A Semi-Mechanistic Mathematical Model of Immune Tolerance Induction to Support Preclinical Studies of Human Monoclonal Antibodies in Rats
Paridhi Gupta, Josiah T. Ryman, Vibha Jawa, Bernd Meibohm
TL;DR
This paper introduces a mathematical model to predict immune tolerance in rats when testing human monoclonal antibodies, helping to reduce immune responses in preclinical studies.
Contribution
A semi-mechanistic model integrating pharmacokinetics and immunogenicity data to simulate immune tolerance in preclinical antibody studies.
Findings
The model accurately described anti-drug antibody (ADA) formation in rats across treatment groups.
The model captured the effect of tacrolimus/sirolimus on suppressing ADA formation and inducing immune tolerance.
The approach provides a framework for simulating immune tolerance scenarios in monoclonal antibody development.
Abstract
Background/Objectives: The administration of human monoclonal antibodies (mAb) in preclinical pharmacokinetics and toxicology studies often triggers an immune response, leading to the formation of anti-drug antibodies (ADA). To mitigate this effect, we have recently performed and reported on studies using short-term immunosuppressive regimens to induce prolonged immune tolerance towards a human mAb, erenumab, in rats. Here, we report on the development of a semi-mechanistic modeling approach that quantitatively integrates pharmacokinetic and immunogenicity assessments from immune tolerance induction studies to provide a framework for the simulation-based evaluation of different immune induction scenarios for the maintenance of prolonged immune tolerance towards human mAbs. Methods: The integrated pharmacokinetic/pharmacodynamic (PK/PD) modeling approach combined a semi-mechanistic model…
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Taxonomy
TopicsMonoclonal and Polyclonal Antibodies Research · Biosimilars and Bioanalytical Methods · T-cell and B-cell Immunology