RESUMEN
Background: Cystic echinococcosis is a zoonotic parasitic infection caused by Echinococcus granulosus worldwide and is associated with economic losses among livestock animals. EG95 is an immunogenic antigen from the E. granulosus. Lactococcus lactis has been prested as a safe vehicle for antigen delivery. The goal of this study was to design a novel L. lactis strain displaying EG95 as a vaccine delivery system. Methods: The eg95 encoding gene fragment fused to the M6 anchoring protein was cloned into the pNZ7021 vector, and L. lactis NZ9000 displaying recombinant EG95 was constructed. The expression of an approximately 32-kDa EG95 protein was confirmed by Western blotting and immunofluorescence analysis. The immune responses were evaluated in BALB/c mice immunized orally and subcutaneously with the live and killed recombinant L. lactis, respectively. Results: Total IgG level in mice immunized with heat-killed recombinant L. lactis (pNZ7021-eg95) significantly increased compared to the control group. Mucosal IgA was significantly higher in mice received live recombinant L. lactis (pNZ7021-eg95) compared to the control mice. Splenic lymphocytes from immunized mice represented the high levels of IFN-γ and the low-levels of IL-4 and IL-10. Conclusion: Our results indicate that immunization with EG95-expressing L. lactis can induce both specific humoral and cellular immune responses in mice.
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Antígenos Helmínticos/inmunología , Echinococcus granulosus/inmunología , Proteínas del Helminto/inmunología , Inmunidad Humoral/inmunología , Fenómenos Inmunogenéticos/fisiología , Lactococcus lactis/inmunología , Animales , Antígenos Helmínticos/administración & dosificación , Femenino , Proteínas del Helminto/administración & dosificación , Inmunidad Humoral/efectos de los fármacos , Fenómenos Inmunogenéticos/efectos de los fármacos , Ratones , Ratones Endogámicos BALB C , Proteínas Recombinantes/inmunologíaRESUMEN
BACKGROUND: MYL-1501D is a proposed biosimilar to insulin glargine. The noninferiority of MYL-1501D was demonstrated in patients with type 1 diabetes and type 2 diabetes in 2 phase 3 trials. Immunogenicity of MYL-1501D and reference insulin glargine was examined in both studies. METHODS: INSTRIDE 1 and INSTRIDE 2 were multicenter, open-label, randomized, parallel-group studies. In INSTRIDE 1, patients with type 1 diabetes received MYL-1501D or insulin glargine over a 52-week period. In INSTRIDE 2, patients with type 2 diabetes treated with oral antidiabetic drugs, insulin naive or not, received MYL-1501D or reference insulin glargine over a 24-week period. Incidence rates and change from baseline in relative levels of antidrug antibodies (ADA) and anti-host cell protein (anti-HCP) antibodies in both treatment groups were determined by a radioimmunoprecipitation assay and a bridging immunoassay, respectively. Results were analyzed using a mixed-effects model (INSTRIDE 1) or a nonparametric Wilcoxon rank sum test (INSTRIDE 2). RESULTS: Total enrollment was 558 patients in INSTRIDE 1 and 560 patients in INSTRIDE 2. The incidence of total and cross-reactive ADA was comparable between treatment groups in INSTRIDE 1 and INSTRIDE 2 (P > 0.05 for both). A similar proportion of patients had anti-HCP antibodies in both treatment groups in INSTRIDE 1 at week 52 (MYL-1501D, 93.9 %; reference insulin glargine, 89.6 %; P = 0.213) and in INSTRIDE 2 at week 24 (MYL-1501D, 87.3 %; reference insulin glargine, 86.9 %; P > 0.999). CONCLUSIONS: In INSTRIDE 1 and INSTRIDE 2, similar immunogenicity profiles were observed for MYL-1501D and reference insulin glargine in patients with type 1 diabetes and type 2 diabetes, respectively. TRIAL REGISTRATION: ClinicalTrials.gov, INSTRIDE 1 ( NCT02227862 ; date of registration, August 28, 2014); INSTRIDE 2 ( NCT02227875 ; date of registration, August 28, 2014).
