Antibody-directed targeting of liposomes to human cell lines: role of binding and internalization on growth inhibition.
Small unilamellar liposomes containing methotrexate or methotrexate-gamma-aspartate were conjugated to Staphylococcus aureus protein A and were thus able to bind cell-specific immunoglobulins for targeting to malignant human B- and T-cell lines. We were able to demonstrate enhanced protein A liposome uptake and growth inhibition by targeting with an anti-major histocompatibility complex class II antibody recognizing two different B-cell lines. The enhanced growth inhibition was specific for the targeting antibody and amounted to a 2- to 3-fold lowering of the concentration of drug required to inhibit cell growth by 50% as compared to nontargeted liposomes or liposomes targeted with an antibody not recognizing a cell surface antigen. A strong association between enhanced growth inhibition and liposome internalization as assessed by fluorescent-activated cell sorter analysis of carboxyfluorescein containing protein A liposomes was seen. By contrast, specific enhancement of growth inhibition was not seen with several anti-idiotype antibodies or antibodies to T-cell differentiation antigens. Liposome internalization did not occur with these antibodies. Failure of growth inhibition and PA liposome internalization could not be explained by differences in cell binding of the antibody PA liposomes or the degree of protein A binding of the targeting antibody. Although the ability of the targeting antibody to bind to the cell and to protein A are important, these factors alone are not sufficient to guarantee internalization and growth inhibition. Variations in rates of internalization of various cell surface antigen-antibody complexes may account for different protein A liposome mediated cytotoxicities.
Berinstein
N
N
Department of Medicine, Stanford University School of Medicine, California 94305.
Matthay
K K
KK
Papahadjopoulos
D
D
Levy
R
R
Sikic
B I
BI
D000818:Animals; D000906:Antibodies; D000954:Antigens, Surface / Q000276:immunology; D000970:Antineoplastic Agents / Q000633:toxicity*; D002455:Cell Division / Q000187:drug effects; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D006801:Humans; D007136:Immunoglobulins; D008081:Liposomes / Q000008:administration & dosage*; D008727:Methotrexate / Q000031:analogs & derivatives* / Q000633:toxicity*; D051379:Mice
D000906:Antibodies; D000954:Antigens, Surface; D000970:Antineoplastic Agents; D007136:Immunoglobulins; D008081:Liposomes; C037394:methotrexate-gamma-aspartate; D008727:Methotrexate