Quantitative analysis of target coverage and germinal center response by a CXCL13 neutralizing antibody in a T-dependent mouse immunization model.
Pharm Res
; 31(3): 635-48, 2014 Mar.
Article
em En
| MEDLINE
| ID: mdl-24190631
ABSTRACT
PURPOSE:
Study the impact of CXCL13 neutralization on germinal center (GC) response in vivo, and build quantitative relationship between target coverage and pharmacological effects at the target tissue.METHODS:
An anti-CXCL13 neutralizing monoclonal antibody was dosed in vivo in a T-dependent mouse immunization (TDI) model. A quantitative site-of-action (SoA) model was developed to integrate antibody PK and total CXCL13 levels in serum and spleen towards estimating target coverage as a function of dose. To aid in the SoA model development, a radio-labeled study using [I(125)] CXCL13 was conducted in mice. Model estimated target coverage was linked to germinal center response using a sigmoidal inhibitory effect model.RESULTS:
In vivo studies demonstrated that CXCL13 inhibition led to an architectural change in B-cell follicles, dislocation of GCs and a significant reduction in the GC absolute numbers per square area (GC/mm(2)). The SoA modeling analysis indicated that ~79% coverage in spleen was required to achieve 50% suppression of GC/mm(2). The 3 mg/kg dose with 52% spleen coverage resulted in no PD suppression, whereas 30 mg/kg with 93% coverage achieved close to maximum PD suppression, highlighting the steepness of PD response.CONCLUSIONS:
This study showcases an application of SoA modeling towards a quantitative understanding of CXCL13 pharmacology.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Linfócitos T
/
Centro Germinativo
/
Quimiocina CXCL13
/
Anticorpos Neutralizantes
Limite:
Animals
Idioma:
En
Revista:
Pharm Res
Ano de publicação:
2014
Tipo de documento:
Article
País de afiliação:
Estados Unidos