PMID- 31588375
OWN - NLM
STAT- PubMed-not-MEDLINE
LR  - 20220410
IS  - 2164-2591 (Print)
IS  - 2164-2591 (Electronic)
IS  - 2164-2591 (Linking)
VI  - 8
IP  - 5
DP  - 2019 Sep
TI  - Uveitis Therapy With Shark Variable Novel Antigen Receptor Domains Targeting 
      Tumor Necrosis Factor Alpha or Inducible T-Cell Costimulatory Ligand.
PG  - 11
LID - 10.1167/tvst.8.5.11 [doi]
LID - 11
AB  - PURPOSE: We assess the efficacy of two next-generation biologic therapies in 
      treating experimental autoimmune uveitis. METHODS: Variable binding domains from 
      shark immunoglobulin novel antigen receptors (VNARs) were fused with a mouse 
      IgG2a constant domain (Fc) to generate VNAR-Fc molecules with binding specificity 
      to tumor necrosis factor alpha (TNFalpha) or inducible T-cell costimulatory ligand 
      (ICOSL). Treatment with VNAR-Fc fusion proteins was compared to treatment with 
      dexamethasone or vehicle in the Lewis rat model of experimental autoimmune 
      uveitis (EAU). Inflammation control was determined by comparing OCT clinical and 
      histologic scores, and aqueous humor protein concentration. The concentration of 
      27 inflammatory cytokines in the aqueous humor was measured using a multiplex 
      enzyme-linked immunosorbent assay platform. RESULTS: Administration of S17-Fc 
      significantly decreased clinical, histologic, and aqueous protein levels when 
      compared to vehicle treatment. Inflammation scores and aqueous protein levels in 
      A5-Fc-treated animals were decreased compared to vehicle treatment, but not 
      significantly. The concentration of vascular endothelial growth factor (VEGF), 
      regulated on activation, normal T cell expressed and secreted (RANTES), 
      macrophage inflammatory protein 1 alpha (MIP-1alpha), interleukin (IL)-1beta, 
      LPS-induced CXC chemokine (LIX), monocyte chemoattractant protein-1 (MCP-1), and 
      interferon (IFN)-gamma were significantly decreased in the eyes of animals treated 
      with dexamethasone. VNAR treatment demonstrated a trend towards decreased 
      cytokine concentrations, but only VEGF and RANTES were significantly decreased by 
      S17-Fc. CONCLUSIONS: Treatment with the anti-TNFalpha VNAR S17-Fc ameliorates EAU as 
      effectively as treatment with corticosteroids. TRANSLATIONAL RELEVANCE: VNAR-Fc 
      molecules are a next-generation therapeutic biologic that overcome the 
      limitations of classical biologic monoclonal antibodies, such as complex 
      structure, large size, and limited tissue penetration. This is a novel drug 
      modality that could result in the development of new therapy options for patients 
      with noninfectious uveitis.
CI  - Copyright 2019 The Authors.
FAU - Pepple, Kathryn L
AU  - Pepple KL
AD  - Department of Ophthalmology, University of Washington, Seattle, WA, USA.
FAU - Wilson, Leslie
AU  - Wilson L
AD  - Department of Ophthalmology, University of Washington, Seattle, WA, USA.
FAU - Van Gelder, Russell N
AU  - Van Gelder RN
AD  - Department of Ophthalmology, University of Washington, Seattle, WA, USA.
AD  - Department of Biological Structure, University of Washington, Seattle, WA, USA.
AD  - Department of Pathology, University of Washington, Seattle, WA, USA.
FAU - Kovaleva, Marina
AU  - Kovaleva M
AD  - Elasmogen Ltd, Aberdeen, UK.
FAU - Ubah, Obinna C
AU  - Ubah OC
AD  - Elasmogen Ltd, Aberdeen, UK.
FAU - Steven, John
AU  - Steven J
AD  - Elasmogen Ltd, Aberdeen, UK.
FAU - Barelle, Caroline J
AU  - Barelle CJ
AD  - Elasmogen Ltd, Aberdeen, UK.
FAU - Porter, Andrew
AU  - Porter A
AD  - Elasmogen Ltd, Aberdeen, UK.
AD  - Department of Molecular and Cell Biology, Institute of Medical Sciences, 
      University of Aberdeen, UK.
LA  - eng
GR  - K08 EY023998/EY/NEI NIH HHS/United States
GR  - P30 EY001730/EY/NEI NIH HHS/United States
PT  - Journal Article
DEP - 20190918
PL  - United States
TA  - Transl Vis Sci Technol
JT  - Translational vision science & technology
JID - 101595919
PMC - PMC6753974
OTO - NOTNLM
OT  - Lewis rat
OT  - TNF-alpha
OT  - experimental autoimmune uveitis
OT  - treatment
OT  - uveitis
EDAT- 2019/10/08 06:00
MHDA- 2019/10/08 06:01
PMCR- 2019/09/18
CRDT- 2019/10/08 06:00
PHST- 2018/12/04 00:00 [received]
PHST- 2019/07/15 00:00 [accepted]
PHST- 2019/10/08 06:00 [entrez]
PHST- 2019/10/08 06:00 [pubmed]
PHST- 2019/10/08 06:01 [medline]
PHST- 2019/09/18 00:00 [pmc-release]
AID - TVST-18-1272R1 [pii]
AID - 10.1167/tvst.8.5.11 [doi]
PST - epublish
SO  - Transl Vis Sci Technol. 2019 Sep 18;8(5):11. doi: 10.1167/tvst.8.5.11. 
      eCollection 2019 Sep.