Impact of DOTA-Chelators on the Antitumor Activity of ¹⁷⁷Lu-DOTA-Rituximab Preparations in Lymphoma Tumor-Bearing Mice

Abstract

Background: This work aimed to evaluate the influence of two chelators: DOTA(SCN) and DOTA(NHS) on radioimmunotherapy using 177 Lu-DOTA-Rituximab preparations in murine lymphoma xenograft models. Subsequently, based on animal data, the organ radiation-absorbed doses were extrapolated to humans (adult male). Materials and Methods: Therapeutic efficacy of 177 Lu-DOTA-Rituximab was evaluated in male nude mice bearing either Raji (B lymphocyte, CD20 +) and Jurkat (T lymphocyte, CD20) xenografts, utilizing an anti-CD20 antibody-Rituximab conjugate with either DOTA(SCN) or DOTA(NHS). The DOTA-Rituximab conjugates were prepared in the form of freeze-dried kits. Results: All radioimmunoconjugates were obtained with high radiolabeling yield (radiochemical purity, RCP > 95%) and specific activity of ca. 0.5 GBq/mg. Therapeutic effects of 177 Lu-DOTA-Rituximab were observed in animals regardless whether DOTA(SCN) or DOTA(NHS) were used for conjugation. Importantly, therapy involving 177 Lu-DOTA-Rituximab was more effective than use of Rituximab alone. Conclusions: The degree of antitumor efficacy was dependent on the type of applied bifunctional chelators conjugated to mAb. However, this difference was not statistically significant. Dosimetry calculations showed that the absorbed radiation doses extrapolated to humans were very low for osteogenic cells regardless of the conjugates. Organs like the liver and spleen, treated with 177 Lu-DOTA(SCN)-Rituximab, showed similar radiation absorbed doses when compared with 177 Lu-DOTA(NHS)-Rituximab.

Does the Number of Bifunctional Chelators Conjugated to a mAb Affect the Biological Activity of Its Radio-Labeled Counterpart? Discussion Using the Example of mAb against CD-20 Labeled with 90Y or 177Lu

“…The covalent bond between chelator and mAb is generally robust, and the BCAs are designed to coordinate the radionuclide stably. − …”

“…Therefore, an investigation of serum stability is performed to assess potential degradation/modification of the radioimminoconjugates by enzymes in plasma. In Table , four publications ,,, describing a biodistribution study are based on Rituximab coupled with a p-SCN-Bz-DOTA chelator. Therefore, a null hypothesis should be separated for distribution in healthy mice claim that there is no statistically significant correlation between target-to-blood and for distribution in xenograft mice model claim that there is no statistically significant correlation between tumor-to-target ratio for considered conjugates.…”

“…A few literature reports cover the use of rats in research on radiolabeled Rituximab, ,− but the overwhelming majority of the reports relate to the murine model, Table . The latter model encompasses both healthy ,− ,,, and immunodeficient mouse strain, that is, NOD/SCID and Nude. ,,, Transplantable xenograft models were subcutaneously grafted with RAJI, DAUDI, or RAMOS cells from existing cell lines, not from the primary tumor origin (patient-derived). The advantage of this approach was undoubtedly rapid result, relative simplicity, high yield, usefulness as first step investigation, determining in vivo proof-of-concept from in vitro findings like immunoreactivity and examining the efficacy of radiotherapeutics on human tumor cells.…”