Recombinant antibody fragments and immunotoxin fusions for cancer therapy.
Recombinant immunotoxins consist of Fv regions of cancer specific antibodies fused to truncated bacterial toxins. Many recombinant immunotoxins contain a truncated version of Pseudomonas Exotoxin as a toxic moiety. This toxin is modified in such a manner that by itself it does not bind to normal human cells, but it retains all other functions of cytotoxicity. The recombinant antibody fragments target the modified toxin to cancer cells which are killed, either by direct inhibition of protein synthesis, or by concomitant induction of apoptosis. Cells that are not recognized by the antibody fragment, because they do not carry the cancer antigen, are spared. Many factors influence the in vivo anti-tumor activity of recombinant immunotoxins. Among them are considerations of which types of cancer and at what stages may be the best targets for immunotoxin therapy and tumor specificity of the antigen that is targeted by the recombinant antibody. Also the affinity of immunotoxins and their ability to enter and penetrate into tissues and tumors, which in turn is dependent on the size of the protein. And, because one very important factor is the stability of immunotoxins, a great deal of protein-engineering is required to stabilize the recombinant antibody moiety of immunotoxins. Excellent activity and specificity can be observed for many recombinant immunotoxins in in vitro assays using cultured cancer cells as well as in animal tumor models. Ongoing clinical trials provide examples where the promising preclinical data correlate with successful results in experimental cancer therapy.
Brinkmann
U
U
Epidauros Biotechnology, Pharmacogenetics Laboratory, Bernried, Germany. uli@epidauros.com
D001427:Bacterial Toxins / Q000235:genetics / Q000627:therapeutic use*; D006801:Humans; D007128:Immunoglobulin Fragments / Q000235:genetics / Q000276:immunology / Q000627:therapeutic use*; D000922:Immunotoxins / Q000235:genetics / Q000276:immunology / Q000627:therapeutic use*; D009369:Neoplasms / Q000188:drug therapy* / Q000276:immunology; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000276:immunology / Q000627:therapeutic use
D001427:Bacterial Toxins; D007128:Immunoglobulin Fragments; D000922:Immunotoxins; D011993:Recombinant Fusion Proteins; C055966:immunoglobulin Fv