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1.
Clin Pharmacol Ther ; 109(5): 1293-1303, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33113155

RESUMO

Activated T cells drive a range of immune-mediated inflammatory diseases. LAG-3 is transiently expressed on recently activated CD4+ and CD8+ T cells. We describe the engineering and first-in-human clinical study (NCT02195349) of GSK2831781 (an afucosylated humanized IgG1 monoclonal antibody enhanced with high affinity for Fc receptors and LAG-3 and antibody-dependent cellular cytotoxicity capabilities), which depletes LAG-3 expressing cells. GSK2831781 was tested in a phase I/Ib, double-blind, placebo-controlled clinical study, which randomized 40 healthy participants (part A) and 27 patients with psoriasis (part B) to single doses of GSK2831781 (up to 0.15 and 5 mg/kg, respectively) or placebo. Adverse events were generally balanced across groups, with no safety or tolerability concern identified. LAG-3+ cell depletion in peripheral blood was observed at doses ≥ 0.15 mg/kg and was dose-dependent. In biopsies of psoriasis plaques, a reduction in mean group LAG-3+ and CD3+ T-cell counts was observed following treatment. Downregulation of proinflammatory genes (IL-17A, IL-17F, IFNγ, and S100A12) and upregulation of the epithelial barrier integrity gene, CDHR1, was observed with the 5 mg/kg dose of GSK2831781. Psoriasis disease activity improved up to day 43 at all GSK2831781 doses (0.5, 1.5, and 5 mg/kg) compared with placebo. Depletion of LAG-3-expressing activated T cells is a novel approach, and this first clinical study shows that GSK2831781 is pharmacologically active and provides encouraging early evidence of clinical effects in psoriasis, which warrants further investigation in T-cell-mediated inflammatory diseases.


Assuntos
Anticorpos Monoclonais/farmacologia , Antígenos CD/imunologia , Psoríase/tratamento farmacológico , Linfócitos T/imunologia , Adulto , Anticorpos Monoclonais/efeitos adversos , Anticorpos Monoclonais/imunologia , Anticorpos Monoclonais/farmacocinética , Antígenos CD/sangue , Complexo CD3/metabolismo , Relação Dose-Resposta Imunológica , Feminino , Regulação da Expressão Gênica , Humanos , Masculino , Pessoa de Meia-Idade , Psoríase/genética , Psoríase/patologia , Resultado do Tratamento , Proteína do Gene 3 de Ativação de Linfócitos
2.
Br J Clin Pharmacol ; 84(10): 2280-2291, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-29900565

RESUMO

AIMS: The oncostatin M (OSM) pathway drives fibrosis, inflammation and vasculopathy, and is a potential therapeutic target for inflammatory and fibrotic diseases. The aim of this first-time-in-human experimental medicine study was to assess the safety, tolerability, pharmacokinetics and target engagement of single subcutaneous doses of GSK2330811, an anti-OSM monoclonal antibody, in healthy subjects. METHODS: This was a phase I, randomized, double-blind, placebo-controlled, single-dose escalation, first-time-in-human study of subcutaneously administered GSK2330811 in healthy adults (NCT02386436). Safety and tolerability, GSK2330811 pharmacokinetic profile, OSM levels in blood and skin, and the potential for antidrug antibody formation were assessed. The in vivo affinity of GSK2330811 for OSM and target engagement in serum and skin blister fluid (obtained via a skin suction blister model) were estimated using target-mediated drug disposition (TMDD) models in combination with compartmental and physiology-based pharmacokinetic (PBPK) models. RESULTS: Thirty subjects were randomized to receive GSK2330811 and 10 to placebo in this completed study. GSK2330811 demonstrated a favourable safety profile in healthy subjects; no adverse events were serious or led to withdrawal. There were no clinically relevant trends in change from baseline in laboratory values, with the exception of a reversible dose-dependent reduction in platelet count. GSK2330811 exhibited linear pharmacokinetics over the dose range 0.1-6 mg kg-1 . The estimated in vivo affinity (nM) of GSK2330811 for OSM was 0.568 [95% confidence interval (CI) 0.455, 0.710] in the compartmental with TMDD model and 0.629 (95% CI 0.494, 0.802) using the minimal PBPK with TMDD model. CONCLUSIONS: Single subcutaneous doses of GSK2330811 were well tolerated in healthy subjects. GSK2330811 demonstrated sufficient affinity to achieve target engagement in systemic circulation and target skin tissue, supporting the progression of GSK2330811 clinical development.


