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

Pepple, Kathryn L.; Wilson, Leslie; Gelder, Russell N. Van; Kovaleva, Marina; Ubah, Obinna C.; Steven, John; Barelle, Caroline; Porter, A.J.

doi:10.1167/tvst.8.5.11

Cited by 7 publications

(3 citation statements)

References 71 publications

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“…Blocking GEF-H1 function can thus effectively inhibit pathological responses relevant to multiple diseases affecting the retina as well as other organs. It will be important to test GEF-H1 inhibitors in the future and directly compare their effectiveness for the treatment of uveitis with current standard treatments such as dexamethasone, a treatment with considerable side effects [ 64 , 65 ]. Moreover, additional ocular disease models with likely involvement of GEF-H1 should be tested, such as other inflammatory models (e.g., conjunctivitis) or other common diseases affecting ocular endothelia and the RPE such as diabetic retinopathy and neovascular age-related macular degeneration (wet AMD).…”

Section: Discussionmentioning

confidence: 99%

Therapeutic Validation of GEF-H1 Using a De Novo Designed Inhibitor in Models of Retinal Disease

Mills

Hemkemeyer

Alimajstorovic

et al. 2022

Cells

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Inflammation and fibrosis are important components of diseases that contribute to the malfunction of epithelia and endothelia. The Rho guanine nucleotide exchange factor (GEF) GEF-H1/ARHGEF-2 is induced in disease and stimulates inflammatory and fibrotic processes, cell migration, and metastasis. Here, we have generated peptide inhibitors to block the function of GEF-H1. Inhibitors were designed using a structural in silico approach or by isolating an inhibitory sequence from the autoregulatory C-terminal domain. Candidate inhibitors were tested for their ability to block RhoA/GEF-H1 binding in vitro, and their potency and specificity in cell-based assays. Successful inhibitors were then evaluated in models of TGFβ-induced fibrosis, LPS-stimulated endothelial cell-cell junction disruption, and cell migration. Finally, the most potent inhibitor was successfully tested in an experimental retinal disease mouse model, in which it inhibited blood vessel leakage and ameliorated retinal inflammation when treatment was initiated after disease diagnosis. Thus, an antagonist that blocks GEF-H1 signaling effectively inhibits disease features in in vitro and in vivo disease models, demonstrating that GEF-H1 is an effective therapeutic target and establishing a new therapeutic approach.

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Section: Discussionmentioning

confidence: 99%

Therapeutic Validation of GEF-H1 Using a De Novo Designed Inhibitor in Models of Retinal Disease

Mills

Hemkemeyer

Alimajstorovic

et al. 2022

Cells

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“…VNARs provide a novel drug modality and may support the development of new therapy alternatives. 156 …”

Section: Emerging Discovery Of a Shark Antibody To Treat Oa ...mentioning

confidence: 99%

Osteoarthritis versus psoriasis arthritis: Physiopathology, cellular signaling, and therapeutic strategies

et al. 2024

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“…Previous studies have isolated anti-TNFα, neutralizing VNARs through immunization of sharks [ 42 , 43 , 44 ]. However, there remains a significant requirement for new anti-TNFα blockades that may avoid or at least limit the drawbacks above.…”

Section: Introductionmentioning

confidence: 99%

Identification of Anti-TNFα VNAR Single Domain Antibodies from Whitespotted Bambooshark (Chiloscyllium plagiosum)

et al. 2022

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Tumor necrosis factor α (TNFα), an important clinical testing factor and drug target, can trigger serious autoimmune diseases and inflammation. Thus, the TNFα antibodies have great potential application in diagnostics and therapy fields. The variable binding domain of IgNAR (VNAR), the shark single domain antibody, has some excellent advantages in terms of size, solubility, and thermal and chemical stability, making them an ideal alternative to conventional antibodies. This study aims to obtain VNARs that are specific for mouse TNF (mTNF) from whitespotted bamboosharks. After immunization of whitespotted bamboosharks, the peripheral blood leukocytes (PBLs) were isolated from the sharks, then the VNAR phage display library was constructed. Through phage display panning against mTNFα, positive clones were validated through ELISA assay. The affinity of the VNAR and mTNFα was measured using ELISA and Bio-Layer Interferometry. The binding affinity of 3B11 VNAR reached 16.7 nM. Interestingly, one new type of VNAR targeting mTNF was identified that does not belong to any known VNAR type. To understand the binding mechanism of VNARs to mTNFα, the models of VNARs-mTNFα complexes were predicted by computational modeling combining HawkDock and RosettaDock. Our results showed that four VNARs’ epitopes overlapped in part with that of mTNFR. Furthermore, the ELISA assay shows that the 3B11 potently inhibited mTNFα binding to mTNFR. This study may provide the basis for the TNFα blockers and diagnostics applications.

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

Abstract: Uveitis therapy with shark variable novel antigen receptor domains targeting tumor necrosis factor alpha or inducible t-cell costimulatory ligand.

Cited by 7 publications

References 71 publications

Therapeutic Validation of GEF-H1 Using a De Novo Designed Inhibitor in Models of Retinal Disease

Therapeutic Validation of GEF-H1 Using a De Novo Designed Inhibitor in Models of Retinal Disease

Osteoarthritis versus psoriasis arthritis: Physiopathology, cellular signaling, and therapeutic strategies

Identification of Anti-TNFα VNAR Single Domain Antibodies from Whitespotted Bambooshark (Chiloscyllium plagiosum)

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