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1.
Invest New Drugs ; 36(6): 1006-1015, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-29728897

RESUMO

Introduction MCLA-128 is a bispecific monoclonal antibody targeting the HER2 and HER3 receptors. Pharmacokinetics (PK) and pharmacodynamics (PD) of MCLA-128 have been evaluated in preclinical studies in cynomolgus monkeys and mice. The aim of this study was to characterize the PK and PD of MCLA-128 and to predict a safe starting dose and efficacious clinical dose for the First-In-Human study. Methods A PK-PD model was developed based on PK data from cynomolgus monkeys and tumor growth data from a mouse JIMT-1 xenograft model. Allometric scaling was used to scale PK parameters between species. Simulations were performed to predict the safe and efficacious clinical dose, based on AUCs, receptor occupancies and PK-PD model simulations. Results MCLA-128 PK in cynomolgus monkeys was described by a two-compartment model with parallel linear and nonlinear clearance. The xenograft tumor growth model consisted of a tumor compartment with a zero-order growth rate and a first-order dying rate, both affected by MCLA-128. Human doses of 10 to 480 mg q3wk were predicted to show a safety margin of >10-fold compared to the cynomolgus monkey AUC at the no-observed-adverse-effect-level (NOAEL). Doses of ≥360 mg resulted in predicted receptor occupancies above 99% (Cmax and Cave). These doses showed anti-tumor efficacy in the PK-PD model. Conclusions This analysis predicts that a flat dose of 10 to 480 mg q3wk is suitable as starting dose for a First-in-Human study with MCLA-128. Flat doses ≥360 mg q3wk are expected to be efficacious in human, based on receptor occupancies and PK-PD model simulations.


Assuntos
Anticorpos Biespecíficos/farmacologia , Anticorpos Biespecíficos/farmacocinética , Anticorpos Monoclonais/farmacologia , Anticorpos Monoclonais/farmacocinética , Imunoglobulina G/farmacologia , Modelos Biológicos , Pesquisa Translacional Biomédica , Animais , Área Sob a Curva , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Simulação por Computador , Relação Dose-Resposta Imunológica , Feminino , Humanos , Macaca fascicularis , Camundongos , Camundongos SCID , Resultado do Tratamento , Carga Tumoral , Ensaios Antitumorais Modelo de Xenoenxerto
2.
Cytokine ; 76(2): 433-441, 2015 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-26303011

RESUMO

RATIONALE: Neutrophils play a fundamental role in a number of chronic lung diseases. Among the mediators of their recruitment to the lung, CXCL8 (IL-8) is considered to be one of the major players. CXCL8 exerts its chemotactic activity by binding to its GPCR receptors (CXCR1/R2) located on neutrophils, as well as through interactions with glycosaminoglycans (GAGs) on cell surfaces including those of the microvascular endothelium. Binding to GAG co-receptors is required to generate a solid-phase haptotactic gradient and to present IL-8/CXCL8 in a proper conformation to its receptors on circulating neutrophils. METHODS: We have engineered increased GAG-binding affinity into human CXCL8, thereby obtaining a competitive inhibitor that displaces wild-type IL-8/CXCL8 from GAGs. By additionally knocking-out the GPCR binding domain of the chemokine, we generated a dominant negative protein (dnCXCL8; PA401) with potent anti-inflammatory characteristics proven in vivo in a murine model of LPS-induced lung inflammation (Adage et al., 2015). Here we have further investigated PA401 activity in this pulmonary model by evaluating plasma changes induced by LPS on white blood cells (WBC) and a broad range of inflammatory markers, especially chemokines, by addressing immediate effects of PA401 on these parameters in healthy and LPS exposed mice. RESULTS: Aerosolized LPS induced a significant increase in bronchoalveolar lavage (BAL) neutrophils after 3 and 7h, as well as an increase in total WBC and changes in 21 of the 59 measured plasma markers, mostly belonging to the chemokine family. PA401 treatment in saline exposed mice didn't induce major changes in any of the measured parameters. When administered to LPS aerosolized mice, PA401 caused a significant normalization of KC/mCXCL1 and other inflammatory markers, as well as of blood WBC count. In addition, BAL neutrophils were significantly reduced, confirming the previously observed lung anti-inflammatory activity of PA401 in this experiment. CONCLUSIONS: PA401 is a new promising biologic therapeutic with a novel and unique mechanism of action for interfering with neutrophilic lung inflammation, that also normalizes plasma inflammatory markers.


