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Immunotoxins as cancer chemotherapeutic agents

Immunotoxins, composed of antibodies linked to protein toxins, are cell‐specific cytotoxic reagents that have been constructed as both chemical conjugates and fusion proteins. A variety of different toxins derived from plants, such as ricin, saporin, and bryodin, and bacteria, including Diphtheria toxin and Pseudomonas exotoxin, have been utilized to construct extremely cytotoxic immunotoxin molecules. Single‐chain immunotoxin fusion proteins composed of cloned antibody variable regions directly fused to toxins have several advantages over chemically conjugated forms, most importantly, enhanced in vivo antitumor activity. BR96 sFv‐PE40 is a single‐chain immunotoxin fusion protein that targets a Lewis‐Y related antigen expressed on the surface of solid tumor cells. Complete regression and, in certain cases, cure of established tumor xenografts have been observed with BR96 sFv‐PE40 administration into rodents. Clinical utility of immunotoxins has shown some promise but has been limited by many factors, most notably vascular leak syndrome (VLS). Our finding that rats serve as a model to study BR96 sFv‐PE40 mediated VLS has led to identification of potential inhibitors of this dose‐limiting toxicity. In summary, immunotoxins, especially single‐chain forms, offer exciting possibilities for therapy of cancer. © 1995 Wiley‐Liss, Inc.