Selective killing of Fc-receptor-bearing tumor cells through endocytosis of a drug-carrying immune complex.
A soluble immune complex was used as a drug carrier targeted to Fc-receptor-positive cells. Two receptor-positive tumor cell lines, WEHI-3 and M5076, were exposed to methotrexate-human serum albumin conjugate (MTX-HSA) in the presence and absence of anti-HSA antiserum. Both cell types were killed by 30 nM MTX when the drug conjugate was given in the presence of antiserum but were totally unaffected in the absence of antiserum. Drug-free HSA given with antiserum had no effect. Both cell lines responded similarly despite their marked difference in phagocytotic activity. One of the two lines, M5076, is defective in MTX transport and hence resistant to free MTX. Since this line would not be affected by MTX released extracellularly from MTX-HSA, its susceptibility implies that MTX is released inside cells, after endocytosis of the complex, and that endocytosis circumvents the transport defect. Two cell lines lacking Fc receptors (CHO and L929) were not influenced by the drug complex. The pharmacologic effect is mediated by a specific ligand-receptor interaction, since Fc receptor-positive cells are protected by an excess of unconjugated HSA and by the addition of a small amount of staphylococcal protein A, which binds to the Fc portion of IgG. These data demonstrate that Fc receptors can be exploited for cellular drug delivery using a common antigen-antibody complex as a drug carrier.
D000818:Animals; D000936:Antigen-Antibody Complex / Q000276:immunology*; D002460:Cell Line; D003602:Cytotoxicity, Immunologic; D004705:Endocytosis; D005260:Female; D006801:Humans; D007167:Immunotherapy; D007942:Leukemia, Experimental / Q000188:drug therapy / Q000276:immunology*; D016403:Lymphoma, Large B-Cell, Diffuse / Q000188:drug therapy / Q000276:immunology*; D008727:Methotrexate / Q000627:therapeutic use; D051379:Mice; D010051:Ovarian Neoplasms / Q000188:drug therapy / Q000276:immunology*; D010587:Phagocytosis; D011961:Receptors, Fc / Q000276:immunology*; D012709:Serum Albumin / Q000627:therapeutic use
D000936:Antigen-Antibody Complex; D011961:Receptors, Fc; D012709:Serum Albumin; C040811:methotrexate-serum albumin; D008727:Methotrexate