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Pharmacokinetic and Pharmacodynamic Modeling of a Humanized Anti-IL-13 Antibody in Naive and Ascaris-Challenged Cynomolgus Monkeys

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Abstract

Purpose

Neutralization of IL-13 is an attractive approach for treatment of asthma. In this report, we developed a novel PK–PD model that described the relationship between the circulating concentrations of total IL-13 and a neutralizing anti-IL-13 antibody (Ab-02) in the model of acute airway inflammation induced by Ascaris challenge to cynomolgus monkeys, as well as in naive monkeys.

Methods

Cynomolgus monkeys were administered a single intravenous or subcutaneous dose of Ab-02. Total IL-13 and Ab-02 concentrations were measured by immunoassays.

Results

Modeling and simulations indicated that: (1) Ascaris challenge induced ∼ three-fold increase in circulating IL-13 concentrations, when compared to naive animals, consistent with the notion that Ascaris-induced airway inflammation was IL-13-mediated; (2) the transient increase in total IL-13 concentrations observed in both naive and Ascaris-challenged monkeys following Ab-02 administration was due to the increase in Ab-02-bound IL-13, while free IL-13 was decreased; and (3) the extent and duration of neutralization of circulating IL-13 were different in naive and Ascaris-challenged monkeys for the same Ab-02 dose regimen.

Conclusions

The PK–PD model presented in this report may be applied to study drug–ligand interactions when a free ligand cannot be directly assayed but total ligand concentrations are modulated by the drug administration.

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References

  1. J. H. Anolik, and M. Aringer. New treatments for SLE: cell-depleting and anti-cytokine therapies. Best Pract. Res. Clin. Rheumatol. 19(5):859–878 (2005) doi:10.1016/j.berh.2005.05.006.

    Article  PubMed  CAS  Google Scholar 

  2. A. N. Economides, L. R. Carpenter, J. S. Rudge, V. Wong, E. M. Koehler-Stec, C. Hartnett et al. Cytokine traps: multi-component, high-affinity blockers of cytokine action. Nat. Med. 9(1):47–52 (2003) doi:10.1038/nm811.

    Article  PubMed  CAS  Google Scholar 

  3. E. Toussirot, and D. Wendling. The use of TNF-alpha blocking agents in rheumatoid arthritis: an update. Expert Opin. Pharmacother. 8(13):2089–2107 (2007) doi:10.1517/14656566.8.13.2089.

    Article  PubMed  CAS  Google Scholar 

  4. M. Ichinose, and P. J. Barnes. Cytokine-directed therapy in asthma. Curr. Drug Targets Inflamm. Allergy. 3(3):263–269 (2004) doi:10.2174/1568010043343688.

    Article  PubMed  CAS  Google Scholar 

  5. K. Margolin, M. S. Gordon, E. Holmgren, J. Gaudreault, W. Novotny, G. Fyfe et al. Phase Ib trial of intravenous recombinant humanized monoclonal antibody to vascular endothelial growth factor in combination with chemotherapy in patients with advanced cancer: pharmacologic and long-term safety data. J. Clin. Oncol. 19(3):851–856 (2001).

    PubMed  CAS  Google Scholar 

  6. H. Ito, M. Takazoe, Y. Fukuda, T. Hibi, K. Kusugami, A. Andoh et al. A pilot randomized trial of a human anti-interleukin-6 receptor monoclonal antibody in active Crohn’s disease. Gastroenterology. 126(4):989–996 (2004)discussion 947 doi:10.1053/j.gastro.2004.01.012.

    Article  PubMed  CAS  Google Scholar 

  7. P. Charles, M. J. Elliott, D. Davis, A. Potter, J. R. Kalden, C. Antoni et al. Regulation of cytokines, cytokine inhibitors, and acute-phase proteins following anti-TNF-alpha therapy in rheumatoid arthritis. J. Immunol. 163(3):1521–1528 (1999).

    PubMed  CAS  Google Scholar 

  8. A. L. Andrews, J. W. Holloway, S. M. Puddicombe, S. T. Holgate, and D. E. Davies. Kinetic analysis of the interleukin-13 receptor complex. J. Biol. Chem. 277(48):46073–46078 (2002) doi:10.1074/jbc.M209560200.

    Article  PubMed  CAS  Google Scholar 

  9. D. B. Corry, and F. Kheradmand. Biology and therapeutic potential of the interleukin-4/interleukin-13 signaling pathway in asthma. Am. J. Respir. Med. 1(3):185–193 (2002).

    PubMed  CAS  Google Scholar 

  10. M. Wills-Karp. Interleukin-13 in asthma pathogenesis. Curr. Allergy Asthma Rep. 4(2):123–131 (2004) doi:10.1007/s11882-004-0057-6.

    Article  PubMed  Google Scholar 

  11. C. Taube, C. Duez, Z. H. Cui, K. Takeda, Y. H. Rha, J. W. Park et al. The role of IL-13 in established allergic airway disease. J. Immunol. 169(11):6482–6489 (2002).

