Radioimmunotherapy: An Anti-Neoplastic Strategy

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DESCRIPTION (provided by applicant): Despite high response rates to first-line chemotherapy after surgery for stage III epithelial ovarian cancer (EOC), the 5Y DFS rate rarely exceeds 15%. More than 50% of the patients with a laparotomy-confirmed complete response will relapse. Clearly, more effective therapy is needed! Since failure to control intra-abdominal disease remains the primary problem, there is considerable interest in the use of radiolabeled antibodies administered intra-peritoneal (IP). Several studies (including ours) targeting IP the tumor-associated antigen TAG-72 in EOC have shown encouraging results. CC49, a second-generation murine (m) anti-TAG-72 antibody, has an affinity constant six times higher than the original anti-TAG-72 antibody B72.3 and has shown a 16-fold increase in tumor: blood ratio using human xenografts in athymic mice compared with B72.3. The immunogenicity of mCC49, the long half-life (50h) and the projected even longer half-life of a chimeric or CDR-grafted version led to studies directed at humanization with deletion of various parts in search of a construct with low immunogenicity and half-life in the range of 15-40h. Humanized CC49 with a deleted CH2 region (HuCC49ACH2) fulfilled the criteria. Pre-clinical studies with HuCC49ACH2 showed that the plasma clearance is faster than the HuCC49 and the tumor to normal tissues ratio was higher compared with the HuCC49. Thus, HuCC49ACn2 was expected to have reduced immunogenicity (humanized version), to retain the dimeric binding site of the intact antibody, and to have relatively short circulation time in humans. Our pilot/phase I study of IV 131I-HuCC49ACH2 in patients with metastatic colorectal cancer showed a plasma T1/2 of 20 +/- 3h compared favorably with our prior data with mCC49 which had a T1/2 of 50 +/- 1h. All patients had positive radioimmune-imaging of at least one known tumor sites and there was low immunogenicity. Thus, in patients with relapsed or primary refractory EOC confined to the peritoneal cavity (+/- retroperitoneal nodes), we will: determine the maximum tolerated dose of IP l31I-HuCC49ACH2 and its toxicity profile; determine the plasma pharmacokinetics, whole body biodistribution, dosimetry and conjugate stability of HuCC49ACH2 administered IP; characterize the human immune response against 131I-HuCC49ACn2 given IP; and as a secondary endpoint, we will monitor for anti-tumor effects. The follow-up trial will be a phase II study to determine the efficacy of 131I-HuCC49ACH2 in resistant/refractory EOC patients.