Uveitis Therapy With Shark Variable Novel Antigen Receptor Domains Targeting Tumor Necrosis Factor Alpha or Inducible T-Cell Costimulatory Ligand

Kathryn L. Pepple (Corresponding Author), Leslie Wilson, Russell N. Van Gelder, Marina Kovaleva, Obinna C. Ubah, John Steven, Caroline J. Barelle, Andrew Porter

Research output: Contribution to journalArticle

Abstract

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 (TNFα) 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-1α), interleukin (IL)-1β, LPS-induced CXC chemokine (LIX), monocyte chemoattractant protein-1 (MCP-1), and interferon (IFN)-γ 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-TNFα 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.
Original languageEnglish
Article number11
Number of pages13
JournalTranslational vision science & technology
Volume8
Issue number5
Early online date18 Sep 2019
DOIs
Publication statusPublished - Sep 2019

Fingerprint

Sharks
Antigen Receptors
T-cells
Uveitis
Antigens
Tumor Necrosis Factor-alpha
Ligands
Proteins
T-Lymphocytes
Animals
Therapeutics
Aqueous Humor
Chemical activation
Interferons
Dexamethasone
Vascular Endothelial Growth Factor A
Molecules
Monoclonal antibodies
Macrophages
Cytokines

Keywords

  • uveitis
  • treatment
  • TNF-alpha
  • experimental autoimmune uveitis
  • Lewis rat

Cite this

Uveitis Therapy With Shark Variable Novel Antigen Receptor Domains Targeting Tumor Necrosis Factor Alpha or Inducible T-Cell Costimulatory Ligand. / Pepple, Kathryn L. (Corresponding Author); Wilson, Leslie; Van Gelder, Russell N.; Kovaleva, Marina; Ubah, Obinna C.; Steven, John; Barelle, Caroline J.; Porter, Andrew.

In: Translational vision science & technology, Vol. 8, No. 5, 11, 09.2019.

Research output: Contribution to journalArticle

Pepple, Kathryn L. ; Wilson, Leslie ; Van Gelder, Russell N. ; Kovaleva, Marina ; Ubah, Obinna C. ; Steven, John ; Barelle, Caroline J. ; Porter, Andrew. / Uveitis Therapy With Shark Variable Novel Antigen Receptor Domains Targeting Tumor Necrosis Factor Alpha or Inducible T-Cell Costimulatory Ligand. In: Translational vision science & technology. 2019 ; Vol. 8, No. 5.
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abstract = "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 (TNFα) 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-1α), interleukin (IL)-1β, LPS-induced CXC chemokine (LIX), monocyte chemoattractant protein-1 (MCP-1), and interferon (IFN)-γ 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-TNFα 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.",
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note = "Acknowledgments Supported by an unrestricted departmental grant from Research to Prevent Blindness (New York, NY), NEI K08EY023998 (KLP), P30-EY001730 (RVG; Bethesda, MD), by a grant from Elasmogen Limited (RVG), and with support from the Mark J. Daily, MD Research Fund (RVG, KLP).",
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AU - Pepple, Kathryn L.

AU - Wilson, Leslie

AU - Van Gelder, Russell N.

AU - Kovaleva, Marina

AU - Ubah, Obinna C.

AU - Steven, John

AU - Barelle, Caroline J.

AU - Porter, Andrew

N1 - Acknowledgments Supported by an unrestricted departmental grant from Research to Prevent Blindness (New York, NY), NEI K08EY023998 (KLP), P30-EY001730 (RVG; Bethesda, MD), by a grant from Elasmogen Limited (RVG), and with support from the Mark J. Daily, MD Research Fund (RVG, KLP).

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N2 - 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 (TNFα) 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-1α), interleukin (IL)-1β, LPS-induced CXC chemokine (LIX), monocyte chemoattractant protein-1 (MCP-1), and interferon (IFN)-γ 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-TNFα 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.

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 (TNFα) 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-1α), interleukin (IL)-1β, LPS-induced CXC chemokine (LIX), monocyte chemoattractant protein-1 (MCP-1), and interferon (IFN)-γ 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-TNFα 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.

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KW - treatment

KW - TNF-alpha

KW - experimental autoimmune uveitis

KW - Lewis rat

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JO - Translational vision science & technology

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