Induction of Tolerance to Recombinant Therapeutic Proteins

Abstract

The specific IgM and IgG antibody responses to subcutaneous (s.c.) treatment of mice with recombinant human IFN-α2a (rHuIFN-α2a) or IFN-β were inhibited in a dose-dependent manner by prior oromucosal (o.m.) administration of rHuIFN-α2a or IFN-β, respectively. Pretreatment of animals once a day for 7 days by the o.m. route with the highest dose of IFN-α2a tested (10⁷ IU) resulted in complete inhibition of the peak IFN-α2a-specific IgG antibody response detected 28 days after subsequent s.c. injection of IFN-α2a (p< 0.001). Similarly, prior o.m. administration of 1–10 μg rHuGM-CSF per day for 7 days resulted in a statistically significant (p < 0.001) inhibition of the peak GM-CSF-specific IgG antibody response detected 28 days after s.c. administration of GM-CSF. In contrast, prior o.m. treatment with a quantity of bovine serum albumin (BSA) (100 μg) or human serum albumin (HSA)(10 μg) equivalent, respectively, to the protein content of the highest dose of IFN-α2a or GM-CSF administered by the o.m. route, did not affect significantly the IFN-α2a-specific or GM-CSF-specific IgG antibody responses detected on subsequent s.c. administration of IFN-α2a or GM-CSF. Oromucosal administration of IFN-α2a, IFN-β, or GM-CSF alone did not induce detectable IFN-α2a-specific, IFN-β-specific, or GM-CSF-specific IgM or IgG antibody responses at any of the time points tested. These results suggest that short-term o.m. administration of a recombinant protein is an effective means of inducing peripheral tolerance to subsequent parenteral administration of a therapeutic protein.