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Diabetes Mellitus Tipo 1/tratamiento farmacológico , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Hipoglucemiantes/uso terapéutico , Fenómenos Inmunogenéticos/efectos de los fármacos , Insulina Glargina/uso terapéutico , Adulto , Biosimilares Farmacéuticos/farmacología , Biosimilares Farmacéuticos/uso terapéutico , Diabetes Mellitus Tipo 1/sangre , Diabetes Mellitus Tipo 1/inmunología , Diabetes Mellitus Tipo 2/sangre , Diabetes Mellitus Tipo 2/inmunología , Femenino , Humanos , Hipoglucemiantes/farmacología , Fenómenos Inmunogenéticos/fisiología , Insulina Glargina/farmacología , Masculino , Persona de Mediana EdadRESUMEN
L-asparaginase (ASNase) from Escherichia coli (EcAII) is used in the treatment of acute lymphoblastic leukaemia (ALL). EcAII activity in vivo has been described to be influenced by the human lysosomal proteases asparaginyl endopeptidase (AEP) and cathepsin B (CTSB); these hydrolases cleave and could expose epitopes associated with the immune response against EcAII. In this work, we show that ASNase resistance to CTSB and/or AEP influences the formation of anti-ASNase antibodies, one of the main causes of hypersensitivity reactions in patients. Error-prone polymerase chain reaction was used to produce variants of EcAII more resistant to proteolytic cleavage by AEP and CTSB. The variants with enzymatic activity and cytotoxicity levels equivalent to or better than EcAII WT were submitted to in vivo assays. Only one of the mutants presented increased serum half-life, so resistance to these proteases is not the only feature involved in EcAII stability in vivo. Our results showed alteration of the phenotypic profile of B cells isolated after animal treatment with different protease-resistant proteoforms. Furthermore, mice that were exposed to the protease-resistant proteoforms presented lower anti-asparaginase antibodies production in vivo. Our data suggest that modulating resistance to lysosomal proteases can result in less immunogenic protein drugs.
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Antineoplásicos/farmacología , Asparaginasa/farmacología , Productos Biológicos/farmacología , Fenómenos Inmunogenéticos/efectos de los fármacos , Lisosomas/inmunología , Péptido Hidrolasas/farmacología , Secuencia de Aminoácidos , Animales , Antineoplásicos/química , Antineoplásicos/uso terapéutico , Asparaginasa/química , Asparaginasa/uso terapéutico , Productos Biológicos/química , Productos Biológicos/uso terapéutico , Bovinos , Supervivencia Celular/efectos de los fármacos , Supervivencia Celular/fisiología , Pollos , Relación Dosis-Respuesta a Droga , Escherichia coli , Femenino , Caballos , Humanos , Fenómenos Inmunogenéticos/fisiología , Células Jurkat , Lisosomas/química , Ratones , Ratones Endogámicos BALB C , Péptido Hidrolasas/química , Péptido Hidrolasas/uso terapéutico , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamiento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras/inmunología , Estructura Secundaria de ProteínaRESUMEN
Methionine is a limiting amino acid (AA) in fish diets, particularly in those containing high levels of plant protein (PP), and is key in the immune system. Accordingly, outcome on the fish immune mechanisms of methionine-deficient and methionine-supplemented diets within the context of 0 % fishmeal formulation, after a short and prolonged feeding period, was studied in European seabass (Dicentrarchus labrax). For this, seabass juveniles were fed a (i) fishmeal-free diet, meeting AA requirements, but deficient in methionine (MET0·65); (ii) as control, the MET0·65 supplemented with l-methionine at 0·22 % of feed weight (CTRL); (iii) two diets, identical to MET0·65 but supplemented at 0·63 and 0·88 % of feed weight of l-methionine (MET1·25 and MET1·5, respectively); and (iv) a fishmeal-based diet (FM), as positive control. After 2 and 12 weeks of feeding, blood and plasma were sampled for leucocyte counting and humoral parameter assays and head-kidney collected for gene expression. After 2 weeks of feeding, a fishmeal-free diet supplemented with methionine led to changes in the expression of methionine- and leucocyte-related genes. A methionine immune-enhancer role was more evident after 12 weeks with an increased neutrophil percentage and a decreased expression of apoptotic genes, possibly indicating an enhancement of fish immunity by methionine dietary supplementation. Furthermore, even though CTRL and FM present similar methionine content, CTRL presented a reduced expression of several immune-related genes indicating that in a practical PP-based diet scenario, the requirement level of methionine for an optimal immune status could be higher.
