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

Abstract

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 211At for targeted alpha therapy and 125I as a surrogate for the imaging radionuclides 123, 124I. 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 211At.

Behaviour, use and safety aspects of astatine-211 solvated in chloroform after dry distillation recovery

“…Evaporating Chloroform Eluate creating a dry residue of astatine is often used as a starting point for many different types of chemical reactions and applications, both organic and aqueous 18 – 20 . Trying to elucidate the actual astatine speciation in the dry form of Chloroform Eluate is naturally difficult.…”

The Different Strategies for the Radiolabeling of [211At]-Astatinated Radiopharmaceuticals

“…The use of sdAbs for TRT with the 211 At is particularly attractive due to the high alignment of the physical half-life (7.2 h) with the pharmacokinetic profile of sdAbs. Yutian Feng et al [ 76 ] have evaluated iso-[ 211 At]-AGMB-PODS via the electrophilic astatodestannylation of the corresponding precursor, which was significantly more stable in vitro compared to its maleimide analog in the presence of cysteine and human serum albumin (HSA), demonstrating excellent tumor uptake and high in vivo stability. On the other hand, in vivo pretargeting is predicated on separate injections of the immunoglobulin and radionuclide and relies upon a biorthogonal ligation to join two components together within the body.…”