Engineered binding to erythrocytes induces immunological tolerance to E. coli asparaginase

Lorentz, Kristen M.; Kontos, Stephan; Diaceri, Giacomo; Henry, Hugues; Hubbell, Jeffrey A.

doi:10.1126/sciadv.1500112

Engineered binding to erythrocytes induces immunological tolerance to E. coli asparaginase

Journal Article · Wed Jul 01 00:00:00 EDT 2015 · Science Advances

DOI:https://doi.org/10.1126/sciadv.1500112· OSTI ID:1625944

Lorentz, Kristen M. ^[1]; Kontos, Stephan ^[2]; Diaceri, Giacomo ^[3]; Henry, Hugues ^[4]; Hubbell, Jeffrey A. ^[5]

Ecole Polytechnique Federale Lausanne (Switzlerland). Inst. of Bioengineering; Anokion SA, Ecublens (Switzerland); DOE/OSTI
Ecole Polytechnique Federale Lausanne (Switzlerland). Inst. of Bioengineering; Anokion SA, Ecublens (Switzerland)
Ecole Polytechnique Federale Lausanne (Switzlerland). Inst. of Bioengineering
Univ. Hospital of Lausanne (Switzerland). Centre Hospitalier Universitaire Vaudois
Ecole Polytechnique Federale Lausanne (Switzlerland). Inst. of Bioengineering; Anokion SA, Ecublens (Switzerland); Univ. of Chicago, IL (United States). Inst. for Molecular Engineering; Argonne National Lab. (ANL), Argonne, IL (United States). Materials Science Division

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.

View Accepted Manuscript (DOE)

Research Organization:: Argonne National Laboratory (ANL), Argonne, IL (United States)

Sponsoring Organization:: USDOE Office of Science (SC)

Grant/Contract Number:: AC02-06CH11357

OSTI ID:: 1625944

Journal Information:: Science Advances, Journal Name: Science Advances Journal Issue: 6 Vol. 1; ISSN 2375-2548

Publisher:: AAASCopyright Statement

Country of Publication:: United States

Language:: English

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Hybrid Erythrocyte Liposomes: Functionalized Red Blood Cell Membranes for Molecule Encapsulation Himbert, Sebastian; Blacker, Matthew J.; Kihm, Alexander Advanced Biosystems, Vol. 4, Issue 3 https://doi.org/10.1002/adbi.201900185	journal	January 2020
Engineering Immune Tolerance with Biomaterials Gammon, Joshua M.; Jewell, Christopher M. Advanced Healthcare Materials https://doi.org/10.1002/adhm.201801419	journal	January 2019
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Hybrid Erythrocyte Liposomes: Functionalized Red Blood Cell Membranes for Molecule Encapsulation Himbert, Sebastian; Blacker, Matthew J.; Kihm, Alexander Universität des Saarlandes https://doi.org/10.22028/d291-33226	collection	January 2020
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Targeting and delivery of therapeutic enzymes Dean, Scott N.; Turner, Kendrick B.; Medintz, Igor L. Therapeutic Delivery, Vol. 8, Issue 7 https://doi.org/10.4155/tde-2017-0020	journal	July 2017

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