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Alimentación Animal/análisis , Lubina/inmunología , Dieta/métodos , Suplementos Dietéticos , Metionina/farmacología , Animales , Expresión Génica/efectos de los fármacos , Fenómenos Inmunogenéticos/efectos de los fármacos , Neutrófilos/efectos de los fármacos , Proteínas de Vegetales Comestibles/farmacologíaRESUMEN
Manufacturing process changes may alter the characteristics of a protein therapeutic. In 2009, somatropin (version 1.0), a recombinant human growth hormone therapeutic, underwent a manufacturing update (version 1.1). The immunogenicity of somatropin version 1.1 as a daily subcutaneous injection was evaluated in 2014 in a prospective, open-label, single-arm clinical study of treatment-naive pediatric patients with idiopathic human growth hormone deficiency for 1 year. The primary end point was the proportion of patients who developed antidrug antibodies (ADAs) after treatment. Eighty-two patients were enrolled. The mean (SD) treatment duration was 347 (53) days. The incidence of ADAs was 3.7%. No neutralizing antibodies were observed in the three patients with ADA-positive samples. Two patients (2.6%) had growth attenuation, but they were not ADA positive. The manufacturing changes for somatropin version 1.1 resulted in a similar safety and efficacy profile compared with somatropin version 1.0 and a different immunogenicity profile with a lower incidence of ADAs.
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Terapia Biológica/métodos , Química Farmacéutica/métodos , Hormona de Crecimiento Humana/síntesis química , Hormona de Crecimiento Humana/uso terapéutico , Fenómenos Inmunogenéticos/efectos de los fármacos , Terapia Biológica/normas , Química Farmacéutica/normas , Niño , Enanismo Hipofisario/tratamiento farmacológico , Enanismo Hipofisario/genética , Enanismo Hipofisario/inmunología , Femenino , Hormona de Crecimiento Humana/inmunología , Humanos , Fenómenos Inmunogenéticos/fisiología , Masculino , Estudios ProspectivosRESUMEN
Vatreptacog alfa (VA), a recombinant activated human factor VII (rFVIIa) variant with 3 amino acid substitutions, was developed to provide increased procoagulant activity in hemophilia patients with inhibitors to factor VIII or factor IX. In phase 3 clinical trials, changes introduced during the bioengineering of VA resulted in the development of undesired anti-drug antibodies in some patients, leading to the termination of a potentially promising therapeutic protein product. Here, we use preclinical biomarkers associated with clinical immunogenicity to validate our deimmunization strategy applied to this bioengineered rFVIIa analog. The reengineered rFVIIa analog variants retained increased intrinsic thrombin generation activity but did not elicit T-cell responses in peripheral blood mononuclear cells isolated from 50 HLA typed subjects representing the human population. Our algorithm, rational immunogenicity determination, offers a broadly applicable deimmunizing strategy for bioengineered proteins.
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Factor VIIa/genética , Ingeniería de Proteínas/métodos , Linfocitos T/inmunología , Pruebas de Coagulación Sanguínea , Células Cultivadas , Factor VIIa/farmacología , Hemofilia A/tratamiento farmacológico , Humanos , Fenómenos Inmunogenéticos/efectos de los fármacos , Proteínas Recombinantes/genética , Proteínas Recombinantes/farmacología , Linfocitos T/efectos de los fármacos , Trombina/biosíntesisRESUMEN
Monophosphoryl lipid A (MPL), a purified and detoxified product of lipopolysaccharide (LPS) of Salmonella minnesota R595, has been used as an adjuvant in different vaccines. In this study, the efficacy of human papillomaviruses (HPV) and hepatitis B virus (HBV) vaccines formulated with aluminum hydroxide combined with two different synthetic MPLs, 3D-(6-acyl)-PHAD or 3D-PHAD, or aluminum hydroxide combined with the mixtures of such MPLs, has been assessed. The immunogenicity in female BALB/c mice was verified by two intramuscular injections of differently formulated HPV and HBV vaccines and the total immunoglobulin G (IgG) antibody response was considered to compare the employed adjuvants. As verified experimentally, a mixture of 3D-(6-acyl)-PHAD and 3D-PHAD was able to induce significantly higher antibody titer than that of either 3D-(6-acyl)-PHAD or 3D-PHAD, when used individually. Interestingly, based on the responses achieved in terms of the total antibody levels, such mixture of synthetic MPLs was found to be even more effective than the bacterially derived MPL. Accordingly, the obtained results indicated that, if designed appropriately, synthetic MPL molecules could provide improved adjuvanticity with high level of consistency.
