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  5. Antibody-Based Theranostics in Ovarian Cancer: Targeting MUC16 For Diagnosis and Radioimmunotherapy

Antibody-Based Theranostics in Ovarian Cancer: Targeting MUC16 For Diagnosis and Radioimmunotherapy

File(s)
kym4001.pdf (21.59 MB)
Permanent Link(s)
https://hdl.handle.net/1813/118280
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Weill Cornell Theses and Dissertations
Author
Mack, Kyeara
Abstract

Ovarian cancer causes more deaths than any other gynecological malignancy, with a five-year relative survival rate of 30% for patients diagnosed at advanced stages. There is a critical clinical need for improved diagnostic and targeted therapeutic approaches. Membrane-bound mucins with aberrantly expressed O-linked glycans have emerged as promising targets for ovarian cancer diagnosis and treatment. The monoclonal antibody (mAb) AR9.6 binds to a unique epitope on the MUC16 mucin, which is influenced by O-glycosylation. Here, we exploit the cancer specificity of AR9.6 to develop a radiotheranostic platform for the detection and treatment of ovarian cancer. This approach was initially evaluated in ovarian cancer mouse models via positron emission tomography (PET), employing mAb AR9.6 —radiolabeled with the imaging-compatible radionuclide zirconium-89 (89Zr). Imaging and biodistribution studies revealed high specific in vivo tumor uptake in MUC16high and relatively low tumor uptake in MUC16low models. A therapeutic radioimmunoconjugate with comparable pharmacokinetics was created upon exchanging the diagnostic radionuclide with the beta-emitter, lutetium-177 (177Lu). 177Lu-labeled AR9.6 displayed strong anti-tumor effects in MUC16high models and no anti-tumor effects in MUC16low expressing models. Furthermore, tumor recurrence was successfully treated when performing fractionated dosing. Another strategy was pursued by investigating targeted alpha therapy (TAT) in combination with pretargeting. TAT is a promising strategy to efficiently treat cancer lesions, while sparing surrounding healthy tissue due to alpha emitters' high linear energy transfer (LET) and short penetration range. The pretargeting approach — leveraging the inverse-electron-demand Diels-Alder reaction between radiolabeled tetrazines and trans-cyclooctene (TCO) modified mAbs — further reduces off-target toxicities by decoupling the radionuclide from slower mAb kinetics and then allowing both components to combine at the target site. Pretargeting TAT with AR9.6-TCO and the alpha-emitting counterpart [225Ac]Ac-Macropa-PEG8-Tz demonstrated complete tumor eradication with no recurrence and mild off-targeting toxicities. These results highlight a new and clinically translatable radiotheranostic solution for ovarian cancer diagnosis and treatment.

Date Issued
2023-11-28
Keywords
WCM Library Coordinated Deposit
•
Hypoglycosylated MUC16
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Ovarian Cancer
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PET Imaging
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Radioimmunotherapy
•
Theranostics
Committee Chair
Lewis, Jason
Committee Member
Heller, Daniel
Scheinberg, David
Grimm, Jan
Pillarsetty, Kishore
Degree Discipline
Pharmacology
Degree Name
Ph. D., Pharmacology
Degree Level
Doctor of Philosophy
Type
dissertation or thesis

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