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Pharmaceutical Research

, Volume 32, Issue 6, pp 1884–1893 | Cite as

Mechanism-Based Pharmacokinetic/Pharmacodynamic Model for THIOMAB™ Drug Conjugates

  • Siddharth Sukumaran
  • Kapil Gadkar
  • Crystal Zhang
  • Sunil Bhakta
  • Luna Liu
  • Keyang Xu
  • Helga Raab
  • Shang-Fan Yu
  • Elaine Mai
  • Aimee Fourie-O’Donohue
  • Katherine R. Kozak
  • Saroja Ramanujan
  • Jagath R. Junutula
  • Kedan Lin
Research Paper

ABSTRACT

Purpose

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.

Method

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.

Results

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.

Conclusion

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 WORDS

antibody drug conjugates PKPD modeling Drug-Antibody-Ratio (DAR) site specific conjugation tumor growth 

Notes

ACKNOWLEDGMENTS AND DISCLOSURES

The authors would like to thank Paul J. Fielder and other PKPD colleagues for their constructive input to this work.

Supplementary material

11095_2014_1582_MOESM1_ESM.docx (219 kb)
ESM 1 (DOCX 219 kb)

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Copyright information

© Springer Science+Business Media New York 2014

Authors and Affiliations

  • Siddharth Sukumaran
    • 1
  • Kapil Gadkar
    • 1
  • Crystal Zhang
    • 1
  • Sunil Bhakta
    • 1
  • Luna Liu
    • 1
  • Keyang Xu
    • 1
  • Helga Raab
    • 1
  • Shang-Fan Yu
    • 1
  • Elaine Mai
    • 1
  • Aimee Fourie-O’Donohue
    • 1
  • Katherine R. Kozak
    • 1
  • Saroja Ramanujan
    • 1
  • Jagath R. Junutula
    • 1
  • Kedan Lin
    • 1
  1. 1.Genentech Research and Early DevelopmentSouth San FranciscoUSA

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