Assuntos
Biomarcadores/metabolismo , Líquido da Lavagem Broncoalveolar , Modelos Animais de Doenças , Glicosaminoglicanos/metabolismo , Interleucina-8/metabolismo , Lipopolissacarídeos/farmacologia , Neutrófilos/efeitos dos fármacos , Pneumonia/induzido quimicamente , Proteínas Recombinantes/metabolismo , Animais , Interleucina-8/farmacologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Neutrófilos/metabolismo , Proteínas Recombinantes/farmacologia
3.
Regul Toxicol Pharmacol ; 59(3): 461-70, 2011 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-21300126

RESUMO

Pharmacokinetic properties and safety profile of a drug are likely influenced by the disease state of a patient. In this study, we investigated the influence of arthritic processes on pharmacokinetics and immunotoxicity of interleukin-1 receptor antagonist (Anakinra) in the rat adjuvant arthritis model. Anakinra dose-dependently suppressed joint inflammation and degradation as demonstrated by reduced clinical arthritis score, paw thickness, synovial infiltration and bone degradation. In addition, plasma levels of chemokines MCP-1 and GRO/KC were reduced. Pharmacokinetic behaviour of Anakinra was influenced by disease state of the rats as judged from a decrease in C(max) and an increase of the MRT as the disease progressed at a dose of 24 and 72 mg Anakinra/kg body weight. The pharmacokinetic parameters increased dose-dependently, but non-proportionally with increasing dose. Low level anti-Anakinra antibody formation was observed at prolonged exposure to the biologic. Safety parameters, including haematology, splenic lymphocyte subset analysis, ex vivo stimulation of spleen cells and histopathology of immune system organs were affected by the disease itself to such extent that no additional effects of Anakinra could be observed. In conclusion, we demonstrated that pharmacokinetic behaviour of Anakinra was influenced by the arthritis background of the rats resulting in decreased internal exposure.


Assuntos
Artrite Experimental/tratamento farmacológico , Artrite Experimental/metabolismo , Modelos Animais de Doenças , Proteína Antagonista do Receptor de Interleucina 1/farmacocinética , Proteína Antagonista do Receptor de Interleucina 1/uso terapêutico , Receptores de Interleucina-1/antagonistas & inibidores , Animais , Células Cultivadas , Relação Dose-Resposta a Droga , Avaliação Pré-Clínica de Medicamentos/métodos , Proteína Antagonista do Receptor de Interleucina 1/toxicidade , Masculino , Distribuição Aleatória , Ratos , Ratos Endogâmicos Lew , Receptores de Interleucina-1/metabolismo , Resultado do Tratamento
4.
Clin Pharmacokinet ; 59(7): 875-884, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32006223

RESUMO

BACKGROUND AND OBJECTIVES: MCLA-128 is a bispecific monoclonal antibody targeting the HER2 and HER3 receptors and is in development to overcome HER3-mediated resistance to anti-HER2 therapies. The aims of this analysis were to characterize the population pharmacokinetics of MCLA-128 in patients with various solid tumors, to evaluate patient-related factors that affect the disposition of MCLA-128, and to assess whether flat dosing is appropriate. METHODS: MCLA-128 concentration data following intravenous administration were collected in a phase I/II clinical trial. Pharmacokinetic data were analyzed using non-linear mixed-effects modeling. Different compartmental models were evaluated. Various body size parameters including body weight, body surface area, and fat-free mass were evaluated as covariates in addition to age, sex, HER2 status, and tumor burden. RESULTS: In total, 1115 serum concentration measurements were available from 116 patients. The pharmacokinetics of MCLA-128 was best described by a two-compartment model with linear and non-linear (Michaelis-Menten) clearance. Fat-free mass significantly affected the linear clearance and volume of distribution of the central compartment of MCLA-128, explaining 8.4% and 5.6% of inter-individual variability, respectively. Tumor burden significantly affected the non-linear clearance capacity. Simulations demonstrated that dosing based on body size parameters resulted in similar area under the plasma concentration-time curve for a dosing interval (AUC0-τ), maximum and trough concentrations of MCLA-128, compared to flat dosing. CONCLUSIONS: This analysis demonstrated that the pharmacokinetics of MCLA-128 exhibits similar disposition characteristics to other therapeutic monoclonal antibodies and that a flat dose of MCLA-128 in patients with various solid tumors is appropriate.


