Mechanism-Based Pharmacokinetic/Pharmacodynamic Model for THIOMAB™ Drug Conjugates
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THIOMAB™ drug conjugates (TDCs) with engineered cysteine residues allow site-specific drug conjugation and defined Drug-to-Antibody Ratios (DAR). In order to help elucidate the impact of drug-loading, conjugation site, and subsequent deconjugation on pharmacokinetics and efficacy, we have developed an integrated mathematical model to mechanistically characterize pharmacokinetic behavior and preclinical efficacy of MMAE conjugated TDCs with different DARs. General applicability of the model structure was evaluated with two different TDCs.
Pharmacokinetics studies were conducted for unconjugated antibody and purified TDCs with DAR-1, 2 and 4 for trastuzumab TDC and Anti-STEAP1 TDC in mice. Total antibody concentrations and individual DAR fractions were measured. Efficacy studies were performed in tumor-bearing mice.
An integrated model consisting of distinct DAR species (DAR0-4), each described by a two-compartment model was able to capture the experimental data well. Time series measurements of each Individual DAR species allowed for the incorporation of site-specific drug loss through deconjugation and the results suggest a higher deconjugation rate from heavy chain site HC-A114C than the light chain site LC-V205C. Total antibody concentrations showed multi-exponential decline, with a higher clearance associated with higher DAR species. The experimentally observed effects of TDC on tumor growth kinetics were successfully described by linking pharmacokinetic profiles to DAR-dependent killing of tumor cells.
Results from the integrated model evaluated with two different TDCs highlight the impact of DAR and site of conjugation on pharmacokinetics and efficacy. The model can be used to guide future drug optimization and in-vivo studies.
KEY WORDSantibody drug conjugates PKPD modeling Drug-Antibody-Ratio (DAR) site specific conjugation tumor growth
ACKNOWLEDGMENTS AND DISCLOSURES
The authors would like to thank Paul J. Fielder and other PKPD colleagues for their constructive input to this work.
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