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1.
Bioanalysis ; 6(11): 1509-23, 2014 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-25046051

RESUMO

All therapeutic proteins have the potential to induce anti-drug antibodies (ADA). Clinically relevant ADA can impact efficacy and/or safety of a biological therapeutic. Immunogenicity assessment strategy evaluates binding and neutralizing ADA, and the need for additional characterization (e.g., epitope, titer and so on) is determined using a risk-based approach. The choice of characterization assays depends on the type, application and immunogenicity of the therapeutic. ADA characterization can impact the interpretation of the risk profile of a given therapeutic, and offers insight into opportunities for risk mitigation and management. This article describes common ADA characterization methods. Strategic assessment and characterization of clinically relevant ADA are discussed, in order to support clinical options for safe and effective patient care and disease management.


Assuntos
Anticorpos/imunologia , Produtos Biológicos/imunologia , Especificidade de Anticorpos , Humanos
2.
J Immunol Methods ; 382(1-2): 93-100, 2012 Aug 31.
Artigo em Inglês | MEDLINE | ID: mdl-22609464

RESUMO

Allotypes of IgG1 molecules can influence the immunogenicity of therapeutic monoclonal antibodies and may account for the presence of some pre-existing antibodies. An electrochemiluminescent (ECL) bridging immunoassay was used to characterize the binding epitopes of anti-therapeutic antibodies (ATAs) in a Phase 1 single ascending dose clinical trial of a therapeutic aglycosylated IgG1monoclonal antibody (mAb). There was no evidence for ATAs specific for a possible neo-epitope created due to the lack of glycosylation. ATAs that developed post-treatment were specific for the F(ab')2, whereas, pre-existing ATAs were specific to the Fc region. Further characterization of the pre-existing ATAs identified the specific epitope to be the G1m1 allotype determinant in the Fc of the therapeutic. A novel competitive bridging assay was developed to verify that serum IgG1 from subjects with pre-existing anti-G1m1 antibodies was homozygous for the antithetical allotype (G1m3). The endogenous G1m allotype of all subjects was assessed and correlation to ATA incidence and adverse events was evaluated. Interestingly, the pre-existing anti-allotype antibody in subjects persisted but was not augmented after dosing, indicating the lack of a secondary immune response to this epitope. These studies indicate the relationship of the therapeutic allotype and the corresponding allotype of subjects is an important component to further understand the impact of immunogenicity on the safety and efficacy of therapeutic antibodies.


Assuntos
Anticorpos Monoclonais/uso terapêutico , Anticorpos/imunologia , Epitopos/imunologia , Alótipos de Imunoglobulina/imunologia , Imunoglobulina G/uso terapêutico , Anticorpos/química , Anticorpos Monoclonais/imunologia , Ensaios Clínicos Fase I como Assunto , Método Duplo-Cego , Epitopos/química , Glicosilação , Humanos , Imunoglobulina G/imunologia , Ensaios Clínicos Controlados Aleatórios como Assunto
3.
J Clin Immunol ; 27(6): 620-7, 2007 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-17629719

RESUMO

The development of a maturing T-cell-mediated immune response was characterized in Parkinson's disease subjects receiving recombinant human glial-derived neurotrophic factor (r-metHuGDNF) via continuous bilateral intraputaminal infusion. Eighteen of 34 subjects tested positive for anti-r-metHuGDNF-binding antibodies. Four subjects developed neutralizing activity, three of which demonstrated classic immunoglobulin class switching from IgM to IgG. An increase of anti-r-metHuGDNF IgG-binding antibodies correlated with the development of neutralizing activity. All serum samples from two subjects with neutralizing activity were characterized for IgG subclasses. These data revealed an initial anti-r-metHuGDNF IgG population where IgG1 >> IgG2 >> IgG4, and IgG3 concentrations were negligible. However, continued antigenic stimulation resulted in concentration changes where IgG4 > IgG1> IgG2, indicating a mature immune response. In addition, using in silico techniques, two immunodominant MHC class II T-cell epitopes were predicted for the native GDNF sequence. These data demonstrate development of a mature T-cell-mediated immune response in these subjects.


Assuntos
Diferenciação Celular/imunologia , Fator Neurotrófico Derivado de Linhagem de Célula Glial/administração & dosagem , Fator Neurotrófico Derivado de Linhagem de Célula Glial/uso terapêutico , Bombas de Infusão Implantáveis , Doença de Parkinson/terapia , Putamen , Proteínas Recombinantes/administração & dosagem , Subpopulações de Linfócitos T/imunologia , Animais , Sítios de Ligação de Anticorpos , Células Clonais , Método Duplo-Cego , Fator Neurotrófico Derivado de Linhagem de Célula Glial/genética , Fator Neurotrófico Derivado de Linhagem de Célula Glial/imunologia , Fator Neurotrófico Derivado de Linhagem de Célula Glial/metabolismo , Humanos , Switching de Imunoglobulina/imunologia , Imunoglobulina G/biossíntese , Imunoglobulina G/metabolismo , Imunoglobulina M/biossíntese , Imunoglobulina M/metabolismo , Injeções Intraventriculares , Estudos Longitudinais , Camundongos , Doença de Parkinson/imunologia , Doença de Parkinson/patologia , Proteínas Recombinantes/imunologia , Proteínas Recombinantes/metabolismo , Subpopulações de Linfócitos T/metabolismo
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