title: Pharmacokinetics and tumor localization of (111)in-labeled HuCC49DeltaC(H)2 in BALB/c mice and athymic murine colon carcinoma xenograft.
abstract: The primary limitation of IgG antibodies for radioimmunotherapy of solid tumors is their prolonged serum half-life, leading to dose-limiting bone marrow toxicity at doses providing inadequate radiation to the tumor. A humanized C(H)2 domain-deleted variant of the anti-TAG-72 antibody CC49 (HuCC49DeltaC(H)2) has faster blood clearance, compared to the IgG, while retaining tumor targeting. We compared the pharmacokinetics and tumor uptake of (111)In-HuCC49DeltaC(H)2 in BALB/c mice and a colon carcinoma (LS-174T) mouse xenograft with that of (111)In-labeled chimeric CC49 (cCC49), an antibody with pharmacokinetics similar to the humanized CC49 parent. Immuno-conjugates of HuCC49DeltaC(H)2 and cCC49 prepared with the (111)In chelator Mx-DTPA (1-isothiocyantobenzyl-3-methyldiethylenetriaminepentaacetic acid) retained low nM affinity and radiolabeling protocols provided greater than 95% radio-incorporation with (111)In while retaining greater than 80% immunoreactivity. Blood clearance of (111)In-HuCC49DeltaC(H)2 in BALB/c mice was monoexponential (t(1/2) 5.4 hours) and faster than (111)In-cCC49 (biexponential clearance; t1/2Delta 1.5 hours; t1/2beta 162 hours). The (111)In-HuCC49DeltaC(H)2 also cleared more rapidly from the blood in the murine xenograft. At 1 hour postinjection, blood concentrations for (111)In-HuCC49DeltaC(H)2 and (111)In-cCC49 were comparable (25.5 injected dose per g [%ID/g] and 21.3 %ID/g, respectively); tumor uptake for (111)In- HuCC49DeltaC(H)2 was 7.9 %ID/g, compared to 7.5 %ID/g for (111)In-cCC49. However, at 24 hours, blood concentration for (111)In-HuCC49DeltaC(H)2 was less than (111)In-cCC49 (0.9 %ID/g versus 5.2 %ID/g, respectively) with comparable tumor retention (14.4 %ID/g versus 19.0 %ID/g, respectively). Faster blood clearance of (111)In-HuCC49DeltaC(H)2 and tumor localization comparable to that of (111)In-cCC49 provided a fourfold improved tumor-to-blood ratio for (111)In-HuCC49DeltaC(H)2 at 24 hours postinjection.
authors.affiliation: Biogen Idec, Cambridge, MA, USA. Paul.Chinn@biogenidic.com
authors.forename: Paul C
authors.initials: PC
authors.lastname: Chinn
authors.forename: Ron A
authors.initials: RA
authors.lastname: Morena
authors.forename: Denise A
authors.initials: DA
authors.lastname: Santoro
authors.forename: Timothy
authors.initials: T
authors.lastname: Kazules
authors.forename: Syed V S
authors.initials: SV
authors.lastname: Kashmiri
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Schlom
authors.forename: Nabil
authors.initials: N
authors.lastname: Hanna
authors.forename: Gary
authors.initials: G
authors.lastname: Braslawsky
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000737:chemistry / Q000276:immunology / Q000493:pharmacokinetics; D000912:Antibodies, Neoplasm / Q000276:immunology; D000951:Antigens, Neoplasm / Q000276:immunology; D001667:Binding, Competitive; D003110:Colonic Neoplasms / Q000097:blood / Q000000981:diagnostic imaging* / Q000276:immunology / Q000378:metabolism*; D005260:Female; D006023:Glycoproteins / Q000276:immunology; D006801:Humans; D007074:Immunoglobulin G / Q000276:immunology / Q000378:metabolism; D000922:Immunotoxins / Q000737:chemistry / Q000493:pharmacokinetics*; D007205:Indium Radioisotopes / Q000493:pharmacokinetics*; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D004369:Pentetic Acid / Q000031:analogs & derivatives / Q000737:chemistry; D011877:Radionuclide Imaging; D023041:Xenograft Model Antitumor Assays
chemical_list: D000911:Antibodies, Monoclonal; D000912:Antibodies, Neoplasm; D000951:Antigens, Neoplasm; C091202:B72.3 antibody; D006023:Glycoproteins; D007074:Immunoglobulin G; D000922:Immunotoxins; D007205:Indium Radioisotopes; C047052:tumor-associated antigen 72; C077295:2-(4-isothiocyanatobenzyl)-6-methyldiethylenetriaminepentaacetic acid; D004369:Pentetic Acid