Assuntos
Anticorpos Biespecíficos/farmacocinética , Anticorpos Monoclonais/farmacocinética , Neoplasias , Humanos , Imunoglobulina G , Modelos Biológicos , Neoplasias/terapia
5.
Expert Opin Biol Ther ; 19(7): 721-733, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31286786

RESUMO

Objective: We report the characterization of MCLA-117, a novel T cell-redirecting antibody for acute myeloid leukaemia (AML) treatment targeting CD3 on T cells and CLEC12A on leukaemic cells. In AML, CLEC12A is expressed on blasts and leukaemic stem cells. Methods: The functional capacity of MCLA-117 to redirect resting T cells to eradicate CLEC12APOS tumor cells was studied using human samples, including primary AML samples. Results: Within the normal hematopoietic compartment, MCLA-117 binds to cells expressing CD3 and CLEC12A but not to early myeloid progenitors or hematopoietic stem cells. MCLA-117 induces T cell activation (EC50 = 44 ng/mL), T cell proliferation, mild pro-inflammatory cytokine release, and redirects T cells to lyse CLEC12APOS target cells (EC50 = 68 ng/mL). MCLA-117-induced targeting of normal CD34POS cells co-cultured with T cells spares erythrocyte and megakaryocyte differentiation as well as preserves mono-myelocytic lineage development. In primary AML patient samples with autologous T cells, MCLA-117 robustly induced AML blast killing (23-98%) at low effector-to-target ratios (1:3-1:97). Conclusion: These findings demonstrate that MCLA-117 efficiently redirects T cells to kill tumour cells while sparing the potential of the bone marrow to develop the full hematological compartment and support further clinical evaluation as a potentially potent treatment option for AML.


Assuntos
Anticorpos Biespecíficos/uso terapêutico , Leucemia Mieloide Aguda/tratamento farmacológico , Linfócitos T/imunologia , Animais , Anticorpos Biespecíficos/metabolismo , Anticorpos Biespecíficos/farmacocinética , Complexo CD3/imunologia , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/metabolismo , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/metabolismo , Proliferação de Células , Citocinas/análise , Citocinas/metabolismo , Células HL-60 , Meia-Vida , Humanos , Lectinas Tipo C/imunologia , Leucemia Mieloide Aguda/imunologia , Ativação Linfocitária , Camundongos , Camundongos Endogâmicos C57BL , Receptores Mitogênicos/imunologia , Linfócitos T/metabolismo
6.
Int Immunopharmacol ; 6(1): 1-7, 2006 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-16332507

RESUMO

Vascular endothelial growth factor (VEGF), oncostatin M (OSM), and granulocyte chemotactic protein-2 (GCP-2/CXCL6) are up-regulated in U937 macrophages and peripheral blood macrophages exposed to LPS, beta-adrenergic receptor (beta2-AR) agonists (e.g. zilpaterol, and clenbuterol) and some other agents that induce intracellular cAMP (prostaglandin E2, forskolin, and butyryl cAMP). LPS in combination with beta2-agonists and cAMP elevating agents had an additional effect on the release of VEGF, OSM, and CXCL6. These proteins are up-regulated after 16-24 h of exposure and this is mediated by the beta2-AR, as determined by time course experiments and the use of a specific beta2-AR antagonist (ICI 118551). Beta2-AR agonists are used as bronchodilators in the treatment of asthma, but appear to have no effect on the chronic inflammation of the disease. However, the up-regulation of VEGF, OSM, and CXCL6 may have adverse effects on the inflammatory process of asthma. These mediators are involved in the recruitment of neutrophils, airway remodelling and angiogenesis, known features of chronic inflammatory diseases. We propose that the up-regulation of these proteins could play a role in the adverse effects of prolonged excessive usage of beta2-AR agonists on the airways besides the desensitization of the beta2-AR.


Assuntos
Agonistas Adrenérgicos beta/farmacologia , Quimiocinas CXC/biossíntese , Citocinas/metabolismo , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Fator A de Crescimento do Endotélio Vascular/biossíntese , Bucladesina/farmacologia , Quimiocina CXCL6 , Clembuterol/farmacologia , Colforsina/farmacologia , AMP Cíclico/biossíntese , Dinoprostona/farmacologia , Humanos , Lipopolissacarídeos/farmacologia , Ativação de Macrófagos/efeitos dos fármacos , Oncostatina M , Compostos de Trimetilsilil/farmacologia , Células U937 , Regulação para Cima/efeitos dos fármacos
7.
FEMS Immunol Med Microbiol ; 45(2): 183-9, 2005 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-15939578

