Truncated O-glycan-dependent mechanisms inducing metastatic dissemination in pancreatic cancer
OpenAlex ID: W4385765697