2008
DOI: 10.1038/nbt.1484
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Neutralizing antibodies to therapeutic enzymes: considerations for testing, prevention and treatment

Abstract: Lysosomal storage diseases are characterized by deficiencies in lysosomal enzymes, allowing accumulation of target substrate in cells and eventually causing cell death. Enzyme replacement therapy is the principal treatment for most of these diseases. However, these therapies are often complicated by immune responses to the enzymes, blocking efficacy and causing severe adverse outcomes by neutralizing product activity. It is thus crucial to understand the relationships between genetic mutations, endogenous resi… Show more

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Cited by 153 publications
(122 citation statements)
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References 86 publications
(89 reference statements)
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“…Immune reactions to all LSDs have been noted in individuals receiving ERT, resulting in hypersensitivity reactions, alteration of enzyme trafficking and half-life, and/or neutralization of enzyme activity. For many, such immune responses can be controlled by the use of modified administration procedures, antihistamines, corticosteroids, and/or other immune-suppressive drugs (Brooks et al, 2003;Wang et al, 2008). Because gene therapy provides a protein that is either foreign (in crossreacting immune material-negative [CRIM -] patients) or in quantities/quality not normally seen (in CRIM + patients), similar immune reactions are not unexpected.…”
Section: Complications Of Gene Therapy For Lsdsmentioning
confidence: 99%
“…Immune reactions to all LSDs have been noted in individuals receiving ERT, resulting in hypersensitivity reactions, alteration of enzyme trafficking and half-life, and/or neutralization of enzyme activity. For many, such immune responses can be controlled by the use of modified administration procedures, antihistamines, corticosteroids, and/or other immune-suppressive drugs (Brooks et al, 2003;Wang et al, 2008). Because gene therapy provides a protein that is either foreign (in crossreacting immune material-negative [CRIM -] patients) or in quantities/quality not normally seen (in CRIM + patients), similar immune reactions are not unexpected.…”
Section: Complications Of Gene Therapy For Lsdsmentioning
confidence: 99%
“…However, the expression of proteins that the patient's immune system has never been exposed to, or only in a truncated form, may prompt an immune response. This risk is apparent in the clinical use of enzyme replacement therapies for lysosomal storage diseases as well as hemophilia A and B, in which neutralizing antibodies to the replacement protein can limit therapeutic efficacy (42).…”
Section: Potential Causes Of Ipsc Immunogenicitymentioning
confidence: 99%
“…Clinical trials in other LSDs using similar ERT approaches were also successful, including Mucopolysaccharidosis I, II and VI [85][86][87][88][89][90]. Regular intravenous administration of a protein involves the risk of developing antibodies that can cause allergic reactions and/or inactivate the activity of the enzyme [91]. However, in general, ERTs proved to be well tolerated and those patients who exhibited seroconversion showed a decrease in the antibody titer during the treatment [60].…”
Section: Enzyme Therapymentioning
confidence: 99%