Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 4 de 4
Filtrar
Mais filtros










Base de dados
Intervalo de ano de publicação
1.
Sci Rep ; 14(1): 5135, 2024 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-38429446

RESUMO

G-protein-coupled receptor class 5 member D (GPRC5D) is detected in malignant plasma cells in approximately 90% of patients diagnosed with multiple myeloma (MM). Here, we constructed BsAb5003, a novel humanized bispecific monoclonal antibody targeting CD3 and GPRC5D, and evaluated its therapeutic impact on MM. BsAb5003 induced specific cytotoxicity of GPRC5D-positive MM cells with concomitant T cell activation and cytokine release. The efficacy of BsAb5003 was associated with GPRC5D expression levels in MM cell lines. Flow cytometry analysis of bone marrow mononuclear cells (BMMNCs) from 49 MM patients revealed that GPRC5D was expressed in a wide population of MM patients, including heavily treated and high-risk patients. In ex vivo assays using BMMNCs, BsAb5003 induced potent efficacy against CD138 + MM cells in both newly diagnosed and relapsed/refractory patient samples in a GPRC5D expression-dependent manner. BsAb5003 significantly enhanced T cell activation and cytokine production in combination with immunomodulatory drugs (IMiDs) against MM cell lines. BsAb5003 also demonstrated significant inhibition of in vivo tumor growth by recruiting T cells. Taken together, these results suggest that T cell-redirecting bispecific antibody targeting GPRC5D as monotherapy and combination therapy with IMiDs could be a highly potent and effective treatment approach for a wide population of MM patients.


Assuntos
Anticorpos Biespecíficos , Mieloma Múltiplo , Humanos , Anticorpos Biespecíficos/uso terapêutico , Citocinas/metabolismo , Agentes de Imunomodulação , Mieloma Múltiplo/imunologia , Mieloma Múltiplo/patologia , Mieloma Múltiplo/terapia , Receptores Acoplados a Proteínas G , Linfócitos T
2.
J Pharm Pharmacol ; 67(8): 1075-82, 2015 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-25787991

RESUMO

OBJECTIVES: Cadherin-11 (CDH11) is an adhesion molecule that anchors ß-catenin and is involved with various functions of synovial fibroblast cells (SFCs) during the development of rheumatoid arthritis (RA). However, the mechanism of CDH11 during RA-SFC proliferation is unclear. The aim of our study was to clarify the involvement of CDH11 and ß-catenin signalling during proliferation. METHODS: IL-1ß-induced and tumour necrosis factor-α (TNF-α)-induced cell proliferation, with CDH11 siRNAs, ß-catenin-specific siRNAs and a CDH11-neutralizing antibody, were assessed by 5-Bromo-2'-deoxy-uridine ELISA. KEY FINDINGS: Using CDH11 siRNAs, there were a 42% reduction in IL-1ß-induced proliferation and a 64% reduction in ß-catenin protein. When ß-catenin siRNAs were applied, there was a 63% reduction in IL-1ß-induced proliferation. The median effective concentration (EC50 ) values for IL-1ß-induced proliferation via CDH11-mediated ß-catenin-dependent, total ß-catenin-dependent and ß-catenin-independent signalling were 0.0015, 0.016 and 0.18 ng/ml, respectively. Blocking CDH11 ligation with a CDH11-neutralizing antibody did not decrease IL-1ß-induced proliferation. CONCLUSIONS: CDH11-mediated ß-catenin signalling was 42% involved in IL-1ß-induced proliferation and had the highest susceptibility to IL-1ß among the proliferative signallings analysed in this study. The mode of action for CDH11 during the cell proliferation was likely associated with a pool of ß-catenin protein. In contrast, CDH11 and ß-catenin were not involved in TNF-α-induced RA-SFC proliferation.


Assuntos
Artrite Reumatoide/fisiopatologia , Caderinas/farmacologia , Fibroblastos/metabolismo , Interleucina-1beta/farmacologia , Fator de Necrose Tumoral alfa/farmacologia , beta Catenina/farmacologia , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Relação Dose-Resposta a Droga , Ensaio de Imunoadsorção Enzimática , Feminino , Humanos , Masculino , RNA Interferente Pequeno/metabolismo , Transdução de Sinais , Membrana Sinovial/fisiopatologia
3.
Biotechnol Bioeng ; 110(10): 2785-9, 2013 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-23592269

RESUMO

Cell-surface display of functional proteins is a powerful and useful tool for regulating and reinforcing cellular functions. Direct incorporation of site-specifically lipidated proteins from the extracellular medium is more rapid, easily controllable and reliable in displaying active proteins than expression through gene transfer. However, undesirable amphiphilic reagents such as organic co-solvents and detergents were required for suppressing aggregation of ordinary lipidated proteins in solution. We report here sortase A-catalyzed modification of proteins with a poly(ethylene glycol)(PEG)-lipid in situ on the surface of living cells. Proteins fused with a recognition tag were site-specifically ligated with the PEG-lipid which was preliminary incorporated into cell membranes. Accordingly, target proteins were successfully displayed on living cells without aggregation under an amphiphilic reagent-free condition. Furthermore, to demonstrate the availability of the present method, Fc domains of immunoglobulin G were displayed on cancer cells, and the phagocytosis of cancer cells with dendritic cells were enhanced through the Fc-Fc receptor interaction. Thus, the present facile chemoenzymatic method for protein display can be utilized for modulating cell-cell interactions in cell and tissue engineering fields.


Assuntos
Técnicas de Visualização da Superfície Celular/métodos , Proteínas de Membrana , Fosfatidiletanolaminas/química , Polietilenoglicóis/química , Sequência de Aminoácidos , Aminoaciltransferases/metabolismo , Animais , Proteínas de Bactérias/metabolismo , Linhagem Celular Tumoral , Cisteína Endopeptidases/metabolismo , Células HeLa , Humanos , Fragmentos Fc das Imunoglobulinas/química , Fragmentos Fc das Imunoglobulinas/metabolismo , Imunoglobulina G/química , Imunoglobulina G/metabolismo , Proteínas de Membrana/análise , Proteínas de Membrana/química , Proteínas de Membrana/metabolismo , Camundongos , Dados de Sequência Molecular , Fosfatidiletanolaminas/metabolismo , Polietilenoglicóis/metabolismo
4.
Pharmaceuticals (Basel) ; 5(5): 405-16, 2012 Apr 26.
Artigo em Inglês | MEDLINE | ID: mdl-24281554

RESUMO

A simple method for attaching immunoglobulin G (IgG) on the cell surface was successfully developed for enhancing phagocytosis of apoptotic tumor cells (ATCs) by dendritic cells (DCs) ex vivo. By conjugating with a poly(ethylene glycol) (PEG)-lipid, named the biocompatible anchor for the membrane (BAM), arbitrary IgG could be incorporated into the cell membrane. In particular, when IgG-BAM conjugates were prepared at the optimal molar ratio of IgG to BAM (1 to 20), almost all cells were efficiently modified with IgG by treatment with IgG-BAM. This simple method was successfully applied to four types of mammalian cells. Furthermore, treatment of ATCs with the IgG-BAM conjugate increased the phagocytosis ratio of ATCs by DCs two-fold when compared to no treatment. This phagocytosis-enhancing effect was nearly identical to treatment with a tumor-specific IgG. Thus, without employing the tumor-specific IgG, which is difficult to obtain for any tumor cells and is expensive, the present method could opsonize ATC with the use of arbitrary IgG. The results strongly indicate that IgG-BAM treatment represents a promising method for opsonizing ATC with human serum IgG, and that this approach will lead to objective clinical responses in DC vaccines.

SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...