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The Pharmacokinetics and Pharmacodynamics of TOL101, a Murine IgM Anti-Human αβ T Cell Receptor Antibody, in Renal Transplant Patients

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Abstract

Background and Objectives

TOL101 is a highly selective murine anti-αβ T cell receptor (TCR) IgM antibody and has recently completed phase II testing in primary renal transplant patients. This study was undertaken to determine the pharmacokinetic, pharmacodynamic, and immunogenic profile of TOL101.

Methods

Nine cohorts of two to six patients received at least five daily doses (of, or combination of, 0.28, 1.4, 7, 14, 28, or 42 mg) of TOL-101 administered at successively higher doses. Semi-logarithmic graphs of serum TOL101 concentration versus time supported the use of a one-compartment intravenous infusion pharmacokinetic model. The model was parameterized in terms of serum clearance (CL) and volume of distribution (V d).

Results

There was a trend toward a decrease in serum CL as the dose increased from 1.4 to 28 mg. However, the mean values for CL and V d were consistent across the cohorts that received 28, 32, and 42 mg. The mean ± standard deviation half-lives for these five cohorts ranged from 15.1 ± 7.35 to 28.6 ± 8.46 h, with an overall mean of 23.8 h, supporting both daily as well as fixed (i.e., not based on weight) dosing. Using CD3+ ≤25 cells/mm3 as the primary pharmacodynamic marker, all non-responders were in the 0.28, 1.4, or 7 mg cohorts, suggesting that starting doses above 14 mg are required. Finally, one patient out of 36 was found to have anti-drug antibody.

Conclusions

Together, the data show that while TOL101 is a highly potent anti-TCR antibody, its pharmacological profile is somewhat versatile, allowing for daily dosing without immunogenicity concerns.

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References

  1. Shapiro R, Young JB, Milford EL, et al. Immunosuppression: evolution in practice and trends, 1993–2003. Am J Transplant. 2005;5(4 Pt 2):874–86. doi:10.1111/j.1600-6135.2005.00833.x.

    Article  PubMed  Google Scholar 

  2. Nankivell BJ, Alexander SI. Rejection of the kidney allograft. N Engl J Med. 2010;363(15):1451–62. doi:10.1056/NEJMra0902927.

    Article  CAS  PubMed  Google Scholar 

  3. Dierselhuis M, Goulmy E. The relevance of minor histocompatibility antigens in solid organ transplantation. Curr Opin Organ Transplant. 2009;14(4):419–25. doi:10.1097/MOT.0b013e32832d399c.

    Article  PubMed  Google Scholar 

  4. Archbold JK, Ely LK, Kjer-Nielsen L, et al. T cell allorecognition and MHC restriction—a case of Jekyll and Hyde? Mol Immunol. 2008;45(3):583–98. doi:10.1016/j.molimm.2006.05.018.

    Article  CAS  PubMed  Google Scholar 

  5. Goggins WC, Pascual MA, Powelson JA, et al. A prospective, randomized, clinical trial of intraoperative versus postoperative thymoglobulin in adult cadaveric renal transplant recipients. Transplantation. 2003;76(5):798–802. doi:10.1097/01.TP.0000081042.67285.91.

    Article  CAS  PubMed  Google Scholar 

  6. Getts DR, Shankar S, Chastain EM, et al. Current landscape for T-cell targeting in autoimmunity and transplantation. Immunotherapy. 2011;3(7):853–70. doi:10.2217/imt.11.61.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  7. Cai J, Terasaki PI. Induction immunosuppression improves long-term graft and patient outcome in organ transplantation: an analysis of United Network for Organ Sharing registry data. Transplantation. 2010;90(12):1511–5. doi:10.1097/TP.0b013e3181fecfcb.

    Article  CAS  PubMed  Google Scholar 

  8. Matsumoto Y, Tsuchida M, Hanawa H, et al. Successful prevention and treatment of autoimmune encephalomyelitis by short-term administration of anti-T-cell receptor alpha beta antibody. Immunology. 1994;81(1):1–7.

    CAS  PubMed Central  PubMed  Google Scholar 

  9. Sempe P, Bedossa P, Richard MF, et al. Anti-alpha/beta T cell receptor monoclonal antibody provides an efficient therapy for autoimmune diabetes in nonobese diabetic (NOD) mice. Eur J Immunol. 1991;21(5):1163–9. doi:10.1002/eji.1830210511.

    Article  CAS  PubMed  Google Scholar 

  10. Khariwala SS, Knott PD, Dan O, et al. Pulsed immunosuppression with everolimus and anti-alphabeta T-cell receptor: laryngeal allograft preservation at six months. Ann Otol Rhinol Laryngol. 2006;115(1):74–80.

    PubMed  Google Scholar 

  11. Siemionow MZ, Izycki DM, Zielinski M. Donor-specific tolerance in fully major histocompatibility major histocompatibility complex-mismatched limb allograft transplants under an anti-alphabeta T-cell receptor monoclonal antibody and cyclosporine A protocol. Transplantation. 2003;76(12):1662–8. doi:10.1097/01.TP.0000105343.49626.6F.

    Article  CAS  PubMed  Google Scholar 

  12. Waid TH, Lucas BA, Thompson JS, et al. Treatment of renal allograft rejection with T10B9.1A31 or OKT3: final analysis of a phase II clinical trial. Transplantation. 1997;64(2):274–81.

    Article  CAS  PubMed  Google Scholar 

  13. Waid TH, Lucas BA, Thompson JS, et al. Treatment of acute cellular rejection with T10B9.1A-31 or OKT3 in renal allograft recipients. Transplantation. 1992;53(1):80–6.