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Adyuvantes Inmunológicos/farmacología , Hidróxido de Aluminio/farmacología , Vacunas contra Hepatitis B/inmunología , Fenómenos Inmunogenéticos/efectos de los fármacos , Lípido A/análogos & derivados , Vacunas contra Papillomavirus/inmunología , Adyuvantes Inmunológicos/administración & dosificación , Hidróxido de Aluminio/inmunología , Animales , Anticuerpos Antivirales/sangre , Femenino , Inmunoglobulina G/sangre , Lípido A/síntesis química , Lípido A/farmacología , Ratones Endogámicos BALB CRESUMEN
OBJECTIVE: Comparable clinical efficacy of the rituximab (RTX) biosimilar GP2013 and reference RTX has been established in blinded randomized trials. However, when switching from a reference biologic to a biosimilar, potential safety implications are often an important consideration. Therefore, the aim of this study was to evaluate the safety of switching from reference RTX to RTX biosimilar GP2013 compared with treatment continuation with reference RTX in patients with rheumatoid arthritis (RA). METHODS: In this multinational, randomized, double-blind, parallel-group safety study, 107 patients with RA who had previously received treatment (of any duration) with reference RTX as part of routine practice and who required continuation of treatment were randomized to receive either GP2013 or to continue treatment with reference RTX. All patients received a stable dosage of methotrexate and folic acid during the study. Study assessments included the incidence of hypersensitivity, infusion-related and anaphylactic reactions, immunogenicity (antidrug antibodies), and general safety. RESULTS: Regardless of whether patients switched to GP2013 or continued treatment with reference RTX, the incidences of hypersensitivity (9.4% and 11.1%, respectively) and infusion-related reactions (11.3% and 18.5%, respectively) were similarly low. Only 1 patient (in the reference RTX group) developed antidrug antibodies to RTX after starting study treatment. No neutralizing antidrug antibodies were observed. Antidrug antibodies were not associated with adverse events (AEs). No clinically meaningful differences in the rate of AEs were observed between treatment groups. CONCLUSION: No safety risks were detected when patients switched from reference RTX to GP2013. The safety profiles of patients in both treatment groups were similar, although the study was not powered for statistical testing of equivalence in safety.
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Antirreumáticos/administración & dosificación , Artritis Reumatoide/tratamiento farmacológico , Biosimilares Farmacéuticos/administración & dosificación , Sustitución de Medicamentos/métodos , Internacionalidad , Rituximab/administración & dosificación , Adolescente , Adulto , Anciano , Anafilaxia/inducido químicamente , Antirreumáticos/efectos adversos , Artritis Reumatoide/epidemiología , Biosimilares Farmacéuticos/efectos adversos , Método Doble Ciego , Sustitución de Medicamentos/efectos adversos , Sustitución de Medicamentos/tendencias , Femenino , Humanos , Fenómenos Inmunogenéticos/efectos de los fármacos , Fenómenos Inmunogenéticos/fisiología , Infusiones Intravenosas , Masculino , Persona de Mediana Edad , Rituximab/efectos adversos , Adulto JovenRESUMEN
BACKGROUND: Antiretroviral therapy (ART) saved millions from HIV-1 infection and AIDS, but some patients do not experience adequate CD4+ T cells gain despite achieving viral suppression. The genetic component of this condition is not yet completely elucidated. OBJECTIVE: To identify predictive genetic markers of immune response to ART. METHODS: Case-control study. Out of 176 HIV-infected patients recruited in the city of Recife, Northeast Brazil, 67 patients with no immunologic response were the cases and the remaining 109 patients who responded were the controls. A set of 94 selected single nucleotide polymorphisms (SNPs) involved in antiretroviral drugs pharmacodynamic pathways and immune system homeostasis were genotyped, while the remaining 48 were ancestry informative markers (AIMs) for controlling for eventual hidden population structure. RESULTS: Male patients were overrepresented in non-responder group (p=0.01). Non-responders also started with lower absolute CD4+ T cell counts (p<0.001). We found five SNPs significantly associated with the outcome, being three more frequent in non-responders than responders: rs2243250 (IL4) A allele (p=0.04), rs1128503 (ABCB1) A allele (p=0.03) and rs707265 (CYP2B6) A allele (p=0.02), whereas the other two were less frequent in non-responders: rs2069762 (IL2) C allele (p=0.004) and rs4646437 (CYP3A4) A allele (p=0.04). CONCLUSION: Some significant univariate associations remained independently associated at multivariate survival analysis modeling, such as pre-treatment CD4+ T cells counts, IL2 and ABCB1 genotypes, and use of protease inhibitors, yielding a predictive model for the probability for immune response. More studies are needed to unravel the genetic basis of ART immunological non-response.