Assuntos
Anticorpos Monoclonais Humanizados/farmacocinética , Oncostatina M/antagonistas & inibidores , Adulto , Anticorpos Monoclonais Humanizados/administração & dosagem , Anticorpos Monoclonais Humanizados/efeitos adversos , Área Sob a Curva , Vesícula/tratamento farmacológico , Vesícula/etiologia , Vesícula/imunologia , Vesícula/patologia , Método Duplo-Cego , Feminino , Voluntários Saudáveis , Humanos , Injeções Subcutâneas , Masculino , Pessoa de Meia-Idade , Modelos Biológicos , Oncostatina M/imunologia , Placebos/administração & dosagem , Placebos/efeitos adversos , Pele/efeitos dos fármacos , Pele/imunologia , Pele/patologia , Sucção/efeitos adversos
5.
Health Promot J Austr ; 17(2): 103-8, 2006 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-16916312

RESUMO

ISSUE ADDRESSED: Indigenous Australians have higher morbidity and mortality rates than non-Indigenous Australians. Until recently, few health promotion interventions have had more than limited success in Indigenous populations. METHODS: This community-based health promotion initiative introduced traditional Indigenous games into schools and community groups in Cherbourg and Stradbroke Island (Queensland, Australia). A joint community forum managed the project, and the Indigenous community-based project officers co-ordinated training in traditional games and undertook community asset audits and evaluations. RESULTS: The games have been included in the activities of a range of community organisations in Cherbourg and Stradbroke Island. Several other organisations and communities in Australia have included them in their projects. A games video and manual were produced to facilitate the initiative's transferability and sustainability. CONCLUSIONS: Conventional approaches to health promotion generally focus on individual risk factors and often ignore a more holistic perspective. This project adopted a culturally appropriate, holistic approach, embracing a paradigm that concentrated on the communities' cultural assets and contributed to sustainable and transferable outcomes. There is a need for appropriate evaluation tools for time-limited community engagement projects.


Assuntos
Promoção da Saúde , Havaiano Nativo ou Outro Ilhéu do Pacífico , Esportes , Adulto , Criança , Exercício Físico , Saúde Holística , Humanos , Grupos Populacionais , Queensland , Características de Residência , Inquéritos e Questionários , Fatores de Tempo , Gravação em Vídeo
6.
Genes Chromosomes Cancer ; 45(1): 42-6, 2006 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-16175573

RESUMO

The protein kinase gene family is the most frequently mutated in human cancer. Previous work has documented activating mutations in the KIT receptor tyrosine kinase in testicular germ-cell tumors (TGCT). To investigate further the potential role of mutated protein kinases in the development of TGCT and to characterize the prevalence and patterns of point mutations in these tumors, we have sequenced the coding exons and splice junctions of the annotated protein kinase family of 518 genes in a series of seven seminomas and six nonseminomas. Our results show a remarkably low mutation frequency, with only a single somatic point mutation, a K277E mutation in the STK10 gene, being identified in a total of more than 15 megabases of sequence analyzed. Sequencing of STK10 in an additional 40 TGCTs revealed no further mutations. Comparative genomic hybridization and LOH analysis using SNP arrays demonstrated that the 13 TGCTs mutationally screened through the 518 protein kinase genes were uniformly aneuploid with consistent chromosomal gains on 12p, 8q, 7, and X and losses on 13q, 18q, 11q, and 4q. Our results do not provide evidence for a mutated protein kinase implicated in the development of TGCT other than KIT. Moreover, they demonstrate that the general prevalence of point mutations in TGCT is low, in contrast to the high frequency of copy number changes.


