Immune response to replacement therapy has been reported for a range of therapeutic strategies being developed for the treatment of patients with genetic disease. The potential problem of immune response to enzyme replacement therapy has been investigated in alpha-L-iduronidase immunized rats, representing a model of the lysosomal storage disorder Hurler syndrome (alpha-L-iduronidase deficiency). The antibody response to alpha-L-iduronidase showed that the positional location of antibody reactivity was similar for different immunized rats, but the precise linear sequence epitopes identified, varied between rats. A monoclonal antibody reacting to an epitope in close proximity to one high antigenicity site on alpha-L-iduronidase was used to reproduce the in vivo effect of altered enzyme tissue distribution, previously observed in immunized rats infused with alpha-L-iduronidase. The study demonstrated that during an immune response, antibody reacting to a single epitope could partially control the tissue distribution of antigen from circulation.