The purpose of this investigation is to use antibody-directed liposomes containing cytotoxic agents to achieve specific in vitro destruction of leukemia cells in murine bone marrow prior to bone marrow transplantation. The model system will be the murine T-cell leukemia, AKR/J SL2, which can be implanted in congenic AKR/Cu mice, who differ only at the Thy 1 antigen. We have already shown effective and specific in vitro cell growth inhibition of SL2 leukemia cells by methotrexate-Gamma-aspartate encapsulated in liposomes conjugated with anti-Thy 1.1 antibody. Drug encapsulated in staphylococcal protein A-conjugated-liposomes (SPA-liposomes) is even more effective against the SL2 cells. The SPA-liposomes are 50-fold more effective against cells that have been pre-incubated with anti-Thy 1.1 than against SL2 cells incubated with non-specific antibody, and 144-fold more effective than free drug. Cell growth assays will be used to determine the optimal SPA-liposomes with regard to lipid composition, choice of drug, and choice of antibody or combinations of antibodies. The liposome efficacy will then be confirmed in a colony assay. The SPA-liposomes will be tested both in vitro and in vivo on mixtures of SL2 tumor cells seeded into congenic AKR/Cu murine bone marrow. The maximum number of cells that can be eradicated will be determined in a colony assay. Finally, lethally irradiated mice will receive an infusion of treated bone marrow to determine the effect of the drug-containing antibody-directed SPA-liposomes on hematologic reconstitution and efficacy for elimination of leukemia. This investigation will provide a new strategy for eradication of tumor cells prior to autologous bone marrow transplant in patients who have leukemia. Antibody-directed liposomes offer the advantages of more flexibility in selection of cytotoxic agent, the possibility of multiple antibody targeting and potential utility in post-transplant adjuvant therapy.
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