Targeted therapy of carcinomas using BR96 sFv-PE40, a single-chain immunotoxin that binds to the Le(y) antigen.
Monoclonal antibody BR96 recognizes a Le(y)-related carbohydrate antigen expressed on a wide range of carcinomas. Immunotoxins composed of BR96 and a binding defective form of Pseudomonas exotoxin A were constructed both as chemical conjugates and as fusion proteins. While both forms of BR96 immunotoxin were equally cytotoxic to human carcinoma cell lines in vitro, the fusion protein form, BR96 sFv-PE40, was > 10-fold more active in vivo as an antitumor agent. BR96 sFv-PE40 was used to target established human tumor xenografts in both mice and in rats. The rat which displays the Le(y) antigen on the same normal tissues as humans appears to be an appropriate model for the preclinical evaluation of this immunotoxin. Complete regressions of lung, breast and bladder carcinomas were obtained in these models upon administration of well-tolerated doses of BR96 sFv-PE40. The clinical limitations of BR96 sFv-PE40, as well as other immunotoxins, depend on the management and/or prevention of neutralizing anti-immunotoxin antibodies and the onset of toxicities, specifically vascular leak syndrome.
Siegall
C B
CB
Molecular Immunology Department, Bristol-Myers Squibb, Pharmaceutical Research Institute, Seattle, WA 98121, USA.
D036002:ADP Ribose Transferases; D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use; D001427:Bacterial Toxins; D002199:Capillary Permeability; D005098:Exotoxins / Q000627:therapeutic use*; D006801:Humans; D007128:Immunoglobulin Fragments / Q000627:therapeutic use; D007074:Immunoglobulin G / Q000627:therapeutic use; D000922:Immunotoxins / Q000627:therapeutic use*; D007983:Lewis Blood Group Antigens / Q000276:immunology*; D051379:Mice; D009374:Neoplasms, Experimental / Q000628:therapy*; D051381:Rats; D037521:Virulence Factors; D000097668:Pseudomonas aeruginosa Exotoxin A
D036002:ADP Ribose Transferases; D000911:Antibodies, Monoclonal; D001427:Bacterial Toxins; D005098:Exotoxins; D007128:Immunoglobulin Fragments; D007074:Immunoglobulin G; D000922:Immunotoxins; D007983:Lewis Blood Group Antigens; D037521:Virulence Factors; D000097668:Pseudomonas aeruginosa Exotoxin A; C094162:Lewis Y antigen; C055966:immunoglobulin Fv