Pharmacokinetics and Tumor Localization of111In-Labeled HuCC49ΔCH2 in BALB/c Mice and Athymic Murine Colon Carcinoma Xenograft
| Autor: | Ron A. Morena, Nabil Hanna, Braslawsky Gary R, Syed V. S. Kashmiri, Jeffrey Schlom, Paul Chinn, Denise A. Santoro, Timothy Kazules |
|---|---|
| Rok vydání: | 2006 |
| Předmět: |
Cancer Research
Pathology medicine.medical_specialty Antibodies Neoplasm medicine.drug_class medicine.medical_treatment Mice Nude Monoclonal antibody Binding Competitive BALB/c Mice Pharmacokinetics Mouse xenograft Colon carcinoma Antigens Neoplasm Carcinoma medicine Animals Humans Radiology Nuclear Medicine and imaging Radionuclide Imaging Glycoproteins Pharmacology Mice Inbred BALB C biology Chemistry Immunotoxins Indium Radioisotopes Antibodies Monoclonal General Medicine Pentetic Acid medicine.disease biology.organism_classification Xenograft Model Antitumor Assays Oncology Immunoglobulin G Radioimmunotherapy Colonic Neoplasms Cancer research biology.protein Female Antibody |
| Zdroj: | Cancer Biotherapy and Radiopharmaceuticals. 21:106-116 |
| ISSN: | 1557-8852 1084-9785 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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