Safety, tolerability, and efficacy of monoclonal CD38 antibody felzartamab in late antibody-mediated renal allograft rejection: study protocol for a phase 2 trial

Katharina A Mayer, Klemens Budde, Philip F Halloran, Konstantin Doberer, Lionel Rostaing, Farsad Eskandary, Anna Christamentl, Markus Wahrmann, Heinz Regele, Sabine Schranz, Sarah Ely, Christa Firbas, Christian Schörgenhofer, Alexander Kainz, Alexandre Loupy, Stefan Härtle, Rainer Boxhammer, Bernd Jilma, Georg A Böhmig, Katharina A Mayer, Klemens Budde, Philip F Halloran, Konstantin Doberer, Lionel Rostaing, Farsad Eskandary, Anna Christamentl, Markus Wahrmann, Heinz Regele, Sabine Schranz, Sarah Ely, Christa Firbas, Christian Schörgenhofer, Alexander Kainz, Alexandre Loupy, Stefan Härtle, Rainer Boxhammer, Bernd Jilma, Georg A Böhmig

Abstract

Background: Antibody-mediated rejection (ABMR) is a cardinal cause of renal allograft loss. This rejection type, which may occur at any time after transplantation, commonly presents as a continuum of microvascular inflammation (MVI) culminating in chronic tissue injury. While the clinical relevance of ABMR is well recognized, its treatment, particularly a long time after transplantation, has remained a big challenge. A promising strategy to counteract ABMR may be the use of CD38-directed treatment to deplete alloantibody-producing plasma cells (PC) and natural killer (NK) cells.

Methods: This investigator-initiated trial is planned as a randomized, placebo-controlled, double-blind, parallel-group, multi-center phase 2 trial designed to assess the safety and tolerability (primary endpoint), pharmacokinetics, immunogenicity, and efficacy of the fully human CD38 monoclonal antibody felzartamab (MOR202) in late ABMR. The trial will include 20 anti-HLA donor-specific antibody (DSA)-positive renal allograft recipients diagnosed with active or chronic active ABMR ≥ 180 days post-transplantation. Subjects will be randomized 1:1 to receive felzartamab (16 mg/kg per infusion) or placebo for a period of 6 months (intravenous administration on day 0, and after 1, 2, 3, 4, 8, 12, 16, and 20 weeks). Two follow-up allograft biopsies will be performed at weeks 24 and 52. Secondary endpoints (preliminary assessment) will include morphologic and molecular rejection activity in renal biopsies, immunologic biomarkers in the blood and urine, and surrogate parameters predicting the progression to allograft failure (slope of renal function; iBOX prediction score).

Discussion: Based on the hypothesis that felzartamab is able to halt the progression of ABMR via targeting antibody-producing PC and NK cells, we believe that our trial could potentially provide the first proof of concept of a new treatment in ABMR based on a prospective randomized clinical trial.

Trial registration: EU Clinical Trials Register (EudraCT) 2021-000545-40 . Registered on 23 June 2021.

Clinicaltrials: gov NCT05021484 . Registered on 25 August 2021.

Keywords: Antibody-mediated rejection; CD38; Donor-specific antibody; Felzartamab; Kidney transplantation; Monoclonal antibody; Natural killer cell; Plasma cell.

Conflict of interest statement

SH and RB are employees of MorphoSys AG, Planegg, Germany. All other authors declare that they have no competing interests.

© 2022. The Author(s).

