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Clin Immunol. 2016 Apr;165:55-9. doi: 10.1016/j.clim.2016.02.009. Epub 2016 Feb 27.

A role for plasma cell targeting agents in immune tolerance induction in autoimmune disease and antibody responses to therapeutic proteins.

Author information

1
Office of Biotechnology Products, CDER, FDA, Bldg 71/2238, 10903 New Hampshire Ave, Silver Spring, MD 20993, United States.
2
Office of Translational Sciences, CDER, FDA, United States.
3
Center for Autoimmune and Musculoskeletal Diseases, The Feinstein Institute for Medical Research, 350 Community Dr, Manhasset, NY 11030, United States.
4
Office of New Drugs, CDER, FDA, United States.
5
Massachusetts General Hospital East Transplantation Biology Research Center, 13th Street, Building 149-9019, Boston, MA 02129, United States.
6
Duke University School of Medicine, 595 Lasalle Street, GSRB 14th Floor, Room 4010, Durham, NC 27710, United States.

Abstract

Antibody responses to life saving therapeutic protein products, such as enzyme replacement therapies (ERT) in the setting of lysosomal storage diseases, have nullified product efficacy and caused clinical deterioration and death despite treatment with immune-suppressive therapies. Moreover, in some autoimmune diseases, pathology is mediated by a robust antibody response to endogenous proteins such as is the case in pulmonary alveolar proteinosis, mediated by antibodies to Granulocyte Macrophage-Colony Stimulating Factor (GM-CSF). In this work, we make the case that in such settings, when the antibody response is high titered, sustained, and refractory to immune suppressive treatments, the antibody response is mediated by long-lived plasma cells which are relatively unperturbed by immune suppressants including rituximab. However, long-lived plasma cells can be targeted by proteasome inhibitors such as bortezomib. Recent reports of successful reversal of antibody responses with bortezomib in the settings of ERT and Thrombotic Thrombocytopenic Purpura (TTP) argue that the safety and efficacy of such plasma cell targeting agents should be evaluated in larger scale clinical trials to delineate the risks and benefits of such therapies in the settings of antibody-mediated adverse effects to therapeutic proteins and autoantibody mediated pathology.

KEYWORDS:

Autoantibodies; Enzyme replacement therapy; Immune tolerance; Plasma cells

PMID:
26928739
DOI:
10.1016/j.clim.2016.02.009
[Indexed for MEDLINE]

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