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Safety, tolerability, and efficacy of monoclonal CD38 antibody felzartamab in late antibody-mediated renal allograft rejection: study protocol for a phase 2 trial
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...
Autores principales: | , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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BioMed Central
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8990453/ https://www.ncbi.nlm.nih.gov/pubmed/35395951 http://dx.doi.org/10.1186/s13063-022-06198-9 |
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author | Mayer, Katharina A. Budde, Klemens Halloran, Philip F. Doberer, Konstantin Rostaing, Lionel Eskandary, Farsad Christamentl, Anna Wahrmann, Markus Regele, Heinz Schranz, Sabine Ely, Sarah Firbas, Christa Schörgenhofer, Christian Kainz, Alexander Loupy, Alexandre Härtle, Stefan Boxhammer, Rainer Jilma, Bernd Böhmig, Georg A. |
author_facet | Mayer, Katharina A. Budde, Klemens Halloran, Philip F. Doberer, Konstantin Rostaing, Lionel Eskandary, Farsad Christamentl, Anna Wahrmann, Markus Regele, Heinz Schranz, Sabine Ely, Sarah Firbas, Christa Schörgenhofer, Christian Kainz, Alexander Loupy, Alexandre Härtle, Stefan Boxhammer, Rainer Jilma, Bernd Böhmig, Georg A. |
author_sort | Mayer, Katharina A. |
collection | PubMed |
description | 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 SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s13063-022-06198-9. |
format | Online Article Text |
id | pubmed-8990453 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | BioMed Central |
record_format | MEDLINE/PubMed |
spelling | pubmed-89904532022-04-10 Safety, tolerability, and efficacy of monoclonal CD38 antibody felzartamab in late antibody-mediated renal allograft rejection: study protocol for a phase 2 trial Mayer, Katharina A. Budde, Klemens Halloran, Philip F. Doberer, Konstantin Rostaing, Lionel Eskandary, Farsad Christamentl, Anna Wahrmann, Markus Regele, Heinz Schranz, Sabine Ely, Sarah Firbas, Christa Schörgenhofer, Christian Kainz, Alexander Loupy, Alexandre Härtle, Stefan Boxhammer, Rainer Jilma, Bernd Böhmig, Georg A. Trials Study Protocol 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 SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s13063-022-06198-9. BioMed Central 2022-04-08 /pmc/articles/PMC8990453/ /pubmed/35395951 http://dx.doi.org/10.1186/s13063-022-06198-9 Text en © The Author(s) 2022 https://creativecommons.org/licenses/by/4.0/Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/ (https://creativecommons.org/publicdomain/zero/1.0/) ) applies to the data made available in this article, unless otherwise stated in a credit line to the data. |
spellingShingle | Study Protocol Mayer, Katharina A. Budde, Klemens Halloran, Philip F. Doberer, Konstantin Rostaing, Lionel Eskandary, Farsad Christamentl, Anna Wahrmann, Markus Regele, Heinz Schranz, Sabine Ely, Sarah Firbas, Christa Schörgenhofer, Christian Kainz, Alexander Loupy, Alexandre Härtle, Stefan Boxhammer, Rainer Jilma, Bernd Böhmig, Georg A. Safety, tolerability, and efficacy of monoclonal CD38 antibody felzartamab in late antibody-mediated renal allograft rejection: study protocol for a phase 2 trial |
title | Safety, tolerability, and efficacy of monoclonal CD38 antibody felzartamab in late antibody-mediated renal allograft rejection: study protocol for a phase 2 trial |
title_full | Safety, tolerability, and efficacy of monoclonal CD38 antibody felzartamab in late antibody-mediated renal allograft rejection: study protocol for a phase 2 trial |
title_fullStr | Safety, tolerability, and efficacy of monoclonal CD38 antibody felzartamab in late antibody-mediated renal allograft rejection: study protocol for a phase 2 trial |
title_full_unstemmed | Safety, tolerability, and efficacy of monoclonal CD38 antibody felzartamab in late antibody-mediated renal allograft rejection: study protocol for a phase 2 trial |
title_short | Safety, tolerability, and efficacy of monoclonal CD38 antibody felzartamab in late antibody-mediated renal allograft rejection: study protocol for a phase 2 trial |
title_sort | safety, tolerability, and efficacy of monoclonal cd38 antibody felzartamab in late antibody-mediated renal allograft rejection: study protocol for a phase 2 trial |
topic | Study Protocol |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8990453/ https://www.ncbi.nlm.nih.gov/pubmed/35395951 http://dx.doi.org/10.1186/s13063-022-06198-9 |
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