title: The chronic lymphocytic leukemia antigen (cCLLa) as immunotherapy target: pharmacokinetics and biodistribution of two divalent, ricin-based immunotoxins in xenografted athymic mice.
abstract: The chronic lymphocytic leukemia (CLL) antigen (cCLLa) is potentially suitable for targeted immunotherapy given its restriction to clonal CLL cells and lack of expression by normal lymphocytes. In order to assess the pharmacokinetics and biodistribution of two potent anti-cCLLa immunotoxins (ITs) were examined in the mouse model. The IgG fraction of anti-cCLLa monoclonal antibody CLL2m was conjugated with 125I-labeled intact (RTA) or deglycosylated (dgA) ricin chain A, injected intravenously into athymic mice engrafted with cCLLa-expressing human tumors, and monitored over 120 hours. Blood concentrations of CLL2m/125I-RTA and CLL2m/125I-dgA were best fit to biexponential equations but the latter exhibited a lower alphaT1/2 and betaT1/2 (4.1 and 102 min vs 5.9 and 126 min), a smaller volume of distribution (5.1 g vs 9.7 g), and a lower blood clearance (2.2 g/hr vs 4.6 g/hr). Both ITs exhibited preferential tumor uptake that followed distinct kinetics: rising tumor uptake for 2 hrs post-injection (while tissue uptake decreased), reaching tumor/non-tumoral tissue uptake ratios up to 16.9; and slower dissociation rates of tumor- vs tissue-bound ITs (>45% vs <20% remaining tissue-bound 6 hrs post-injection, respectively). Non-specific liver uptake was not prominent for either IT. In vivo IT deconjugation reached 50% approximately 12 hours pos-injection. The pharmacokinetics and biodistribution data in the mouse model suggest that ricin-based anti-cCLLa ITs are suitable for use in human trials.
authors.affiliation: Department of Medicine, Medical College of Georgia, VA Medical Center, Augusta 30910, USA.
authors.forename: G B
authors.initials: GB
authors.lastname: Faguet
authors.forename: J F
authors.initials: JF
authors.lastname: Agee
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000493:pharmacokinetics / Q000627:therapeutic use; D000951:Antigens, Neoplasm / Q000276:immunology*; D001345:Autoradiography; D006801:Humans; D007167:Immunotherapy / Q000379:methods; D000922:Immunotoxins / Q000493:pharmacokinetics* / Q000627:therapeutic use / Q000652:urine; D007457:Iodine Radioisotopes; D007668:Kidney / Q000378:metabolism; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000188:drug therapy / Q000378:metabolism* / Q000628:therapy*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D012276:Ricin / Q000493:pharmacokinetics* / Q000627:therapeutic use / Q000652:urine; D014018:Tissue Distribution; D014183:Transplantation, Heterologous
chemical_list: D000911:Antibodies, Monoclonal; D000951:Antigens, Neoplasm; D000922:Immunotoxins; D007457:Iodine Radioisotopes; C058497:common chronic lymphatic leukemia antigen gp69, human; D012276:Ricin