    PubMed  CAS  Google Scholar 

  12. J. Padilla, E. Daley, A. Chow, K. Robinson, K. Parthasarathi, A. N. McKenzie et al. IL-13 regulates the immune response to inhaled antigens. J. Immunol. 174(12):8097–8105 (2005).

    PubMed  CAS  Google Scholar 

  13. G. Grunig, M. Warnock, A. E. Wakil, R. Venkayya, F. Brombacher, D. M. Rennick et al. Requirement for IL-13 independently of IL-4 in experimental asthma. Science. 282(5397):2261–2263 (1998) doi:10.1126/science.282.5397.2261.

    Article  PubMed  CAS  Google Scholar 

  14. D. Vercelli. Genetics of IL-13 and functional relevance of IL-13 variants. Curr. Opin. Allergy Clin. Immunol. 2(5):389–393 (2002) doi:10.1097/00130832-200210000-00004.

    Article  PubMed  Google Scholar 

  15. R. K. Kumar, C. Herbert, D. C. Webb, L. Li, and P. S. Foster. Effects of anticytokine therapy in a mouse model of chronic asthma. Am. J. Respir. Crit. Care Med. 170(10):1043–1048 (2004) doi:10.1164/rccm.200405-681OC.

    Article  PubMed  Google Scholar 

  16. G. Yang, L. Li, A. Volk, E. Emmell, T. Petley, J. Giles-Komar et al. Therapeutic dosing with anti-interleukin-13 monoclonal antibody inhibits asthma progression in mice. J. Pharmacol. Exp. Ther. 313(1):8–15 (2005) doi:10.1124/jpet.104.076133.

    Article  PubMed  CAS  Google Scholar 

  17. M. Wills-Karp, J. Luyimbazi, X. Xu, B. Schofield, T. Y. Neben, C. L. Karp et al. Interleukin-13: central mediator of allergic asthma. Science. 282(5397):2258–2261 (1998) doi:10.1126/science.282.5397.2258.

    Article  PubMed  CAS  Google Scholar 

  18. A. Bree, F. J. Schlerman, M. Wadanoli, L. Tchistiakova, K. Marquette, X. Y. Tan et al. IL-13 blockade reduces lung inflammation after Ascaris suum challenge in cynomolgus monkeys. J. Allergy Clin. Immunol. 119(5):1251–1257 (2007) doi:10.1016/j.jaci.2007.02.009.

    Article  PubMed  CAS  Google Scholar 

  19. M. T. Kasaian, X. Y. Tan, M. Jin, L. Fitz, K. Marquette, N. Wood, et al. IL-13 Neutralization by two distinct receptor blocking mechanisms reduces IgE responses and lung inflammation in cynomolgus monkeys. J. Pharmacol. Exp. Ther. 325(3):88 (2008).

    Article  Google Scholar 

  20. Y. Vugmeyster, P. Szklut, L. Tchistiakova, W. Abraham, M. Kasaian, and X. Xu. Preclinical pharmacokinetics, interspecies scaling, and tissue distribution of humanized monoclonal anti-IL-13 antibodies with different IL-13 neutralization mechanisms. Int. Immunopharmacol. 8(3):477–483 (2008) doi:10.1016/j.intimp.2007.12.004.

    Article  PubMed  CAS  Google Scholar 

  21. L. J. Benincosa, F. S. Chow, L. P. Tobia, D. C. Kwok, C. B. Davis, and W. J. Jusko. Pharmacokinetics and pharmacodynamics of a humanized monoclonal antibody to factor IX in cynomolgus monkeys. J. Pharmacol. Exp. Ther. 292(2):810–816 (2000).

    PubMed  CAS  Google Scholar 

  22. D. E. Mager, and W. J. Jusko. General pharmacokinetic model for drugs exhibiting target-mediated drug disposition. J. Pharmacokinet. Pharmacodyn. 28(6):507–532 (2001) doi:10.1023/A:1014414520282.

    Article  PubMed  CAS  Google Scholar 

  23. C. M. Ng, E. Stefanich, B. S. Anand, P. J. Fielder, and L. Vaickus. Pharmacokinetics/pharmacodynamics of nondepleting anti-CD4 monoclonal antibody (TRX1) in healthy human volunteers. Pharm. Res. 23(1):95–103 (2006) doi:10.1007/s11095-005-8814-3.

    Article  PubMed  CAS  Google Scholar 

  24. F. S. Chow, L. J. Benincosa, S. B. Sheth, D. Wilson, C. B. Davis, E. A. Minthorn et al. Pharmacokinetic and pharmacodynamic modeling of humanized anti-factor IX antibody (SB 249417) in humans. Clin. Pharmacol. Ther. 71(4):235–245 (2002) doi:10.1067/mcp.2002.122276.