Figures

Fig. 1
Fig. 1
Study flowchart. ADA, anti-drug antibody; DSA, donor-specific antibody; eGFR, estimated glomerular filtration rate; EP; endpoint; FU-Bx, follow-up biopsy; KTX, kidney transplantation; PD, pharmacodynamics; PK, pharmacokinetics; TTV, torque teno virus
Fig. 2
Fig. 2
Schedule of events. CMV, cytomegalovirus; CNI, calcineurin inhibitor; DSA, donor-specific antibody; eGFR, estimated glomerular filtration rate; HSV, herpes simplex virus; HZV, herpes zoster virus; Ig, immunoglobulin; mTOR, mammalian target of rapamycin; PK, pharmacokinetics; TTV, torque teno virus

References

    1. Sellarés J, de Freitas DG, Mengel M, Reeve J, Einecke G, Sis B, Hidalgo LG, Famulski K, Matas A, Halloran PF. Understanding the causes of kidney transplant failure: the dominant role of antibody-mediated rejection and nonadherence. Am J Transplant. 2012;12(2):388. doi: 10.1111/j.1600-6143.2011.03840.x.
    1. Loupy A, Lefaucheur C. Antibody-mediated rejection of solid-organ allografts. N Engl J Med. 2018;379(12):1150. doi: 10.1056/NEJMra1802677.
    1. Mayrdorfer M, Liefeldt L, Wu K, Rudolph B, Zhang Q, Friedersdorff F, Lachmann N, Schmidt D, Osmanodja B, Naik MG, et al. Exploring the complexity of death-censored kidney allograft failure. J Am Soc Nephrol. 2021;32(6):1513. doi: 10.1681/ASN.2020081215.
    1. Loupy A, Haas M, Roufosse C, Naesens M, Adam B, Afrouzian M, Akalin E, Alachkar N, Bagnasco S, Becker JU, et al. The Banff 2019 Kidney Meeting Report (I): updates on and clarification of criteria for T cell- and antibody-mediated rejection. Am J Transplant. 2020;20(9):2318. doi: 10.1111/ajt.15898.
    1. Böhmig GA, Eskandary F, Doberer K, Halloran PF. The therapeutic challenge of late antibody-mediated kidney allograft rejection. Transpl Int. 2019;32(8):775. doi: 10.1111/tri.13436.
    1. Schinstock CA, Mannon RB, Budde K, Chong AS, Haas M, Knechtle S, Lefaucheur C, Montgomery RA, Nickerson P, Tullius SG, et al. Recommended treatment for antibody-mediated rejection after kidney transplantation: the 2019 Expert Consensus From the Transplantion Society Working Group. Transplantation. 2020;104(5):911. doi: 10.1097/TP.0000000000003095.
    1. Eskandary F, Regele H, Baumann L, Bond G, Kozakowski N, Wahrmann M, Hidalgo LG, Haslacher H, Kaltenecker CC, Aretin M-A, et al. A randomized trial of bortezomib in late antibody-mediated rejection (BORTEJECT) J Am Soc Nephrol. 2018;29(2):591. doi: 10.1681/ASN.2017070818.
    1. Moreso F, Crespo M, Ruiz JC, Torres A, Gutierrez-Dalmau A, Osuna A, Perello M, Pascual J, Torres IB, Redondo-Pachon D, 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. doi: 10.1111/ajt.14520.
    1. Kulkarni S, Kirkiles-Smith NC, Deng YH, Formica RN, Moeckel G, Broecker V, Bow L, Tomlin R, Pober JS. Eculizumab therapy for chronic antibody-mediated injury in kidney transplant recipients: a pilot randomized controlled trial. Am J Transplant. 2017;17(3):682. doi: 10.1111/ajt.14001.
    1. Choi J, Aubert O, Vo A, Loupy A, Haas M, Puliyanda D, Kim I, Louie S, Kang A, Peng A, et al. Assessment of tocilizumab (anti-interleukin-6 receptor monoclonal) as a potential treatment for chronic antibody-mediated rejection and transplant glomerulopathy in HLA-sensitized renal allograft recipients. Am J Transplant. 2017;17(9):2381. doi: 10.1111/ajt.14228.
