Expression analysis and specific blockade of the receptor for human thymic stromal lymphopoietin (TSLP) by novel antibodies to the human TSLPRα receptor chain

Borowski, Andreas; Vetter, Tina; Kuepper, Michael; Wohlmann, Andreas; Krause, Sebastian; Lorenzen, Thomas; Virchow, J. Christian; Luttmann, Werner; Friedrich, Karlheinz

doi:10.1016/j.cyto.2012.10.025

Cited by 30 publications

(13 citation statements)

References 41 publications

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“…TSLPR has low affinity for TSLP, but in combination with IL-7Rα generates a high-affinity binding site for TSLP and triggers signaling through signal transducer and activator of transcription STAT1, STAT3, STAT5 and JAK1 and JAK2 [76]. In approximately 10–60% of patients with B-cell acute lymphoblastic leukemias (ALL) and in some with T-ALL, investigators have described somatic gain-of-function mutations in TSLP-R associated with the aberrant expression of TSLPRα and mutant IL-7R proteins have formed a functional receptor TSLP.…”

Section: Tslp-r Signalingmentioning

confidence: 99%

The importance of TSLP in allergic disease and its role as a potential therapeutic target

Cianferoni¹,

Spergel

2014

Expert Review of Clinical Immunology

170

116

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Thymic stromal lymphopoietin (TSLP) is an epithelial-derived cytokine similar to IL- 7, whose gene is located on chromosome 5q22.1 and it exerts its biological function through the TSLP-Receptor (TSLP-R). TSLP is expressed primarily by epithelial cells at barrier surfaces such as the skin, gut and lung in response to danger signals. Since it was cloned in 1994, there has been accumulating evidence that TSLP is crucial for the maturation of antigen presenting cells and hematopoietic cells. TSLP genetic variants and its dysregulated expression have been linked to atopic diseases such as atopic dermatitis, asthma, allergic rhinitis and eosinophilic esophagitis.

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Section: Tslp-r Signalingmentioning

confidence: 99%

The importance of TSLP in allergic disease and its role as a potential therapeutic target

Cianferoni¹,

Spergel

2014

Expert Review of Clinical Immunology

170

116

View full text Add to dashboard Cite

show abstract

“…Such a broad pathophysiology profile and the soaring rates of atopic and autoimmune diseases in the second half of the 20th century have motivated therapeutic targeting of TSLP and TSLP-mediated signalling3132. For instance, blockade of TSLPR in a primate animal model was shown to attenuate allergic inflammation33, and TSLP was shown to be pivotal for the development of resistance to corticosteroid treatment during airway inflammation34.…”

mentioning

confidence: 99%

Structure and antagonism of the receptor complex mediated by human TSLP in allergy and asthma

et al. 2017

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The pro-inflammatory cytokine thymic stromal lymphopoietin (TSLP) is pivotal to the pathophysiology of widespread allergic diseases mediated by type 2 helper T cell (Th2) responses, including asthma and atopic dermatitis. The emergence of human TSLP as a clinical target against asthma calls for maximally harnessing its therapeutic potential via structural and mechanistic considerations. Here we employ an integrative experimental approach focusing on productive and antagonized TSLP complexes and free cytokine. We reveal how cognate receptor TSLPR allosterically activates TSLP to potentiate the recruitment of the shared interleukin 7 receptor α-chain (IL-7Rα) by leveraging the flexibility, conformational heterogeneity and electrostatics of the cytokine. We further show that the monoclonal antibody Tezepelumab partly exploits these principles to neutralize TSLP activity. Finally, we introduce a fusion protein comprising a tandem of the TSLPR and IL-7Rα extracellular domains, which harnesses the mechanistic intricacies of the TSLP-driven receptor complex to manifest high antagonistic potency.

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“…a number of previous studies have demonstrated an important role for TSlP in different diseases (17,18). Blocking the binding of TSlP to TSlPr may inhibit TSlP signalling, which may provide a therapeutic strategy to treat various diseases (19). The present study successfully constructed an anti-TSlP-scFv-Fc recombinant antibody.…”

Section: Discussionmentioning

confidence: 86%

Affinity improvement of the fully human anti‑TSLP recombinant antibody

Chen

Xian

et al. 2019

Mol Med Report

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Thymic stromal lymphopoietin (TSlP) is a potentially important target for the treatment of asthma and malignancies. However, a fully human antibody reactive with TSlP is currently unavailable for clinical use. in a previous study, a human anti-TSlP-single-chain antibody variable fragment (anti-TSlP-scFv) 84 was selected by phage display from a constructed human scFv library. in the present study, a computer simulation method was developed using Discovery Studio 4.5 software, to increase the affinity of anti-TSLP-scFv-84. Specific primers were designed and mutated dna sequences of anti-TSlP-scFvs were obtained by overlap extension Pcr. The mutant scFvs were expressed in plZ16 and affinity-enhanced anti-TSlP-scFv-M4 was screened using eliSa. However, in general the scFvs have low stability and short half-lives in vivo. Therefore, scFv-84 and scFv-M4 were inserted into eukaryotic expression vectors (pcdna3.1-sp-Fc and PMH3 en -sp-Fc) and then transfected into 293F cells to express anti-TSlP-scFv-Fc. eliSa and western blotting results indicated the size of the anti-TSlP-scFv-Fc to be ~50 kda. Binding of anti-TSlP-scFv-Fc-M4 to TSlP was enhanced compared with the pre-mutated scFv-Fc-84. The affinity of the mutated recombinant antibody was determined using the Biacore technique and found to be ~10-fold greater than the pre-mutated antibody.

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Expression analysis and specific blockade of the receptor for human thymic stromal lymphopoietin (TSLP) by novel antibodies to the human TSLPRα receptor chain

Cited by 30 publications

References 41 publications

The importance of TSLP in allergic disease and its role as a potential therapeutic target

The importance of TSLP in allergic disease and its role as a potential therapeutic target

Structure and antagonism of the receptor complex mediated by human TSLP in allergy and asthma

Affinity improvement of the fully human anti‑TSLP recombinant antibody

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