Quantitative Analysis of Target Coverage and Germinal Center Response by a CXCL13 Neutralizing Antibody in a T-Dependent Mouse Immunization Model

• Published in: Pharmaceutical research 2014-03, Vol.31 (3), p.635-648
• Main Authors: Brodfuehrer, Joanne, Rankin, Andrew, Edmonds, Jason, Keegan, Sean, Andreyeva, Tatyana, Lawrence-Henderson, Rosemary, Ozer, Josef, Gao, Huilan, Bloom, Laird, Boisvert, Angela, Lam, Khetemenee, Lee, Julie, LaBranche, Timothy, Syed, Jameel, Miao, Wenyan, Singh, Pratap
• Format: Article
• Language: English
• Subjects: Animals; Antibodies, Neutralizing - administration & dosage; Antibodies, Neutralizing - blood; Antibodies, Neutralizing - immunology; Antibodies, Neutralizing - pharmacology; B-Lymphocytes - drug effects; B-Lymphocytes - immunology; Biochemistry; Biomedical and Life Sciences; Biomedical Engineering and Bioengineering; Biomedicine; Chemokine CXCL13 - immunology; Chemokines; Female; Germinal Center - drug effects; Germinal Center - immunology; Germinal Center - ultrastructure; Immunization; Immunology; Medical Law; Mice; Mice, Inbred C57BL; Models, Biological; Monoclonal antibodies; Pharmaceutical sciences; Pharmacology/Toxicology; Pharmacy; Rats; Rats, Sprague-Dawley; Research Paper; Rodents; Spleen - drug effects; Spleen - immunology; T-Lymphocytes - drug effects; T-Lymphocytes - immunology
• ISSN: 0724-8741; 1573-904X
• DOI: 10.1007/s11095-013-1185-2

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.