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Regional Localization of a Glioma-associated Antigen Defined by Monoclonal Antibody 81C6 in Vivo: Kinetics and Implications for Diagnosis and Therapy¹

Nuclear Medicine Department, NIH, Bethesda, Maryland 20892 [R. G. B., H. N.]; Department of Pathology, Duke University Medical Center, Durham, North Carolina 27710 [M. A. B., D. D. B.]; Division of Neurology, Northwestern University, Evanston Hospital, Evanston, Illinois 60201 [D. R. G.]; and Theoretical Statistics and Mathematics Branch, National Institute of Mental Health, NIH, Bethesda, Maryland 20892 [C. S. P.]

The pharmacokinetics and regional tissue distribution of two IgG2b immunoglobulins were studied in athymic mice with D₅₄MG human glioma xenografts. Monoclonal antibody (Mab) 81C6, an antiglioma antibody, had a plasma half-life of 2.7 ± 0.3 (SE) days; 45.6, a control immunoglobulin, had a plasma half-life of 3.3 ± 0.4 days. The immunoreactive fraction of 81C6 in plasma fell slowly from 0.37 to 0.23 over 9 days. The blood-to-tissue transfer constant (K₁) of Mab was 0.11 ± 0.05 ml/g/h in brain xenografts and 0.07 ± 0.02 ml/g/h in s.c. xenografts. In contrast, K₁ in muscle (0.005 ± 0.002) and brain (0.0004 ± 0.0001 ml/g/h) was much lower. The equilibration half-time of Mab in extracellular space was 1.1 ± 0.2 h in the brain xenografts, 3.6 ± 1.4 h in s.c. xenografts, and 8.1 and 24 h in muscle and brain, respectively. Distribution and binding of 81C6 was heterogeneous in the xenografts. A binding potential of 5–14 was found centrally and a binding potential of 0.8–1.0 was found peripherally in the brain xenografts. In the s.c. xenografts, the binding potential was higher peripherally than centrally. The exposure of D₅₄MG xenograft tissue to Mab 81C6 was not significantly limited by the permeability of the blood vessels or blood flow due to the long plasma half-life of the immunoglobulin. A comparison of Mab and -aminoisobutyric acid influx constants suggests that Mab entry into intracerebral xenografts occurs through large pores without significant sieving or steric restriction. Under such conditions the differences in influx constants between immunoglobulin and smaller immunoglobulin fragments will be proportional to the differences in their aqueous diffusion constants.

¹ An abstract of part of these studies has been presented, in Ann. Neurol., 16: 133, 1984.

² To whom requests for reprints should be addressed, at Nuclear Medicine Department, Clinical Center, Building 10 1C401, NIH, Bethesda, MD 20892.

³ Present address: Cancer Center, La Jolla Cancer Research Foundation, La Jolla, CA 92037.

Received 10/24/86. Revised 4/22/87. Accepted 5/22/87.

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