A Semi-Mechanistic Model of Immune Tolerance Induction to Support Preclinical Development of a Human Monoclonal Antibody

Author

Paridhi Gupta, University of Tennessee Health Science Center

Date of Award

4-2025

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Program

Pharmaceutical Sciences

Track

PHARMACOMETRICS

Research Advisor

Bernd Meibohm, Ph.D.

Committee

Vibha Jawa, PhD; Frank Park, PhD; Josiah Ryman, PhD; Udai Pratap Singh, PhD; Amber M. Smith, PhD

Keywords

monoclonal antibodies; immunogenicity; immune tolerance; pharmacokinetics; anti-drug antibodies; toxicology assessments; preclinical

Abstract

Administration of human monoclonal antibodies (mAb) in preclinical species often triggers an immunogenic response, leading to the formation of anti-drug antibodies (ADA). ADA can bind to the mAb and reduce their systemic exposure by enhancing immune-complex mediated clearance. Thus, ADA complicates the accurate assessment of preclinical pharmacokinetics and toxicology studies. To mitigate this effect, we explored short-term immunosuppressive therapy (methotrexate or combination of tacrolimus and sirolimus) to induce prolonged immune tolerance towards a human mAb, erenumab, in rats. The results demonstrated that tacrolimus/sirolimus but not the methotrexate regimens prevented ADA formation in all treated animals relative to the non-immunocompromised control group. A semi-mechanistic model of immune tolerance induction was developed to support model-based simulations of ADA responses to prolonged erenumab exposures following initial immune tolerance induction with tacrolimus/sirolimus. The model adequately described the observed ADA magnitude-time profiles in both the control and tacrolimus/sirolimus groups and reasonably simulated the kinetics of selected immune cells (CD4+ T-helper and T-regulatory) responsible for ADA formation. The model successfully captured the impact of tacrolimus/sirolimus treatment on ADA formation, demonstrating that the regimen effectively suppressed ADA responses and induced tolerance. Simulation of a 6-month toxicology study suggested that immune tolerance induced with an initial treatment cycle of tacrolimus/sirolimus can maintain a T-regulatory cell-mediated tolerance with continued antigen challenge, thereby facilitating the conductance of chronic toxicology studies for 6 months of duration without ADA formation. This work demonstrates the utility of modeling approaches in prospective planning of long-term toxicology studies to support preclinical development of mAbs.

Declaration of Authorship

Declaration of Authorship is included in the supplemental files.

DOI

10.21007/aetd.cghs.2025.0018

Recommended Citation

Gupta, Paridhi , "A Semi-Mechanistic Model of Immune Tolerance Induction to Support Preclinical Development of a Human Monoclonal Antibody" (2025). Alternative Theses and Dissertations (AETDs). Paper 18. http://dx.doi.org/10.21007/aetd.cghs.2025.0018.
https://dc.uthsc.edu/aetd/18