Immune response to enzyme replacement therapies in lysosomal storage diseases and the role of immune tolerance induction

Priya S. Kishnani, Patricia I. Dickson, Laurie Muldowney, Jessica J. Lee, Amy Rosenberg, Rekha Abichandani, Jeffrey A. Bluestone, Barbara K. Burton, Maureen Dewey, Alexandra Freitas, Derek Gavin, Donna Griebel, Melissa Hogan, Stephen Holland, Pranoot Tanpaiboon, Laurence A. Turka, Jeanine J. Utz, Yow Ming Wang, Chester B Whitley, Zoheb B. KaziAnne R. Pariser

Research output: Contribution to journalReview articlepeer-review

40 Scopus citations


The US Food and Drug Administration (FDA) and National Organization for Rare Disease (NORD) convened a public workshop titled "Immune Responses to Enzyme Replacement Therapies: Role of Immune Tolerance Induction" to discuss the impact of anti-drug antibodies (ADAs) on efficacy and safety of enzyme replacement therapies (ERTs) intended to treat patients with lysosomal storage diseases (LSDs). Participants in the workshop included FDA staff, clinicians, scientists, patients, industry, and advocacy group representatives. The risks and benefits of implementing prophylactic immune tolerance induction (ITI) to reduce the potential clinical impact of antibody development were considered. Complications due to immune responses to ERT are being recognized with increasing experience and lengths of exposure to ERTs to treat several LSDs. Strategies to mitigate immune responses and to optimize therapies are needed. Discussions during the workshop resulted in the identification of knowledge gaps and future areas of research, as well as the following proposals from the participants: (1) systematic collection of longitudinal data on immunogenicity to better understand the impact of ADAs on long-term clinical outcomes; (2) development of disease-specific biomarkers and outcome measures to assess the effect of ADAs and ITI on efficacy and safety; (3) development of consistent approaches to ADA assays to allow comparisons of immunogenicity data across different products and disease groups, and to expedite reporting of results; (4) establishment of a system to widely share data on antibody titers following treatment with ERTs; (5) identification of components of the protein that are immunogenic so that triggers and components of the immune responses can be targeted in ITI; and (6) consideration of early ITI in patients who are at risk of developing clinically relevant ADA that have been demonstrated to worsen treatment outcomes.

Original languageEnglish (US)
Pages (from-to)66-83
Number of pages18
JournalMolecular Genetics and Metabolism
Issue number2
StatePublished - Feb 1 2016

Bibliographical note

Funding Information:
P. I. Dickson: consulting fees, honoraria and/or research funding from BioMarin, Genzyme, Shire, Isis and Armagen Pharmaceuticals

Funding Information:
P. S. Kishnani: consulting fees, honoraria and/or research funding from Genzyme Corporation; Amicus Therapeutics; Shire Pharmaceuticals; Lysosomal Disease Network

Funding Information:
P. Tanpaiboon: honoraria and/or research funding from BioMarin and Genzyme

Funding Information:
J. Bluestone: consulting fees, honoraria and/or research funding from Juno Therapeutics, Macrogenics, Becton-Dickinson Biosciences, Flexus Biosciences, and Pfizer

Funding Information:
L. Turka: consulting fees, honoraria and/or research funding from Novartis, Myriad Genetics, NeXeption, Pelican Therapeutics, Ipsum

Publisher Copyright:
© 2015 Published by Elsevier Inc.


  • Enzyme replacement therapy
  • Immune tolerance
  • Inborn errors of metabolism
  • Lysosomal storage diseases
  • Neutralizing antibodies
  • Orphan drugs
  • Rare diseases


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