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Immunospecific Targeting of Cytosine Arabinonucleoside-containing Liposomes to the Idiotype on the Surface of a Murine B-Cell Tumor in Vitro and in Vivo¹

Department of Molecular Immunology [R. B. B., S. Y., S. K. G., Y-H. J.], and Department of Experimental Pathology [E. M.], Roswell Park Memorial Institute,^,4 Buffalo, New York 14263

A new tumor model is described that is suitable for the evaluation of antibody-directed drug-delivery protocols and a modification in the procedure for covalently coupling antibody to the surface of drug-containing liposomes is presented. These immunospecific liposomes containing cytosine arabinonucleoside (Ara-C) have been tested in vitro and in vivo for their ability to kill a B-cell tumor. The target of the immunospecific-Ara-C liposomes is the idiotype associated with an antigen-specific immunoglobulin receptor on the cell surface of a murine B-cell hybrid (2C3). Affinity-purified antibodies specific for the idiotype were covalently coupled to modified lipid on the surface of the large unilamelar liposomes containing drug. These liposomes were shown to kill idiotype-positive 2C3 cells in vitro, but not idiotype-negative variants of this same cell line. It was also established in vitro that the drug-containing liposomes were at least 40 times more efficient than free Ara-C in the killing of the tumor cells. The 2C3 tumor was also propagated in vivo following the i.p. administration of tumor cells. The tumor grew initially as multiple foci within the peritoneum and subsequently spread to the spleen. Tumorbearing mice were treated either with free Ara-C or with immunospecific liposomes containing Ara-C. Tumor growth in the primary tumor nodules and in the spleen was monitored by the administration of bromodeoxyuridine to the tumor-bearing animals followed by the immunofluorescent staining of cells with a monoclonal anti-bromodeoxyuridine antibody to estimate the proportion of cells in S phase. Our data from five out of seven animal experiments shows that the immunospecific-Ara-C liposomes, but not free drug, reduced tumor growth in the spleen. However, neither the liposomes containing drug nor the free drug were able to alter the growth of the primary tumor nodules growing in the peritoneal cavity. These results suggest that immunospecific-Ara-C containing liposomes may be useful in conjunction with other cytoreductive protocols in controlling tumor growth or preventing the spread of the tumor to other sites, but that immunospecific-Ara-C containing liposomes by themselves are not likely to eliminate an established tumor in vivo. We also demonstrate here that the administration of immunospecific-Ara-C containing liposomes in an animal having high levels of circulating tumor-associated antigen (i.e., IgG containing the idiotype) represents a potential clinically relevant hazard which must be considered when designing antibody-directed drug-delivery protocols.

¹ This work was supported in part by USPHS Grants CA33462, CA25253, CA22786 [R. B. B.], and CA39536 [S. K. G.] awarded by the National Cancer Institute, DHHS.

² To whom requests for reprints should be addressed, at Department of Molecular Immunology, Roswell Park Memorial Institute, 666 Elm Street, Buffalo, NY 14263.

³ Present address: Abbott Laboratory, Abbott Park, IL 60064.

⁴ A unit of the New York State Department of Health.

Received 9/29/87. Revised 7/20/88. Revised 9/16/88. Accepted 10/13/88.

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