Design and characterization of α1-antitrypsin variants for treatment of contact system–driven thromboinflammation

Maat, Steven de; Sanrattana, Wariya; Mailer, Reiner K.; Parr, Naomi M. J.; Hessing, M.; Koetsier, Robert M.; Meijers, Joost C. M.; Pasterkamp, Gérard; Renné, Thomas; Maas, Coen

doi:10.1182/blood.2019000481

Cited by 23 publications

(40 citation statements)

References 78 publications

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“…29 In contrast to the natural form of α1AT, α1AT Pittsburg is a mutant serpin known to rapidly inhibit not only APC but also procoagulant proteases such as thrombin. 30 To improve specificity for APC over other coagulation serine proteases, the investigators mutated the amino acid residues around the cleavage site of the RCL with Lys substitution creating a KRK α1AT mutant. This engineered serpin, named serpinPC, 31 was shown to be effective in increasing thrombin generation in vitro and, after injection in HB mice to restore fibrin and platelet deposition in an intravital laser injury model and to reduce blood loss in the tail clip assay.…”

Section: Serpinpcmentioning

confidence: 99%

Serpins, New Therapeutic Targets for Hemophilia

et al. 2020

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Hemostasis is a tightly regulated process characterized by a finely tuned balance between procoagulant and anticoagulant systems. Among inherited hemostatic conditions, hemophilia is one of the most well-known bleeding disorders. Hemophilia A (HA) and B (HB) are due to deficiencies in coagulation factor VIII (FVIII) or FIX, respectively, leading to unwanted bleeding. Until recently, hemophilia treatment has consisted of prophylactic replacement therapy using plasma-derived or recombinant FVIII in cases of HA or FIX in cases of HB. Because FVIII and FIX deficiencies lead to an imbalance between procoagulant and anticoagulant systems, a recent upcoming strategy implies blocking of endogenous anticoagulant proteins to compensate for the procoagulant factor deficit, thus restoring hemostatic equilibrium. Important physiological proteins of the anticoagulant pathways belong to the serpin (serine protease inhibitor) family and, recently, different experimental and clinical studies have demonstrated that targeting natural serpins could decrease bleeding in hemophilia. Here, we aim to review the different, recent studies demonstrating that blocking serpins such as antithrombin, protein Z-dependent protease inhibitor, and protease nexin-1 or modifying a serpin like α1-antitrypsin could rebalance coagulation in hemophilia. Furthermore, we underline the potential therapeutic use of serpins for the treatment of hemophilia.

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Section: Serpinpcmentioning

confidence: 99%

Serpins, New Therapeutic Targets for Hemophilia

et al. 2020

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“…The latter were eliminated in α 1 ‐AT‐SLLRV, which exhibited k 2 values of 1.88 × 10 5 M −1 s −1 for PKa and 1.34 × 10 4 M −1 s −1 for FXIIa. This variant, when given to mice at 8 mg/kg body weight, reduced ferric chloride‐induced arterial thrombosis, prevented carrageenan‐induced paw swelling, and reduced epithelial leakage of fluorescent dextran in the dextran sulfate colitis model …”

Section: Rationale For α1‐at Mutagenesis and Engineering Of Novel Promentioning

confidence: 99%

“…Researchers recently engineered α 1 -AT M358R to inhibit plasma kallikrein (PKa). 134 de Maat et al sought a novel therapeutic agent to control disorders of excessive bradykinin generation, which arises from PKa digestion of high molecular weight kininogen. One such disorder is hereditary angioedema, which results from C1 esterase inhibitor (C1INH, SERPING1) deficiency, which releases FXIIa, FXIa, and PKa from C1INH control.…”

Section: Inhibition Of Contact Pathway Proteinasesmentioning

confidence: 99%

“…This variant, when given to mice at 8 mg/kg body weight, reduced ferric chloride-induced arterial thrombosis, prevented carrageenan-induced paw swelling, and reduced epithelial leakage of fluorescent dextran in the dextran sulfate colitis model. 134…”