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Antirretrovirales/farmacología , Infecciones por VIH/tratamiento farmacológico , Infecciones por VIH/inmunología , Sistema Inmunológico/efectos de los fármacos , Polimorfismo de Nucleótido Simple/inmunología , Adolescente , Adulto , Terapia Antirretroviral Altamente Activa , Brasil , Recuento de Linfocito CD4 , Femenino , Frecuencia de los Genes , Estudios de Asociación Genética , Marcadores Genéticos , Humanos , Fenómenos Inmunogenéticos/efectos de los fármacos , Fenómenos Inmunogenéticos/genética , Masculino , Persona de Mediana Edad , Análisis Multivariante , Estudios Retrospectivos , Estadísticas no Paramétricas , Carga Viral , Adulto JovenRESUMEN
ABSTRACT Background: Antiretroviral therapy (ART) saved millions from HIV-1 infection and AIDS, but some patients do not experience adequate CD4+ T cells gain despite achieving viral suppression. The genetic component of this condition is not yet completely elucidated. Objective: To identify predictive genetic markers of immune response to ART. Methods: Case-control study. Out of 176 HIV-infected patients recruited in the city of Recife, Northeast Brazil, 67 patients with no immunologic response were the cases and the remaining 109 patients who responded were the controls. A set of 94 selected single nucleotide polymorphisms (SNPs) involved in antiretroviral drugs pharmacodynamic pathways and immune system homeostasis were genotyped, while the remaining 48 were ancestry informative markers (AIMs) for controlling for eventual hidden population structure. Results: Male patients were overrepresented in non-responder group (p = 0.01). Non-responders also started with lower absolute CD4+ T cell counts (p < 0.001). We found five SNPs significantly associated with the outcome, being three more frequent in non-responders than responders: rs2243250 (IL4) A allele (p = 0.04), rs1128503 (ABCB1) A allele (p = 0.03) and rs707265 (CYP2B6) A allele (p = 0.02), whereas the other two were less frequent in non-responders: rs2069762 (IL2) C allele (p = 0.004) and rs4646437 (CYP3A4) A allele (p = 0.04). Conclusion: Some significant univariate associations remained independently associated at multivariate survival analysis modeling, such as pre-treatment CD4+ T cells counts, IL2 and ABCB1 genotypes, and use of protease inhibitors, yielding a predictive model for the probability for immune response. More studies are needed to unravel the genetic basis of ART immunological non-response.
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Humanos , Masculino , Femenino , Adolescente , Adulto , Persona de Mediana Edad , Adulto Joven , Infecciones por VIH/inmunología , Infecciones por VIH/tratamiento farmacológico , Polimorfismo de Nucleótido Simple/inmunología , Antirretrovirales/farmacología , Sistema Inmunológico/efectos de los fármacos , Brasil , Marcadores Genéticos , Análisis Multivariante , Estudios Retrospectivos , Estadísticas no Paramétricas , Recuento de Linfocito CD4 , Carga Viral , Terapia Antirretroviral Altamente Activa , Fenómenos Inmunogenéticos/efectos de los fármacos , Fenómenos Inmunogenéticos/genética , Estudios de Asociación Genética , Frecuencia de los GenesAsunto(s)
Catecoles/inmunología , Factores Inmunológicos/inmunología , Extractos Vegetales/inmunología , Catecoles/efectos adversos , Catecoles/química , Atención a la Salud/tendencias , Humanos , Hipersensibilidad/etiología , Hipersensibilidad/inmunología , Hipersensibilidad/prevención & control , Fenómenos Inmunogenéticos/efectos de los fármacos , Fenómenos Inmunogenéticos/fisiología , Factores Inmunológicos/efectos adversos , Factores Inmunológicos/química , Extractos Vegetales/efectos adversos , Extractos Vegetales/químicaRESUMEN
Cancer is evading the host's defense mechanisms leading to avoidance of immune destruction. During tumor progression, immune-evading cancer cells arise due to selective pressure from the hypoxic and nutrient-deprived microenvironment. Thus, therapies aiming at re-establishing immune destruction of pathological cells constitute innovating anti-cancer strategies. Accumulating evidence suggests that selected conventional chemotherapeutic drugs increase the immunogenicity of stressed and dying cancer cells by triggering a form of cell death called immunogenic cell death (ICD), which is characterized by the release of danger-associated molecular patterns (DAMPs). In this review, we summarize the effects of ICD inducers on DAMP signaling leading to adjuvanticity and antigenicity. We will discuss the associated stress response pathways that cause the release of DAMPs leading to improved immune recognition and their relevance in cancer immunotherapy. Our aim is to highlight the contribution of adaptive immunity to the long-term clinical benefits of anticancer treatments and the properties of immune memory that can protect cancer patients against relapse.
