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J Transl Autoimmun ; 4: 100103, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34041473


Impaired interleukin-2 (IL-2) production and regulatory T-cell dysfunction have been implicated as immunological mechanisms central to the pathogenesis of multiple autoimmune and inflammatory diseases. NKTR-358, a novel regulatory T-cell stimulator, is an investigational therapeutic that selectively restores regulatory T-cell homeostasis in these diseases. We investigated NKTR-358's selectivity for regulatory T-cells, receptor-binding properties, ex vivo and in vivo pharmacodynamics, ability to suppress conventional T-cell proliferation in mice and non-human primates, and functional activity in a murine model of systemic lupus erythematosus. In vitro, NKTR-358 demonstrated decreased affinity for IL-2Rα, IL-2Rß, and IL-2Rαß compared with recombinant human IL-2 (rhIL-2). A single dose of NKTR-358 in cynomolgus monkeys produced a greater than 15-fold increase in regulatory T-cells, and the increase lasted until day 14, while daily rhIL-2 administration for 5 days only elicited a 3-fold increase, which lasted until day 7. Repeated dosing of NKTR-358 over 6 months in cynomolgus monkeys elicited cyclical, robust increases in regulatory T-cells with no loss in drug activity over the course of treatment. Regulatory T-cells isolated from NKTR-358-treated mice displayed a sustained, higher suppression of conventional T-cell proliferation than regulatory T-cells isolated from vehicle-treated mice. NKTR-358 treatment in a mouse model (MRL/MpJ-Faslpr) of systemic lupus erythematosus for 12 weeks maintained elevated regulatory T-cells for the treatment duration and ameliorated disease progression. Together, these results suggest that NKTR-358 has the ability to elicit sustained and preferential proliferation and activation of regulatory T-cells without corresponding effects on conventional T-cells, with improved pharmacokinetics compared with rhIL-2.

Cancer Chemother Pharmacol ; 79(1): 57-67, 2017 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-27904955


PURPOSE: The relationship between incidences of neutropenia and 10-hydroxy-7-ethyl camptothecin (SN38) exposure was explored using SN38 pharmacokinetic and neutrophil count data from toxicology studies of etirinotecan pegol (EP) and irinotecan in beagle dogs. METHODS: Dogs received four weekly intravenous infusions of either vehicle control (n = 22), EP (6, 15, 20, 25, 40/25 mg/kg; n = 3-9 dogs/dose group/sex; n = 48), or irinotecan (20 or 25 mg/kg n = 3-4 dogs/dose group/sex; n = 14). Blood samples were collected up to 50 days post-dose for characterization of SN38 pharmacokinetics. Two separate models were created describing SN38 concentration time profiles after either irinotecan or EP administrations to project the AUC0-168h after Day 1 and Day 22 doses. The relationship between incidence of neutropenia and SN38 exposure was explored using logistic regression. RESULTS: The incidence of neutropenia in dogs receiving weekly doses of irinotecan or EP was strongly correlated with maximum plasma SN38 concentration (C max), but not SN38 area under the concentration-time curve (AUC). Neutropenia occurred in approximately 80% of dogs receiving irinotecan (mean SN38 C max of 13.5 and 26.3 ng/mL for 20 and 25 mg/kg, respectively). No neutropenia occurred in dogs receiving EP at doses up to and including 25 mg/kg (mean SN38 C max of 3.4 and 4.9 ng/mL for 20 and 25 mg/kg, respectively), despite 2.5-3.6 times greater SN38 AUC after EP compared to irinotecan at equivalent doses. CONCLUSIONS: EP administration avoids both high SN38 C max values and development of dose-limiting neutropenia observed after irinotecan, while maintaining greater and sustained SN38 exposure between doses.

Antineoplásicos/toxicidade , Camptotecina/análogos & derivados , Compostos Heterocíclicos de 4 ou mais Anéis/toxicidade , Neutropenia/induzido quimicamente , Polietilenoglicóis/toxicidade , Animais , Área Sob a Curva , Camptotecina/farmacocinética , Camptotecina/toxicidade , Cães , Feminino , Incidência , Irinotecano , Masculino
MAbs ; 8(6): 999-1009, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27266390


Monoclonal antibody (mAb) therapeutics have tremendous potential to benefit patients with lung diseases, for which there remains substantial unmet medical need. To capture the current state of mAb research and development in the area of respiratory diseases, the Research Center of Respiratory Diseases (CEPR-INSERM U1100), the Laboratory of Excellence "MAbImprove," the GDR 3260 "Antibodies and therapeutic targeting," and the Grant Research program ARD2020 "Biotherapeutics" invited speakers from industry, academic and government organizations to present their recent research results at the Therapeutic Monoclonal Antibodies for Respiratory Diseases: Current challenges and perspectives congress held March 31 - April 1, 2016 in Tours, France.

