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

Access of recombinant proteins to the retina following intravitreal adminis tration 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 (125)Iodine (I)-labeled full -length humanized rhuMAb HER2 antibody (148 kD) and of I-125-labeled humani zed rhuMAb vascular endothelial growth factor Fab antibody (48.3 kD) follow ing bilateral bolus intravitreal injection on day 0 (5 animals/group). The dose administered to each eye was 25 mu g (9-10 mu Ci) in 50 mu 1. Animals were euthanatized on day 0 (1 hr postdose) and on days 1, 4, 7, and 14. Saf ety assessment included direct ophthalmoscopy, intraocular pressure measure ments, clinical observations, body weight, and hematology and clinical chem istry panels. Blood and vitreous samples were collected daily (blood only) and at necropsy for pharmacokinetics and analysis for antibodies to the tes t materials: the ocular tissue distribution of the test material was evalua ted by microautoradiography. All animals completed the study. Microautoradi ography demonstrated that the full-length antibody did not penetrate the in ner limiting membrane of the retina at any of the rime points examined. In contrast, the Fab antibody fragment diffused through the neural retina to t he 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 remaine d below the limit of quantitation (i.e., <7.8 ng/ml). An immune response to the test material was not evident in either treatment group. The half-life in vitreous was 5.6 days for the full-length antibody and 3.2 days for the Fab antibody. The shorter intravitreal half-life of the Fab antibody is re lated to its smaller size and its significant diffusion through the retinal layers. The differences in pharmacokinetics and tissue distribution that a re noted between the full-length and Fab antibodies in this study identify potential therapeutic approaches that may be exploited in specific disease conditions.