RESUMO

Microbial metabolites may influence the metabolic integrity of intestinal epithelial cells and induce mucosal immune responses. Therefore, we investigated the effects of the microbial metabolites butyrate, iso-valerate, and ammonium on Caco-2 cells and macrophages. Barrier functioning was determined by measuring transepithelial electrical resistance and basolateral recoveries of metabolites. The barrier function of Caco-2 cells remained intact after exposures. Basolateral recoveries ranged from 6.2% to 15.2%. Tumour necrosis factor-alpha and interleukin-10 were measured to determine immune reactions. The Caco-2 cells did not secrete both cytokines. Physiological concentrations of butyrate and iso-valerate stimulated the secretion of tumour necrosis factor-alpha and suppressed the secretion of interleukin-10 by macrophages that are not protected by an epithelial barrier. In contrast, ammonium concentrations as high as those produced by microbiotas of IBD patients suppressed the release of both cytokines when the barrier function is impaired.


Assuntos
Intestinos/imunologia , Intestinos/microbiologia , Macrófagos/imunologia , Macrófagos/microbiologia , Cloreto de Amônio/metabolismo , Cloreto de Amônio/farmacologia , Butiratos/metabolismo , Butiratos/farmacologia , Células CACO-2 , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/imunologia , Células Epiteliais/microbiologia , Hemiterpenos , Humanos , Imunidade nas Mucosas/efeitos dos fármacos , Técnicas In Vitro , Doenças Inflamatórias Intestinais/etiologia , Doenças Inflamatórias Intestinais/imunologia , Doenças Inflamatórias Intestinais/microbiologia , Interleucina-10/metabolismo , Intestinos/efeitos dos fármacos , Macrófagos/efeitos dos fármacos , Ácidos Pentanoicos/metabolismo , Ácidos Pentanoicos/farmacologia , Fator de Necrose Tumoral alfa/metabolismo , Células U937
8.
J Proteome Res ; 4(6): 2015-23, 2005.
Artigo em Inglês | MEDLINE | ID: mdl-16335946

RESUMO

Two-dimensional difference gel electrophoresis (DIGE) in combination with univariate (Student's t-test) and multivariate data analysis, principal component analysis (PCA) and partial least squares discriminant analysis (PLS-DA) were used to study the anti-inflammatory effects of the beta(2)-adrenergic receptor (beta(2)-AR) agonist zilpaterol. U937 macrophages were exposed to the endotoxin lipopolysaccharide (LPS) to induce an inflammatory reaction, which was inhibited by the addition of zilpaterol (LZ). This inhibition was counteracted by addition of the beta(2)-AR antagonist propranolol (LZP). The extracellular proteome of the U937 cells induced by the three treatments were examined by DIGE. PCA was used as an explorative tool to investigate the clustering of the proteome dataset. Using this tool, the dataset obtained from cells treated with LPS and LZP were separated from those obtained from LZ treated cells. PLS-DA, a multivariate data analysis tool that also takes correlations between protein spots and class assignment into account, correctly classified the different extracellular proteomes and showed that many proteins were differentially expressed between the proteome of inflamed cells (LPS and LZP) and cells in which the inflammatory response was inhibited (LZ). The Student's t-test revealed 8 potential protein biomarkers, each of which was expressed at a similar level in the LPS and LZP treated cells, but differently expressed in the LZ treated cells. Two of the identified proteins, macrophage inflammatory protein-1beta (MIP-1beta) and macrophage inflammatory protein-1alpha (MIP-1alpha) are known secreted proteins. The inhibition of MIP-1beta by zilpaterol and the involvement of the beta(2)-AR and cAMP were confirmed using a specific immunoassay.


Assuntos
Agonistas Adrenérgicos/farmacologia , Agonistas de Receptores Adrenérgicos beta 2 , Anti-Inflamatórios/farmacologia , Eletroforese em Gel Bidimensional/métodos , Antagonistas Adrenérgicos beta/farmacologia , Biomarcadores , Quimiocina CCL3 , Quimiocina CCL4 , Análise por Conglomerados , Regulação para Baixo , Ensaio de Imunoadsorção Enzimática , Humanos , Imunoensaio , Inflamação , Lipopolissacarídeos/metabolismo , Proteínas Inflamatórias de Macrófagos/metabolismo , Macrófagos/metabolismo , Espectrometria de Massas , Monócitos/metabolismo , Análise Multivariada , Análise de Componente Principal , Propranolol/farmacologia , Proteoma , Proteômica/métodos , Estatística como Assunto , Compostos de Trimetilsilil/farmacologia , Células U937 , Regulação para Cima
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