Biomeasures and mechanistic modeling highlight PK/PD risks for a monoclonal antibody targeting Fn14 in kidney disease

Area of Science:

• Pharmacology
• Immunology
• Biotechnology

Background:

• Fibroblast growth factor-inducible-14 (Fn14) receptor is upregulated after tissue injury.
• Fn14 is a potential biotherapeutic target for chronic kidney diseases and other conditions.
• Monoclonal antibody (mAb) development increasingly uses biomeasures and pharmacokinetic/pharmacodynamic (PK/PD) modeling for early decision-making.

Purpose of the Study:

• To develop a mechanistic site-of-action (SoA) PK/PD model for human application to guide preclinical efforts in designing anti-Fn14 antibodies.
• To incorporate experimental biomeasures, including soluble Fn14 (sFn14) and membrane Fn14 (mFn14) concentrations and sFn14 turnover rates.
• To predict human dose requirements and optimize antibody affinity for improved therapeutic properties.

Main Methods:

• Developed a mechanistic SoA PK/PD model for human application.
• Incorporated biomeasures: sFn14 concentration in plasma, mFn14 in kidney tissue, and sFn14 turnover rate.
• Utilized pulse-chase studies with stable isotope-labeled amino acids and mass spectrometry to determine sFn14 half-life.

Main Results:

• Determined sFn14 half-life in healthy volunteers to be approximately 5 hours.
• Identified challenges in designing anti-Fn14 antibodies due to sFn14 concentration and turnover.
• Projected potential high and frequent dosing requirements (>1 mg/kg/wk) for 90% target coverage.
• Revealed a unique bell-shaped relationship between target coverage and antibody affinity.

Conclusions:

• The developed PK/PD model aids in assessing risks during early target validation for Fn14-targeted therapies.
• The model facilitates human dose prediction and optimization of anti-Fn14 drug candidates.
• A unique affinity-based optimization strategy for anti-Fn14 mAbs was identified, guiding antibody engineering efforts.