Research Karuna Adhikari

Abstract

Positron emission tomography (PET) imaging of radiolabeled monoclonal antibodies (mAb) is a powerful in vivo research tool with applications in diagnostic as well as in prognostic and therapeutic settings. The molecular precision of antigen-mAb interaction turns radiolabeled mAbs into highly specific radiotracers with a very high affinity. However, the high molecular weight and the long circulation times of mAbs are associated with unsatisfactory target to background ratios, thus requiring the use of long-lived isotopes which yields high radiation burden to the patient. A pretargeting strategy based in biorthogonal chemistry offers a solution to this problem. In this approach, the mAb with biorthogonal tag will be labeled in vivo with a short lived radiotracer through bioorthogonal reaction at the target site. This allows in vivo imaging of the target with superior image contrast and reduced radiation doses. An additional challenge is that many mAbs internalize upon binding to their target on the cell surface, before the pretargeting reaction. To overcome this issue, this project aims to develop a novel pretargeted intracellular PET imaging strategy. We will develop novel cell permeable fluorinated trans-cyclooctene analogues (TCOs) and investigate their potential for pretargeted intracellular imaging using an innovative approach of "turn-on" FluoroBOT labeled mAbs. Finally, following optimization of radiochemistry, the 18F-TCO will be used in an in vivo imaging study.

Researcher(s)

• Promoter: Augustyns Koen
• Co-promoter: Stroobants Sigrid
• Fellow: Adhikari Karuna

Research team(s)

• Medicinal Chemistry (UAMC)

Project type(s)

• Research Project

Abstract

Radiolabeling of monoclonal antibodies (mAbs) is a powerful preclinical and clinical research tool that finds applications in diagnostic as well as in prognostic and therapeutic settings. Positron Emission Tomography (PET) differs from traditional imaging in that probes known as radiotracers carrying a radioisotope are used to visualize, characterize, and quantify biological processes in vivo. However, despite their attractive properties radiolabeled mAbs have a few important shortcomings. One of the most critical ones is their long circulation time in the body associated with low target to non-target ratios, thus requiring the use of long lived isotopes which yields high radiation dose to the patient. A solution for this problem is offered by pretargeting based on bioorthogonal chemistry. This allows in vivo imaging of the target with superior image contrast and reduced radiation doses. An additional challenge is that many mAbs are internalized upon binding to their target on the cell surface, before the pretargeting reaction. To overcome this issue, this project aims at developing a pretargeted intracellular PET imaging strategy. We will develop novel fluorinated trans-cyclooctene analogues (TCOs) and characterize their potential for pretargeted intracellular imaging using an innovative approach of "turn-on" FluoroBOT labeled mAbs. Finally, following optimization of radiochemistry, the 18F-TCO will be used in an in vivo imaging study.

Researcher(s)

• Promoter: Augustyns Koen
• Co-promoter: Elvas Filipe
• Co-promoter: Wyffels Leonie
• Fellow: Adhikari Karuna

Research team(s)

• Medicinal Chemistry (UAMC)

Project type(s)

• Research Project