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1.
J Biochem ; 168(3): 231-241, 2020 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-32271918

RESUMO

This study introduces a novel monoclonal anti-α9 integrin antibody (MA9-413) with human variable regions, isolated by phage display technology. MA9-413 specifically binds to both human and mouse α9 integrin by recognizing a conserved loop region designated as L1 (amino acids 104-122 of human α9 integrin). MA9-413 inhibits human and mouse α9 integrin-dependent cell adhesion to ligands and suppresses synovial inflammation and osteoclast activation in a mouse model of arthritis. This is the first monoclonal anti-α9 integrin antibody that can react with and functionally inhibit both human and mouse α9 integrin. MA9-413 allows data acquisition both in animal and human pharmacological studies without resorting to surrogate antibodies. Since MA9-413 showed certain therapeutic effects in the mouse arthritis model, it can be considered as a useful therapy against rheumatoid arthritis and other α9 integrin-associated diseases.


Assuntos
Anticorpos Monoclonais/imunologia , Anticorpos Monoclonais/uso terapêutico , Artrite Reumatoide/tratamento farmacológico , Cadeias alfa de Integrinas/imunologia , Cadeias alfa de Integrinas/metabolismo , Animais , Anticorpos Monoclonais/farmacologia , Adesão Celular/efeitos dos fármacos , Diferenciação Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Técnicas de Visualização da Superfície Celular , Reações Cruzadas , Modelos Animais de Doenças , Proteínas de Fluorescência Verde/genética , Proteínas de Fluorescência Verde/metabolismo , Humanos , Região Variável de Imunoglobulina/imunologia , Inflamação/tratamento farmacológico , Cadeias alfa de Integrinas/genética , Masculino , Camundongos , Camundongos Endogâmicos DBA , Osteoclastos/metabolismo , Transfecção , Resultado do Tratamento
2.
Eur J Pharmacol ; 843: 190-198, 2019 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-30472202

RESUMO

Interleukin (IL)-23 is thought to be critical in the pathogenesis of psoriasis, and anti-IL-23 monoclonal antibodies (mAbs) have been approved for the treatment of psoriasis. We speculated that an anti-IL-23 receptor mAb might have greater efficacy than an anti-IL-23 mAb in the treatment of local inflamed lesions with high IL-23 levels. We previously generated an anti-human IL-23 receptor mAb, AS2762900-00, which potently blocked IL-23-induced cell proliferation, regardless of the concentration of IL-23. Here, we evaluated the therapeutic potential of AS2762900-00 in the treatment of psoriasis. Compared with untreated control, AS2762900-00 significantly reduced the epidermal thickness of lesions in a clinically relevant psoriatic human skin xenograft model. The expression of inflammatory genes including genes downstream of IL-23 signaling in the lesion tended to be lower in the AS2762900-00 group than the untreated group, suggesting that the inhibitory effects of AS2762900-00 in the psoriatic human skin xenograft model might occur via blockade of IL-23 signaling pathways. Further, AS2762900-00 showed an inhibitory effect on signal transducer and activator of transcription 3 (STAT3) phosphorylation as a downstream signal of IL-23 receptor activation in whole blood from patients with psoriasis. We also confirmed that AS2762900-00 inhibited IL-23-induced STAT3 phosphorylation in a concentration-dependent manner using whole blood from healthy donors. These data suggest that AS2762900-00 is a promising drug candidate for the treatment of psoriasis. In addition, STAT3 phosphorylation in whole blood may be a useful biomarker for the evaluation of the pharmacodynamic effects of AS2762900-00 in healthy volunteers in clinical development.


Assuntos
Anticorpos Monoclonais/farmacologia , Psoríase/tratamento farmacológico , Receptores de Interleucina/imunologia , Fator de Transcrição STAT3/metabolismo , Pele/efeitos dos fármacos , Animais , Modelos Animais de Doenças , Feminino , Humanos , Hiperplasia/prevenção & controle , Imunoglobulina G/imunologia , Camundongos , Fosforilação/efeitos dos fármacos , Psoríase/imunologia , Psoríase/metabolismo , Pele/imunologia , Pele/patologia , Transplante Heterólogo
3.
Eur J Pharmacol ; 828: 89-96, 2018 Jun 05.
Artigo em Inglês | MEDLINE | ID: mdl-29588152