Section: Inhibition Of Contact Pathway Proteinasesmentioning

confidence: 99%

“…Researchers recently engineered α 1 ‐AT M358R to inhibit plasma kallikrein (PKa) . de Maat et al sought a novel therapeutic agent to control disorders of excessive bradykinin generation, which arises from PKa digestion of high molecular weight kininogen.…”

Section: Rationale For α1‐at Mutagenesis and Engineering Of Novel Promentioning

confidence: 99%

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Engineering the serpin α₁‐antitrypsin: A diversity of goals and techniques

Scott

Sheffield

2019

Protein Science

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α1‐Antitrypsin (α1‐AT) serves as an archetypal example for the serine proteinase inhibitor (serpin) protein family and has been used as a scaffold for protein engineering for >35 years. Techniques used to engineer α1‐AT include targeted mutagenesis, protein fusions, phage display, glycoengineering, and consensus protein design. The goals of engineering have also been diverse, ranging from understanding serpin structure–function relationships, to the design of more potent or more specific proteinase inhibitors with potential therapeutic relevance. Here we summarize the history of these protein engineering efforts, describing the techniques applied to engineer α1‐AT, specific mutants of interest, and providing an appended catalog of the >200 α1‐AT mutants published to date.

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Validation of diagnostic and predictive biomarkers for hereditary angioedema via plasma N‐glycomics

Zhang

Wang

et al. 2021

Clinical & Translational All

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Background Hereditary angioedema (HAE) is a rare disease with heterogeneous clinical symptoms. It is vitally important to predict whether an HAE patient will develop severe symptoms in clinical practice, but there are currently no predictive biomarkers for HAE stratification. Plasma N‐glycomes are disease‐specific and have great potential for the discovery of non‐invasive biomarkers. In this study, we profiled the plasma N‐glycome of HAE patients from two independent cohorts to identify candidate biomarkers. Methods Linkage‐specific sialylation derivatization combined with matrix‐assisted laser desorption/ionization time‐of‐flight mass spectrometry detection and automated data processing was employed to analyze the plasma N‐glycome of two independent type‐1 HAE cohorts. Results HAE patients had abnormal glycan complexity, galactosylation, and α2,3‐ and α2,6‐linked sialylation compared to healthy controls (HC). The classification models based on dysregulated glycan traits could successfully discriminate between HAE and HC with area under the curves (AUCs) being greater than 0.9. Some of the aberrant glycans showed response to therapy. Moreover, we identified a series of glycan traits with strong associations with the occurrence of laryngeal or gastrointestinal angioedema or disease severity score. Predictive models based on these traits could be used to predict disease severity (AUC > 0.9). These results were replicated in an independent cohort. Conclusions We reported the full plasma N‐glycomic signature of HAE for the first time, and identified potential biomarkers. These findings may play a critical role in predicting disease severity and guide the treatment of HAE in clinical practice. Further protein‐specific and prospective studies are needed to validate our findings.

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Design and characterization of α1-antitrypsin variants for treatment of contact system–driven thromboinflammation

Cited by 23 publications

References 78 publications

Serpins, New Therapeutic Targets for Hemophilia

Serpins, New Therapeutic Targets for Hemophilia

Engineering the serpin α₁‐antitrypsin: A diversity of goals and techniques

Validation of diagnostic and predictive biomarkers for hereditary angioedema via plasma N‐glycomics

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Design and characterization of α1-antitrypsin variants for treatment of contact system–driven thromboinflammation

Cited by 23 publications

References 78 publications

Serpins, New Therapeutic Targets for Hemophilia

Serpins, New Therapeutic Targets for Hemophilia

Engineering the serpin α1‐antitrypsin: A diversity of goals and techniques

Validation of diagnostic and predictive biomarkers for hereditary angioedema via plasma N‐glycomics

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Product

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Engineering the serpin α₁‐antitrypsin: A diversity of goals and techniques