Dataset Information

CCL20 neutralization by a monoclonal antibody in healthy subjects selectively inhibits recruitment of CCR6+ cells in an experimental suction blister.

ABSTRACT: AIMS:GSK3050002, a humanized IgG1? antibody with high binding affinity to human CCL20, was administered in a first-in-human study to evaluate safety, pharmacokinetics (PK) and pharmacodynamics (PD). An experimental skin suction blister model was employed to assess target engagement and the ability of the compound to inhibit recruitment of inflammatory CCR6 expressing cells. METHODS:This study was a randomized, double-blind (sponsor open), placebo-controlled, single-centre, single ascending intravenous dose escalation trial in 48 healthy male volunteers. RESULTS:GSK3050002 (0.1-20 mg kg-1 ) was well tolerated and no safety concerns were identified. The PK was linear over the dose range, with a half-life of approximately 2 weeks. Complex of GSK3050002/CCL20 increased in serum and blister fluid with increasing doses of GSK3050002. There were dose-dependent decreases in CCR6+ cell recruitment to skin blisters with maximal effects at doses of 5 mg kg-1 and higher, doses at which GSK3050002/CCL20 complex in serum and blister fluid also appeared to reach maximum levels. CONCLUSIONS:These results indicate a relationship between PK, target engagement and PD, suggesting a selective inhibition of recruitment of CCR6+ cells by GSK3050002 and support further development of GSK3050002 in autoimmune and inflammatory diseases.

SUBMITTER: Bouma G

PROVIDER: S-EPMC5555862 | biostudies-literature | 2017 Sep

REPOSITORIES: biostudies-literature

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CCL20 neutralization by a monoclonal antibody in healthy subjects selectively inhibits recruitment of CCR6<sup>+</sup> cells in an experimental suction blister.

Bouma Gerben G Zamuner Stefano S Hicks Kirsty K Want Andrew A Oliveira João J Choudhury Arpita A Brett Sara S Robertson Darren D Felton Leigh L Norris Virginia V Fernando Disala D Herdman Michael M Tarzi Ruth R

British journal of clinical pharmacology 20170422 9

<h4>Aims</h4>GSK3050002, a humanized IgG1κ antibody with high binding affinity to human CCL20, was administered in a first-in-human study to evaluate safety, pharmacokinetics (PK) and pharmacodynamics (PD). An experimental skin suction blister model was employed to assess target engagement and the ability of the compound to inhibit recruitment of inflammatory CCR6 expressing cells.<h4>Methods</h4>This study was a randomized, double-blind (sponsor open), placebo-controlled, single-centre, single ...[more]

PMID: 28295451

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Project description:BackgroundChemokine networks play a key and complex role in tumor progression. CCL20 and its unique receptor CCR6 have been reported to mediate malignant biological activities in various cancers, but their role in ovarian cancer metastasis remains unclear.PurposeOur study aims to explore the effect of CCL20-CCR6 axis on ovarian cancer metastasis and its potential mechanism.MethodsThe transwell assay was used to detect the cell migration and invasion after CCL20 treatment. The CCK-8 assay was used to detect the cell viability after CCL20 treatment and CCR6 depletion. The mRNA and protein expression were assayed through qRT-PCR and Western blotting. The siRNAs and CRISPR-Cas9 system were adopted to suppress CCR6 expression. Intraperitoneal xenograft mouse model was constructed to test the pro-metastasis effect of CCL20-CCR6 axis in vivo. The differentially expressed genes induced by CCL20 were identified through RNA-sequencing, and immunohistochemistry staining was used to detect their protein expression in tumor tissues.ResultsOur results revealed that CCL20 treatment selectively promoted the migration and invasion of CCR6high ovarian cancer cells, but had no effect on CCR6low cells. Blockade of CCR6 expression effectively reversed the cell migration and invasion induced by CCL20 stimulation. Animal experiment proved that CCL20-CCR6 axis mediated ovarian cancer metastasis in vivo. The differentially expressed genes after CCL20 stimulation were associated with metastasis, and CCL20 induced an increased expression of CDH2 and VCAN and decreased CDH1 expression in cancer cells. Moreover, CCL20 stimulated the expression of N-cadherin and versican in tumor tissues and inhibited the expression of E-cadherin, while CCR6 knockout successfully blocked the expression changes.ConclusionOur findings revealed that CCL20-CCR6 axis promotes ovarian cancer metastasis both in vivo and in vitro, probably through increasing cancer cell adhesion and epithelial-mesenchymal transition. Blockade of CCL20-CCR6 axis might become a novel anti-tumor therapeutic target for ovarian cancer.

Dataset Information

CCL20 neutralization by a monoclonal antibody in healthy subjects selectively inhibits recruitment of CCR6+ cells in an experimental suction blister.

Publications

CCL20 neutralization by a monoclonal antibody in healthy subjects selectively inhibits recruitment of CCR6<sup>+</sup> cells in an experimental suction blister.

Similar Datasets

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