Abstract
Radioimmunotherapy (RIT) uses mAbs to deliver radionuclides to cancer cells or the tumor microenvironment and has shown promise in treating localized and diffuse tumors. While RIT agents have gained FDA/EMA approval for certain hematological malignancies, effectiveness of RIT in treating solid tumors remains limited. Here we present PreTarg-it®, a novel approach for pretargeted radioimmunotherapy, providing optimized delivery of payloads in a two-step regimen. The effectiveness of PreTarg-it® is demonstrated by a powerful combination of ON105, a novel bispecific antibody against both oxMIF and the histamine-succinyl-glycyl (HSG) hapten, as the first component and the radioactively labeled DOTA-di-HSG peptide as the second component in murine models of cancer. Mice bearing either subcutaneous mouse colorectal CT26 or human pancreatic CFPAC-1 tumors received an intravenous injection of ON105. After ON105 had accumulated in the tumor and cleared from circulation to approximately 1-3% of its peak concentration, 177Lu-DOTA-di-HSG peptide was administered. A single PreTarg-it® treatment cycle resulted in tumor regression when mice bearing CT26 tumors were given the highest treatment dose with a pretargeting delay of three days. Administered with a 5-day interval, the highest dose arrested tumor growth in both CT26 syngrafts and CFPAC-1 xenografts. In all cases, the highest treatment dose resulted in 100% survival at the study endpoint whereas the control cohorts showed 0% and 60% survival in the CT26 and CFPAC-1 models, respectively. Therefore, PreTarg-it® holds potential as a novel and potent therapy for patients with hard-to-treat solid tumors such as pancreatic cancer, as well as those with late-stage malignancies.