Title: a Preclinical Model of Cd38-pretargeted Radioimmunotherapy for Plasma Cell Malignancies Authors

Running title: CD38 pretargeted RIT for plasma cell malignancies Disclosure of COI: The authors have no conflicts of interest to disclose. Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. ABSTRACT The vast majority of patients with plasma cell neoplasms die of progressive disease despite high response rates to novel agents. Malignant plasma cells are very radiosensitive, but the potential role of radioimmunotherapy (RIT) in the management of plasmacytomas and multiple myeloma (MM) has undergone only limited evaluation. Furthermore, CD38 has not been explored as a RIT target despite its uniform high expression on plasma cell malignancies. In this report, both conventional RIT (directly radiolabeled antibody) and streptavidin-biotin pretargeted RIT (PRIT) directed against the CD38 antigen, were assessed as approaches to deliver radiation doses sufficient for MM cell eradication. PRIT demonstrated biodistributions that were markedly superior to conventional RIT. Tumor-to-blood ratios as high as 638:1 were seen 24hr after PRIT, while ratios never exceeded 1:1 with conventional RIT. 90 Yttrium absorbed dose estimates demonstrated excellent target-to-normal organ ratios (6:1 for the kidney, lung, liver; 10:1 for the whole body). Objective remissions were observed within 7 days in 100% of the mice treated with doses ranging from 800 µCi to 1200 µCi of anti-CD38 pretargeted 90 Y-DOTA-biotin, including 100% complete remissions (no detectable tumor in treated mice compared to tumors that were 2982±2834% of initial tumor volume in control animals) by day 23. Furthermore, 100% of animals bearing NCI-H929 multiple myeloma tumor xenografts treated with 800 µCi of anti-CD38 pretargeted 90 Y-DOTA-biotin achieved long-term myeloma-free survival (>70 days) compared to none (0%) of the control animals. Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited.