title: Quantitative analysis of target coverage and germinal center response by a CXCL13 neutralizing antibody in a T-dependent mouse immunization model.
abstract: OBJECTIVE
  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.
authors.affiliation: Department of Pharmacokinetics, Dynamics and Metabolism, Pfizer Inc., Cambridge, Massachusetts, USA.
authors.forename: Joanne
authors.initials: J
authors.lastname: Brodfuehrer
authors.forename: Andrew
authors.initials: A
authors.lastname: Rankin
authors.forename: Jason
authors.initials: J
authors.lastname: Edmonds
authors.forename: Sean
authors.initials: S
authors.lastname: Keegan
authors.forename: Tatyana
authors.initials: T
authors.lastname: Andreyeva
authors.forename: Rosemary
authors.initials: R
authors.lastname: Lawrence-Henderson
authors.forename: Josef
authors.initials: J
authors.lastname: Ozer
authors.forename: Huilan
authors.initials: H
authors.lastname: Gao
authors.forename: Laird
authors.initials: L
authors.lastname: Bloom
authors.forename: Angela
authors.initials: A
authors.lastname: Boisvert
authors.forename: Khetemenee
authors.initials: K
authors.lastname: Lam
authors.forename: Julie
authors.initials: J
authors.lastname: Lee
authors.forename: Timothy
authors.initials: T
authors.lastname: LaBranche
authors.forename: Jameel
authors.initials: J
authors.lastname: Syed
authors.forename: Wenyan
authors.initials: W
authors.lastname: Miao
authors.forename: Pratap
authors.initials: P
authors.lastname: Singh
mesh_terms: D000818:Animals; D057134:Antibodies, Neutralizing / Q000008:administration & dosage / Q000097:blood / Q000276:immunology / Q000494:pharmacology*; D001402:B-Lymphocytes / Q000187:drug effects / Q000276:immunology; D054382:Chemokine CXCL13 / Q000276:immunology*; D005260:Female; D018858:Germinal Center / Q000187:drug effects* / Q000276:immunology / Q000648:ultrastructure; D007114:Immunization; D051379:Mice; D008810:Mice, Inbred C57BL; D008954:Models, Biological; D051381:Rats; D017207:Rats, Sprague-Dawley; D013154:Spleen / Q000187:drug effects / Q000276:immunology; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology*
chemical_list: D057134:Antibodies, Neutralizing; D054382:Chemokine CXCL13; C486386:Cxcl13 protein, mouse