Tracy R Daniels, University of California at Los Angeles, for cr

Tracy R. Daniels, University of California at Los Angeles, for critically reading the manuscript, and Raymond Kong and Ben Alderete for their technical assistance. These studies were supported by the NIH/NCI grants R01 CA107023, NIH/NCI R01 supplement CA107023-02S1 and CA57152-13S1, the UC MEXUS-CONACYT Postdoctoral Fellowship Program, the Howard Hughes Selleck PI3K inhibitor Medical Institute (HHMI) Gilliam Fellowship for Ph.D. studies, and the Whitcome Fellowship of the Molecular Biology Interdepartmental Ph.D. Program (MBIDP) at UCLA. GH is a member

of the National Council for Scientific and Technological Research (CONICET), Argentina.”" “
“Anti-drug antibodies occur with virtually all therapeutic proteins, although the incidence varies considerably, ranging from less than 10% of patients to nearly 100% (Schellekens, 2004). Factors pre-disposing to antibody development check details are a complex interaction between the therapeutic proteins, the formulation, dose, rate of administration, excipients, and patient-specific factors (Patten and Schellekens, 2003), making it very difficult to predict which individuals will

develop antibodies to therapeutic proteins. Type 1 Gaucher disease was one of the first enzyme deficiencies to be treated with a replacement enzyme. Gaucher disease is a lysosomal storage disorder resulting from deficiency of glucocerebrosidase; the lack of this enzyme leads

to accumulation of glucosylceramide within macrophages, which in turn leads to spleen, liver, bone, and hematologic abnormalities (Goker-Alpan, 2010). Replacement of the deficient enzyme by infusion of purified or recombinant human enzyme is associated with improvement in symptoms (Barton et al., 1991 and Grabowski PRKACG et al., 1995). Initially, replacement enzyme was purified from human placental tissue (Ceredase®, Genzyme Corporation, Cambridge, MA), but was limited by supply, and subsequently a recombinant protein produced in transformed Chinese hamster ovary cells, imiglucerase (Cerezyme®, Genzyme Corporation, Cambridge, MA), was made more widely available. Typically, patients receive infusions every 2 weeks, usually in the long-term if not for the remainder of their lives. Imiglucerase has been used in this way in several thousand patients to date, with a consistent rate of elicitation of antibodies, at approximately 15% (Starzyk et al., 2007). In 2010, another replacement glucocerebroside, velaglucerase alfa (VPRIV®, Shire Human Genetic Therapies, Cambridge, MA) was approved by the Food and Drug Administration (FDA), European Medicines Agency (EMA), and other regulatory agencies for use in patients with type 1 Gaucher disease. Velaglucerase alfa is produced by gene-activation of human glucocerebrosidase in a human fibroblast cell line, and contains the native human enzyme sequence.

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