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Biodistribution of Monoclonal Antibodies: Scale-up from Mouse to Human Using a Physiologically Based Pharmacokinetic Model¹

Steele Laboratory, Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114 [L. T. B., H. Z., R. K. J.]; Radiological Sciences Program, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139 [H. Z.]; and Hybritech, Inc., San Diego, California 92121 [D. G. M., W. F. B.]

The efficacy of a novel diagnostic or therapeutic agent depends on its selective localization in a target tissue. Biodistribution studies are expensive and difficult to carry out in humans, but such data can be obtained easily in rodents. We have developed a physiologically based pharmacokinetic model for scaling up data from mice to humans, the first such model for genetically engineered macromolecules that bind to their targets in vivo, such as mAbs. The mathematical model uses physiological parameters including organ volumes, blood flow rates, and vascular permeabilities; the compartments (organs) are connected anatomically. This allows the use of scale-up techniques to predict antibody distribution in humans. The model was tested with data obtained in human patients for the biodistribution of a mAb against carcinoembryonic antigen. The model was further tested for a two-step protocol: bifunctional antibodies and radiolabeled hapten, which compared favorably with data in both mice and humans. The model was useful for optimization of treatment parameters, such as dose and time interval of injections, binding affinities, and choice of molecular carrier. This framework may be applicable to other genetically engineered molecules (e.g., growth factors, antisense oligonucleotides, and gene-carrying vectors).

¹ This work was supported by grants from Hybritech and the National Cancer Institute (Grant R35-CA-56591). This work was presented at the 86th Annual Meeting of the American Institute of Chemical Engineers, San Francisco, CA, November 13–18, 1994, and at the Keystone Symposium on Drug Delivery, Hilton Head, SC, January 8–13, 1995.

Received 6/ 1/95. Accepted 8/14/95.

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