title: Engineered binding to erythrocytes induces immunological tolerance to E. coli asparaginase.
abstract: Antigen-specific immune responses to protein drugs can hinder efficacy and compromise safety because of drug neutralization and secondary clinical complications. We report a tolerance induction strategy to prevent antigen-specific humoral immune responses to therapeutic proteins. Our modular, biomolecular approach involves engineering tolerizing variants of proteins such that they bind erythrocytes in vivo upon injection, on the basis of the premise that aged erythrocytes and the payloads they carry are cleared tolerogenically, driving the deletion of antigen-specific T cells. We demonstrate that binding the clinical therapeutic enzyme Escherichia coli l-asparaginase to erythrocytes in situ antigen-specifically abrogates development of antibody titers by >1000-fold and extends the pharmacodynamic effect of the drug 10-fold in mice. Additionally, a single pretreatment dose of erythrocyte-binding asparaginase tolerized mice to multiple subsequent doses of the wild-type enzyme. This strategy for reducing antigen-specific humoral responses may enable more effective and safer treatment with therapeutic proteins and drug candidates that are hampered by immunogenicity.
authors.affiliation: Institute of Bioengineering, Ecole Polytechnique Fédérale de Lausanne, CH-1015 Lausanne, Switzerland. ; Anokion SA, CH-1024 Ecublens, Switzerland.
authors.forename: Kristen M
authors.initials: KM
authors.lastname: Lorentz
authors.affiliation: Institute of Bioengineering, Ecole Polytechnique Fédérale de Lausanne, CH-1015 Lausanne, Switzerland. ; Anokion SA, CH-1024 Ecublens, Switzerland.
authors.forename: Stephan
authors.initials: S
authors.lastname: Kontos
authors.affiliation: Institute of Bioengineering, Ecole Polytechnique Fédérale de Lausanne, CH-1015 Lausanne, Switzerland.
authors.forename: Giacomo
authors.initials: G
authors.lastname: Diaceri
authors.affiliation: Centre Hospitalier Universitaire Vaudois, University Hospital of Lausanne, CH-1011 Lausanne, Switzerland.
authors.forename: Hugues
authors.initials: H
authors.lastname: Henry
authors.affiliation: Institute of Bioengineering, Ecole Polytechnique Fédérale de Lausanne, CH-1015 Lausanne, Switzerland. ; Anokion SA, CH-1024 Ecublens, Switzerland. ; Institute for Molecular Engineering, University of Chicago, Chicago, IL 60637, USA. ; Materials Science Division, Argonne National Laboratory, Argonne, IL 60439, USA.
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Hubbell
keywords: Immunological tolerance; asparaginase; erythrocyte; protein drug