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Role of Ligand in Antibody-directed Endocytosis of Liposomes by Human T-Leukemia Cells¹

Department of Pediatrics [K. K. M., S. C.], Cancer Research Institute [K. K. M., A. M. A., K. H., D. P.], and Department of Pharmacology [R. M. S., D. P.], University of California, San Francisco, California 94143

The rate of uptake and intracellular processing of ligand-directed drug carriers may depend heavily on the endocytic pathway of the target antigen. We examined the role of the target antigen and type of antibodyliposome linkage in determining endocytosis of liposomes by three human T-cell leukemias, Jurkat, CEM, and Molt-4. Liposome-cell binding and internalization over time were studied using two independent assays for intracellular delivery of liposome contents: a new fluorescence assay using a pH-sensitive fluorescent dye; and a growth inhibition assay for delivery of cytotoxic drug, methotrexate--aspartate. Liposomes targeted against the transferrin receptor showed greater surface binding, internalization, and growth inhibition than liposomes targeted against the T-cell surface antigens, CD2, CD3, or CD5. Furthermore, liposomes made by conjugating the targeting antibody directly to the liposome surface were more efficiently internalized and retained than were liposomes linked to antibody-coated cells via Protein A. Selection of the type of antibodyliposome conjugate as well as the appropriate surface receptor to facilitate endocytosis is essential in antibody-directed drug treatment of cancer.

¹ Supported by USPHS Grants CA39448 (K. K. M.) and CA35340 (D. P.) awardec by the National Cancer Institute, Department of Health and Human Services.

² To whom requests for reprints should be addressed: Department of Pediatrics, Box 0106, 653 M, University of California, School of Medicine, San Francisco, CA 94143.

³ Recipient of Pediatric Clinical Research Center Summer Fellowship, USPHS Grant RR01271.

⁴ Present address: Department of Pharmaceutics, 539 Cooke Hall, State University of New York at Buffalo, Amherst, NY 14260.

Received 9/15/88. Revised 2/15/89. Revised 5/ 9/89. Accepted 5/16/89.

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