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Antigen-Drug Conjugates as a Novel Therapeutic Class for the Treatment of Antigen-Specific Autoimmune Disorders
Pickens, Chad J. Christopher, Matthew A. Leon, Martin A. Pressnall, Melissa M. Johnson, Stephanie N. Thati, Sharadvi Sullivan, Bradley P. Berkland, Cory
Pickens, Chad J.
Christopher, Matthew A.
Leon, Martin A.
Pressnall, Melissa M.
Johnson, Stephanie N.
Thati, Sharadvi
Sullivan, Bradley P.
Berkland, Cory
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Abstract
Multiple sclerosis represents the world’s most common cause of neurological disability in young people and is attributed to a loss of immune tolerance toward proteins of the myelin sheath. Typical treatment options for MS patients involve immunomodulatory drugs, which act non-specifically, resulting in global immunosuppression. The study discussed herein aims to demonstrate the efficacy of antigen-specific immunotherapies involving conjugation of disease causing auto-antigen, PLP139–151, and a potent immunosuppressant, dexamethasone. Antigen-drug conjugates (AgDCs) were formed using copper-catalyzed azide-alkyne cycloaddition chemistry with the inclusion of a hydrolyzable linker to maintain activity of released dexamethasone. Subcutaneous administration of this antigen-drug conjugate to SJL mice induced with experimental autoimmune encephalomyelitis protected the mice from symptom onset throughout the 25-day study, demonstrating enhanced efficacy in comparison to dexamethasone treatment. These results highlight the benefits of co-delivery of auto-antigens with immunosuppressant drugs as AgDCs for the treatment of autoimmune diseases.
Description
This document is the Accepted Manuscript version of a Published Work that appeared in final form in Molecular Pharmaceutics, copyright © American Chemical Society after peer review and technical editing by the publisher. To access the final edited and published work see doi.org/10.1021/acs.molpharmaceut.9b00063.
Date
2019-05-14
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American Chemical Society
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Keywords
Autoimmunity, Antigen-specific immunotherapy, Copper-catalyzed azide-alkyne cycloaddition, Experimental autoimmune encephalomyelitis, Antigen-drug conjugate
Citation
Pickens, C. J., Christopher, M. A., Leon, M. A., Pressnall, M. M., Johnson, S. N., Thati, S., Sullivan, B. P., & Berkland, C. (2019). Antigen-Drug Conjugates as a Novel Therapeutic Class for the Treatment of Antigen-Specific Autoimmune Disorders. Molecular pharmaceutics, 16(6), 2452–2461. https://doi.org/10.1021/acs.molpharmaceut.9b00063