Anti-Human VEGF Repebody Effectively Suppresses Choroidal Neovascularization and Vascular Leakage

Hwang, Dosam; Ryou, Jeong-Hyun; Oh, Jong Rok; Han, Jung Woo; Park, Tae Kwann; Kim, Kwang Ho

doi:10.1371/journal.pone.0152522

Cited by 26 publications

(14 citation statements)

References 35 publications

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“…Our observations in the HDMEC model possibly reflect this compensatory mechanism, in which BK induces lymphangiogenesis through VEGF‐C to resolve the edema. However, it is also known that an excessive amount of VEGF triggers the abnormal growth and leakage of blood vessels . Additional experiments are needed to clarify whether these findings predispose a lymphatic breakdown or whether they will improve AE resolution in the long‐term.…”

Section: Discussionmentioning

confidence: 99%

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Bradykinin signaling regulates solute permeability and cellular junction organization in lymphatic endothelial cells

et al. 2019

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Objective Determine the effect of bradykinin on solute permeability and cellular junctional proteins in human dermis microvascular endothelial cells. Methods Cells were characterized by immunofluorescence and fluorescence‐activated cell sorting. Macromolecular transport of dextran and albumin was monitored. Junctional protein expression and phosphorylation were determined by immunoblot analyses. Intracellular calcium and cAMP levels were evaluated. Target gene expression at mRNA and protein levels was determined. Results Human dermis microvascular endothelial cells comprised 97% lymphatic endothelial cells. Bradykinin increased the permeability to dextran in a concentration‐dependent manner, while reduced the permeability to albumin. Bradykinin treatment down‐regulated VE‐cadherin expression and affected its phosphorylation status at Tyr731. It also down‐regulated claudin‐5 expression at the transcriptional level through bradykinin‐2‐receptor signaling. An increase in the intracellular calcium levels and a reduction in the cAMP concentration were associated effects. Finally, bradykinin induced the up‐regulation of vascular endothelial growth factor‐C protein which was found increased in BK‐induced human dermis microvascular endothelial cells culture supernates. Conclusions Human dermis microvascular endothelial cells represent a model of lymphatic endothelial cells, in which bradykinin‐2‐receptor is expressed. Bradykinin‐induced bradykinin‐2‐receptor signaling through intracellular calcium mobilization and reduction in cAMP levels, triggered changes in solute permeability and cellular junction expression. It further up‐regulated vascular endothelial growth factors‐C protein expression, which is a key modulator of lymphatic vessels function and lymphangiogenesis.

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Section: Discussionmentioning

confidence: 99%

“…However, it is also known that an excessive amount of VEGF triggers the abnormal growth and leakage of blood vessels. 75,76 Additional experiments are needed to clarify whether these findings predispose a lymphatic breakdown or whether they will improve AE resolution in the long-term.…”

Section: Fold Changementioning

confidence: 99%

Bradykinin signaling regulates solute permeability and cellular junction organization in lymphatic endothelial cells

et al. 2019

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“…First, in a direct binding format, an evolved high affinity IL-6-binding repebody could inhibit IL-6 induced signaling in non-small cell lung cancer cells and suppress their growth in xenograft models [29]. As additional repebody examples, a C5a repebody could suppress proinflammatory response [27], and an anti-VEGF repebody could block neovascularization and vascular leakage in a mouse model of age-related macular degeneration [33]. Another approach is to employ a VLR as the recognition domain of a chimeric antigen receptor (CAR), and Moot and colleagues successfully created VLR-CARs that were expressed on T cells and could mediate cytotoxicity of the target cell [34].…”

Section: Engineering Of Vlrs For Downstream Applicationsmentioning

confidence: 99%

The variable lymphocyte receptor as an antibody alternative

Waters

Shusta

2018

Current Opinion in Biotechnology

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Variable lymphocyte receptors (VLRs) are leucine-rich repeat proteins in jawless vertebrates that function similarly to Ig antibodies. However, VLRs possess a distinct crescent-shaped structure and modularity that results in a concave binding interface that contrasts significantly with Ig antibodies. Antigen binding interactions result in specific, high affinity VLR binding interactions with both proteins and glycans. The natural sourcing of VLRs allows for immunization strategies, while the modularity enables a whole host of protein engineering approaches including consensus scaffolds, designed libraries and directed evolution with display technologies. VLR technologies have been recently deployed for applications in cell-specific targeting, drug delivery, tumor diagnostics and even protein stabilization. It is anticipated that the VLR field will continue to emerge to provide unique solutions for targeting glycans, evolutionarily conserved proteins and cellular specificity.

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“…It is of interest to note that the VLRB system has shown the capability of producing high affinity antibodies against glycotopes, much more so than the immunoglobulin-based system [14]. VLRBs have also made their way into therapeutic and diagnostic applications, including monitoring of chronic lymphocytic leukemia [15], blocking the IL-6/STAT3 signaling pathway in non-small cell lung cancer cells [16], delivery of protein-drug conjugates for tumor regression [17], visualizing protein-protein interaction in live cells [18], suppression of neovascularization in age-related macular degeneration by blocking the VEGF signaling pathway [19], neutralizing anaphylatoxin C5a to combat inflammatory disease [20], and applications in gene therapy with chimeric antigen receptors targeting leukemic B cells and effector T cells [21].…”

Section: Introductionmentioning

confidence: 99%

Generation of Lamprey Monoclonal Antibodies (Lampribodies) Using the Phage Display System

et al. 2019

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The variable lymphocyte receptors (VLRs) consist of leucine rich repeats (LRRs) and comprise the humoral antibodies produced by lampreys and hagfishes. The diversity of the molecules is generated by stepwise genomic rearrangements of LRR cassettes dispersed throughout the VLRB locus. Previously, target-specific monovalent VLRB antibodies were isolated from sea lamprey larvae after immunization with model antigens. Further, the cloned VLR cDNAs from activated lamprey leukocytes were transfected into human cell lines or yeast to select best binders. Here, we expand on the overall utility of the VLRB technology by introducing it into a filamentous phage display system. We first tested the efficacy of isolating phage into which known VLRB molecules were cloned after a series of dilutions. These experiments showed that targeted VLRB clones could easily be recovered even after extensive dilutions (1 to 10 9 ). We further utilized the system to isolate target-specific "lampribodies" from phage display libraries from immunized animals and observed an amplification of binders with relative high affinities by competitive binding. The lampribodies can be individually purified and ostensibly utilized for applications for which conventional monoclonal antibodies are employed.

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Anti-Human VEGF Repebody Effectively Suppresses Choroidal Neovascularization and Vascular Leakage

Cited by 26 publications

References 35 publications

Bradykinin signaling regulates solute permeability and cellular junction organization in lymphatic endothelial cells

Bradykinin signaling regulates solute permeability and cellular junction organization in lymphatic endothelial cells

The variable lymphocyte receptor as an antibody alternative

Generation of Lamprey Monoclonal Antibodies (Lampribodies) Using the Phage Display System

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