Speaker
Description
The TEM1/endosialin is a receptor over-expressed in several human solid tumours and silenced in normal adult tissues, representing a suitable and potentially safe target for radioimmunotherapy of sarcoma.1,2 Taking advantage of the very fast in vivo kinetic of the click reaction between tetrazines (Tz) and trans-cyclooctene (TCO), we intent to explore a pre-targeting approach for the in-vivo recognition of TEM1 using a single chain fusion protein (scFv-Fc) that recognizes both the human and the murine TEM1. The optimization of the design of the final conjugates, using commercially available radioisotopes like 111In and 125I, included:
i) Evaluation of radioiodinated scFv-Fc’s directed towards TEM1
A panel of TEM1 scFv-Fc’s were labelled with 125I and evaluated to select the best candidate for pre-clinical studies. The evaluation comprised the in-vitro studies of their uptake and internalization in human and murine TEM1-positive tumor cells, the assessment of their binding affinity and quantification of specific versus nonspecific binding. Once the best scFv-Fc identified, biodistribution studies in tumor bearing mice were also performed.
ii) Evaluation of 111In-labelled tetrazine-containing macrocyclic chelators
A small family of macrocyclic chelators carrying tetrazine groups were synthesized and used to obtain clickable 111In-radiocomplexes for further targeting of TEM1 based on in-vivo click chemistry strategies. Their stability and pharmacokinetics were studied in normal mice.
The developed research work is expected to provide important insights for the development of TEM1-targeted radiopharmaceuticals, for which few studies have been reported so far but that can contribute to the rise of a more personalized approach in cancer treatment.
