Safety, tolerability, and efficacy of monoclonal CD38 antibody felzartamab in late antibody-mediated renal allograft rejection: study protocol for a phase 2 trial.
Antibody-mediated rejection
CD38
Donor-specific antibody
Felzartamab
Kidney transplantation
Monoclonal antibody
Natural killer cell
Plasma cell
Journal
Trials
ISSN: 1745-6215
Titre abrégé: Trials
Pays: England
ID NLM: 101263253
Informations de publication
Date de publication:
08 Apr 2022
08 Apr 2022
Historique:
received:
25
09
2021
accepted:
25
03
2022
entrez:
9
4
2022
pubmed:
10
4
2022
medline:
13
4
2022
Statut:
epublish
Résumé
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. 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). 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. EU Clinical Trials Register (EudraCT) 2021-000545-40 . Registered on 23 June 2021. gov NCT05021484 . Registered on 25 August 2021.
Sections du résumé
BACKGROUND
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
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
CONCLUSIONS
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
BACKGROUND
EU Clinical Trials Register (EudraCT) 2021-000545-40 . Registered on 23 June 2021.
CLINICALTRIALS
RESULTS
gov NCT05021484 . Registered on 25 August 2021.
Identifiants
pubmed: 35395951
doi: 10.1186/s13063-022-06198-9
pii: 10.1186/s13063-022-06198-9
pmc: PMC8990453
doi:
Substances chimiques
Antibodies, Monoclonal, Humanized
0
Isoantibodies
0
felzartamab
3O9FA4XC02
Banques de données
ClinicalTrials.gov
['NCT05021484']
Types de publication
Clinical Trial Protocol
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
270Subventions
Organisme : MorphoSys AG
ID : n.a.
Informations de copyright
© 2022. The Author(s).
Références
Transplantation. 2021 Mar 1;105(3):e30-e31
pubmed: 33617204
J Immunol. 2011 Feb 1;186(3):1840-8
pubmed: 21187443
Molecules. 2020 Oct 21;25(20):
pubmed: 33096610
Transplant Res. 2013 Oct 25;2(1):17
pubmed: 24160259
Nat Commun. 2019 Nov 25;10(1):5350
pubmed: 31767837
Nat Rev Nephrol. 2016 Sep;12(9):534-48
pubmed: 27345248
Lancet. 2019 Jul 6;394(10192):29-38
pubmed: 31171419
Am J Transplant. 2017 Sep;17(9):2381-2389
pubmed: 28199785
J Am Soc Nephrol. 2021 Mar;32(3):708-722
pubmed: 33443079
Am J Transplant. 2020 Sep;20(9):2318-2331
pubmed: 32463180
Transplantation. 2021 Apr 1;105(4):916-927
pubmed: 32496356
J Am Soc Nephrol. 2017 Nov;28(11):3353-3362
pubmed: 28729289
J Am Soc Nephrol. 2018 Feb;29(2):591-605
pubmed: 29242250
Am J Transplant. 2017 Mar;17(3):682-691
pubmed: 27501352
N Engl J Med. 2018 Feb 8;378(6):518-528
pubmed: 29231133
Am J Transplant. 2012 Feb;12(2):388-99
pubmed: 22081892
MAbs. 2015;7(2):311-21
pubmed: 25760767
Curr Opin Organ Transplant. 2021 Feb 1;26(1):97-105
pubmed: 33315763
Front Med (Lausanne). 2020 Apr 09;7:114
pubmed: 32328494
Clin Transplant. 2021 Mar;35(3):e14214
pubmed: 33389755
Transplantation. 2021 Mar 1;105(3):648-659
pubmed: 33617203
Am J Transplant. 2020 Aug;20(8):2081-2090
pubmed: 32034850
J Am Soc Nephrol. 2021 Aug;32(8):2070-2082
pubmed: 34301794
J Am Soc Nephrol. 2021 Jun 1;32(6):1513-1526
pubmed: 33883251
Blood. 2018 Jan 4;131(1):13-29
pubmed: 29118010
Am J Transplant. 2018 Apr;18(4):927-935
pubmed: 28949089
Lancet Haematol. 2020 May;7(5):e381-e394
pubmed: 32171061
Am J Transplant. 2015 Aug;15(8):2197-202
pubmed: 26095765
N Engl J Med. 2018 Sep 20;379(12):1150-1160
pubmed: 30231232
Am J Transplant. 2021 Apr;21(4):1641-1649
pubmed: 33141487
Transplantation. 2014 Jun 27;97(12):1279-85
pubmed: 24621535
Front Immunol. 2021 May 20;12:688301
pubmed: 34093594
Ther Drug Monit. 2021 Apr 1;43(2):150-200
pubmed: 33711005
Transplantation. 2021 Feb 1;105(2):451-457
pubmed: 32235256
Am J Transplant. 2015 May;15(5):1336-48
pubmed: 25787894
BMJ. 2019 Sep 17;366:l4923
pubmed: 31530561
Transplantation. 2017 Apr;101(4):e102-e111
pubmed: 27906829
JCI Insight. 2017 Jun 15;2(12):
pubmed: 28614805
J Immunol. 2016 Aug 1;197(3):807-13
pubmed: 27316683
Case Rep Nephrol Dial. 2019 Nov 13;9(3):149-157
pubmed: 31828078
J Am Soc Nephrol. 2019 Jul;30(7):1206-1219
pubmed: 31227636
Transpl Int. 2019 Aug;32(8):775-788
pubmed: 30955215
Transplantation. 2020 May;104(5):911-922
pubmed: 31895348