Intravenous immunoglobulin significantly reduces exposure of concomitantly administered anti-C5 monoclonal antibody tesidolumab

Stanley C Jordan, Klaus Kucher, Morten Bagger, Hans-Ulrich Hockey, Kristina Wagner, Noriko Ammerman, Ashley Vo, Stanley C Jordan, Klaus Kucher, Morten Bagger, Hans-Ulrich Hockey, Kristina Wagner, Noriko Ammerman, Ashley Vo

Abstract

Awareness of drug-drug interactions is critical in organ transplant recipient management. However, biologic agents interfering with monoclonal antibodies is not widely considered. We report the effect of high-dose intravenous immunoglobulin (IVIg) on safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of the human anti-C5 monoclonal antibody tesidolumab (LFG316) in end-stage renal disease patients awaiting kidney transplant. In this single-center, phase 1, open-label, parallel-group study, 8 patients were assigned to receive either single-dose tesidolumab + IVIg or tesidolumab alone, with 56-day follow-up. Within-group PK parameters were consistent. Mean tesidolumab exposure decreased 34%, clearance increased 63%, and half-life decreased 41% comparing tesidolumab + IVIg to tesidolumab alone. IVIg influence on tesidolumab elimination was most evident in the first 3 weeks. Complete suppression of both total and alternative complement activities was maintained for 4 weeks in the tesidolumab alone group and for 2 weeks in the tesidolumab + IVIg group. Tesidolumab was well tolerated. IVIg infused before tesidolumab affected tesidolumab PK and PD, resulting in a shortened period of full complement activity inhibition. These findings suggest a clinically relevant impact of IVIg on monoclonal antibody clearance and indirectly hint at an IVIg mechanism of action in treating autoimmune diseases and allosensitization by accelerating pathogenic IgG antibody degradation. Trial registration number: NCT02878616.

Keywords: clinical research/practice; clinical trial; desensitization; immunosuppression/immune modulation; intravenous immunoglobulin/IVIG; kidney transplantation/nephrology; pharmacokinetics/pharmacodynamics; pharmacology; rejection: antibody-mediated (ABMR); translational research/science.

© 2020 The American Society of Transplantation and the American Society of Transplant Surgeons.

