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

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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 [I125] 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/mm2). The SoA modeling analysis indicated that ~79% coverage in spleen was required to achieve 50% suppression of GC/mm2. 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.

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Abbreviations

CXCL13:

CXC chemokine 13

ELISA:

Enzyme-linked immunosorbent assay

GC:

Germinal center

GC/mm2 :

Germinal centers per mm2

PD:

Pharmacodynamics

PK:

Pharmacokinetics

SoA:

Site of action

TDI:

T-dependent immunization model

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ACKNOWLEDGMENTS AND DISCLOSURES

Authors wish to thank Quintus Medley, Ph.D. and Jill Wright, Ph.D. for reviewing the manuscript and proving useful suggestions.

This study was supported by Pfizer, Inc. All authors were employees of Pfizer at the time of study.

Author information

Authors and Affiliations

  1. Department of Pharmacokinetics, Dynamics and Metabolism, Pfizer Inc., Cambridge, Massachusetts, USA

    Joanne Brodfuehrer, Rosemary Lawrence-Henderson, Josef Ozer & Pratap Singh

  2. Department of Immunology and Autoimmunity, Pfizer Inc., Cambridge, Massachusetts, USA

    Andrew Rankin, Jason Edmonds, Sean Keegan, Tatyana Andreyeva, Julie Lee & Wenyan Miao

  3. Department of Global Biotherapeutics Technologies, Pfizer Inc., Cambridge, Massachusetts, USA

    Huilan Gao, Laird Bloom, Angela Boisvert & Khetemenee Lam

  4. Department of Drug Safety R&D, Pfizer Inc., Cambridge, Massachusetts, USA

    Timothy LaBranche & Jameel Syed

  5. 35 Cambridgepark Drive, Cambridge, Massachusetts, 02140, USA

    Pratap Singh

Authors
  1. Joanne Brodfuehrer
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  2. Andrew Rankin
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  15. Wenyan Miao
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  16. Pratap Singh
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Correspondence to Pratap Singh.

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Brodfuehrer, J., Rankin, A., Edmonds, J. et al. Quantitative Analysis of Target Coverage and Germinal Center Response by a CXCL13 Neutralizing Antibody in a T-Dependent Mouse Immunization Model. Pharm Res 31, 635–648 (2014). https://doi.org/10.1007/s11095-013-1185-2

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  • DOI: https://doi.org/10.1007/s11095-013-1185-2

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