    1. Doberer K, Duerr M, Halloran PF, Eskandary F, Budde K, Regele H, Reeve J, Borski A, Kozakowski N, Reindl-Schwaighofer R, et al. A randomized clinical trial of anti-IL-6 antibody clazakizumab in late antibody-mediated kidney transplant rejection. J Am Soc Nephrol. 2021;32(3):708. doi: 10.1681/ASN.2020071106.
    1. Mayer KA, Doberer K, Eskandary F, Halloran PF, Böhmig GA. New concepts in chronic antibody-mediated kidney allograft rejection: prevention and treatment. Curr Opin Organ Transplant. 2021;26(1):97. doi: 10.1097/MOT.0000000000000832.
    1. Horenstein AL, Faini AC, Morandi F, Bracci C, Lanza F, Giuliani N, Paulus A, Malavasi F. The circular life of human CD38: from basic science to clinics and back. Molecules. 2020;25(20):4844. doi: 10.3390/molecules25204844.
    1. van de Donk N, Richardson PG, Malavasi F. CD38 antibodies in multiple myeloma: back to the future. Blood. 2018;131(1):13. doi: 10.1182/blood-2017-06-740944.
    1. de Weers M, Tai YT, van der Veer MS, Bakker JM, Vink T, Jacobs DC, Oomen LA, Peipp M, Valerius T, Slootstra JW, et al. Daratumumab, a novel therapeutic human CD38 monoclonal antibody, induces killing of multiple myeloma and other hematological tumors. J Immunol. 2011;186(3):1840. doi: 10.4049/jimmunol.1003032.
    1. Endell J, Samuelsson C, Boxhammer R, Strauss S, Steidl S. Effect of MOR202, a human CD38 antibody, in combination with lenalidomide and bortezomib, on bone lysis and tumor load in a physiologic model of myeloma. Proc Am Soc. Clin Oncol. 2011;29(suppl15):8078 (abstr).
    1. Endell J, Boxhammer R, Wurzenberger C, Ness D, Steidl S. The activity of MOR202, a fully human anti-CD38 antibody, is complemented by ADCP and is synergistically enhanced by lenalidomide in vitro and in vivo. Blood. 2012;120:4018 (abstr). doi: 10.1182/blood.V120.21.4018.4018.
    1. Overdijk MB, Verploegen S, Bogels M, van Egmond M, Lammerts van Bueren JJ, Mutis T, Groen RW, Breij E, Martens AC, Bleeker WK, et al. Antibody-mediated phagocytosis contributes to the anti-tumor activity of the therapeutic antibody daratumumab in lymphoma and multiple myeloma. MAbs. 2015;7(2):311. doi: 10.1080/19420862.2015.1007813.
    1. Overdijk MB, Jansen JH, Nederend M, Lammerts van Bueren JJ, Groen RW, Parren PW, Leusen JH, Boross P. The therapeutic CD38 monoclonal antibody daratumumab induces programmed cell death via Fcγ receptor-mediated cross-linking. J Immunol. 2016;197(3):807. doi: 10.4049/jimmunol.1501351.
    1. Venner JM, Hidalgo LG, Famulski KS, Chang J, Halloran PF. The molecular landscape of antibody-mediated kidney transplant rejection: evidence for NK involvement through CD16a Fc receptors. Am J Transplant. 2015;15(5):1336. doi: 10.1111/ajt.13115.
    1. Parkes MD, Halloran PF, Hidalgo LG. Evidence for CD16a-mediated NK cell stimulation in antibody-mediated kidney transplant rejection. Transplantation. 2017;101(4):e102. doi: 10.1097/TP.0000000000001586.
    1. Koenig A, Chen CC, Marcais A, Barba T, Mathias V, Sicard A, Rabeyrin M, Racape M, Duong-Van-Huyen JP, Bruneval P, et al. Missing self triggers NK cell-mediated chronic vascular rejection of solid organ transplants. Nat Commun. 2019;10(1):5350. doi: 10.1038/s41467-019-13113-5.
    1. Callemeyn J, Senev A, Coemans M, Lerut E, Sprangers B, Kuypers D, Koenig A, Thaunat O, Emonds MP, Naesens M. Missing self-induced microvascular rejection of kidney allografts: a population-based study. J Am Soc Nephrol. 2021;32(8):2070. doi: 10.1681/ASN.2020111558.
