A Novel Monoclonal Antibody Design for Radioimmunotherapy

Academic Article

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 T1/2) 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 CH2 domain deletion (ΔCH2) was developed from the MAb CC49. Preclinical studies have demonstrated that HuCC49ΔC H2 clears more rapidly from the plasma of mice than HuCC49. This preliminary report describes the initial human experience with HuCC49ΔCH2 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 HuCC49ΔCH2 (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-HuCC49Δ CH2 with a plasma mean T1/2 of 20 ± 3 hours, a mean residence time (MRT) of 29 ± 4 hours and a clearance rate (CI) 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-HuCC49ΔCH2 biodistribution was similar to murine CC49. Three patients had no evidence of antibody response to HuCC49ΔCH2 over 6 weeks of observation, and one patient had a marginal response by week 6. Intravenous administration of HuCC49ΔC H2 is safe and well tolerated. The deleted CH2 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.
  • Digital Object Identifier (doi)

    Pubmed Id

  • 2141043
  • Author List

  • Forero A; Meredith RF; Khazaeli MB; Carpenter DM; Shen S; Thornton J; Schlom J; LoBuglio AF
  • Start Page

  • 751
  • End Page

  • 759
  • Volume

  • 18
  • Issue

  • 5