Immune response to enzyme replacement therapy: clinical signs of hypersensitivity reactions and altered enzyme distribution in a high titre rat model.
Immune responses to enzyme replacement therapy (ERT) have been reported and can result in a hypersensitivity/anaphylactic reaction during or immediately after enzyme infusion. We have investigated the infusion of the lysosomal enzyme N-acetylgalactosamine 4-sulphatase (4-sulphatase) into immunized, high titre rats as a model of immune response to ERT. To simulate ERT, high and low titre rats were infused with different doses of radiolabelled recombinant human 4-sulphatase (3H-rh4S). There was evidence of altered targeting, inactivation and degradation of 4-sulphatase in high titre (titre 1024000) 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, suggesting that the antibodies could be saturable in vivo. However, the rats treated with 5 mg/kg 3H-rh4S all had clinical signs of hypersensitivity reactions to 4-sulphatase infusion. There were no apparent signs 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 changes in 3H-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).
Brooks
D A
DA
Lysosomal Diseases Research Unit, Department of Chemical Pathology, Women's and Children's Hospital, North Adelaide, SA 5006, Australia. dbrooks@medicine.adelaide.edu.ac
Hopwood
J J
JJ
King
B M
BM
D000707:Anaphylaxis / Q000276:immunology; D000818:Animals; D002499:Centrifugation, Density Gradient; D004195:Disease Models, Animal; D006967:Hypersensitivity / Q000276:immunology*; D007109:Immunity / Q000276:immunology; D008099:Liver / Q000201:enzymology; D008661:Metabolism, Inborn Errors / Q000235:genetics / Q000628:therapy; D009087:Mucopolysaccharidosis VI / Q000235:genetics / Q000628:therapy; D020051:N-Acetylgalactosamine-4-Sulfatase; D051381:Rats; D011994:Recombinant Proteins / Q000276:immunology; D013429:Sulfatases / Q000276:immunology*
D011994:Recombinant Proteins; D013429:Sulfatases; D020051:N-Acetylgalactosamine-4-Sulfatase