Anti-CD3 antibody induced immune tolerance to infused enzyme in enzyme replacement therapy for lysosomal storage disease

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Animal and human studies of enzyme replacement therapy for Pompe disease have indicated that antibodies(Abs) generated against infused recombinant humanα-glucosidase can have a negative impact on the therapeutic outcome and cause hypersensitivity reactions. We showed that parenteral administration of anti-CD3 Abs into mice can reduce the titer of anti-humanα-glucosidase Abs in wild-type mice administered the enzyme. Mice that had been treated with anti-CD3 Abs and then subjected to a secondary challenge withα-glucosidase showed a lower increase in Ab titers than control mice. Moreover, the administration of anti-CD3 Abs also reduced the levels of pre-existing Abs. Treatment with anti-CD3 Abs also prevented a lethal hypersensitivity reaction and reduced the Ab titers in a mouse model of Pompe disease. Mice treated with anti-CD3 Abs showed reduced numbers of CD4^+and CD8^+cells, and an increased ratio of CD4^+CD25^+/CD4^+and CD4^+CD25^+FoxP3^+/CD4^+cells. When the CD4^+CD25^+cells were depleted using anti-CD25 Abs, the observed reduction in Abs against the enzyme by anti-CD3 Abs was abrogated. This suggests that CD4^+CD25^+cells are important for the immune suppressive activity of anti-CD3 Abs. In summary, anti-CD3 Abs are useful for inducing immune tolerance to enzyme replacement therapy for Pompe disease.