Novel strategies to increase the therapeutic ratio in clinical radio-immunotherapy (RIT) studies are needed. The primary dose-limiting toxicity has been hematological. A humanized construct of the CC49 (HuCC49) high affinity anti-TAG-72 monoclonal antibody (MAb) is now available, as well as with the CH2 region deleted (HuCC49ACH2). The CH2 domain deleted MAb may have more rapid tumor penetration, a decreased circulation time and retain tumor localization/persistence characteristics. This project focuses on the development of bifunctional chelating agents (BCAs), derived from the hydroxamic acid class of organic compounds, for radiometal labeling of MAbs with 188Re for therapy. Based on the promising clinical results obtained in ovarian cancer patients at UAB with 177Lu-CC49, it would be valuable to determine in preclinical studies whether 188Re-HuCC49ACH2 administered in the peritoneum produces a higher relative tumor uptake in Jp. colon cancer nodules compared to blood, and to determine the relative tumor efficacy at the maximum tolerated dose of 188Re-HuCC49ACH2 VS. 188Re-HuCC49.
The specific aims are to: 1) expand the hydroxamate family of BCAs by the rational design and synthesis of new members with improved characteristics; 2) optimize antibody conjugation chemistries of novel, rationally designed pyridine diglycine dihydroxamate (PG2H2), pyridine dihydroxamate (PH2), cyclic peptide trihydroxamate (cyc-PH3), and diethylene triamine pentahydroxamic acid (DTPH) BCAs; 3) radiolabel hydroxamate-MAb conjugates with 99mTc and 188Re; 4) characterize the immunoreactivity and the in vitro and in vivo stabilities of 99mTc- and 188Re-labeled hydroxamate-conjugated MAbs HuCC49 and HuCC49ACH2; 5) compare the tumor localization and biodistribution of 188Re-labeled hydroxamate-MAbs HuCC49 and HuCC49ACH2 to those of 188Re-labeled MAG2-GABA conjugated MAbs; and 6) compare the relative therapeutic efficacy of 188Re-labeled MAbs HuCC49 and HuCC49ACH2 in athymic nude mice bearing intraperitoneal human cancer xenografts at escalating radionuclide doses at comparable maximum tolerated doses, and to compare to those of 188Relabeled MAG2-GABA conjugated MAbs. The investigators hypothesize that the use of HuCC49ACH2 will result in high Jp. tumor binding following ip. injection relative to HuCC49, but a much more rapid clearance from blood. It remains to be determined whether regionally administered CH2 deleted antibody administered into the peritoneum will produce a greater therapeutic effect against Jp. cancer at its maximum tolerated dose compared to intact antibody. The experiments described in this application will provide answers to these questions. These studies would establish the rationale for human clinical RIT trials in patients with Jp. cancer using HuCC49ACH2.
