(T1330-05-28) Analyzing the Influence of Target-Mediated Drug Disposition (TMDD) on Affinity Binding Dynamics in an investigational mRNA Therapeutic Encoding a Human Monovalent Antibody

Purpose: The primary goal of this study was to evaluate the impact of target-mediated drug disposition (TMDD) on the pharmacokinetics and pharmacodynamics of an investigational mRNA therapy encoding a human monovalent antibody. The study aimed to simulate the effects of affinity data (e.g. dissociation constants (Kd), association rate constants (Kon), and dissociation rate constants (Koff)), on protein concentration, receptor occupancy (RO), and the resulting implications for dosage regimen projection.

Methods: Single and multiple dose data from four preclinical NHP studies, including mRNA, encoded monovalent antibody concentrations, along with receptor occupancy (%), IgG and IgM readout were used to develop a pharmacokinetics (PK) - Receptor Occupancy (RO) - T Cell-Dependent Antibody Response (TDAR) model. The model includes the translation of mRNA into the encoded protein and its interactions with target receptors. The protein affinity data of the investigational mRNA therapeutic was generated from multiple engineered constructs to enhance target affinity, prolong half-life, and optimize dosing frequency and drug delivery methods. Simulations to achieve target receptor occupancy in humans were conducted using allometric scaling principles and the affinity data of the investigational mRNA therapy

Results: The final model for interpreting the data was a single-compartment model that incorporated both linear and Michaelis-Menten nonlinear kinetics for mRNA degradation, coupled with first-order kinetics for the translation into the therapeutic antibody, and TMDD for antibody disposition. The affinity data in the model was parametrized using Kon and KD as inputs and the Koff was derived using the relationship Koff = KD × Kon. The simulations demonstrated that ~20-fold lower Kd values correlate with a reduced maximum concentration (Cmax) of the protein, faster clearance, and no accumulation, attributed to the TMDD effect. Additionally, a ~20-fold higher Kon resulted into lower free receptor concentration post-administration, which, however, recovers rapidly due to the limited availability of the antibody to form additional complexes. This dynamic also results in a high RO that decreases sharply over time. Decreasing Kd by increasing Kon did not result into an increase in RO or a decrease in dosing requirements. Instead, the simulations indicated that a reduction in Kd via an increased Kon necessitates increase in the dose following intravenous (IV) administration of multiple mRNA doses

Conclusion: In summary, enhancing Kon to decrease Kd did not lead to increased protein concentration or accumulation or sustained RO. Consequently, improving binding affinity alone may not always translate into a prolonged effect or higher receptor occupancy. Further investigation from in vivo experimental data is warranted to corroborate the findings from the human simulation of the impact of TMDD of a monovalent antibody with differing affinity constants

Acknowledgements: This study was funded by Moderna, Inc. We would like to acknowledge Brian Wikpe and Karen Keating for their contributions to this study. Disclosures: JIM, YF,DE,SR, and LV are all employees of Moderna, Inc., and have stock options with Moderna Inc. ET and KK were employees of Moderna, Inc., at the time of the study and held stock/stock options in the company.