title: 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 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 C(H)2 domain deletion (DeltaC(H)2) was developed from the MAb CC49. Preclinical studies have demonstrated that HuCC49 DeltaC(H)2 clears more rapidly from the plasma of mice than HuCC49. This preliminary report describes the initial human experience with HuCC49 DeltaC(H)2 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 DeltaC(H)2 (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 DeltaC(H)2 with a plasma mean T1/2 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 DeltaC(H)2 biodistribution was similar to murine CC49. Three patients had no evidence of antibody response to HuCC49 DeltaC(H)2 over 6 weeks of observation, and one patient had a marginal response by week 6. Intravenous administration of HuCC49 DeltaC(H)2 is safe and well tolerated. The deleted C(H)2 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.
authors: Department of Medicine, Division of Hematology/Oncology, Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, AL, USA. Andres.Forero@ccc.uab.edu
authors: Andres
authors: A
authors: Forero
authors: Ruby F
authors: RF
authors: Meredith
authors: M B
authors: MB
authors: Khazaeli
authors: D Mark
authors: DM
authors: Carpenter
authors: Sui
authors: S
authors: Shen
authors: Jennifer
authors: J
authors: Thornton
authors: Jeffrey
authors: J
authors: Schlom
authors: Albert F
authors: AF
authors: LoBuglio
mesh_terms: D000328:Adult; D000911:Antibodies, Monoclonal / Q000009:adverse effects / Q000276:immunology* / Q000493:pharmacokinetics / Q000627:therapeutic use*; D015179:Colorectal Neoplasms / Q000000981:diagnostic imaging / Q000276:immunology / Q000473:pathology / Q000532:radiotherapy*; D015195:Drug Design; D005260:Female; D006207:Half-Life; D006801:Humans; D008297:Male; D008875:Middle Aged; D009362:Neoplasm Metastasis / Q000000981:diagnostic imaging / Q000276:immunology / Q000473:pathology / Q000532:radiotherapy; D010865:Pilot Projects; D016499:Radioimmunotherapy / Q000379:methods*; D011877:Radionuclide Imaging
chemical_list: D000911:Antibodies, Monoclonal