Pretargeted Alpha Therapy of Disseminated Cancer Combining Click Chemistry and Astatine-211

• Published in: Pharmaceuticals (Basel, Switzerland) Vol. 16; no. 4; p. 595
• Main Authors: Timperanza, Chiara, Jensen, Holger, Bäck, Tom, Lindegren, Sture, Aneheim, Emma
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 01.04.2023; MDPI
• Subjects: Antibodies; Antigens; Astatine; astatine-211; Cancer therapies; click chemistry; Dosage and administration; Iodine; Molecular weight; Optimization; Pharmacokinetics; Polymers; pretargeting; Radiation; Radioimmunotherapy; radionuclide therapy; targeted alpha therapy; Testing; Tumors; X-rays; Denmark; astatine-211; radiopharmaceuticals; pretargeting; radioimmunotherapy; radionuclide therapy; drug design; click chemistry; theranostics; targeted alpha therapy
• ISSN: 1424-8247; 1424-8247
• DOI: 10.3390/ph16040595

To enhance targeting efficacy in the radioimmunotherapy of disseminated cancer, several pretargeting strategies have been developed. In pretargeted radioimmunotherapy, the tumor is pretargeted with a modified monoclonal antibody that has an affinity for both tumor antigens and radiolabeled carriers. In this work, we aimed to synthesize and evaluate poly-L-lysine-based effector molecules for pretargeting applications based on the tetrazine and trans-cyclooctene reaction using At for targeted alpha therapy and I as a surrogate for the imaging radionuclides I. Poly-L-lysine in two sizes was functionalized with a prosthetic group, for the attachment of both radiohalogens, and tetrazine, to allow binding to the trans-cyclooctene-modified pretargeting agent, maintaining the structural integrity of the polymer. Radiolabeling resulted in a radiochemical yield of over 80% for astatinated poly-L-lysines and a range of 66-91% for iodinated poly-L-lysines. High specific astatine activity was achieved without affecting the stability of the radiopharmaceutical or the binding between tetrazine and transcyclooctene. Two sizes of poly-L-lysine were evaluated, which displayed similar blood clearance profiles in a pilot in vivo study. This work is a first step toward creating a pretargeting system optimized for targeted alpha therapy with At.