RESUMO

Interleukin (IL)-12 and IL-23 share a common subunit (p40) and function in T-helper (Th) 1 and Th17 immunity, respectively. Anti-IL-12/23p40 and specific anti-IL-23 antibodies are currently in clinical use for psoriasis and undergoing trials for autoimmune diseases. Since expression levels of the IL-23 receptor are likely to be much lower than those of IL-23, an anti-IL-23 receptor antibody might offer greater promise in inhibiting the IL-23-IL-17 pathways involved in inflammatory disorders. To our knowledge, no anti-IL-23 receptor antibody has been trialed in clinical studies to date. This study describes the generation and characterization of AS2762900-00, a fully human monoclonal antibody against the IL-23 receptor. AS2762900-00 bound both human and cynomolgus monkey IL-23 receptors. AS2762900-00 showed potent inhibitory effects on IL-23-induced Kit-225 cell proliferation compared to the existing anti-IL-12/23p40 antibody, ustekinumab. In a single dose administration pharmacodynamics study in cynomolgus monkeys, 1 mg/kg of AS2762900-00 significantly inhibited (> 85%) IL-23-induced STAT3 phosphorylation in blood for up to 84 days. Therefore, AS2762900-00 represents a potent novel IL-23-IL-17 pathway inhibitor with the potential to be developed into a new therapy for the treatment of autoimmune diseases.


Assuntos
Anticorpos Monoclonais/imunologia , Receptores de Interleucina/imunologia , Animais , Proliferação de Células/efeitos dos fármacos , Feminino , Humanos , Interleucina-23/farmacologia , Macaca fascicularis , Masculino
4.
Eur J Pharmacol ; 824: 163-169, 2018 Apr 05.
Artigo em Inglês | MEDLINE | ID: mdl-29391156

RESUMO

Experimental colitis studies, including T cell-mediated colitis, indicate that IL-23 rather than IL-12 orchestrates intestinal inflammation in inflammatory bowel disease (IBD). Previous studies have identified the roles of IL-12 and IL-23 using mice deficient for their specific subunits, p35 and p19, respectively. However, these studies do not completely reflect the difference in roles between IL-12 and IL-23, especially since the discovery of novel IL-12 family cytokines, which also include p35 or p19 subunits. Here, to clarify the contribution of IL-12 and IL-23 in T cell-mediated colitis, we compared the efficacy of a monoclonal antibody (mAb) to an IL-23-specific receptor subunit with that of an anti-IL-12/23p40 mAb in a naive CD4+ T cell transfer model of experimental colitis, which is associated with enhanced Th1 and Th17 responses. Both antibodies almost completely prevented the development of colitis and showed reduced associated histological changes, including mucosal hyperplasia, infiltration of inflammatory cells and loss of goblet cells. The anti-IL-23 receptor mAb inhibited not only the systemic Th17-response but also the Th1-response, both of which were up-regulated in this model. These results suggest that IL-23, but not IL-12, signaling is critical for the development of colitis. Blockade of IL-23 signaling is a promising therapeutic approach for IBD.


Assuntos
Anticorpos Monoclonais/imunologia , Linfócitos T CD4-Positivos/imunologia , Colite/imunologia , Colite/prevenção & controle , Interleucina-23/imunologia , Células Th1/imunologia , Células Th17/imunologia , Animais , Anticorpos Monoclonais/sangue , Masculino , Camundongos
5.
Biol Pharm Bull ; 35(1): 72-7, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-22223340

RESUMO

We determined the binding affinity of tamsulosin, a selective α(1)-adrenoceptor antagonist, for human α(1)-adrenoceptor subtypes in comparison with those of other α(1)-adrenoceptor antagonists including silodosin, prazosin, 5-methylurapidil, terazosin, alfuzosin, nafopidil, urapidil and BMY7378. The association and dissociation kinetics of [(3)H]tamsulosin for recombinant human α(1)-adrenoceptor subtypes were compared with those of [(3)H]prazosin. Tamsulosin competitively inhibited [(3)H]prazosin binding to human α(1A)-, α(1B)- and α(1D)-adrenoceptors (pK(i) values were 10.38, 9.33, 9.85) indicating 11 and 3.4-fold higher affinities for human α(1A)-adrenoceptor than those for α(1B)- and α(1D)-adrenoceptors, respectively. The affinity of tamsulosin for the human α(1A)-adrenoceptor was, respectively, 5, 9.9, 38, 120, 280, 400, 1200 and 10000 fold higher than those of silodosin, prazosin, 5-methylurapidil, terazosin, alfuzosin, naftopidil, urapidil and BMY7378, respectively. [(3)H]Tamsulosin dissociated from the α(1A)-adrenoceptor slower than from the α(1B)- and α(1D)-adrenoceptors (α(1B)>α(1D)>α(1A)). Moreover, [(3)H]tamsulosin dissociated slower than [(3)H]prazosin from the α(1A)-adrenoceptor and faster from the α(1B)- and α(1D)-adrenoceptors. In conclusion, tamsulosin potently and selectively antagonized α(1A/1D)-adrenoceptor ligand binding, and slowly dissociated from the α(1A)-adrenoceptor subtype.


