A Novel Monoclonal Antibody Design for Radioimmunotherapy

Abstract

The generation of chimeric and complementary-determining region (CDR) grafted monoclonal antibodies (MAb) have reduced the immunogenicity problem in the clinical application of radioimmunotherapy with monoclonal antibodies. However, humanization (Hu) has prolonged the circulation (plasma T½) of radiolabeled antibodies, resulting in an increased normal tissue exposure to radioactivity and greater dose-limiting bone marrow suppression. To overcome this problem, a tumor-associated glycoprotein (TAG)-72-specific CDR grafted MAb with C_H2 domain deletion (ΔC_H2) was developed from the MAb CC49. Preclinical studies have demonstrated that HuCC49 ΔC_H2 clears more rapidly from the plasma of mice than HuCC49. This preliminary report describes the initial human experience with HuCC49 ΔC_H2 radiolabeled with ¹³¹I and administered to patients with metastatic colorectal carcinoma. In this pilot study we enrolled four patients who received a single infusion of 20 mg of HuCC49 ΔC_H2 (total protein dose) labeled with 10 mCi of ¹³¹I. Pharmacokinetics, biodistribution, dosimetry, and immune response were evaluated over 2-6 weeks. No toxicity was observed in this group of patients. A one-compartment bolus model using the non-linear (NLIN) procedures in Statistical Analysis Software (SAS®; SAS, Incorporated, Cary, NC) best describes the pharmacokinetics of the ¹³¹I-HuCC49 ΔC_H2 with a plasma mean T½ of 20 ± 3 hours, a mean residence time (MRT) of 29 ± 4 hours and a clearance rate(Cl) of 1.5 ± 0.1 mL/hours/kg. The whole body and marrow radiation dose estimates were 0.55 ± 0.06 rad/mCi and 1.00 ± 0.14 rad/mCi, respectively. All patients had positive localization of antibody to metastatic tumor sites. The ¹³¹I-HuCC49 ΔC_H2 biodistribution was similar to murine CC49. Three patients had no evidence of antibody response to HuCC49ΔC_H2 over 6 weeks of observation, and one patient had a marginal response by week 6. Intravenous administration of HuCC49 ΔC_H2 is safe and well tolerated. The deleted C_H2 construct has a shorter half-life compared with prior studies of murine CC49 but with similar biodistribution and low immunogenicity. These studies support the further clinical investigation of this agent in phase I trials by intravenous and intraperitoneal routes.