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Inmunidad Celular/inmunología , Inmunoterapia/métodos , Neoplasias/inmunología , Neoplasias/terapia , Estrés Fisiológico/inmunología , Animales , Muerte Celular/efectos de los fármacos , Muerte Celular/inmunología , Estrés del Retículo Endoplásmico/efectos de los fármacos , Estrés del Retículo Endoplásmico/inmunología , Humanos , Inmunidad Celular/efectos de los fármacos , Fenómenos Inmunogenéticos/efectos de los fármacos , Fenómenos Inmunogenéticos/fisiología , Transducción de Señal/efectos de los fármacos , Transducción de Señal/inmunología , Estrés Fisiológico/efectos de los fármacosRESUMEN
HLA-G is a nonclassical HLA immunotolerogenic molecule expressed in different human cell types. Successful embryo implantation is a consequence of information exchange between the uterus and the blastocyst. It is widely accepted that HLA-G expression by the fetus promotes the establishment of several mechanisms that, ultimately, would protect the developing embryo from maternal immune rejection and seems to be essential to both an adequate implantation and a healthy pregnancy. MicroRNAs miR-148a and miR-152 down-regulate HLA-G expression. The levels of both microRNAs in the placenta are very low. Although various contraceptive methods are available in the market, several of the most popular are based on hormone administration, an approach that have been causing concerns regarding their adverse effects. This scenario has led the research and development of new contraceptive methods meant to induce low disturbances in women body. Based on this context, we hypothesize that the delivery of miR-148a and miR-152 microRNAs, carried by liposomes, into the uterus, would locally induce a down-regulation of the immunotolerogenic HLA-G molecule. In this sense, a local concentration increase of both miR-148a and miR-152 would counteract HLA-G expression and therefore prevent pregnancy development, being a potential tool for the development of a new contraceptive therapy.
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Anticoncepción Inmunológica/métodos , Terapia Genética/métodos , Antígenos HLA-G/genética , Antígenos HLA-G/inmunología , Fenómenos Inmunogenéticos/efectos de los fármacos , Fenómenos Inmunogenéticos/fisiología , Modelos Inmunológicos , Regulación hacia Abajo/inmunología , Femenino , Regulación de la Expresión Génica/efectos de los fármacos , Regulación de la Expresión Génica/inmunología , Humanos , Modelos Genéticos , Vacunas Anticonceptivas/administración & dosificación , Vacunas Anticonceptivas/inmunologíaRESUMEN
One of the factors that may impact drug levels of therapeutic antibodies in patients is immunogenicity, with potential loss of efficacy. Nowadays, many immunogenicity assays are available for testing antidrug antibodies (ADA). In this article, we discuss different types of immunogenicity assays and their clinical relevance in terms of drug tolerance, relation with pharmacokinetics (PK), neutralizing antibodies, potential adverse events associated with ADA, and prediction of ADA production. Drug-tolerant assays can provide insight into the process of immunogenicity, but for clinical management, these assays do not necessarily outperform drug-sensitive assays. The usefulness of any ADA assay for clinical decision making will be larger when drug concentrations are also measured, and this is true, in particular, for drug-tolerant assays.
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Anticuerpos Monoclonales/sangre , Productos Biológicos/sangre , Monitoreo de Drogas/métodos , Fenómenos Inmunogenéticos/fisiología , Anticuerpos Monoclonales/administración & dosificación , Anticuerpos Monoclonales/inmunología , Productos Biológicos/administración & dosificación , Productos Biológicos/inmunología , Enfermedad de Crohn/sangre , Enfermedad de Crohn/tratamiento farmacológico , Enfermedad de Crohn/inmunología , Humanos , Inmunoensayo , Fenómenos Inmunogenéticos/efectos de los fármacos , Infliximab/sangre , Infliximab/inmunología , Infliximab/uso terapéuticoRESUMEN
INTRODUCTION: Hidradenitis suppurativa (HS) is a serious, debilitating, chronic inflammatory skin disease. Adalimumab is a fully human, immunoglobulin G1 monoclonal antibody specific for tumor necrosis factor-alpha recently approved for use in patients with HS. The aim of this study is to describe the population pharmacokinetics and immunogenicity of adalimumab in adult patients with HS. METHODS: Data from one phase II and two phase III studies were included in the analysis. Serial serum adalimumab concentrations and anti-adalimumab antibody (AAA) development status were used to develop the population pharmacokinetic model. The population pharmacokinetic analysis involved evaluating the effects of potential covariates on adalimumab pharmacokinetics. RESULTS: Mean serum adalimumab concentrations after 40-mg weekly dosing reached steady state (10-12 µg/mL in the phase II study and 7 µg/mL in the phase III studies) by week 2 and were maintained through week 12. The percentage of patients testing positive for AAA was low (10% in the phase II study and 7% in the phase III studies). Adalimumab pharmacokinetics was described by a one-compartment model with first-order absorption. Significant covariates for clearance included the presence of AAA, baseline C-reactive protein, and baseline body weight. CONCLUSIONS: Adalimumab pharmacokinetics in HS patients was described using a one-compartment model with weight, baseline C-reactive protein, and AAA affecting adalimumab exposure. AAA development results in decreased adalimumab concentrations with a potential decrease in efficacy. Serum adalimumab concentrations in HS patients receiving 40-mg weekly dosing were similar to those observed in other indications under approved dosing regimens.
