Abstract:
:Reliable risk assessment for biotherapeutics requires accurate evaluation of risk factors associated with immunogenicity. Immunogenicity risk assessment tools were developed and applied to investigate the immunogenicity of a fully human therapeutic monoclonal antibody, ATR-107 [anti-interleukin (IL)-21 receptor] that elicited anti-drug antibodies (ADA) in 76% of healthy subjects in a Phase 1 study. Because the ATR-107 target is expressed on dendritic cells (DCs), the immunogenicity risk related to engagement with DC and antigen presentation pathways was studied. Despite the presence of IL-21R on DCs, ATR-107 did not bind to the DCs more extensively than the control therapeutic antibody (PF-1) that had elicited low clinical ADA incidence. However, ATR-107, but not the control therapeutic antibody, was translocated to the DC late endosomes, co-localized with intracellular antigen-D related (HLA-DR) molecules and presented a dominant T cell epitope overlapping the complementarity determining region 2 (CDR2) of the light chain. ATR-107 induced increased DC activation exemplified by up-regulation of DC surface expression of CD86, CD274 (PD-L1) and CD40, increased expansion of activated DC populations expressing CD86(hi), CD40(hi), CD83(hi), programmed death ligand 1 (PD-L1)(hi), HLA-DR(hi) or CCR7(hi), as well as elevated secretion of tumour necrosis factor (TNF)-α by DCs. DCs exposed to ATR-107 stimulated an autologous T cell proliferative response in human donor cells, in concert with the detection of immunoglobulin (Ig)G-type anti-ATR-107 antibody response in clinical samples. Collectively, the enhanced engagement of antigen presentation machinery by ATR-107 was suggested. The approaches and findings described in this study may be relevant to identifying lower immunogenicity risk targets and therapeutic molecules.
journal_name
Clin Exp Immunoljournal_title
Clinical and experimental immunologyauthors
Xue L,Hickling T,Song R,Nowak J,Rup Bdoi
10.1111/cei.12711subject
Has Abstractpub_date
2016-01-01 00:00:00pages
102-13issue
1eissn
0009-9104issn
1365-2249journal_volume
183pub_type
杂志文章abstract::A randomized controlled trial of treatment with thymic humoral factor (THF) in 20 children with severe complicated acute measles infection, resulted in objective benefit as evidenced by improvement in the ESR and a fall in C-reactive protein, fewer complications and a reduced incidence of secondary herpes infection. A...
journal_title:Clinical and experimental immunology
pub_type: 临床试验,杂志文章,随机对照试验
doi:
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abstract::We report a case of a combined immunodeficiency (CID) in a child affected by trichothiodystrophy (TTD) characterized by an altered response to ultraviolet (UV) light due to a defect in the XPD gene. The XPD gene encodes a subunit of the transcription factor II H (TFIIH), a complex involved in nucleotide-excision repai...
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journal_title:Clinical and experimental immunology
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doi:10.1111/j.1365-2249.1993.tb05979.x
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journal_title:Clinical and experimental immunology
pub_type: 杂志文章
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更新日期:1978-07-01 00:00:00
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journal_title:Clinical and experimental immunology
pub_type: 杂志文章
doi:
更新日期:1975-07-01 00:00:00
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journal_title:Clinical and experimental immunology
pub_type: 杂志文章
doi:
更新日期:1986-12-01 00:00:00
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journal_title:Clinical and experimental immunology
pub_type: 杂志文章
doi:
更新日期:1987-03-01 00:00:00
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doi:
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journal_title:Clinical and experimental immunology
pub_type: 杂志文章
doi:
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pub_type: 杂志文章
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journal_title:Clinical and experimental immunology
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journal_title:Clinical and experimental immunology
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pub_type: 杂志文章
doi:10.1046/j.1365-2249.1997.4581478.x
更新日期:1997-12-01 00:00:00
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pub_type: 杂志文章,多中心研究
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journal_title:Clinical and experimental immunology
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journal_title:Clinical and experimental immunology
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doi:
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journal_title:Clinical and experimental immunology
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journal_title:Clinical and experimental immunology
pub_type: 杂志文章
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journal_title:Clinical and experimental immunology
pub_type: 杂志文章
doi:
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