Assuntos
Antagonistas de Receptores Adrenérgicos alfa 1/farmacologia , Hiperplasia Prostática/tratamento farmacológico , Receptores Adrenérgicos alfa 1/química , Sulfonamidas/farmacologia , Antagonistas de Receptores Adrenérgicos alfa 1/química , Antagonistas de Receptores Adrenérgicos alfa 1/uso terapêutico , Ligação Competitiva , Humanos , Cinética , Masculino , Proteínas Recombinantes , Sulfonamidas/química , Sulfonamidas/uso terapêutico , Tansulosina
6.
J Pharmacol Exp Ther ; 317(1): 244-50, 2006 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-16339911

RESUMO

CC chemokine ligand 11 (CCL11/eotaxin) and other CC chemokine receptor 3 (CCR3) ligands (CCL24/eotaxin-2, CCL26/eotaxin-3, CCL13/monocyte chemotactic protein-4, etc.) play important roles in the chemotaxis and activation of eosinophils and other CCR3-expressing cells (basophils, mast cells, and CD4(+) T helper 2 cells) in allergic inflammation incidents, including asthma and rhinitis. A newly synthesized compound, N-{(3R)-1-[(6-fluoro-2-naphthyl)methyl]pyrrolidin-3-yl}-2-{1-[(5-hydroxy-3-methylpyridin-2-yl)carbonyl]piperidin-4-ylidene}-acetamide hemifumarate (YM-355179), inhibited the binding of CCL11 and CCL5/regulated on activation normal T cell expressed and secreted to CCR3-expressing B300-19 cells with IC(50) values of 7.6 and 24 nM, respectively. In contrast, YM-355179 did not affect the binding of CCL5 to CCR1 or CCR5. In functional assays, YM-355179 inhibited CCL11-induced, intracellular Ca(2+) influx, chemotaxis, and eosinophil degranulation with IC(50) values of 8.0, 24, and 29 nM, respectively. YM-355179 did not, however, affect any CC chemokine receptor (CCR1, CCR2, CCR4, or CCR5)-mediated Ca(2+) influx signals. Furthermore, oral administration of YM-355179 (1 mg/kg) inhibited CCL11-induced shape change of whole blood eosinophils in cynomolgus monkeys. Intravenous injection of YM-355179 (1 mg/kg) also inhibited eosinophil infiltration into airways of cynomolgus monkeys after segmental bronchoprovocation with CCL11. These results indicate that YM-355179 is a novel, selective, and orally available CCR3 antagonist with therapeutic potential for treating eosinophil-related allergic inflammatory diseases.


Assuntos
Degranulação Celular/efeitos dos fármacos , Quimiocinas CC/metabolismo , Quimiotaxia de Leucócito/efeitos dos fármacos , Eosinófilos/efeitos dos fármacos , Compostos de Epóxi/farmacologia , Morfinanos/farmacologia , Receptores de Quimiocinas/antagonistas & inibidores , Administração Oral , Animais , Ligação Competitiva , Líquido da Lavagem Broncoalveolar/citologia , Cálcio/metabolismo , Linhagem Celular Tumoral , Quimiocina CCL11 , Clonagem Molecular , Eosinófilos/fisiologia , Compostos de Epóxi/administração & dosagem , Humanos , Injeções Intravenosas , Ligantes , Pulmão/efeitos dos fármacos , Macaca fascicularis , Camundongos , Estrutura Molecular , Morfinanos/administração & dosagem , Receptores CCR3
7.
Arzneimittelforschung ; 52(11): 857-61, 2002.
Artigo em Inglês | MEDLINE | ID: mdl-12489258

RESUMO

Interleukin-11 (IL-11, CAS 145941-26-0) is a cytokine that ameliorates thrombocytopenia induced by chemotherapy. Granulocyte colony-stimulating factor (G-CSF) is frequently used clinically as an adjuvant therapy to ameliorate neutropenia. In this study, it has been investigated whether IL-11 influences the hematopoietic action of G-CSF in vitro. IL-11 alone did not stimulate CFU-Meg colony formation in the absence of interleukin-3 (IL-3), but did in the presence of IL-3. However, IL-11 alone stimulated the formation of CFU-E, BFU-E and CFU-GM colonies, which were further enhanced by IL-3. G-CSF alone stimulated in a concentration dependent manner colony formation of CFU-GM and CFU-E, but not BFU-E or CFU-Meg. The addition of IL-11 enhanced the stimulatory effect of G-CSF on CFU-GM colony formation, and enabled G-CSF to stimulate colony formation of BFU-E, but not CFU-E. The addition of IL-3 further enhanced the stimulatory effect of G-CSF on CFU-E, BFU-E, and CFU-GM colony formation. However, G-CSF was unable to stimulate CFU-Meg colony formation for any of the cytokine combinations tested. These studies demonstrate that IL-11 has significant stimulatory effects on G-CSF-induced CFU-GM colony formation, suggesting that the therapeutic combination of the two growth factors could be beneficial for the treatment of myelosuppression induced by chemotherapy.