    1. Doberer K, Kläger J, Gualdoni GA, Mayer KA, Eskandary F, Farkash EA, Agis H, Reiter T, Reindl-Schwaighofer R, Wahrmann M, et al. CD38 antibody daratumumab for the treatment of chronic active antibody-mediated kidney allograft rejection. Transplantation. 2021;105(2):451. doi: 10.1097/TP.0000000000003247.
    1. Kwun J, Matignon M, Manook M, Guendouz S, Audard V, Kheav D, Poullot E, Gautreau C, Ezekian B, Bodez D, et al. Daratumumab in sensitized kidney transplantation: potentials and limitations of experimental and clinical use. J Am Soc Nephrol. 2019;30(7):1206. doi: 10.1681/ASN.2018121254.
    1. Raab MS, Engelhardt M, Blank A, Goldschmidt H, Agis H, Blau IW, Einsele H, Ferstl B, Schub N, Rollig C, et al. MOR202, a novel anti-CD38 monoclonal antibody, in patients with relapsed or refractory multiple myeloma: a first-in-human, multicentre, phase 1-2a trial. Lancet Haematol. 2020;7(5):e381. doi: 10.1016/S2352-3026(19)30249-2.
    1. Irish W, Nickerson P, Astor BC, Chong E, Wiebe C, Moreso F, Seron D, Crespo M, Gache L, Djamali A. Change in estimated GFR and risk of allograft failure in patients diagnosed with late active antibody-mediated rejection following kidney transplantation. Transplantation. 2021;105(3):648. doi: 10.1097/TP.0000000000003274.
    1. Loupy A, Aubert O, Orandi BJ, Naesens M, Bouatou Y, Raynaud M, Divard G, Jackson AM, Viglietti D, Giral M, et al. Prediction system for risk of allograft loss in patients receiving kidney transplants: international derivation and validation study. BMJ. 2019;366:l4923. doi: 10.1136/bmj.l4923.
    1. Bergan S, Brunet M, Hesselink DA, Johnson-Davis KL, Kunicki PK, Lemaitre F, Marquet P, Molinaro M, Noceti O, Pattanaik S, et al. Personalized therapy for mycophenolate: consensus report by the International Association of Therapeutic Drug Monitoring and Clinical Toxicology. Ther Drug Monit. 2021;43(2):150. doi: 10.1097/FTD.0000000000000871.
    1. Glander P, Waiser J, Hambach P, Bachmann F, Budde K, Eckardt KU, Friedersdorff F, Gaedeke J, Kron S, Lorkowski C, et al. Inosine 5′-monophosphate dehydrogenase activity for the longitudinal monitoring of mycophenolic acid treatment in kidney allograft recipients. Transplantation. 2021;105(4):916. doi: 10.1097/TP.0000000000003336.
    1. Halloran PF, Famulski KS, Reeve J. Molecular assessment of disease states in kidney transplant biopsy samples. Nat Rev Nephrol. 2016;12(9):534. doi: 10.1038/nrneph.2016.85.
    1. Reeve J, Böhmig GA, Eskandary F, Einecke G, Lefaucheur C, Loupy A, Halloran PF, group MM-Ks Assessing rejection-related disease in kidney transplant biopsies based on archetypal analysis of molecular phenotypes. JCI Insight. 2017;2(12):e94197. doi: 10.1172/jci.insight.94197.
    1. Schwaiger E, Wahrmann M, Bond G, Eskandary F, Böhmig GA. Complement component C3 activation: the leading cause of the prozone phenomenon affecting HLA antibody detection on single-antigen beads. Transplantation. 2014;97(12):1279. doi: 10.1097/01.TP.0000441091.47464.c6.
    1. Mühlbacher J, Doberer K, Kozakowski N, Regele H, Camovic S, Haindl S, Bond G, Haslacher H, Eskandary F, Reeve J, et al. Non-invasive chemokine detection: improved prediction of antibody-mediated rejection in donor-specific antibody-positive renal allograft recipients. Front Med (Lausanne). 2020;7:114. doi: 10.3389/fmed.2020.00114.
