IMMUNE-RESPONSE TO ENZYME REPLACEMENT THERAPY - CLINICAL SIGNS OF HYPERSENSITIVITY REACTIONS AND ALTERED ENZYME DISTRIBUTION IN A HIGH-TITER RAT MODEL

Immune responses to enzyme replacement therapy (ERT) have been reporte d and can result in a hypersensitivity/ anaphylactic reaction during o r immediately after enzyme infusion. We have investigated the infusion of the lysosomal enzyme N-acetylgalactosamine 4-sulphatase (4-sulphat ase) into immunized, high titre rats as a model of immune response to ERT. To simulate ERT, high and low titre rats were infused with differ ent doses of radiolabelled recombinant human 4-sulphatase (H-3-rh4S). There was evidence of altered targeting, inactivation and degradation of 4-sulphatase in high titre (titre 1 024 000) compared to low titre (titre 64) rats. There was more 4-sulphatase enzyme activity detected in 5 mg/kg high titre rats when compared to 1 mg/kg high titre rats, s uggesting that the antibodies could be saturable in vivo. However, the rats treated with 5 mg/kg H-3-rh4S all had clinical signs of hypersen sitivity reactions to 4-sulphatase infusion. There were no apparent si gns of adverse reactions in either the high titre 1 mg/kg rats or the low titre rats (1, 5 mg/kg). The high titre 5 mg/kg rats also had chan ges in H-3-rh4S distribution, with lower levels delivered to the liver and a marked increase in the level remaining in plasma, when compared to either 1 mg/kg high titre rats or low titre rats (1, 5 mg/kg). (C) 1998 Elsevier Science B.V. All rights reserved.