Radioimmunotherapy (RIT) is an extremely promising area of cancer treatment that combines the targeting power of monoclonal antibodies with localized radiation in order to damage tumor cells. Currently, there is great interest in RIT due to the recent progress in production of cancer targeting antibodies and the FDA approval of the first RIT agent, Zevalin. The high linear energy transfer (LET) and relatively short penetration range (a few cell diameters) makes alpha particles particularly attractive for the treatment of micro tumors. Of all alpha-emitters (Bi-213, Bi-212, Ra-223 and At-211) that are being evaluated for the RIT, Ra-223 (Tl/2 = 11.4 days) is very attractive because of its availability from a generator and longer half-life. However, the research and clinical application of this isotope are hindered by the limited availability of an in vivo stable chelator. To overcome this limitation, Lynntech is proposing to evaluate three hexaaza macrocyclic chelators of different ring sizes (24, 26 and 28-membered) for use as bifunctional chelating agents for Ra-223 based RIT. The preliminary results based on theoretical calculations have demonstrated that these macrocycles will have cavity size suitable for binding Ra. During Phase I, the compounds will be synthesized, characterized and evaluated for their kinetic stability in preliminary in vitro experiments. The conditions for the conjugation of the chelators to the antibodies and Ba-133 (a surrogate for Ra-223) labeling for the chelator-antibody conjugate will also be optimized at Lynntech. Finally, the in vitro stability of the Ba-133 chelator-antibody conjugate will be evaluated. The ultimate goal of this project is to make these macrocyclic chelators commercially available for labeling a variety of cancer targeting antibodies for the RIT applications.
