title: Immune response to enzyme replacement therapies in lysosomal storage diseases and the role of immune tolerance induction.
abstract: 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.
authors.affiliation: Division of Medical Genetics, Department of Pediatrics, Duke University Medical Center, Durham, NC 27710, USA. Electronic address: priya.kishnani@duke.edu.
authors.forename: Priya S
authors.initials: PS
authors.lastname: Kishnani
authors.affiliation: Division of Medical Genetics, Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance, CA 90505-2006, USA. Electronic address: pdickson@labiomed.org.
authors.forename: Patricia I
authors.initials: PI
authors.lastname: Dickson
authors.affiliation: Division of Gastroenterology and Inborn Errors of Metabolism Products, Office of New Drugs, Center for Drug Evaluation and Research (CDER), Food and Drug Administration (FDA), Silver Spring, MD 20993-0002, USA. Electronic address: laurie.muldowney@fda.hhs.gov.
authors.forename: Laurie
authors.initials: L
authors.lastname: Muldowney
authors.affiliation: Division of Gastroenterology and Inborn Errors of Metabolism Products, Office of New Drugs, Center for Drug Evaluation and Research (CDER), Food and Drug Administration (FDA), Silver Spring, MD 20993-0002, USA. Electronic address: jessica.j.lee@fda.hhs.gov.
authors.forename: Jessica J
authors.initials: JJ
authors.lastname: Lee
authors.affiliation: Division of Therapeutic Proteins, Office of Biotechnology Products, CDER, FDA, Silver Spring, MD 20993-0002, USA. Electronic address: amy.rosenberg@fda.hhs.gov.
authors.forename: Amy
authors.initials: A
authors.lastname: Rosenberg
authors.affiliation: Shire, Lexington, MA 02421, USA. Electronic address: rabichan@shire.com.
authors.forename: Rekha
authors.initials: R
authors.lastname: Abichandani
authors.affiliation: Diabetes Center, University of California, San Francisco, San Francisco, CA 94143-0540, USA. Electronic address: jeff.bluestone@ucsf.edu.
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Bluestone
authors.affiliation: Northwestern University Feinberg School of Medicine, Ann & Robert H. Lurie Children's Hospital, Chicago, IL 60611, USA. Electronic address: bburton@luriechildrens.org.
authors.forename: Barbara K
authors.initials: BK
authors.lastname: Burton
authors.affiliation: Division of Gastroenterology and Inborn Errors of Metabolism Products, Office of New Drugs, Center for Drug Evaluation and Research (CDER), Food and Drug Administration (FDA), Silver Spring, MD 20993-0002, USA. Electronic address: maureen.dewey@fda.hhs.gov.
authors.forename: Maureen
authors.initials: M
authors.lastname: Dewey
authors.affiliation: National Organization for Rare Disorders, Washington, DC 20036, USA. Electronic address: afreitas@rarediseases.org.
authors.forename: Alexandra
authors.initials: A
authors.lastname: Freitas
authors.affiliation: National Organization for Rare Disorders, Washington, DC 20036, USA. Electronic address: dgavin@rarediseases.org.
authors.forename: Derek
authors.initials: D
authors.lastname: Gavin
authors.affiliation: Division of Gastroenterology and Inborn Errors of Metabolism Products, Office of New Drugs, Center for Drug Evaluation and Research (CDER), Food and Drug Administration (FDA), Silver Spring, MD 20993-0002, USA. Electronic address: donna.griebel@fda.hhs.gov.
authors.forename: Donna
authors.initials: D
authors.lastname: Griebel
authors.affiliation: Saving Case & Friends, Inc., a Hunter Syndrome Research Foundation, Thompson's Station, TN 37179, USA. Electronic address: melissa@savingcase.com.
authors.forename: Melissa
authors.initials: M
authors.lastname: Hogan
authors.affiliation: National MPS Society, Durham, NC 27709, USA. Electronic address: steve.holland@thomsonreuters.com.
authors.forename: Stephen
authors.initials: S
authors.lastname: Holland
authors.affiliation: Children's National Medical Center, Washington, DC 20010, USA. Electronic address: ptanpaib@childrensnational.org.
authors.forename: Pranoot
authors.initials: P
authors.lastname: Tanpaiboon
authors.affiliation: Center for Transplantation Sciences, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02129, USA. Electronic address: lturka@partners.org.
authors.forename: Laurence A
authors.initials: LA
authors.lastname: Turka
authors.affiliation: University of Minnesota, Masonic Children's Hospital, Minneapolis, MN 55455, USA. Electronic address: utz002@umn.edu.
authors.forename: Jeanine J
authors.initials: JJ
authors.lastname: Utz
authors.affiliation: Division of Clinical Pharmacology III, Office of Clinical Pharmacology, Office of Translational Sciences (OTS), CDER, FDA, Silver Spring, MD 20993-0002, USA. Electronic address: yowming.wang@fda.hhs.gov.
authors.forename: Yow-Ming
authors.initials: YM
authors.lastname: Wang
authors.affiliation: University of Minnesota, Masonic Children's Hospital, Minneapolis, MN 55455, USA. Electronic address: whitley@umn.edu.
authors.forename: Chester B
authors.initials: CB
authors.lastname: Whitley
authors.affiliation: Division of Medical Genetics, Department of Pediatrics, Duke University Medical Center, Durham, NC 27710, USA. Electronic address: zoheb.kazi@dm.duke.edu.
authors.forename: Zoheb B
authors.initials: ZB
authors.lastname: Kazi
authors.affiliation: OTS, CDER, FDA, Silver Spring, MD 20993-0002, USA. Electronic address: anne.pariser@fda.hhs.gov.
authors.forename: Anne R
authors.initials: AR
authors.lastname: Pariser
mesh_terms: D000818:Animals; D056947:Enzyme Replacement Therapy; D006801:Humans; D006867:Hydrolases / Q000276:immunology / Q000627:therapeutic use*; D007108:Immune Tolerance; D016464:Lysosomal Storage Diseases / Q000188:drug therapy* / Q000276:immunology; D011994:Recombinant Proteins / Q000276:immunology / Q000627:therapeutic use
chemical_list: D011994:Recombinant Proteins; D006867:Hydrolases
keywords: Enzyme replacement therapy; Immune tolerance; Inborn errors of metabolism; Lysosomal storage diseases; Neutralizing antibodies; Orphan drugs; Rare diseases