Immunotoxins containing single-chain ribosome-inactivating proteins.
We have summarized what is currently known about the distribution, biological role, and the mechanism of action of the single chain ribosome-inactivating proteins and described the purification of one of them, gelonin, as an example. ITs have been made with several of these proteins and, depending upon the antibody used for conjugation, these immunoconjugates can show specific in vitro cytotoxicity which is similar to that shown by equivalent ITs prepared with ricin A chain. The most potent of these conjugates have shown antitumor efficacy in a variety of animal tumor models, including both syngeneic rodent tumors and xenografts in nude or immunosuppressed mice. An important point needs to be addressed, however, before concluding that ITs containing single chain toxins will be clinically useful. A major problem with this approach is that it is likely that both the antibody and the toxin components of these conjugates will be immunogenic. Both antitoxin and antixenogenic immunoglobulin responses have been shown to occur in animals after infusion of IT, although it has not yet been clearly demonstrated that such antibody responses adversely effect the pharmacokinetics or the efficacy of immunoconjugates. Thus, preliminary enthusiasm over the efficacy of these new reagents must be tempered with the knowledge that their use in the clinic may be limited by the host immune responses or other as yet undefined factors. The fact that there are many immunologically distinct single chain ribosome-inactivating proteins does suggest one way of evading the antitoxin response, by a sequential treatment with a panel of immunoconjugates, each containing a different single chain toxin.
Lambert
J M
JM
Blättler
W A
WA
McIntyre
G D
GD
Goldmacher
V S
VS
Scott
C F
CF
D000818:Animals; D000911:Antibodies, Monoclonal; D002478:Cells, Cultured; D003432:Cross-Linking Reagents; D004354:Drug Screening Assays, Antitumor; D006207:Half-Life; D000922:Immunotoxins / Q000276:immunology / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use; D009374:Neoplasms, Experimental / Q000188:drug therapy; D010940:Plant Proteins / Q000302:isolation & purification / Q000494:pharmacology / Q000633:toxicity; D010947:Plants, Toxic / Q000032:analysis; D011500:Protein Synthesis Inhibitors / Q000302:isolation & purification / Q000494:pharmacology / Q000633:toxicity; D012270:Ribosomes / Q000187:drug effects*; D014118:Toxins, Biological / Q000302:isolation & purification / Q000494:pharmacology / Q000633:toxicity
D000911:Antibodies, Monoclonal; D003432:Cross-Linking Reagents; D000922:Immunotoxins; D010940:Plant Proteins; D011500:Protein Synthesis Inhibitors; D014118:Toxins, Biological