Methotrexate reduces antibody responses to recombinant human α‐galactosidase A therapy in a mouse model of Fabry disease

• Published in: Clinical and experimental immunology Vol. 137; no. 3; pp. 496 - 502
• Main Authors: GARMAN, R. D., MUNROE, K., RICHARDS, S. M.
• Format: Journal Article
• Language: English
• Published: Oxford, UK Blackwell Science Ltd 01.09.2004; Blackwell; Blackwell Science Inc
• Subjects: alpha-Galactosidase - administration & dosage; alpha-Galactosidase - genetics; alpha-Galactosidase - immunology; Animal Studies; Animals; Antibodies - blood; antibody; Biological and medical sciences; enzyme replacement therapy; Fabry disease; Fabry Disease - drug therapy; Fabry Disease - immunology; Fabry Disease - therapy; Female; Fundamental and applied biological sciences. Psychology; Fundamental immunology; Immunopathology; Immunosuppressive Agents - therapeutic use; lysosomal storage disease; Male; Medical sciences; methotrexate; Methotrexate - therapeutic use; Mice; Mice, Inbred BALB C; Mice, Knockout; Models, Animal; mouse model; Recombinant Proteins - administration & dosage; Recombinant Proteins - immunology; Spleen - immunology; Antineoplastic agent; Animal model; Fabry disease enzyme replacement therapy methotrexate lysosomal storage disease antibody mouse model; Fabry disease; Cardiovascular disease; Lipids; Enzymopathy; Antifolate; Vascular disease; Immunology; Recombinant protein; Methotrexate; Lipoidosis; Human; Immunopathology; Nervous system diseases; Immune response; Enzyme; Antibody; Rodentia; Metabolic diseases; Genetic disease; Vertebrata; Mammalia; Treatment; Antimetabolic; Mouse; α-Galactosidase; Glycosidases; Hydrolases; O-Glycosidases
• ISSN: 0009-9104; 1365-2249
• DOI: 10.1111/j.1365-2249.2004.02567.x

SUMMARY Therapeutic enzymes are often recognized as foreign by the immune system of patients undergoing enzyme replacement therapy. The antibodies that develop may alter pharmacokinetics and biodistribution of the therapeutic protein, may be able to neutralize the activity of the enzyme, or may cause immune reactions in certain patients. We have explored treatment regimens to reduce the antibody response to human α‐galactosidase A (r‐hαGAL) in Fabry (αGAL knock‐out) and normal BALB/c mice. A wide variety of treatment modalities were tested, including high dose tolerance induction, increased frequency of therapeutic doses and immunosuppressive drugs in combination with administration of enzyme. The most substantial effects were observed in mice injected intravenously with r‐hαGAL in combination with methotrexate (MTX), which significantly lowered r‐hαGAL‐specific serum antibody levels. A short course of treatment with MTX was able to reduce antibody and spleen cell proliferative responses to long‐term r‐hαGAL treatment. MTX was able to suppress the development of r‐hαGAL‐specific IgG in antigen‐primed mice. However, MTX was not effective in dampening robust ongoing antibody responses. These experiments provide a framework for the design of clinical protocols to prevent the drug‐specific antibody responses of patients undergoing enzyme replacement therapy.