In vivo therapy of the BCL1 tumor: effect of immunotoxin valency and deglycosylation of the ricin A chain.
The in vivo therapeutic effects of Fab' and IgG anti-delta (anti-IgD)-ricin A chain immunotoxins were compared in mice bearing the surface IgD-positive BCL1 leukemia. The immunotoxins were prepared with either native or deglycosylated ricin A chain. Immunotoxin therapy was assessed both by the number of cells bearing the BCL1 immunoglobulin idiotype which remained in the spleen 24-48 h after injection with immunotoxin and by adoptive transfer of these spleen cells into normal mice. Immunotoxins prepared with either Fab'-anti-delta or IgG-anti-delta and native A chain induced a dose-dependent reduction in the number of idiotype-positive BCL1 cells present in the spleens of the tumor-bearing mice. The maximal therapeutic response was achieved with 250 micrograms of immunotoxin (containing 80-100 micrograms A chain) per mouse for both immunotoxins, resulting in tumor reduction of approximately 90%. This represents an elimination of 3-4 X 10(8) tumor cells. Reduction in the number of tumor cells was not observed with control reagents including antibody alone, antibody mixed with A chain, or an immunotoxin of irrelevant specificity. A Fab' immunotoxin prepared with deglycosylated ricin A chain was approximately 5-fold more effective as an antitumor reagent than the same immunotoxin prepared with native A chain; thus, optimal therapy was achieved after injection of 50 micrograms of immunotoxin (containing 15-20 micrograms A chain). Since the immunotoxins prepared with deglycosylated A chain were only 2-3-fold more toxic to the mice than those prepared with native A chain, the former resulted in a 2-3-fold increase in the therapeutic index.
Fulton
R J
RJ
Department of Microbiology, University of Texas Southwestern Medical Center, Dallas 75235.
Uhr
J W
JW
Vitetta
E S
ES
D000818:Animals; D001402:B-Lymphocytes / Q000276:immunology; D003602:Cytotoxicity, Immunologic; D004305:Dose-Response Relationship, Drug; D005260:Female; D006031:Glycosylation; D007072:Immunoglobulin D / Q000276:immunology; D007140:Immunoglobulin Fab Fragments / Q000276:immunology; D007074:Immunoglobulin G / Q000276:immunology; D000922:Immunotoxins / Q000627:therapeutic use* / Q000633:toxicity; D007928:Lethal Dose 50; D007942:Leukemia, Experimental / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D051379:Mice; D008807:Mice, Inbred BALB C; D012276:Ricin / Q000627:therapeutic use*; D013329:Structure-Activity Relationship
D007072:Immunoglobulin D; D007140:Immunoglobulin Fab Fragments; D007074:Immunoglobulin G; D000922:Immunotoxins; D012276:Ricin