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Adalimumab/administración & dosificación , Adalimumab/farmacocinética , Antiinflamatorios/administración & dosificación , Antiinflamatorios/farmacocinética , Hidradenitis Supurativa/sangre , Hidradenitis Supurativa/tratamiento farmacológico , Adolescente , Adulto , Anciano , Método Doble Ciego , Femenino , Hidradenitis Supurativa/inmunología , Humanos , Fenómenos Inmunogenéticos/efectos de los fármacos , Fenómenos Inmunogenéticos/fisiología , Masculino , Persona de Mediana Edad , Índice de Severidad de la Enfermedad , Adulto JovenRESUMEN
Unwanted immune responses to therapeutic proteins can severely impact their safety and efficacy. Studies show that the presence of trace amounts of host cells and process-related impurities that stimulate pattern recognition receptors (PRR) can cause local inflammation and enhance product immunogenicity. Here we used purified PRR agonists as model impurities to assess the minimal level of individual innate immune response modulating impurities (IIRMIs) that could activate a local immune response. We show that levels of endotoxin as low as 10 pg (0.01 EU), 1 ng for polyinosinic:polycytidylic acid (PolyI:C), 100 ng for synthetic diacylated liopprotein, thiazoloquinolone compound, or muramyl dipeptide, 1 µg for flagellin or ß-glucan, or 5 µg for CpG-oligodeoxynucleotide increased expression of genes linked to innate immune activation and inflammatory processes in the skin of rhesus macaques. Furthermore, spiking studies using rasburicase as a model therapeutic showed that the levels of PRR agonists that induced detectable gene upregulation in the skin were associated with increased immunogenicity for rasburicase. This study underscores the need for testing multiple IIRMIs in biologics, strengthening the connection between the local mRNA induction in skin, innate immune activation, and antibody development in primates, and provides an indication of the levels of IIRMI in therapeutic products that could impact product immunogenicity.
Asunto(s)
Endotoxinas/inmunología , Inmunidad Innata/inmunología , Fenómenos Inmunogenéticos/fisiología , Modelos Animales , Piel/inmunología , Animales , Anticuerpos/inmunología , Endotoxinas/administración & dosificación , Femenino , Células HEK293 , Humanos , Inmunidad Innata/efectos de los fármacos , Fenómenos Inmunogenéticos/efectos de los fármacos , Inyecciones Subcutáneas , Macaca mulatta , Masculino , Poli C/administración & dosificación , Poli C/inmunología , Receptores de Reconocimiento de Patrones/inmunología , Piel/efectos de los fármacosRESUMEN
Small-molecule inhibitors of the Janus kinase family (JAKis) are clinically efficacious in multiple autoimmune diseases, albeit with increased risk of certain infections. Their precise mechanism of action is unclear, with JAKs being signaling hubs for several cytokines. We assessed the in vivo impact of pan- and isoform-specific JAKi in mice by immunologic and genomic profiling. Effects were broad across the immunogenomic network, with overlap between inhibitors. Natural killer (NK) cell and macrophage homeostasis were most immediately perturbed, with network-level analysis revealing a rewiring of coregulated modules of NK cell transcripts. The repression of IFN signature genes after repeated JAKi treatment continued even after drug clearance, with persistent changes in chromatin accessibility and phospho-STAT responsiveness to IFN. Thus, clinical use and future development of JAKi might need to balance effects on immunological networks, rather than expect that JAKis affect a particular cytokine response and be cued to long-lasting epigenomic modifications rather than by short-term pharmacokinetics.
