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231224s2017 xx |||||o 00| ||eng c |
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|a 10.1016/j.clim.2017.01.003
|2 doi
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|a pubmed25n0893.xml
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|a (DE-627)NLM268019444
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|a (NLM)28089609
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|a (PII)S1521-6616(16)30373-4
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|a DE-627
|b ger
|c DE-627
|e rakwb
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| 041 |
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|a eng
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| 100 |
1 |
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|a Mufarrege, Eduardo F
|e verfasserin
|4 aut
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| 245 |
1 |
0 |
|a De-immunized and Functional Therapeutic (DeFT) versions of a long lasting recombinant alpha interferon for antiviral therapy
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| 264 |
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1 |
|c 2017
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| 336 |
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|a Text
|b txt
|2 rdacontent
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| 337 |
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|a ƒaComputermedien
|b c
|2 rdamedia
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| 338 |
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|a ƒa Online-Ressource
|b cr
|2 rdacarrier
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| 500 |
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|a Date Completed 05.06.2017
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|a Date Revised 06.02.2018
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|a published: Print-Electronic
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|a Citation Status MEDLINE
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|a Copyright © 2017 Elsevier Inc. All rights reserved.
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|a Interferon α (IFN-α) exerts potent antiviral, immunomodulatory, and antiproliferative activity and have proven clinical utility in chronic hepatitis B and C virus infections. However, repeated IFN-α administration induces neutralizing antibodies (NAb) against the therapeutic in a significant number of patients. Associations between IFN-α immunogenicity and loss of efficacy have been described. So as to improve the in vivo biological efficacy of IFN-α, a long lasting hyperglycosylated protein (4N-IFN) derived from IFN-α2b wild type (WT-IFN) was developed. However, in silico analysis performed using established in silico methods revealed that 4N-IFN had more T cell epitopes than WT-IFN. In order to develop a safer and more efficient IFN therapy, we applied the DeFT (De-immunization of Functional Therapeutics) approach to producing functional, de-immunized versions of 4N-IFN. Using the OptiMatrix in silico tool in ISPRI, the 4N-IFN sequence was modified to reduce HLA binding potential of specific T cell epitopes. Following verification of predictions by HLA binding assays, eight modifications were selected and integrated in three variants: 4N-IFN(VAR1), (VAR2) and (VAR3). Two of the three variants (VAR1 and VAR3) retained anti-viral function and demonstrated reduced T-cell immunogenicity in terms of T-cell proliferation and Th1 and Th2 cytokine levels, when compared to controls (commercial NG-IFN (non-glycosylated), PEG-IFN, WT-IFN and 4N-IFN). It was previously demonstrated that N-glycosylation improved IFN-α pharmacokinetic properties. Here, we further reduce immunogenicity as measured in vitro using T cell assays and cytokine profiling by modifying the T cell epitope content of a protein (de-immunizing). Taking into consideration the present results and previously reported immunogenicity data for commercial IFN-α2b variants, 4N-IFN(VAR1) and 4N-IFN-4N(VAR3) appear to be promising candidates for improved IFN-α therapy of HCV and HBV
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| 650 |
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4 |
|a Journal Article
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| 650 |
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|a De-immunization
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| 650 |
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|a Hepatitis therapy
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| 650 |
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4 |
|a IFN alpha
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| 650 |
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4 |
|a IFN-α
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| 650 |
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4 |
|a Immunogenicity
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| 650 |
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4 |
|a In silico prediction
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| 650 |
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4 |
|a T cell epitope
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| 650 |
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4 |
|a T-cell proliferation assay
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| 650 |
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7 |
|a Antibodies, Neutralizing
|2 NLM
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| 650 |
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7 |
|a Antiviral Agents
|2 NLM
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| 650 |
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7 |
|a Cytokines
|2 NLM
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| 650 |
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7 |
|a Epitopes, T-Lymphocyte
|2 NLM
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| 650 |
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7 |
|a Interferon-alpha
|2 NLM
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| 650 |
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7 |
|a Recombinant Proteins
|2 NLM
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| 700 |
1 |
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|a Giorgetti, Sofía
|e verfasserin
|4 aut
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| 700 |
1 |
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|a Etcheverrigaray, Marina
|e verfasserin
|4 aut
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| 700 |
1 |
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|a Terry, Frances
|e verfasserin
|4 aut
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| 700 |
1 |
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|a Martin, William
|e verfasserin
|4 aut
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| 700 |
1 |
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|a De Groot, Anne S
|e verfasserin
|4 aut
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| 773 |
0 |
8 |
|i Enthalten in
|t Clinical immunology (Orlando, Fla.)
|d 1999
|g 176(2017) vom: 06. März, Seite 31-41
|w (DE-627)NLM098196855
|x 1521-7035
|7 nnns
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| 773 |
1 |
8 |
|g volume:176
|g year:2017
|g day:06
|g month:03
|g pages:31-41
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| 856 |
4 |
0 |
|u http://dx.doi.org/10.1016/j.clim.2017.01.003
|3 Volltext
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| 912 |
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|a GBV_USEFLAG_A
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|a SYSFLAG_A
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|a GBV_NLM
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| 912 |
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|a GBV_ILN_11
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| 912 |
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|a GBV_ILN_24
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| 912 |
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|a GBV_ILN_350
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| 951 |
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|a AR
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| 952 |
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|d 176
|j 2017
|b 06
|c 03
|h 31-41
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