Anticorpos Monoclonais/uso terapêutico , Doenças Respiratórias/terapia , Administração por Inalação , Anticorpos Monoclonais/administração & dosagem , Terapia Biológica/métodos , Terapia Biológica/tendências , Humanos
Clin Cancer Res ; 22(3): 680-90, 2016 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-26832745


PURPOSE: Aldesleukin, recombinant human IL2, is an effective immunotherapy for metastatic melanoma and renal cancer, with durable responses in approximately 10% of patients; however, severe side effects limit maximal dosing and thus the number of patients able to receive treatment and potential cure. NKTR-214 is a prodrug of conjugated IL2, retaining the same amino acid sequence as aldesleukin. The IL2 core is conjugated to 6 releasable polyethylene glycol (PEG) chains. In vivo, the PEG chains slowly release to generate active IL2 conjugates. EXPERIMENTAL DESIGN: We evaluated the bioactivity and receptor binding of NKTR-214 and its active IL2 conjugates in vitro; the tumor immunology, tumor pharmacokinetics, and efficacy of NKTR-214 as a single agent and in combination with anti-CTLA-4 antibody in murine tumor models. Tolerability was evaluated in non-human primates. RESULTS: In a murine melanoma tumor model, the ratio of tumor-killing CD8(+) T cells to Foxp3(+) regulatory T cells was greater than 400 for NKTR-214 compared with 18 for aldesleukin, supporting preferential activation of the IL2 receptor beta over IL2 receptor alpha, due to the location of PEG molecules. NKTR-214 provides a 500-fold greater exposure of the tumor to conjugated IL2 compared with aldesleukin. NKTR-214 showed efficacy as a single agent and provided durable immunity that was resistant to tumor rechallenge in combination with anti-CTLA-4 antibody. NKTR-214 was well tolerated in non-human primates. CONCLUSIONS: These data support further evaluation of NKTR-214 in humans for a variety of tumor types, adding to the repertoire of potent and potentially curative cancer immunotherapies.

Antineoplásicos/farmacologia , Interleucina-2/análogos & derivados , Neoplasias/metabolismo , Neoplasias/patologia , Polietilenoglicóis/farmacologia , Pró-Fármacos , Receptores de Interleucina-2/metabolismo , Proteínas Recombinantes de Fusão/farmacologia , Animais , Antineoplásicos/química , Linfócitos T CD8-Positivos/efeitos dos fármacos , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/metabolismo , Antígeno CTLA-4/antagonistas & inibidores , Linhagem Celular Tumoral , Modelos Animais de Doenças , Sinergismo Farmacológico , Feminino , Humanos , Memória Imunológica , Interleucina-2/química , Interleucina-2/farmacologia , Linfócitos do Interstício Tumoral , Masculino , Melanoma Experimental , Camundongos , Modelos Moleculares , Conformação Molecular , Neoplasias/tratamento farmacológico , Neoplasias/imunologia , Polietilenoglicóis/química , Ligação Proteica , Receptores de Interleucina-2/química , Proteínas Recombinantes de Fusão/química , Proteínas Recombinantes/farmacologia , Linfócitos T Reguladores/efeitos dos fármacos , Linfócitos T Reguladores/imunologia , Linfócitos T Reguladores/metabolismo , Carga Tumoral/efeitos dos fármacos
J Antimicrob Chemother ; 67(4): 970-6, 2012 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-22240402