Asunto(s)
Citocinas/metabolismo , Inhibidores de las Cinasas Janus/farmacología , Quinasas Janus/antagonistas & inhibidores , Transducción de Señal/efectos de los fármacos , Animales , Citocinas/genética , Redes Reguladoras de Genes/efectos de los fármacos , Redes Reguladoras de Genes/inmunología , Fenómenos Inmunogenéticos/efectos de los fármacos , Fenómenos Inmunogenéticos/genética , Quinasas Janus/genética , Quinasas Janus/metabolismo , Células Asesinas Naturales/efectos de los fármacos , Células Asesinas Naturales/inmunología , Células Asesinas Naturales/metabolismo , Macrófagos/efectos de los fármacos , Macrófagos/inmunología , Macrófagos/metabolismo , Masculino , Ratones Endogámicos C57BL , Transducción de Señal/genética , Transcriptoma/efectos de los fármacos , Transcriptoma/inmunologíaRESUMEN
Botulinum toxin (BoNT) formulations are being used for a variety of medical applications. The use of BoNT preparations is continuously expanding with new formulations and indications. Of the seven antigenically distinct BoNTs, only two serotypes, type A and type B are commonly available for therapeutic use. The four available BoNT products are not equivalent and the knowledge of their formulations is crucial for product selection, avoidance of medication errors, therapeutic efficacy and safety. Generally, BoNT injection is a safe procedure when administered by an experienced injector. Side effects are always transient, and in the majority of cases they are mild and tolerable.
Asunto(s)
Toxinas Botulínicas/administración & dosificación , Toxinas Botulínicas/inmunología , Fenómenos Inmunogenéticos , Animales , Formación de Anticuerpos/efectos de los fármacos , Formación de Anticuerpos/inmunología , Toxinas Botulínicas/efectos adversos , Composición de Medicamentos , Humanos , Fenómenos Inmunogenéticos/efectos de los fármacos , Trastornos Migrañosos/tratamiento farmacológico , Debilidad Muscular/inducido químicamente , Dolor/tratamiento farmacológicoRESUMEN
Nanoparticle immunogenicity and antigenicity have been under investigation for many years. During the past decade, significant progress has been made in understanding what makes a nanoparticle immunogenic, how immune cells respond to nanoparticles, what consequences of nanoparticle-specific antibody formation exist and how they challenge the application of nanoparticles for drug delivery. Moreover, it has been recognized that accidental contamination of therapeutic protein formulations with nanosized particulate materials may contribute to the immunogenicity of this type of biotechnology products. While the immunological properties of engineered nanomaterials and their application as vaccine carriers and adjuvants have been given substantial consideration in the current literature, little attention has been paid to nanoparticle immuno- and antigenicity. To fill in this gap, we herein provide an overview of this subject to highlight the current state of the field, review past and present research, and discuss future research directions.
Asunto(s)
Modulación Antigénica/inmunología , Comprensión , Inmunidad Celular/inmunología , Fenómenos Inmunogenéticos/inmunología , Nanoestructuras/toxicidad , Adyuvantes Inmunológicos/administración & dosificación , Adyuvantes Inmunológicos/toxicidad , Animales , Modulación Antigénica/efectos de los fármacos , Portadores de Fármacos/administración & dosificación , Portadores de Fármacos/toxicidad , Sistemas de Liberación de Medicamentos/efectos adversos , Sistemas de Liberación de Medicamentos/métodos , Predicción , Humanos , Inmunidad Celular/efectos de los fármacos , Fenómenos Inmunogenéticos/efectos de los fármacos , Nanoestructuras/administración & dosificaciónRESUMEN
The impact of an anti-drug antibody (ADA) response on pharmacokinetic (PK) of a therapeutic protein (TP) requires an in-depth understanding of both PK parameters and ADA characteristics. The ADA and PK bioanalytical assays have technical limitations due to high circulating levels of TP and ADA, respectively, hence, significantly hindering the interpretation of this assessment. The goal of this study was to develop a population-based modeling and simulation approach that can identify a more relevant PK parameter associated with ADA-mediated clearance. The concentration-time data from a single dose PK study using five monoclonal antibodies were modeled using a non-compartmental analysis (NCA), one-compartmental, and two-compartmental Michaelis-Menten kinetic model (MMK). A novel PK parameter termed change in clearance time of the TP (α) derived from the MMK model could predict variations in α much earlier than the time points when ADA could be bioanalytically detectable. The model could also identify subjects that might have been potentially identified as false negative due to interference of TP with ADA detection. While NCA and one-compartment models can estimate loss of exposures, and changes in clearance, the two-compartment model provides this additional ability to predict that loss of exposure by means of α. Modeling data from this study showed that the two-compartment model along with the conventional modeling approaches can help predict the impact of ADA response in the absence of relevant ADA data.