Assuntos
Neoplasias Embrionárias de Células Germinativas/genética , Proteínas Quinases/genética , Proteínas Serina-Treonina Quinases/genética , Seminoma/genética , Neoplasias Testiculares/genética , Adolescente , Adulto , Aberrações Cromossômicas , Éxons , Dosagem de Genes , Humanos , Masculino , Pessoa de Meia-Idade , Mutação Puntual
7.
Cancer Res ; 65(17): 7591-5, 2005 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-16140923

RESUMO

Protein kinases are frequently mutated in human cancer and inhibitors of mutant protein kinases have proven to be effective anticancer drugs. We screened the coding sequences of 518 protein kinases (approximately 1.3 Mb of DNA per sample) for somatic mutations in 26 primary lung neoplasms and seven lung cancer cell lines. One hundred eighty-eight somatic mutations were detected in 141 genes. Of these, 35 were synonymous (silent) changes. This result indicates that most of the 188 mutations were "passenger" mutations that are not causally implicated in oncogenesis. However, an excess of approximately 40 nonsynonymous substitutions compared with that expected by chance (P = 0.07) suggests that some nonsynonymous mutations have been selected and are contributing to oncogenesis. There was considerable variation between individual lung cancers in the number of mutations observed and no mutations were found in lung carcinoids. The mutational spectra of most lung cancers were characterized by a high proportion of C:G > A:T transversions, compatible with the mutagenic effects of tobacco carcinogens. However, one neuroendocrine cancer cell line had a distinctive mutational spectrum reminiscent of UV-induced DNA damage. The results suggest that several mutated protein kinases may be contributing to lung cancer development, but that mutations in each one are infrequent.


Assuntos
Neoplasias Pulmonares/enzimologia , Neoplasias Pulmonares/genética , Mutação , Proteínas Quinases/genética , Adenocarcinoma/enzimologia , Adenocarcinoma/genética , Tumor Carcinoide/enzimologia , Tumor Carcinoide/genética , Carcinoma de Células Grandes/enzimologia , Carcinoma de Células Grandes/genética , Carcinoma de Células Escamosas/enzimologia , Carcinoma de Células Escamosas/genética , Linhagem Celular Tumoral , Análise Mutacional de DNA , Humanos
8.
Nat Genet ; 37(6): 590-2, 2005 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-15908952

RESUMO

We examined the coding sequence of 518 protein kinases, approximately 1.3 Mb of DNA per sample, in 25 breast cancers. In many tumors, we detected no somatic mutations. But a few had numerous somatic mutations with distinctive patterns indicative of either a mutator phenotype or a past exposure.


Assuntos
Neoplasias da Mama/genética , Carcinoma Ductal de Mama/genética , Mutação , Proteínas Quinases/genética , Idoso , Análise Mutacional de DNA , Feminino , Humanos , Família Multigênica
9.
Nature ; 431(7008): 525-6, 2004 Sep 30.
Artigo em Inglês | MEDLINE | ID: mdl-15457249

RESUMO

The protein-kinase family is the most frequently mutated gene family found in human cancer and faulty kinase enzymes are being investigated as promising targets for the design of antitumour therapies. We have sequenced the gene encoding the transmembrane protein tyrosine kinase ERBB2 (also known as HER2 or Neu) from 120 primary lung tumours and identified 4% that have mutations within the kinase domain; in the adenocarcinoma subtype of lung cancer, 10% of cases had mutations. ERBB2 inhibitors, which have so far proved to be ineffective in treating lung cancer, should now be clinically re-evaluated in the specific subset of patients with lung cancer whose tumours carry ERBB2 mutations.


Assuntos
Neoplasias Pulmonares/genética , Mutação/genética , Receptor ErbB-2/genética , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/genética , Análise Mutacional de DNA , Ativação Enzimática , Receptores ErbB/química , Receptores ErbB/genética , Gefitinibe , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Modelos Moleculares , Neoplasias/tratamento farmacológico , Neoplasias/genética , Estrutura Terciária de Proteína , Quinazolinas/uso terapêutico , Receptor ErbB-2/química , Receptor ErbB-2/metabolismo
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