Click-It’s Overall Objectives
Companion diagnostics are crucial for patient selection, therapy planning and monitoring of disease management. They are medical tools that help tailor treatment options and dosages to patients. Hence, companion diagnostics lead to a more effective and cost efficient use of drugs, increased survival rates, reducing healthcare expenses.
Nanomedicines like monoclonal antibodies (mAbs) have been proven as optimal disease-targeting vehicles, since they generally exhibit superior target uptake and retention in comparison to many other targeting constructs (e.g. mAb fragments and peptides). For example, human epidermal growth factor receptor 2 (HER2)-positive breast cancers can be treated with targeted therapy using trastuzumab. An outstanding therapy response rate up to 86% has been observed. Unfortunately, only 20-25% of all breast cancer cases are HER2-positive and the treatment is expensive (in Denmark ~40,000 EUR/year). Therefore, it is a prerequisite to test whether a patient is HER2-positive before such treatment is initiated. In this regard, positron emission tomography (PET) companion diagnostic imaging can be used to select patients and monitor therapy. Whereas radiolabeled and fast-clearing HER2-binding antibody fragments can be used for HER2 patient selection, other essential companion diagnostic aspects - for example the target-binding characteristics and the in vivo fate of the parent mAb drug - are less well covered by looking at a smaller fragment. To date, there are no technologies available that allow for the direct in vivo monitoring of the parent, slow clearing monoclonal antibody, with minimal patient radiation doses. Long-lived radionuclides such as zirconium-89 (89Zr; half-life of 3.3 days) must be used to be compatible with the slow pharmacokinetics of mAbs. This results in a substantial and by most viewed as unacceptable radiation dose, especially to the bone marrow (radionuclide dilemma). For example, a 89Zr-labeled mAb was reported to result in a mean effective dose of 0.66 mSv/MBq for women. In comparison, 18F-tracers (fluorine-18, half-life of 110 min) result in effective doses of approximately 0.02 mSv/MBq (ca. 30 times lower) and thus in a substantial lowered radiation burden5. An effective dose of 0.66 mSv/MBq restricts repeated applications, the absolute radioactivity amount that can be administered and the human populations that can be imaged. Also, when 89Zr- labeled mAbs are administered a poor image contrast (target-to-background) is obtained due to long-circulating, radiolabeled mAb.
Click-It will circumvent these major limitations using a pretargeting approach that separates the targeting from the actual imaging process. In this regard, a tagged nanomedicine such as a mAb is administered and allowed to bind to the target (for example, to a receptor over-expressed on a tumor) as the first step. Subsequently, a fast-clearing, short-lived radiolabeled imaging probe is administered. The imaging probe then binds to the target-bound mAb, enabling imaging (in vivo click chemistry). PET scan snapshots at multiple time points provide long-term imaging information by applying short-lived radionuclides. This strategy reduces the absorbed radiation dose resulting in a boost in target-blood ratios, as the nanomedicine can be imaged at a time point when the blood concentration of unbound nanomedicine has lowered to an acceptable level.
In conclusion, the consortium´s overall goal is to develop innovative and effective companion diagnostics for (pre)clinical use of long circulating nanomedicines (like mAbs). Click-It addresses an unmet need both within healthcare and drug development based on pretargeted in vivo imaging.
Click to see an animation of the Click-It pre-targeting principle:
Figure 1: Kick-off meeting in Copenhagen, March 2016. From the left: Research manager Raffaella Rossin (TAGWORKS), Professor Andreas region (RegionH), Associate professor Matthias Herth (UCPH), Research coordinator Anne Mette F Hag (RegionH), Scientist Matthias Barz (JGU), Chief production manager Jacob Madsen (RegionH), Associate professor Jesper Kristensen (UCPH), Scientist Thomas Wanek (AIT), Principal investigator Mikula Hannes (TU Wien) and Chief executive officer Marc Robillard (TAGWORKS).
This project has received funding from the European Union's EU Framework Programme for Research and Innovation Horizon 2020 under Grant Agreement no. 668532