    Article  CAS  PubMed  Google Scholar 

  14. Beelen DW, Graeven U, Schulz G, et al. Treatment of acute graft-versus-host disease after HLA-partially matched marrow transplantation with a monoclonal antibody (BMA031) against the T cell receptor. First results of a phase-I/II trial. Onkologie. 1988;11(1):56–8.

    Article  CAS  PubMed  Google Scholar 

  15. Getts DR, Getts MT, McCarthy DP, et al. Have we overestimated the benefit of human(ized) antibodies? mAbs. 2010;2(6):682–94.

    Article  PubMed Central  PubMed  Google Scholar 

  16. Siemionow MB, Brown SB, Thompson JS, et al. TOL101; a novel alpha beta TCR targeting monoclonal antibody. Am J Transplant. 2010;10(Supp):1.

    Google Scholar 

  17. Goldstein G, Norman DJ, Henell KR, et al. Pharmacokinetic study of orthoclone OKT3 serum levels during treatment of acute renal allograft rejection. Transplantation. 1988;46(4):587–9.

    Article  CAS  PubMed  Google Scholar 

  18. Waid TH, Lucas BA, Thompson JS, et al. Treatment of acute rejection with anti-T-cell antigen receptor complex alpha beta (T10B9.1A-31) or anti-CD3 (OKT3) monoclonal antibody: results of a prospective randomized double-blind trial. Transplant Proc. 1991;23(1 Pt 2):1062–5.

    CAS  PubMed  Google Scholar 

  19. Waid TH, Thompson JS, McKeown JW, et al. Induction immunotherapy in heart transplantation with T10B9.1A-31: a phase I study. J Heart Lung Transplant. 1997;16(9):913–6.

    CAS  PubMed  Google Scholar 

  20. Flechner SM, Goldfarb DA, Fairchild R, et al. A randomized prospective trial of low-dose OKT3 induction therapy to prevent rejection and minimize side effects in recipients of kidney transplants. Transplantation. 2000;69(11):2374–81.

    Article  CAS  PubMed  Google Scholar 

  21. Midtvedt K, Fauchald P, Lien B, et al. Individualized T cell monitored administration of ATG versus OKT3 in steroid-resistant kidney graft rejection. Clin Transplant. 2003;17(1):69–74.

    Article  PubMed  Google Scholar 

  22. Thistlethwaite JR Jr, Cosimi AB, Delmonico FL, et al. Evolving use of OKT3 monoclonal antibody for treatment of renal allograft rejection. Transplantation. 1984;38(6):695–701.

    Article  PubMed  Google Scholar 

  23. Cosimi AB, Burton RC, Colvin RB, et al. Treatment of acute renal allograft rejection with OKT3 monoclonal antibody. Transplantation. 1981;32(6):535–9.

    Article  CAS  PubMed  Google Scholar 

  24. Knight RJ, Kurrle R, McClain J, et al. Clinical evaluation of induction immunosuppression with a murine IgG2b monoclonal antibody (BMA 031) directed toward the human alpha/beta-T cell receptor. Transplantation. 1994;57(11):1581–8.

    Article  CAS  PubMed  Google Scholar 

  25. Broeders N, Wissing KM, Crusiaux A, et al. Mycophenolate mofetil, together with cyclosporin A, prevents anti-OKT3 antibody response in kidney transplant recipients. J Am Soc Nephrol. 1998;9(8):1521–5.

    CAS  PubMed  Google Scholar 

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Acknowledgments

This study was funded, in part, by a Food and Drug Administration Orphan Drug Grant. The authors would like to acknowledge the TOL101 clinical trial team physicians, including Drs Shamkant Mulgoankar, Larry B. Melton, Thomas H. Waid, Ellen C. Cooper, Randall S. Sung, and Fuad Shihab, as well as the following individuals who assisted in study monitoring, and assay and protocol development: Frank Fokta, Ellen Cooper, Amy Morris, Meghann T. Getts, Terra J. Frederick, James J. Herrman, John P. Puisis, and Leslie O’Toole.

The authors have the following conflicts of interest to report. Daniel Getts and Alexander Wiseman received salary support and grant funding from Tolera. William G. Kramer received salary support from Tolera Therapeutics. Stuart Flechner has no conflicts to report in relation to this study.

Author information

Authors and Affiliations

  1. Department of Research and Development, Tolera Therapeutics Inc, Kalamazoo, MI, USA

    Daniel R. Getts & Alexander C. Wiseman

  2. Department of Microbiology and Immunology, Interdepartmental Immunobiology Center, Northwestern University, Chicago, IL, 60611, USA

    Daniel R. Getts

  3. Kramer Consulting LLC, North Potomac, MD, USA

    William G. Kramer

  4. University of Colorado Hospital, University of Colorado, Denver, CO, USA

    Alexander C. Wiseman

  5. Department of Urology, Cleveland Clinic Foundation, Cleveland, OH, USA

    Stuart M. Flechner

Authors
  1. Daniel R. Getts
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  2. William G. Kramer
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  3. Alexander C. Wiseman
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  4. Stuart M. Flechner
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Corresponding author

Correspondence to Daniel R. Getts.

Additional information

Clinicaltrials.gov registration number NCT01154387.

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Getts, D.R., Kramer, W.G., Wiseman, A.C. et al. The Pharmacokinetics and Pharmacodynamics of TOL101, a Murine IgM Anti-Human αβ T Cell Receptor Antibody, in Renal Transplant Patients. Clin Pharmacokinet 53, 649–657 (2014). https://doi.org/10.1007/s40262-014-0138-1

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  • DOI: https://doi.org/10.1007/s40262-014-0138-1

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