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Antibody-directed Liposomes: Comparison of Various Ligands for Association, Endocytosis, and Drug Delivery¹

Departments of Pediatrics [K. K. M.] and Pharmacology [T. D. H., D. P.] and the Cancer Research Institute [K. K. M., T. D. H., D. P.], University of California, San Francisco, California 94143, and the Fred Hutchinson Cancer Research Center [C. C. B., I. D. B.], University of Washington, Seattle, Washington 98104

We have developed and compared the cytotoxicity of methotrexate--aspartate encapsulated in several liposome formulations which bind mouse monoclonal antibody in order to define conditions for screening cell lines and antibodies for liposomal efficacy. Liposomes conjugated to Staphylococcus aureus Protein A were more potent than liposomes conjugated to either rabbit or affinity-purified goat anti-mouse immunoglobulin (Ig) when incubated with AKR/J SL2 cells sensitized with specific antibody. The antibody-directed Protein A liposomes were also 10-fold more potent than liposomes conjugated directly to specific antibody against the AKR/J SL2. We examined the effect of antibody specificity, concentration, and isotype on liposome-mediated drug delivery to AKR/J SL2 cells. The growth-inhibitory effect of the drug in the antibody-directed Protein A liposomes varied with the target antigen on the cell. The potency of the liposomes with a given antibody was proportional to their relative binding and endocytosis by the cells, and to the reactivity of the particular antibody with the cell as demonstrated by indirect immunofluorescence. The Protein A liposomes maintained maximal potency down to antibody concentrations as low as 1 µg/ml with the anti-Thy 1.1-sensitized AKR/J SL2 cells, thus demonstrating the possible use of these liposomes for hybridoma screening. Use of isotype-switched variants of the anti-Thy 1.1 antibody with the AKR/J SL2 cells showed the superior efficacy of the IgG2a, IgG2b, and IgG3 isotypes to the IgG1 with the Protein A liposomes. The large differential potency of the free drug and the drug encapsulated in antibody-directed Protein A liposomes was maintained even at short incubation times, thus providing a system which may be useful for eradication of tumor cells from bone marrow in vitro.

¹ Supported in part by USPHS Grant CA39448 (K. K. M.) awarded by the National Cancer Institute, Department of Health and Human Services; University of California, San Francisco, Academic Senate grant (K. K. M.); and University of California, San Francisco, Faculty Development award (K. K. M.).

² Recipient of American Cancer Society Junior Clinical Faculty Fellowship 723 and a Leukemia Society Special Fellowship. To whom requests for reprints should be addressed, at Cancer Research Institute, 1282 M, University of California School of Medicine, San Francisco, CA 94143.

³ Present address: School of Pharmacy, University of Wisconsin, Madison, WI 53706.

⁴ Recipient of an American Cancer Society Junior Faculty Clinical Fellowship.

Received 1/13/86. Revised 6/10/86. Accepted 6/13/86.

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