Assuntos
Fator Estimulador de Colônias de Granulócitos/farmacologia , Hematínicos/farmacologia , Interleucina-11/farmacologia , Animais , Células da Medula Óssea/efeitos dos fármacos , Células Cultivadas , Sinergismo Farmacológico , Células Precursoras Eritroides/efeitos dos fármacos , Feminino , Células-Tronco Hematopoéticas/efeitos dos fármacos , Interleucina-3/farmacologia , Camundongos , Camundongos Endogâmicos C57BL , Proteínas Recombinantes/farmacologia , Trombopoetina/efeitos dos fármacos
8.
Cancer Chemother Pharmacol ; 49(2): 161-6, 2002 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-11862431

RESUMO

PURPOSE: Interleukin-11 (IL-11) is a stromal cell derived multifunctional cytokine, which plays important roles in the hematopoietic and nonhematopoietic systems. Recombinant human IL-11 (rhIL-11) is used in the treatment of chemotherapy-induced thrombocytopenia. We have investigated the effects of rhIL-11 on the antitumor activity of chemotherapeutic agents and on thrombocytopenia in myelosuppressed mice bearing tumor cells. METHODS: We tested the effect of rhIL-11 on Lewis lung carcinoma (LLC) cell proliferation when used alone or in combination with three antitumor agents in vitro. Also, a newly developed chemotherapy-induced myelosuppressed mice model bearing LLC cells was used to study the effects of rhIL-11 on the antitumor activity and on thrombocytopenia. RESULTS: On its own, rhIL-11 (1-100 ng/ml) did not stimulate cell proliferation, and did not alter the antitumor activities of carboplatin, mitomycin C, or etoposide in vitro. In mice implanted with LLC cells (1 x 10(4)), carboplatin (50 mg/kg/day for 2 consecutive days, i.p.) inhibited tumor growth and caused thrombocytopenia. Treatment with rhIL-11 (500 microg/kg/day, from the day following the last dosing with carboplatin for 14 days, s.c.) successfully prevented thrombocytopenia without affecting the antitumor activity of carboplatin. With rhIL-11 there was no obvious effect on the red blood cell count, white blood cell count, or body weight. CONCLUSION: These results support the assertion that rhIL-11 may be a significant therapeutic agent for thrombocytopenia following cancer chemotherapy, and that it need be associated with little fear of tumor proliferation.


Assuntos
Antineoplásicos/efeitos adversos , Carboplatina/efeitos adversos , Carcinoma Pulmonar de Lewis/tratamento farmacológico , Interleucina-11/uso terapêutico , Trombocitopenia/prevenção & controle , Animais , Medula Óssea/efeitos dos fármacos , Carcinoma Pulmonar de Lewis/sangue , Camundongos , Proteínas Recombinantes/uso terapêutico , Trombocitopenia/induzido quimicamente , Células Tumorais Cultivadas
9.
Dev Growth Differ ; 32(3): 303-314, 1990 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-37282139

RESUMO

Ryanodine, miconazole, clotrimazole, doxorubicin, quercetin, halothane, caffeine and chloroform, which activate Ca2+ -induced Ca2+ release from Ca2+ stores, induced Ca2+ release from a particulate fraction isolated from sea urchin eggs, Ca2+ influx into eggs and formation of a fertilization membrane in an appreciable number of eggs. Their minimum effective concentrations for inducing a fertilization membrane increased in the order of these drugs listed above, and this order was also the same as that of their minimum effective concentrations for inducing Ca2+ release from the isolated particulate fraction. Their effect in inducing a fertilization membrane was blocked by ruthenium red and procaine, which inhibit Ca2+ release from Ca2+ stores. Thus these drugs probably induced sufficient Ca2+ release to make the cytosolic Ca2+ level high enough in many eggs for formation of a fertilization membrane. In the absence of external Ca2+ , fewer eggs treated with these drugs formed a fertilization membrane and more eggs did so on further treatment with either A23187 or carbonylcyanide-p-trifluoromethoxy-phenylhydrazone (FCCP). Thus, a high level of Ca2+ is probably derived from Ca2+ release through Ca2+ releasing channels (by A23187), from mitochondria (by FCCP) and its transport from the external medium.

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