Recombinant immunotoxins for cancer therapy.
Recombinant immunotoxins consist of Fv regions of tumour-selective antibodies fused to toxins found in bacteria, plants or fungi. These toxins must be modified to remove normal-tissue binding sites but to retain 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 recognised by the antibody fragment because they do not carry the tumour antigen, are spared. Many factors influence the in vivo antitumour activity of recombinant immunotoxins. Among them are considerations of which types of cancer may be the best targets for immunotoxin therapy as well as tumour specificity of the antigen that is targeted by the recombinant antibody. Other relevant issues are the affinity of immunotoxins and their ability to enter and penetrate into tissues and tumours, which in turn is dependent on the size of the protein. A great deal of protein-engineering is required to stabilise the recombinant antibody moiety of immunotoxins, since stability of the molecules is crucial for good clinical efficacy. Excellent activity and specificity can be observed for many recombinant immunotoxins in in vitro assays using cultured cancer cells as well as in animal tumour 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 Lab, Bernried, FRG, Germany. uli@epidauros.com
Keppler-Hafkemeyer
A
A
Hafkemeyer
P
P
D000818:Animals; D000912:Antibodies, Neoplasm / Q000235:genetics / Q000276:immunology; D000951:Antigens, Neoplasm / Q000276:immunology; D017321:Clinical Trials, Phase I as Topic; D017322:Clinical Trials, Phase II as Topic; D006801:Humans; D000922:Immunotoxins / Q000737:chemistry / Q000235:genetics / Q000627:therapeutic use* / Q000633:toxicity; D009369:Neoplasms / Q000188:drug therapy* / Q000276:immunology; D015202:Protein Engineering; D017433:Protein Structure, Secondary; D011993:Recombinant Fusion Proteins / Q000737:chemistry / Q000235:genetics / Q000276:immunology / Q000627:therapeutic use / Q000633:toxicity
D000912:Antibodies, Neoplasm; D000951:Antigens, Neoplasm; D000922:Immunotoxins; D011993:Recombinant Fusion Proteins