title: Enzyme Replacement Therapies and Immunogenicity in Lysosomal Storage Diseases: Is There a Pattern?
abstract: Lysosomal storage diseases arise because of genetic mutations that result in nonfunctioning or dysfunctional lysosomal enzymes responsible for breaking down molecules such as glycosaminoglycans or glycogen. Many of these storage diseases, such as the mucopolysaccharidosis (MPS) disorders and Pompe disease, can now be treated with infusion therapies to replace the dysfunctional protein with active enzyme. Although these therapies are effective, in at least one condition, infantile-onset Pompe disease, antibodies that develop against the drug significantly reduce its efficacy. However, this influence on efficacy does not appear to manifest across all enzyme replacement therapies. An example is MPS IVA, or Morquio A syndrome, in which the glycosaminoglycans keratan sulfate and chondroitin-6-sulfate accumulate in tissues as a result of N-acetylgalactosamine-6-sulfatase deficiency. The current approved treatment for MPS IVA is elosulfase alfa, a recombinant human enzyme replacement therapy. Although all patients receiving elosulfase alfa treatment develop antidrug antibodies and most develop neutralizing antibodies, clinical data to date show no effect on drug efficacy or safety. Overall, the relevance of antidrug antibodies specific to enzyme replacement therapies for the lysosomal storage diseases remains a mixed picture that will require time and continued clinical follow-up to resolve for each specific condition and treatment.
authors.affiliation: UCSF Benioff Children's Hospital Oakland, Oakland, California. Electronic address: pharmatz@mail.cho.org.
authors.forename: Paul
authors.initials: P
authors.lastname: Harmatz
mesh_terms: D057134:Antibodies, Neutralizing; D002811:Chondroitinsulfatases / Q000276:immunology* / Q000627:therapeutic use*; D056947:Enzyme Replacement Therapy; D006801:Humans; D009085:Mucopolysaccharidosis IV / Q000188:drug therapy*
chemical_list: D057134:Antibodies, Neutralizing; D002811:Chondroitinsulfatases; C102295:GALNS protein, human
keywords: Morquio A syndrome; antidrug antibody; elosulfase alfa; enzyme replacement therapy; immunogenicity; mucopolysaccharidosis