Report
Teaser, summary, work performed and final results
Periodic Reporting for period 2 - Click-It (“In Vivo Click PET Imaging Agentsâ€: Improving clinical companion diagnostics)
Teaser
Companion diagnostics are crucial for drug development and disease management with regard to patient selection, therapy planning and monitoring. Nanomedicines such as antibodies have been proven to be optimal disease-targeting agents because they generally exhibit superior...
Summary
Companion diagnostics are crucial for drug development and disease management with regard to patient selection, therapy planning and monitoring. Nanomedicines such as antibodies have been proven to be optimal disease-targeting agents because they generally exhibit superior target uptake and retention. However, to date, nuclear imaging of nanomedicines has been limited to the use of long-lived isotopes to be compatible with the slow pharmacokinetics of these large molecules. Major drawbacks are high radiation doses, precluding routine and repeated companion imaging procedures.
The Click-It consortium aims to circumvent this issue by using pretargeting approach, which centers on the administration and target binding of a tagged nanomedicine followed by administration and binding of a small, fast-clearing, short-lived radiolabelled probe to the tag of the nanomedicine. This results in lower absorbed radiation doses and in a boost in target-blood ratios, which in turn leads to a superior imaging contrast. PET scan snapshots at multiple time-points provide long-term imaging information by applying short-lived nuclides. So far, only the fastest click reaction, the tetrazine ligation, has demonstrated potential in clinically relevant conditions. Recently, we have shown in a SPECT imaging study that this click reaction can be applied for non-internalizing nanomedicines in vivo.
This project aims at expanding the scope of click-pretargeted imaging to intracellular targets, because a majority of nanomedicines internalize and is thus not accessible with the current approach. Furthermore, we will expand our approach to short-lived, non-metal based, small molecule 18F-PET tracers, since PET offers a higher spatial and temporal resolution enabling quantitative decision making in disease diagnosis and management. Finally, the project aims to translate the developed click-pretargeting technology into a clinically applicable nanomedicine-based imaging approach in canine patients.
Work performed
Work Package 1 - Development of short-lived 18F-labeled TTAs
Several strategies have been established and evaluated. Currently, we have prepared and characterized more than 30 18F-labeled TTA and will continue to set up a library of click imaging agents.
Work Package 2 - Development of biodegradable/biocompatible clear agent
Several clearing agents (CA) have been synthesized. They are currently undergoing tests for clearing ability and stability. Our consortium has started to radiolabel a set of interesting clearing agents with the aim to explore their in vivo biodistribution. The first 3 CAs have been tested and show similar clearing ability and stability that albumin-based CAs.
Work Package 3 - Development of innovative tags: increasing reactivity and stability
Based on computational modelling several TCO precursors have been prepared and used to obtain 4 new TCOs so far. Additional TCO tags are currently being synthesized. Cysteine and lysine conjugated mAb-TCOs have been synthesized and are currently evaluated.
Work Package 4 - Translation of in vivo click imaging agents: from small animals to canine patients
A screening system has been established to save time and reduce the number of animals needed to test. Approximately 40 18F-labeled TTAs have been tested in respect to in vitro and in vivo stability, clearance, biodistribution and in vivo tetrazine ligation ability. So far 5 structures have been selected to proceed further to cancer models. Our consortium has set up tumor models for extracellular and intracellular targets that are used to evaluate 18F-labeled TTAs.
Final results
The ultimate goal of this consortium is to enable pretargeted imaging for extracellular and intracellular targets with PET and fluorine-18. The possibility to perform this experiments will enable society to develop efficient companions diagnostics which display high contrast and low radiation burden. Pretargeted imaging is especially interesting for slow targeting vectors such as antibodies.
Website & more info
More info: http://click-it-imaging.eu/index.html.