References

REFERENCES

    1. Jordan SC, Tyan D, Stablein D, et al. Evaluation of intravenous immunoglobulin as an agent to lower allosensitization and improve transplantation in highly sensitized adult patients with end-stage renal disease: report of the NIH IG02 trial. J Am Soc Nephrol. 2004;15(12):3256-3262.
    1. Vo AA, Petrozzino J, Yeung K, et al. Efficacy, outcomes, and cost-effectiveness of desensitization using IVIG and rituximab. Transplantation. 2013;95(6):852-858.
    1. Abu Jawdeh BG, Cuffy MC, Alloway RR, et al. Desensitization in kidney transplantation: review and future perspectives. Clin Transplant. 2014;28(4):494-507.
    1. Loupy A, Lefaucheur C, Vernerey D, et al. Complement-binding anti-HLA antibodies and kidney-allograft survival. N Engl J Med. 2013;369(13):1215-1226.
    1. Bouquegneau A, Loheac C, Aubert O, et al. Complement-activating donor-specific anti-HLA antibodies and solid organ transplant survival: a systematic review and meta-analysis. PLoS Med. 2018;15(5):e1002572.
    1. Fernandez-Cruz E, Alecsandru D, Sanchez RS. Mechanisms of action of immune globulin. Clin Exp Immunol. 2009;157(S1):1-2.
    1. Gelfand EW. Intravenous immune globulin in autoimmune and inflammatory diseases. N Engl J Med. 2012;367(21):2015-2025.
    1. Stapleton NM, Einarsdottir HK, Stemerding AM, et al. The multiple facets of FcRn in immunity. Immunol Rev. 2015;268(1):253-268.
    1. Jordan SC, Choi J, Kahwaji J, et al. Complement inhibition for prevention and treatment of antibody-mediated rejection in renal allograft recipients. Transplant Proc. 2016;48(3):806-808.
    1. Stegall MD, Diwan T, Raghavaiah S, et al. Terminal complement inhibition decreases antibody-mediated rejection in sensitized renal transplant recipients. Am J Transplant. 2011;11(11):2405-2413.
    1. Vo AA, Zeevi A, Choi J, et al. A phase I/II placebo-controlled trial of C1-inhibitor for prevention of antibody-mediated rejection in HLA sensitized patients. Transplantation. 2015;99(2):299-308.
    1. Legendre C, Sberro-Soussan R, Zuber J, et al. Eculizumab in renal transplantation. Transplant Rev. 2013;27(3):90-92.
    1. Lefaucheur C, Viglietti D, Hidalgo LG, et al. Complement-activating anti-HLA antibodies in kidney transplantation: allograft gene expression profiling and response to treatment. J Am Soc Nephrol. 2018;29(2):620-635.
    1. Roguska M, Splawski I, Diefenbach-Streiber B, et al. Generation and characterization of LFG316, a fully-human anti-C5 antibody for the treatment of age-related macular degeneration. Invest Ophthalmol Vis Sci. 2014;55(13):3433.
    1. Nebbioso M, Lambiase A, Cerini A, et al. Therapeutic approaches with intravitreal injections in geographic atrophy secondary to age-related macular degeneration: current drugs and potential molecules. Int J Mol Sci. 2019;20(7):pii:E1693. .
    1. NCT01624636. Safety and tolerability of intravenous LFG316 in wet age-related macular degeneration (AMD). April 25, 2016. . Accessed September 6, 2019.
    1. NCT01527500. Intravitreal LFG316 in patients with age-related macular degeneration (AMD). April 9, 2019. . Accessed September 6, 2019.
    1. NCT02534909. Proof of concept study to assess the efficacy, safety and pharmacokinetics of LFG316 in patients with paroxysmal nocturnal hemoglobinuria. July 19, 2019. . Accessed September 6, 2019.
    1. Roopenian DC, Christianson GJ, Sproule TJ, et al. The MHC class I-like IgG receptor controls perinatal IgG transport, IgG homeostasis, and fate of IgG-Fc-coupled drugs. J Immunol. 2003;170(7):3528-3533.
    1. Raghavan M, Bonagura VR, Morrison SL, et al. Analysis of the pH dependence of the neonatal Fc receptor/immunoglobulin G interaction using antibody and receptor variants. Biochemistry. 1995;34(45):14649-14657.
    1. West AP Jr, Bjorkman PJ. Crystal structure and immunoglobulin G binding properties of the human major histocompatibility complex-related Fc receptor(,). Biochemistry. 2000;39(32):9698-9708.
    1. Montoyo HP, Vaccaro C, Hafner M, et al. Conditional deletion of the MHC class I-related receptor FcRn reveals the sites of IgG homeostasis in mice. Proc Natl Acad Sci USA. 2009;106(8):2788-2793.
    1. Li N, Zhao M, Hilario-Vargas J, et al. Complete FcRn dependence for intravenous Ig therapy in autoimmune skin blistering diseases. J Clin Invest. 2005;115(12):3440-3450.
    1. Fitzpatrick AM, Mann CA, Barry S, et al. An open label clinical trial of complement inhibition in multifocal motor neuropathy. J Peripher Nerv Syst. 2011;16(2):84-91.
    1. Sautenet B, Blancho G, Büchler M, et al. One-year results of the effects of rituximab on acute antibody-mediated rejection in renal transplantation: RITUX ERAH, a multicenter double-blind randomized placebo-controlled trial. Transplantation. 2016;100(2):391-399.
    1. Macklin PS, Morris PJ, Knight SR. A systematic review of the use of rituximab for the treatment of antibody-mediated renal transplant rejection. Transplant Rev. 2017;31(2):87-95.
    1. Moreso F, Crespo M, Ruiz JC, et al. Treatment of chronic antibody mediated rejection with intravenous immunoglobulins and rituximab: a multicenter, prospective, randomized, double-blind clinical trial. Am J Transplant. 2018;18(4):927-935.
    1. Kiessling P, Lledo-Garcia R, Watanabe S, et al. The FcRn inhibitor rozanolixizumab reduces human serum IgG concentration: a randomized phase 1 study. Sci Transl Med. 2017;9(414):eaan1208.
    1. Seijsing J, Yu S, Frejd FY, et al. In vivo depletion of serum IgG by an affibody molecule binding the neonatal Fc receptor. Sci Rep. 2018;8(1):5141.

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