Anti-tumor activities of immunotoxins made of monoclonal antibody B3 and various forms of Pseudomonas exotoxin.
B3 is a monoclonal antibody that reacts with a carbohydrate epitope present on a variety of proteins located on the surface of many cancer cells and a limited number of normal tissues. We evaluated the cytotoxic activity of immunotoxins composed of monoclonal antibody B3 coupled to native Pseudomonas exotoxin (PE) or two recombinant forms of Pseudomonas exotoxin, PEArg57 or LysPE40, a form of PE with a deletion of the cell binding domain. All three conjugates were cytotoxic to human cell lines expressing the B3 antigen on their surface. The survival of each of the three immunotoxins in the circulation of mice was determined after administering the immunotoxin i.v. The half-life in blood of B3-PE and B3-PEArg57 was 20 hr, whereas the half-life of B3-LysPE40 was 4 hr. The short half-life of B3-LysPE40 may be due to the absence of domain I of PE. To determine the therapeutic effects of the three immunotoxins, they were given intraperitoneally to nude mice bearing subcutaneous A431 tumors. All three immunotoxins caused complete regression of 50-mm3 tumors with no toxic effects to the animals at therapeutic doses. Furthermore, substantial regression was also noted with much larger tumors. Our data indicate that the monoclonal antibody B3, when coupled to PE or recombinant forms of PE, may be useful for the treatment of tumors expressing B3 antigen. The therapeutic window was largest with B3-LysPE40, which can be administered in higher doses because it lacks sequences in domain I of PE that enable PE to bind to nontarget cells.
Pai
L H
LH
Laboratory of Molecular Biology, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892.
Batra
J K
JK
FitzGerald
D J
DJ
Willingham
M C
MC
Pastan
I
I
D036002:ADP Ribose Transferases; D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage* / Q000276:immunology / Q000493:pharmacokinetics; D000912:Antibodies, Neoplasm / Q000008:administration & dosage*; D001427:Bacterial Toxins; D001943:Breast Neoplasms / Q000276:immunology; D002277:Carcinoma / Q000276:immunology* / Q000628:therapy; D002294:Carcinoma, Squamous Cell / Q000276:immunology / Q000628:therapy; D003602:Cytotoxicity, Immunologic; D005098:Exotoxins / Q000008:administration & dosage*; D006801:Humans; D000922:Immunotoxins / Q000276:immunology* / Q000493:pharmacokinetics; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D009374:Neoplasms, Experimental / Q000276:immunology / Q000628:therapy; D011549:Pseudomonas / Q000472:pathogenicity; D011994:Recombinant Proteins; D037521:Virulence Factors; D000097668:Pseudomonas aeruginosa Exotoxin A
D036002:ADP Ribose Transferases; D000911:Antibodies, Monoclonal; D000912:Antibodies, Neoplasm; D001427:Bacterial Toxins; D005098:Exotoxins; D000922:Immunotoxins; D011994:Recombinant Proteins; D037521:Virulence Factors; D000097668:Pseudomonas aeruginosa Exotoxin A