OBJECTIVES: Amphotericin B inhalation powder (ABIP) is a novel dry-powder amphotericin B formulation that is directly delivered to the lung, resulting in elevated lung tissue drug concentrations of this polyene. We evaluated the prophylactic efficacy of single dose administration of ABIP in a guinea pig model of invasive pulmonary aspergillosis. METHODS: Guinea pigs were immunosuppressed with cyclophosphamide and cortisone acetate and challenged with Aspergillus fumigatus conidia in an aerosol chamber. Guinea pigs received prophylaxis with a single inhaled dose of ABIP at 0.05, 0.5, 4 or 10 mg/kg administered 24 h prior to infection. Treatment with oral voriconazole at doses of 5 or 10 mg/kg twice daily beginning 24 h post-challenge served as the positive control. RESULTS: Improvements in survival were observed with ABIP prophylaxis. A single inhaled dose of 4 mg/kg ABIP and treatment with 5 mg/kg voriconazole both improved median and percentage survival compared with untreated controls. In addition, pulmonary fungal burden, as assessed by cfu, quantitative PCR and galactomannan, was also reduced in a dose-dependent fashion with ABIP prophylaxis as well as with both doses of voriconazole treatment. CONCLUSIONS: Single-dose prophylaxis with inhaled ABIP as prophylaxis demonstrated a significant survival advantage and reductions in pulmonary fungal burden in this model of invasive pulmonary aspergillosis. Optimization of the dose and dosing frequency of ABIP dose may help to further enhance the anti-Aspergillus activity of this novel amphotericin B formulation.

Anfotericina B/administração & dosagem , Antifúngicos/administração & dosagem , Aspergillus fumigatus/patogenicidade , Quimioprevenção/métodos , Aspergilose Pulmonar Invasiva/prevenção & controle , Administração por Inalação , Animais , Aspergillus fumigatus/efeitos dos fármacos , Contagem de Colônia Microbiana , Cortisona/administração & dosagem , Cortisona/análogos & derivados , Ciclofosfamida/administração & dosagem , Modelos Animais de Doenças , Cobaias , Imunossupressores/administração & dosagem , Pulmão/microbiologia , Masculino , Pirimidinas/administração & dosagem , Análise de Sobrevida , Triazóis/administração & dosagem , Voriconazol
Pharm Res ; 19(5): 634-9, 2002 May.
Artigo em Inglês | MEDLINE | ID: mdl-12069166


PURPOSE: Polysorbate 20 is a commonly used excipient in biopharmaceutical formulations, some of which may have an enzymatic activity. The action(s) of polysorbate 20 in biopharmaceutical formulations as a stabilizer require this surfactant to maintain its intact structure. This manuscript evaluates a new analytic method for the analysis of polysorbate 20 degradation in the format of a biopharmaceutical formulation and makes a comparison with several established methods of analysis. METHODS: Polysorbate 20 samples were degraded in a controlled environment utilizing the enzyme pancreatic lipase to generate degradants that included lauric acid and the sorbitan polyoxyethylene side chain. A new method was developed with sufficient sensitivity to analyze the degraded solutions. Lauric acid was derivatized with the fluorescent reagent 9-anthryldiazomethane to form 9-anthrylmethylethyl ester. The derivatized lauric acid was separated by reversed-phase chromatography and detected by fluorescence or UV spectroscopy. Three established methods utilized to measure polysorbate 20 were evaluated for their ability to detect degraded polysorbate 20. These methods were: (1) fluorescence analysis with N-phenyl-1-naphthylamine fluorescent dye; (2) UV spectroscopy with ammonium cobaltothiocyanate colorimetric reagent; and (3) nuclear magnetic resonance (NMR). RESULTS: Polysorbate 20 incubation with lipase resulted in degraded polysorbate 20 as determined by the derivatized lauric acid assay. The UV spectroscopy assay utilizing ammonium cobaltothiocyanate reagent was not able to detect the degradation of polysorbate 20 in the samples. The fluorescence method of analysis detected polysorbate 20 degradation as an approximate 50% decrease in micelles in comparison to standard nondegraded polysorbate 20 solutions. NMR analysis resulted in similar proton peak areas for both degraded and nondegraded polysorbate 20 samples. NMR spectra did contain minor differences between the samples. CONCLUSIONS: It is essential to choose the appropriate method of polysorbate 20 evaluation to assess the content, stability, and compatibility of a formulation. Current established methods to assess polysorbate 20 may overlook and do not necessarily monitor the potential degradation of this surfactant, which results in the formation of lauric acid. Because this type of degradation may occur in a formulation by an enzymatically active biopharmaceutical, a new method of analysis has been established.

Polissorbatos/análise , Química Farmacêutica , Estabilidade de Medicamentos , Fluorometria , Ácidos Láuricos/química , Espectroscopia de Ressonância Magnética , Micelas , Polissorbatos/química , Espectrofotometria Ultravioleta