(T-050) A Mechanistic Pharmacokinetic-Pharmacodynamic Model Framework for Degrader-Antibody Conjugates

Martha Balthasar – University of North Carolina at Chapel Hill; Derek Bartlett – University of North Carolina at Chapel Hill

Objectives: Degrader-antibody conjugates (DACs) represent an emerging class of innovative therapeutics that combine the unique delivery capabilities of antibody-drug conjugates (ADCs) with the catalytic targeted protein degradation capabilities of proteolysis-targeting chimeras (PROTACs). PROTACs frequently suffer from low permeability, suboptimal half-lives, and the potential for off-site on-target toxicities. ADCs, on the other hand, offer tunable exposure profiles and highly specific delivery to desired cell populations. Several preclinical DACs have shown in vitro and in vivo efficacy, although current approaches for DAC design remain largely empirical. Therefore, this project aimed to create a mechanistic pharmacokinetic-pharmacodynamic (PK-PD) model framework to elucidate key parameters influencing DAC efficacy to enable the rational design and optimization of DACs.

Methods: The DAC PK-PD model was developed in MATLAB SimBiology by integrating our previous mechanistic PK-PD model of targeted protein degradation with a model for antibody-mediated drug delivery. The integrated model was calibrated with previously published in vitro and in vivo data for DACs and their PROTAC payloads. The PK module for antibody-mediated PROTAC delivery was linked to a PD module capturing ternary complex formation and protein degradation by the released PROTAC. Downstream pharmacological activity, including inhibition of cell proliferation, was driven by the changes in target protein levels.

Results: Model fitting yielded parameter estimates with good precision and low uncertainty. The model framework captured the PK and PD of unconjugated and antibody-conjugated PROTACs, linking intracellular PROTAC concentration to protein degradation, in vitro cell proliferation, and in vivo tumor growth inhibition. Model simulations identified key parameters influencing DAC efficacy, including PROTAC payload potency and permeability, expression level and internalization efficiency of the surface antigen for antibody targeting, and the composition and stability of the antibody-PROTAC linker. Low permeability PROTACs improved intracellular retention following DAC delivery, although impaired endosomal escape of the released PROTAC payload reduced the amount available to drive protein degradation. As a result, optimal antibody-PROTAC linkers remained stable in circulation while providing efficient release of the PROTAC payload in a form that enabled transport to the intracellular site of action and engagement of the protein degradation machinery. Low antigen expression levels served as an intrinsic barrier to DAC efficacy in the context of slow internalization rates or low PROTAC payload potency, highlighting the importance of antigen selection and PROTAC payload optimization for DAC design.

Conclusions: A DAC PK-PD model framework was developed to identify key parameters impacting DAC efficacy, inform antigen selection for DAC-mediated delivery, and prioritize PROTACs with properties most suitable for the DAC format.

Citations: Citations:
[1] Bartlett, Derek W, and Adam M Gilbert. “A kinetic proofreading model for bispecific protein degraders.” Journal of pharmacokinetics and pharmacodynamics vol. 48,1 (2021): 149-163. doi:10.1007/s10928-020-09722-z
[2] Bartlett, Derek W, and Adam M Gilbert. “Translational PK-PD for targeted protein degradation.” Chemical Society reviews vol. 51,9 (2022): 3477-3486. doi:10.1039/d2cs00114d
[3] Maneiro, María et al. “Antibody-PROTAC Conjugates Enable HER2-Dependent Targeted Protein Degradation of BRD4.” ACS chemical biology vol. 15,6 (2020): 1306-1312. doi:10.1021/acschembio.0c00285
[4] Pillow, Thomas H et al. “Antibody Conjugation of a Chimeric BET Degrader Enables in vivo Activity.” ChemMedChem vol. 15,1 (2020): 17-25. doi:10.1002/cmdc.201900497
[5] Shah, Dhaval K et al. “Bench to bedside translation of antibody drug conjugates using a multiscale mechanistic PK/PD model: a case study with brentuximab-vedotin.” Journal of pharmacokinetics and pharmacodynamics vol. 39,6 (2012): 643-59. doi:10.1007/s10928-012-9276-y
[6] Zhang, Alan et al. “Design, Synthesis, and In Vitro and In Vivo Evaluation of Cereblon Binding Bruton's Tyrosine Kinase (BTK) Degrader CD79b Targeted Antibody-Drug Conjugates.” Bioconjugate chemistry vol. 35,2 (2024): 140-146. doi:10.1021/acs.bioconjchem.3c00535

Keywords: Mechanistic PK-PD modeling, targeted protein degradation, model informed drug design