Comparisons of the intraocular tissue distribution, pharmacokinetics, and safety of 125I-labeled full-length and Fab antibodies in rhesus monkeys following intravitreal administration

Autor: Joyce Mordenti, Valverde Cr, Fei Dt, Licko, Lea T. Berleau, Anne M. Ryan, R A Cuthbertson, Napoleone Ferrara, Fourre Km, Y G Meng, Allen Pc, K Thomsen
Rok vydání: 1999
Předmět:
Male
Vascular Endothelial Growth Factor A
Intraocular pressure
Pathology
medicine.medical_specialty
Eye Diseases
medicine.drug_class
Endothelial Growth Factors
Biology
Pharmacology
Toxicology
Monoclonal antibody
Antibodies
Monoclonal
Humanized
Eye
Weight Gain
030226 pharmacology & pharmacy
Pathology and Forensic Medicine
Injections
Iodine Radioisotopes
03 medical and health sciences
chemistry.chemical_compound
Immunoglobulin Fab Fragments
0302 clinical medicine
Bolus (medicine)
Pharmacokinetics
medicine
Animals
Humans
Tissue Distribution
Molecular Biology
Intraocular Pressure
Inflammation
Lymphokines
Vascular Endothelial Growth Factors
Antibodies
Monoclonal
Retinal
Inner limiting membrane
Cell Biology
Intravitreal administration
Trastuzumab
Macaca mulatta
Recombinant Proteins
Vitreous Body
medicine.anatomical_structure
chemistry
biology.protein
Autoradiography
Antibody
Zdroj: Toxicologic pathology. 27(5)
ISSN: 0192-6233
Popis: Access of recombinant proteins to the retina following intravitreal administration is poorly understood. A study was conducted in male Rhesus monkeys (15 to 28 mo of age; 2.8-3.3 kg) in order to compare the intraocular tissue distribution, pharmacokinetics, and safety of 125Iodine (I)-labeled full-length humanized rhuMAb HER2 antibody (148 kD) and of 125I-labeled humanized rhuMAb vascular endothelial growth factor Fab antibody (48.3 kD) following bilateral bolus intravitreal injection on day 0 (5 animals/group). The dose administered to each eye was 25 μg (9-10 μCi) in 50 μl. Animals were euthanatized on day 0 (1 hr postdose) and on days 1, 4, 7, and 14. Safety assessment included direct ophthalmoscopy, intraocular pressure measurements, clinical observations, body weight, and hematology and clinical chemistry panels. Blood and vitreous samples were collected daily (blood only) and at necropsy for pharmacokinetics and analysis for antibodies to the test materials; the ocular tissue distribution of the test material was evaluated by microautoradiography. All animals completed the study. Microautoradiography demonstrated that the full-length antibody did not penetrate the inner limiting membrane of the retina at any of the time points examined. In contrast, the Fab antibody fragment diffused through the neural retina to the retinal pigment epithelial layer at the 1-hr time point and persisted in this location for up to 7 days. Systemic exposure to test material was low but variable: the highest plasma concentration of the full-length antibody was 20.3 ng/ml, whereas plasma concentrations for the Fab antibody remained below the limit of quantitation (i.e.
Databáze: OpenAIRE
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