A flexible peptide spacer increases the efficacy of holoricin anti-T cell immunotoxins.

摘要: Immunotoxins, constructed by chemically cross-linking an antibody and protein toxin, do not possess the high efficacy of native toxin. Decreases in toxicity are due part to steric constraints imposed on two macromolecules, which result both decreased binding toxin function. In examining structural features that influence holotoxin-antibody conjugates, it was found incorporation a 29-residue polypeptide, derived from insulin B chain between ricin moiety, resulted increase potency efficacy. murine model system, peptide spacer conjugate increased nearly 10-fold; however, when examined procedure used purge bone marrow, demonstrably more toxic nontarget cells than nonspacer conjugate. Thus, addition increases potency, this novel immunotoxin demonstrated specificity approximately 10-fold. To test general utility inclusion, T101-ricin with spacer. It yielded synthesis inhibition rate -0.6 log/h MOLT-3 cells, greater 10-fold efficacious previously under similar conditions.