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Delivery of Melanoma-associated Immunoglobulin Monoclonal Antibody and Fab Fragments to Normal Brain Utilizing Osmotic Blood-Brain Barrier Disruption¹

Oregon Health Sciences University, Division of Neurosurgery, Portland, Oregon 97201 [E. A. N., P. A. B.]; Oncogen, Seattle, Washington 98121 [I. H., K. E. H.]; NeoRx, Seattle, Washington 98119 [P. B.]; Division of Neurosurgery, Oregon Health Sciences University, Portland, Oregon 97201 [C. I. M.]; and Department of Psychology, Veterans Administration Hospital, Portland, Oregon 97201 [R. M. W.]

Iodinated monoclonal antibodies (IgG 96.5 and two monomeric Fab fragments 96.5 and 48.7) to melanoma-associated antigens were administered after osmotic blood-brain barrier (BBB) opening in normal rats. Osmotic BBB disruption significantly (P <0.0001) increased monoclonal antibody delivery to the brain. Following BBB opening and intracarotid administration, there was no difference in the disrupted brain concentration integral area under the curve between Fab and IgG over the 72-h experimental period. However, Fab concentration in the disrupted brain was initially higher than IgG, and the clearance was more rapid (P < 0.001), decreasing 50% by approximately 4.5 h compared to 25.5 h for IgG. Plasma clearance was also more rapid for the Fab than IgG. The levels decreased 50% by 1.5 h for Fab and 15 h for IgG. The route and timing of antibody infusion had a significant effect on delivery to the disrupted brain with the Fab fragments but not with the intact IgG. Antibody recovered from disrupted brain retained its immunological reactivity as measured by a cell binding assay for at least 24 h. IgG and Fab delivery to the ipsilateral brain after BBB disruption increased (P < 0.001) with increasing dose over a more than 3-log dose range. These data provide information applicable to the therapeutic use of monoclonal antibodies in brain tumor treatment.

¹ These studies were supported by the Veterans Administration, USPHS Grants CA31770 and CA38011, and the Preuss Foundation.

² To whom requests for reprints should be addressed, at The Oregon Health Sciences University, 3181 S.W. Sam Jackson Park Road, Portland, OR 97201.

Received 7/23/87. Revised 1/ 4/88. Revised 4/22/88. Accepted 5/19/88.