    Article  PubMed  CAS  Google Scholar 

  25. N. Hayashi, Y. Tsukamoto, W. M. Sallas, and P. J. Lowe. A mechanism-based binding model for the population pharmacokinetics and pharmacodynamics of omalizumab. Br. J. Clin. Pharmacol. 63(5):548–561 (2007) doi:10.1111/j.1365-2125.2006.02803.x.

    Article  PubMed  CAS  Google Scholar 

  26. K. M. Muller, K. M. Arndt, and A. Pluckthun. Model and simulation of multivalent binding to fixed ligands. Anal. Biochem. 261(2):149–158 (1998) doi:10.1006/abio.1998.2725.

    Article  PubMed  CAS  Google Scholar 

  27. W. L. Tseng, H. T. Chang, S. M. Hsu, R. J. Chen, and S. Lin. Immunoaffinity capillary electrophoresis: determination of binding constant and stoichiometry for antibody–antigen interaction. Electrophoresis. 23(6):836–846 (2002) doi:10.1002/1522-2683(200203)23:6<836::AID-ELPS836>3.0.CO;2-J.

    Article  PubMed  CAS  Google Scholar 

  28. M. Danhof, J. de Jongh, E. C. De Lange, O. Della Pasqua, B. A. Ploeger, and R. A. Voskuyl. Mechanism-based pharmacokinetic–pharmacodynamic modeling: biophase distribution, receptor theory, and dynamical systems analysis. Annu. Rev. Pharmacol. Toxicol. 47:357–400 (2007) doi:10.1146/annurev.pharmtox.47.120505.105154.

    Article  PubMed  CAS  Google Scholar 

  29. C. W. Adams, D. E. Allison, K. Flagella, L. Presta, J. Clarke, N. Dybdal et al. Humanization of a recombinant monoclonal antibody to produce a therapeutic HER dimerization inhibitor, pertuzumab. Cancer Immunol. Immunother. 55(6):717–727 (2006) doi:10.1007/s00262-005-0058-x.

    Article  PubMed  CAS  Google Scholar 

  30. Y. S. Lin, C. Nguyen, J. L. Mendoza, E. Escandon, D. Fei, Y. G. Meng et al. Preclinical pharmacokinetics, interspecies scaling, and tissue distribution of a humanized monoclonal antibody against vascular endothelial growth factor. J. Pharmacol. Exp. Ther. 288(1):371–378 (1999).

    PubMed  CAS  Google Scholar 

  31. P. Zia-Amirhosseini, E. Minthorn, L. J. Benincosa, T. K. Hart, C. S. Hottenstein, L. A. Tobia et al. Pharmacokinetics and pharmacodynamics of SB-240563, a humanized monoclonal antibody directed to human interleukin-5, in monkeys. J. Pharmacol. Exp. Ther. 291(3):1060–1067 (1999).

    PubMed  CAS  Google Scholar 

  32. P. Fiumara, F. Cabanillas, and A. Younes. Interleukin-13 levels in serum from patients with Hodgkin disease and healthy volunteers. Blood. 98(9):2877–2878 (2001) doi:10.1182/blood.V98.9.2877.

    Article  PubMed  CAS  Google Scholar 

  33. S. M. Wang, H. Y. Lei, M. C. Huang, L. Y. Su, H. C. Lin, C. K. Yu et al. Modulation of cytokine production by intravenous immunoglobulin in patients with enterovirus 71-associated brainstem encephalitis. J. Clin. Virol. 37(1):47–52 (2006) doi:10.1016/j.jcv.2006.05.009.

    Article  PubMed  CAS  Google Scholar 

  34. J. Gabrielsson, and D. Weiner. Pharmacokinetic and pharmacodynamic data analysis: concept and applications. Swedish Pharmaceutical, Stockholm, 2000.

    Google Scholar 

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Acknowledgments

We thank Macy Jin, Xiang-Yang Tan, and Lioudmila Tchistiakova for generation and humanization of Ab-02; Tamera Ashworth, Nicole Duriga, Nick Bauer, and David DeFranco for technical help with bioanalytical aspects of the studies; Andrea Bree, Franklin Schlerman, and Michael Wadanoli for help with Ascaris challenge studies in monkeys; Vikram Patel, Joann Scatina, Qin Wang, Mauricio Leal, Stan Spence, and Garvin Warner for scientific discussions on data interpretation.

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Authors and Affiliations

  1. Department of Drug Safety and Metabolism, Wyeth Research, One Burtt Road, Andover, MA, 01810, USA

    Yulia Vugmeyster, Xianbin Tian, Pamela Szklut & Xin Xu

  2. Department of Discovery, Wyeth Research, Cambridge, MA, USA

    Marion Kasaian

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  1. Yulia Vugmeyster
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Correspondence to Yulia Vugmeyster.

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Vugmeyster, Y., Tian, X., Szklut, P. et al. Pharmacokinetic and Pharmacodynamic Modeling of a Humanized Anti-IL-13 Antibody in Naive and Ascaris-Challenged Cynomolgus Monkeys. Pharm Res 26, 306–315 (2009). https://doi.org/10.1007/s11095-008-9739-4

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