ArticleThe Journal of biological chemistry2013
Directed evolution of an angiopoietin-2 ligand trap by somatic hypermutation and cell surface display.
Article in The Journal of biological chemistry, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 11 papers.
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Who cites it
11 citing papers in PubMed, 18 citations in OpenAlex.
- Article
- Blockade of Activin Receptor IIB Protects Arthritis Pathogenesis by Non-Amplification of Activin A-ACVR2B-NOX4 Axis Pathway.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2023Article
- In vitro evolution predicts emerging SARS-CoV-2 mutations with high affinity for ACE2 and cross-species binding.PLoS pathogens · 2022Article
- Ex vivo modelling of the formation of inflammatory platelet-leucocyte aggregates and their adhesion on endothelial cells, an early event in sepsis.Clinical and experimental medicine · 2019Article
- The directed evolution of ligand specificity in a GPCR and the unequal contributions of efficacy and affinity.Scientific reports · 2017Article
- Classical VEGF, Notch and Ang signalling in cancer angiogenesis, alternative approaches and future directions (Review).Molecular medicine reports · 2017Review
- Regulation of Angiopoietin Signalling by Soluble Tie2 Ectodomain and Engineered Ligand Trap.Scientific reports · 2017Article
- Using experimental evolution to probe molecular mechanisms of protein function.Protein science : a publication of the Protein Society · 2016Review
- Anti-angiogenic alternatives to VEGF blockade.Clinical & experimental metastasis · 2016Review
- Directed evolution of human scFvs in DT40 cells.Protein engineering, design & selection : PEDS · 2016Article
- Article
Corrections and comments
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Authors and funding
7 authors at 4 institutions in 3 countries.
Funding
Abstract
Tie2 is a receptor tyrosine kinase that is essential for the development and maintenance of blood vessels through binding the soluble ligands angiopoietin 1 (Ang1) and 2 (Ang2). Ang1 is constitutively produced by perivascular cells and is protective of the adult vasculature. Ang2 plays an important role in blood vessel formation and is normally expressed during development. However, its re-expression in disease states, including cancer and sepsis, results in destabilization of blood vessels contributing to the pathology of these conditions. Ang2 is thus an attractive therapeutic target. Here we report the directed evolution of a ligand trap for Ang2 by harnessing the B cell somatic hypermutation machinery and coupling this to selectable cell surface display of a Tie2 ectodomain. Directed evolution produced an unexpected combination of mutations resulting in loss of Ang1 binding but maintenance of Ang2 binding. A soluble form of the evolved ectodomain binds Ang2 but not Ang1. Furthermore, the soluble evolved ectodomain blocks Ang2 effects on endothelial cells without interfering with Ang1 activity. Our study has created a novel Ang2 ligand trap and provided proof of concept for combining surface display and exogenous gene diversification in B cells for evolution of a non-immunoglobulin target.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.