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Development and Translational Application of an Integrated, Mechanistic Model of Antibody-Drug Conjugate Pharmacokinetics

  • Research Article
  • Theme: Systems Pharmacokinetics Models for Antibody-Drug Conjugates
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Abstract

Antibody drug conjugates (ADC), in which small molecule cytotoxic agents are non-specifically linked to antibodies, can enable targeted delivery of chemotherapeutics to tumor cells. ADCs are often produced and administered as a mixture of conjugated antibodies with different drug to antibody ratios (DAR) resulting in complex and heterogeneous disposition kinetics. We developed a mechanism-based platform model that can describe and predict the complex pharmacokinetic (PK) behavior of ADCs with protease-cleavable valine-citrulline (VC) linker linked to Monomethylmonomethyl auristatin F/E by incorporating known mechanisms of ADC disposition. The model includes explicit representation of all DAR species; DAR-dependent sequential deconjugation of the drug, resulting in the conversion of higher DAR to lower DAR species; and DAR-dependent antibody/ADC clearance. PK profiles of multiple analytes (total antibody, drug-conjugated antibody, and/or antibody-conjugated drug) for different ADC molecules and targets in rodents and cynomolgus monkeys were used for model development. The integrated cross-species model was successful in capturing the multi-analyte PK profiles after administration of purified ADCs with defined DAR species and ADCs with mixtures of DAR. Human PK predictions for DSTP3086S (anti-STEAP1-vc-MMAE) with the platform model agreed well with PK (total antibody and antibody-conjugated drug concentrations) measurements in the dose-ranging phase I clinical study. The integrated model is applicable to various other ADCs with different formats, conjugated drugs, and linkers, and provides a valuable tool for the exploration of mechanisms governing disposition of ADCs and enables translational predictions.

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References

  1. Diamantis N, Banerji U. Antibody-drug conjugates-an emerging class of cancer treatment. Br J Cancer. 2016;114(4):362–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Lin K, Tibbitts J, Shen BQ. Pharmacokinetics and ADME characterizations of antibody-drug conjugates. Methods Mol Biol. 2013;1045:117–31.

    Article  PubMed  Google Scholar 

  3. Nolting B. Linker technologies for antibody-drug conjugates. Methods Mol Biol. 2013;1045:71–100.

    Article  PubMed  Google Scholar 

  4. Sukumaran S, Lin K. Pharmacokinetics/pharmacodynamics and disposition of antibody-drug conjugates. In: Wang J, Shen W-C, Zaro LJ, editors. Antibody-drug conjugates: the 21st century magic bullets for cancer. Cham: Springer International Publishing; 2015. p. 117–31.

    Google Scholar 

  5. Kaur S, Xu K, Saad OM, Dere RC, Carrasco-Triguero M. Bioanalytical assay strategies for the development of antibody-drug conjugate biotherapeutics. Bioanalysis. 2013;5(2):201–26.

    Article  CAS  PubMed  Google Scholar 

  6. Shen BQ, Xu K, Liu L, Raab H, Bhakta S, Kenrick M, et al. Conjugation site modulates the in vivo stability and therapeutic activity of antibody-drug conjugates. Nat Biotechnol. 2012;30(2):184–9.

    Article  CAS  PubMed  Google Scholar 

  7. Singh R, Erickson HK. Antibody-cytotoxic agent conjugates: preparation and characterization. Methods Mol Biol. 2009;525:445–67. xiv.

    Article  CAS  PubMed  Google Scholar 

  8. Lin K, Rubinfeld B, Zhang C, Firestein R, Harstad E, Roth L, et al. Preclinical development of an anti-NaPi2b (SLC34A2) antibody-drug conjugate as a therapeutic for non-small cell lung and ovarian cancers. Clin Cancer Res. 2015;21(22):5139–50.

    Article  CAS  PubMed  Google Scholar 

  9. Boswell CA, Mundo EE, Zhang C, Bumbaca D, Valle NR, Kozak KR, et al. Impact of drug conjugation on pharmacokinetics and tissue distribution of anti-STEAP1 antibody-drug conjugates in rats. Bioconjug Chem. 2011;22(10):1994–2004.

    Article  CAS  PubMed  Google Scholar 

  10. Doronina SO, Toki BE, Torgov MY, Mendelsohn BA, Cerveny CG, Chace DF, et al. Development of potent monoclonal antibody auristatin conjugates for cancer therapy. Nat Biotechnol. 2003;21(7):778–84.

    Article  CAS  PubMed  Google Scholar 

  11. Danila DC, Szmulewitz RZ, Higano CS, Gilbert H, Kahn R, Wood K, et al. A phase I study of the safety and pharmacokinetics of DSTP3086S, an Anti-STEAP1 Antibody-Drug Conjugate, in Patients with Metastatic Castration-Resistant Prostate Cancer. American Society of Clinical Oncology (ASCO) Annual Meeting, Chicago, IL; 2013.

