title: Human/murine chimeric 81C6 F(ab')(2) fragment: preclinical evaluation of a potential construct for the targeted radiotherapy of malignant glioma.
abstract: We have obtained encouraging responses in recent Phase I studies evaluating (131)I-labeled human/murine chimeric 81C6 anti-tenascin monoclonal antibody (ch81C6) administered into surgically-created tumor resection cavities in brain tumor patients. However, because the blood clearance is slow, hematologic toxicity has been higher than seen with murine 81C6 (mu81C6). In the current study, a series of paired-label experiments were performed in athymic mice bearing subcutaneous D-245 MG human glioma xenografts to compare the biodistribution of the fragment ch81C6 F(ab')(2) labeled using Iodogen to a) intact ch81C6, b) mu81C6, and c) ch81C6 F(ab')(2) labeled using N-succinimidyl 3-[(131)I]iodobenzoate. Tumor retention of radioiodine activity for the F(ab')(2) fragment was comparable to that for intact ch81C6 for the first 24 h and to that for mu81C6 for the first 48 h; as expected, blood and other normal tissue levels declined faster for ch81C6 F(ab')(2.) Radiation dosimetry calculations suggest that (131)I-labeled ch81C6 F(ab')(2) may warrant further evaluation as a targeted radiotherapeutic for the treatment of brain tumors.
authors.affiliation: Department of Pathology, Duke University Medical Center, Durham, NC 27710, USA.
authors.forename: Abraham
authors.initials: A
authors.lastname: Boskovitz
authors.forename: Gamal H
authors.initials: GH
authors.lastname: Akabani
authors.forename: Charles N
authors.initials: CN
authors.lastname: Pegram
authors.forename: Darrell D
authors.initials: DD
authors.lastname: Bigner
authors.forename: Michael R
authors.initials: MR
authors.lastname: Zalutsky
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000493:pharmacokinetics* / Q000627:therapeutic use; D001822:Body Burden; D004353:Drug Evaluation, Preclinical; D005240:Feasibility Studies; D005910:Glioma / Q000378:metabolism* / Q000532:radiotherapy; D006801:Humans; D007140:Immunoglobulin Fab Fragments / Q000378:metabolism / Q000627:therapeutic use; D007457:Iodine Radioisotopes / Q000493:pharmacokinetics* / Q000627:therapeutic use; D008657:Metabolic Clearance Rate; D051379:Mice; D008819:Mice, Nude; D009928:Organ Specificity; D011829:Radiation Dosage; D016499:Radioimmunotherapy / Q000379:methods*; D019275:Radiopharmaceuticals / Q000493:pharmacokinetics / Q000627:therapeutic use; D011993:Recombinant Fusion Proteins / Q000493:pharmacokinetics / Q000627:therapeutic use; D014018:Tissue Distribution; D014407:Tumor Cells, Cultured
chemical_list: D000911:Antibodies, Monoclonal; D007140:Immunoglobulin Fab Fragments; D007457:Iodine Radioisotopes; D019275:Radiopharmaceuticals; D011993:Recombinant Fusion Proteins