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CA125 Targeted Molecular Imaging of Epithelial Ovarian Cancer Open Access


Other title
single-chain antibody fragment
Positron Emission Tomography
Epithelial Ovarian Cancer
Molecular Imaging
Type of item
Degree grantor
University of Alberta
Author or creator
Sharma, Sai Kiran
Supervisor and department
Wuest, Frank (Oncologic Imaging, Department of Experimental Oncology)
Klotz, Lars-Oliver (Faculty of Pharmacy and Pharmaceutical Sciences)
Examining committee member and department
Lewis, John (Department of Experimental Oncology)
Doschak, Michael (Faculty of Pharmacy and Pharmaceutical Sciences)
Rogers, Buck (Department of Radiology)
Fu, Yangxin (Department of Experimental Oncology)
Faculty of Pharmacy and Pharmaceutical Sciences
Pharmaceutical Sciences
Date accepted
Graduation date
Doctor of Philosophy
Degree level
Rationale: Ovarian cancer is the most lethal malignancy of the female reproductive system. ~80% of ovarian cancers are epithelial in origin and commonly classified as Epithelial Ovarian Cancer (EOC). This malignancy is characterized by an overexpression of Cancer Antigen-125 (CA125) – a cell surface mucinous glycoprotein that serves as a USFDA approved ovarian tumor associated antigen. However, the early detection of EOC is plagued by its asymptomatic nature of progression and the limitations of currently used front-line diagnostic tools such as immunoassays that are capable of detecting CA125 as a shed antigen in the serum of patients presenting in the clinic with pelvic masses suspected for ovarian cancer. At present, there is no technique available for the in vivo evaluation of CA125 expression in malignant tissues, which has been shown to be an early event in the recurrence of epithelial ovarian cancer. Hypothesis: CA125 is a suitable target for the molecular imaging of epithelial ovarian cancer. Methods: An immuno-PET strategy was devised to employ CA125-targeted monoclonal antibody (MAb B43.13) and its derivative single chain Fragment variable (scFv) as molecular probes for imaging in vivo expression of CA125 via positron emission tomography. Anti-CA125 MAb and scFv were prepared and functionally characterized for their targeting capabilities prior to and post radiolabeling them for use in immuno-PET imaging. In separate applications of this strategy, we employed three different PET-radionuclides – 18F, 64Cu and 89Zr with suitable versions of the antibody molecule as targeting vectors to carry out same-day, next day or later time point in vivo imaging of EOC in subcutaneously xenografted mice models. Results: Biochemical methods of analysis including immunofluorescence, flow cytometry and immunoblotting revealed highly specific binding of the antibody vectors to CA125-positive NIH:OVCAR-3 cells with no binding to CA125-negative SKOV3 cells. Radiolabeled versions of the anti-CA125 MAb and scFv were obtained with high specific activity and both radioimmunoconjugate vectors demonstrated highly selective binding to NIH:OVCAR-3 cells and virtually no binding to SKOV3 cells. In vivo radiopharmacological evaluation of the anti-CA125 radioimmunoconjugate vectors in xenograft mice models provided consistently high absolute uptake values in NIH:OVCAR-3 tumors and minimal uptake in SKOV3 tumors. Results from small animal PET imaging were confirmed by ex vivo digital autoradiography, immunofluorescence and immunohistochemistry. Conclusions: CA125 is a suitable target for non-invasive imaging of epithelial ovarian cancer. Radiolabeling of anti-CA125 MAb and scFv with positron emitting radionuclides did not compromise their immunoreactivity to the target antigen. Both the antibody-based radioimmunoconjugates presented targeted tumor accumulation and an expected in vivo biological clearance profile. This renders them as potential immuno-PET probes for targeted in vivo molecular imaging of CA125 in Epithelial Ovarioan Cancer.
Permission is hereby granted to the University of Alberta Libraries to reproduce single copies of this thesis and to lend or sell such copies for private, scholarly or scientific research purposes only. The author reserves all other publication and other rights in association with the copyright in the thesis and, except as herein before provided, neither the thesis nor any substantial portion thereof may be printed or otherwise reproduced in any material form whatsoever without the author's prior written permission.
Citation for previous publication
Sharma SK, Suresh MR, Wuest FR. Improved soluble expression of a single-chain antibody fragment in E.coli for targeting CA125 in epithelial ovarian cancer. Protein Expr Purif 2014;102:27-37

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