  12. Deng R, Iyer S, Theil FP, Mortensen DL, Fielder PJ, Prabhu S. Projecting human pharmacokinetics of therapeutic antibodies from nonclinical data: what have we learned? mAbs. 2011;3(1):61–6.

    Article  PubMed  PubMed Central  Google Scholar 

  13. Jumbe NL, Xin Y, Leipold DD, Crocker L, Dugger D, Mai E, et al. Modeling the efficacy of trastuzumab-DM1, an antibody drug conjugate, in mice. J Pharmacokinet Pharmacodyn. 2010;37(3):221–42.

    Article  CAS  PubMed  Google Scholar 

  14. Lu D, Girish S, Gao Y, Wang B, Yi JH, Guardino E, et al. Population pharmacokinetics of trastuzumab emtansine (T-DM1), a HER2-targeted antibody-drug conjugate, in patients with HER2-positive metastatic breast cancer: clinical implications of the effect of covariates. Cancer Chemother Pharmacol. 2014;74(2):399–410.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Shah DK, Haddish-Berhane N, Betts A. Bench to bedside translation of antibody drug conjugates using a multiscale mechanistic PK/PD model: a case study with brentuximab-vedotin. J Pharmacokinet Pharmacodyn. 2012;39(6):643–59.

    Article  PubMed  Google Scholar 

  16. Bender B, Leipold DD, Xu K, Shen BQ, Tibbitts J, Friberg LE. A mechanistic pharmacokinetic model elucidating the disposition of trastuzumab emtansine (T-DM1), an antibody-drug conjugate (ADC) for treatment of metastatic breast cancer. AAPS J. 2014;16(5):994–1008.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Lu D, Jin JY, Girish S, Agarwal P, Li D, Prabhu S, et al. Semi-mechanistic multiple-analyte pharmacokinetic model for an antibody-drug-conjugate in cynomolgus monkeys. Pharm Res. 2015;32(6):1907–19.

    Article  CAS  PubMed  Google Scholar 

  18. Gibiansky L, Gibiansky E. Target-mediated drug disposition model and its approximations for antibody-drug conjugates. J Pharmacokinet Pharmacodyn. 2014;41(1):35–47.

    Article  CAS  PubMed  Google Scholar 

  19. Adem YT, Schwarz KA, Duenas E, Patapoff TW, Galush WJ, Esue O. Auristatin antibody drug conjugate physical instability and the role of drug payload. Bioconjug Chem. 2014;25(4):656–64.

    Article  CAS  PubMed  Google Scholar 

  20. Hamblett KJ, Senter PD, Chace DF, Sun MM, Lenox J, Cerveny CG, et al. Effects of drug loading on the antitumor activity of a monoclonal antibody drug conjugate. Clin Cancer Res. 2004;10(20):7063–70.

    Article  CAS  PubMed  Google Scholar 

  21. Sukumaran S, Gadkar K, Zhang C, Bhakta S, Liu L, Xu K, et al. Mechanism-based pharmacokinetic/pharmacodynamic model for THIOMAB drug conjugates. Pharm Res. 2015;32(6):1884–93.

    Article  CAS  PubMed  Google Scholar 

  22. Leipold DD, Jumbe N, Dugger D, Crocker L, Leach W, Sliwkowski MX et al. Trastuzumab-MC-vc-PAB-MMAF: the effects of the Drug:Antibody Ratio (DAR) on efficacy, toxicity and pharmacokinetics. AACR Annual Meeting; 2007.

  23. Lu D, Joshi A, Wang B, Olsen S, Yi JH, Krop IE, et al. An integrated multiple-analyte pharmacokinetic model to characterize trastuzumab emtansine (T-DM1) clearance pathways and to evaluate reduced pharmacokinetic sampling in patients with HER2-positive metastatic breast cancer. Clin Pharmacokinet. 2013;52(8):657–72.

    Article  CAS  PubMed  Google Scholar 

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    Authors and Affiliations

    1. Genentech Research and Early Development, 1 DNA Way, South San Francisco, California, 94080, USA

      Siddharth Sukumaran, Crystal Zhang, Douglas D. Leipold, Ola M. Saad, Keyang Xu, Kapil Gadkar, Divya Samineni, Bei Wang, Marija Milojic-Blair, Montserrat Carrasco-Triguero, Bonnee Rubinfeld, Paul Fielder, Kedan Lin & Saroja Ramanujan

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    1. Siddharth Sukumaran
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    2. Crystal Zhang
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    3. Douglas D. Leipold
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    4. Ola M. Saad
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    5. Keyang Xu
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    14. Saroja Ramanujan
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    Correspondence to Saroja Ramanujan.

    Additional information

    Guest Editor: Dhaval K. Shah

    Kedan Lin and Saroja Ramanujan contributed equally to this work.

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    Sukumaran, S., Zhang, C., Leipold, D.D. et al. Development and Translational Application of an Integrated, Mechanistic Model of Antibody-Drug Conjugate Pharmacokinetics. AAPS J 19, 130–140 (2017). https://doi.org/10.1208/s12248-016-9993-z

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    • DOI: https://doi.org/10.1208/s12248-016-9993-z

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