    1. Streitz M, Miloud T, Kapinsky M, Reed MR, Magari R, Geissler EK, Hutchinson JA, Vogt K, Schlickeiser S, Kverneland AH, et al. Standardization of whole blood immune phenotype monitoring for clinical trials: panels and methods from the ONE study. Transplant Res. 2013;2(1):17. doi: 10.1186/2047-1440-2-17.
    1. Doberer K, Schiemann M, Strassl R, Haupenthal F, Dermuth F, Gorzer I, Eskandary F, Reindl-Schwaighofer R, Kikic Z, Puchhammer-Stockl E, et al. Torque teno virus for risk stratification of graft rejection and infection in kidney transplant recipients-a prospective observational trial. Am J Transplant. 2020;20(8):2081. doi: 10.1111/ajt.15810.
    1. Massat M, Congy-Jolivet N, Hebral AL, Esposito L, Marion O, Delas A, Colombat M, Faguer S, Kamar N, Del Bello A, et al. Do anti-IL-6R blockers have a beneficial effect in the treatment of antibody-mediated rejection resistant to standard therapy after kidney transplantation? Am J Transplant. 2021;21(4):1641. doi: 10.1111/ajt.16391.
    1. Joher N, Matignon M, Grimbert P. HLA Desensitization in solid organ transplantation: anti-CD38 to across the immunological barriers. Front Immunol. 2021;12:688301. doi: 10.3389/fimmu.2021.688301.
    1. Spica D, Junker T, Dickenmann M, Schaub S, Steiger J, Rüfli T, Halter J, Hopfer H, Holbro A, Hirt-Minkowski P. Daratumumab for treatment of antibody-mediated rejection after ABO-incompatible kidney transplantation. Case Rep Nephrol Dial. 2019;9(3):149. doi: 10.1159/000503951.
    1. Aguilera Agudo C, Gomez Bueno M, Krsnik Castello I. Daratumumab for antibody-mediated rejection in heart transplant-a novel therapy: successful treatment of antibody-mediated rejection. Transplantation. 2021;105(3):e30. doi: 10.1097/TP.0000000000003505.
    1. Mateos MV, Dimopoulos MA, Cavo M, Suzuki K, Jakubowiak A, Knop S, Doyen C, Lucio P, Nagy Z, Kaplan P, et al. Daratumumab plus bortezomib, melphalan, and prednisone for untreated myeloma. N Engl J Med. 2018;378(6):518. doi: 10.1056/NEJMoa1714678.
    1. Moreau P, Attal M, Hulin C, Arnulf B, Belhadj K, Benboubker L, Bene MC, Broijl A, Caillon H, Caillot D, et al. Bortezomib, thalidomide, and dexamethasone with or without daratumumab before and after autologous stem-cell transplantation for newly diagnosed multiple myeloma (CASSIOPEIA): a randomised, open-label, phase 3 study. Lancet. 2019;394(10192):29. doi: 10.1016/S0140-6736(19)31240-1.
    1. Gokhale A, Chancay J, Shapiro R, Randhawa P, Menon MC. Chronic transplant glomerulopathy: new insights into pathogenesis. Clin Transplant. 2021;35(3):e14214. doi: 10.1111/ctr.14214.
    1. Wiebe C, Nevins TE, Robiner WN, Thomas W, Matas AJ, Nickerson PW. The synergistic effect of class II HLA epitope-mismatch and nonadherence on acute rejection and graft survival. Am J Transplant. 2015;15(8):2197. doi: 10.1111/ajt.13341.
    1. Wiebe C, Rush DN, Nevins TE, Birk PE, Blydt-Hansen T, Gibson IW, Goldberg A, Ho J, Karpinski M, Pochinco D, et al. Class II eplet mismatch modulates tacrolimus trough levels required to prevent donor-specific antibody development. J Am Soc Nephrol. 2017;28(11):3353. doi: 10.1681/ASN.2017030287.

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