Date of Degree

2-2019

Document Type

Dissertation

Degree Name

Ph.D.

Program

Chemistry

Advisor

Brian M. Zeglis

Committee Members

Lynn C. Francesconi

Benjamin Burton-Pye

Prabodhika Mallikaratchy

Subject Categories

Biochemistry | Biotechnology | Radiochemistry

Keywords

Pretargeting, radioimmunotherapy, click chemistry

Abstract

Radioimmunotherapy capitalizes on the specificity and affinity of antibodies for their antigens to localize radioactivity at the tumor site. One limitation in using antibodies is their long circulation time, which can take days to weeks to fully clear from blood circulation. When a radioisotope is directly conjugated to this immunoglobulin vector, the red marrow and other healthy organs are receiving a constant radiation dose while it is in blood circulation. This not only harms healthy organs, but limits the dose of radioactivity that can be administered thus prolonging treatment. A promising alternative to limit the radiation dose to non-tumor tissue is in vivo pretargeting based on the inverse electron demand Diels-Alder (IEDDA) reaction between tetrazine (Tz) and trans-cyclooctene (TCO). This method separates the localization of the antibody at the tumor site from administration of the radioactivity. It functions in 4 steps: 1) administration of a TCO-modified antibody, 2) passage of sufficient time for the antibody to accumulate at tumor site and concurrently clear from blood circulation, 3) injection of a tetrazine-bearing small molecule radioligand, 4) shorter time interval for the small molecule to clear from the bloodstream. This method capitalizes on the tumor targeting properties of antibodies while detatching the radioactivity from their pharmacokinetic drawback.

Herein, we discuss the in vitro, in vivo, and therapeutic establishment of pretargeted radioimmunotherapy (PRIT) based on the IEDDA reaction in a pancreatic ductal adenocarcinoma and colorectal cancer mouse model. Dosimetry caluclations were performed and strategies for the dosimetric optimization are suggested. The PRIT approach presented here can be applied to other disease models and has the potential to further advance the use of pretargeted radiotherapy in the clinic.

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