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1.
AAPS J ; 18(2): 311-20, 2016 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-26821802

RESUMO

Pre-existing antibodies to biotherapeutic drugs have been detected in drug-naïve subjects for a variety of biotherapeutic modalities. Pre-existing antibodies are immunoglobulins that are either specific or cross-reacting with a protein or glycan epitopes on a biotherapeutic compound. Although the exact cause for pre-existing antibodies is often unknown, environmental exposures to non-human proteins, glycans, and structurally similar products are frequently proposed as factors. Clinical consequences of the pre-existing antibodies vary from an adverse effect on patient safety to no impact at all and remain highly dependent on the biotherapeutic drug modality and therapeutic indication. As such, pre-existing antibodies are viewed as an immunogenicity risk factor requiring a careful evaluation. Herein, the relationships between biotherapeutic modalities to the nature, prevalence, and clinical consequences of pre-existing antibodies are reviewed. Initial evidence for pre-existing antibody is often identified during anti-drug antibody (ADA) assay development. Other interfering factors known to cause false ADA positive signal, including circulating multimeric drug target, rheumatoid factors, and heterophilic antibodies, are discussed.


Assuntos
Anticorpos Monoclonais/sangue , Produtos Biológicos/sangue , Terapia Biológica/métodos , Animais , Anticorpos Monoclonais/imunologia , Autoanticorpos/sangue , Autoanticorpos/imunologia , Produtos Biológicos/imunologia , Humanos
2.
Drug Metab Dispos ; 43(6): 803-11, 2015 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-25805881

RESUMO

PF-05231023, a long-acting fibroblast growth factor 21 (FGF21) analog, was generated by covalently conjugating two engineered [des-His1, Ala129Cys]FGF21 molecules to a nontargeting human IgG1 κ scaffold. The pharmacokinetics (PK) of PF-05231023 after i.v. and s.c. administration was evaluated in rats and monkeys using two enzyme-linked immunosorbent assays with high specificity for biologically relevant intact N termini (NT) and C termini (CT) of FGF21. Intact CT of FGF21 displayed approximately 5-fold faster systemic plasma clearance (CL), an approximately 2-fold lower steady-state volume of distribution, and at least 5-fold lower bioavailability compared with NT. In vitro serum stability studies in monkeys and humans suggested that the principal CL mechanism for PF-05231023 was degradation by serum proteases. Direct scaling of in vitro serum degradation rates for intact CT of FGF21 underestimated in vivo CL 5-fold, 1.4-fold, and 2-fold in rats, monkeys, and humans, respectively. The reduced steady-state volume of distribution and the bioavailability for intact CT relative to NT in rats and monkeys were compatible with proteolytic degradation occurring outside the plasma compartment via an unidentified mechanism. Human CL and PK profiles for intact NT and CT of FGF21 were well predicted using monkey single-species allometric and Dedrick scaling. Physiologically based pharmacokinetic models incorporating serum stability data and an extravascular extraction term based on differential bioavailability of intact NT and CT of FGF21 in monkeys improved accuracy of human PK predictions relative to Dedrick scaling. Mechanistic physiologically based pharmacokinetic models of this nature may be highly valuable for predicting human PK of fusion proteins, synthetically conjugated proteins, and other complex biologics.


Assuntos
Anticorpos Monoclonais Humanizados/farmacologia , Drogas em Investigação/farmacocinética , Fatores de Crescimento de Fibroblastos/química , Fatores de Crescimento de Fibroblastos/farmacologia , Hipoglicemiantes/farmacocinética , Hipolipemiantes/farmacocinética , Imunoglobulina G/química , Modelos Biológicos , Proteínas Recombinantes/farmacocinética , Substituição de Aminoácidos , Animais , Anticorpos Monoclonais Humanizados/administração & dosagem , Anticorpos Monoclonais Humanizados/sangue , Anticorpos Monoclonais Humanizados/química , Avaliação Pré-Clínica de Medicamentos , Drogas em Investigação/administração & dosagem , Drogas em Investigação/análise , Drogas em Investigação/química , Fatores de Crescimento de Fibroblastos/administração & dosagem , Fatores de Crescimento de Fibroblastos/sangue , Fatores de Crescimento de Fibroblastos/genética , Fatores de Crescimento de Fibroblastos/metabolismo , Meia-Vida , Humanos , Hipoglicemiantes/administração & dosagem , Hipoglicemiantes/sangue , Hipoglicemiantes/química , Hipolipemiantes/administração & dosagem , Hipolipemiantes/sangue , Hipolipemiantes/química , Imunoglobulina G/sangue , Imunoglobulina G/genética , Imunoglobulina G/metabolismo , Cadeias kappa de Imunoglobulina/sangue , Cadeias kappa de Imunoglobulina/química , Cadeias kappa de Imunoglobulina/genética , Cadeias kappa de Imunoglobulina/metabolismo , Injeções Intravenosas , Injeções Subcutâneas , Macaca fascicularis , Masculino , Taxa de Depuração Metabólica , Proteínas Mutantes/administração & dosagem , Proteínas Mutantes/sangue , Proteínas Mutantes/química , Proteínas Mutantes/farmacocinética , Fragmentos de Peptídeos/sangue , Proteólise , Ratos , Proteínas Recombinantes/administração & dosagem , Proteínas Recombinantes/sangue , Proteínas Recombinantes/química
3.
AAPS J ; 15(3): 852-5, 2013 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-23620231

RESUMO

The immunogenicity profile of a biotherapeutic is determined by a multitude of product and patient-related risk factors that can influence the observed incidence and clinical consequences of immunogenicity. Pre-existing antibodies, i.e., biotherapeutic-reactive antibodies present in samples from treatment-naïve subjects, have been commonly observed during immunogenicity assessments; however their relevance in terms of the safety and efficacy of a biotherapeutic is poorly understood. An American Association of Pharmaceutical Scientists-sponsored survey was conducted to gather information about the prevalence, nature, and consequences of pre-existing antibodies in clinical and nonclinical studies. The survey results indicate that pre-existing antibodies against a variety of biotherapeutics (e.g., mAbs, fusion proteins) are frequently encountered, especially in the context of autoimmune diseases, but that the methods and approaches used to detect, characterize, and report these antibodies vary. In most cases, pre-existing antibodies did not appear to have clinical consequences; however, a few of the respondents reported having observed an effect on pharmacokinetic, pharmacodynamic, safety, and/or efficacy parameters. The findings from this survey are an important first step in evaluating the potential risks associated with the presence of pre-existing antibodies and highlight the importance of standardizing the approaches for detection and characterization of these antibodies. Cross-industry sharing of case studies and relevant data collection will help better inform biotherapeutic risk/benefit profiles and provide deeper understanding of the biological consequences of pre-existing antibodies.


Assuntos
Anticorpos/sangue , Fatores Biológicos/sangue , Coleta de Dados , Indústria Farmacêutica/métodos , Sociedades Científicas , Anticorpos/imunologia , Fatores Biológicos/imunologia , Terapia Biológica/métodos , Coleta de Dados/métodos , Humanos , Fatores de Risco , Estados Unidos
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