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      CD38-targeted therapy with daratumumab reduces autoantibody levels in multiple myeloma patients

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          Abstract

          Autoantibody-producing plasma cells are frequently resistant to conventional immunosuppressive treatments and B-cell depletion therapy. As a result of this resistance, autoreactive plasma cells survive conventional therapy, resulting in persistent autoantibody production and inflammation. CD38 is highly and uniformly expressed on normal and malignant plasma cells. Daratumumab is the first in class CD38-targeting monoclonal antibody approved for the treatment of multiple myeloma (MM). To evaluate the potential activity of daratumumab in antibody-mediated autoimmune disorders by targeting autoantibody-producing plasma cells, we evaluated serum levels of autoantibodies in MM patients during daratumumab treatment. We found that 6 out of 41 (15%) had detectable autoantibodies before initiation of daratumumab therapy, and that these autoantibodies rapidly disappeared in 5 out of 6 patients during daratumumab treatment. Our data provide support for the evaluation of daratumumab in patients with autoantibody-dependent autoimmune disorders.

          Highlights

          • •

            Autoantibody-producing plasma cells express CD38.

          • •

            The CD38-targeting antibody daratumumab reduces autoantibody levels.

          • •

            Our data provide support for the evaluation of daratumumab in antibody-mediated autoimmune disease.

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          Targeting CD38 with Daratumumab Monotherapy in Multiple Myeloma.

          Henk Lokhorst, Torben Plesner, Jacob Laubach … (2015)
          Multiple myeloma cells uniformly overexpress CD38. We studied daratumumab, a CD38-targeting, human IgG1κ monoclonal antibody, in a phase 1-2 trial involving patients with relapsed myeloma or relapsed myeloma that was refractory to two or more prior lines of therapy.
          Article 0 comments Cited 419 times – based on 0 reviews     Review now
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            Monoclonal antibodies targeting CD38 in hematological malignancies and beyond

            Niels W C J van de Donk, Maarten Janmaat, Tuna Mutis … (2016)
            Summary CD38 is a multifunctional cell surface protein that has receptor as well as enzyme functions. The protein is generally expressed at low levels on various hematological and solid tissues, while plasma cells express particularly high levels of CD38. The protein is also expressed in a subset of hematological tumors, and shows especially broad and high expression levels in plasma cell tumors such as multiple myeloma (MM). Together, this triggered the development of various therapeutic CD38 antibodies, including daratumumab, isatuximab, and MOR202. Daratumumab binds a unique CD38 epitope and showed strong anti‐tumor activity in preclinical models. The antibody engages diverse mechanisms of action, including complement‐dependent cytotoxicity, antibody‐dependent cellular cytotoxicity, antibody‐dependent cellular phagocytosis, programmed cell death, modulation of enzymatic activity, and immunomodulatory activity. CD38‐targeting antibodies have a favorable toxicity profile in patients, and early clinical data show a marked activity in MM, while studies in other hematological malignancies are ongoing. Daratumumab has single agent activity and a limited toxicity profile, allowing favorable combination therapies with existing as well as emerging therapies, which are currently evaluated in the clinic. Finally, CD38 antibodies may have a role in the treatment of diseases beyond hematological malignancies, including solid tumors and antibody‐mediated autoimmune diseases.
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              Plasma cells as an innovative target in autoimmune disease with renal manifestations.

              Falk Hiepe, Andreas Radbruch (2016)
              Autoantibodies are secreted by plasma cells and have an essential role in driving the renal manifestations of autoimmune diseases such as systemic lupus erythematosus and antineutrophil cytoplasmic autoantibody-associated vasculitis. Effective depletion of autoreactive plasma cells might be the key to curative treatment of these diseases. Two major plasma-cell compartments exist: short-lived plasmablasts or plasma cells, which result from differentiation of activated B cells, and long-lived plasma cells, which result from secondary immune responses. Long-lived plasma cells reside in survival niches in bone marrow and inflamed tissue and provide the basis of humoral memory and refractory autoimmune disease activity. Unlike short-lived plasmablasts, long-lived plasma cells do not respond to conventional immunosuppression or to therapies that target B cells. Existing therapies that target long-lived plasma cells, such as proteasome inhibitors and antithymocyte globulin, as well as promising approaches that target survival factors, cell homing or surface molecules, deplete the whole memory plasma cell pool, including cells that secrete protective antibodies. By contrast, we have developed a novel strategy that uses an affinity matrix to deplete pathogenic long-lived plasma cells in an autoantigen-specific manner without removing protective plasma cells. Targeting B-cell precursors to prevent replenishment of autoreactive long-lived plasma cells should also be considered.
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                Author and article information

                Contributors
                Niels W.C.J. van de Donk
                Journal
                Journal ID (nlm-ta): J Transl Autoimmun
                Journal ID (iso-abbrev): J Transl Autoimmun
                Title: Journal of Translational Autoimmunity
                Publisher: Elsevier
                ISSN (Electronic): 2589-9090
                Publication date PMC-release: 11 November 2019
                Publication date Collection: December 2019
                Publication date (Electronic): 11 November 2019
                Volume: 2
                Electronic Location Identifier: 100022
                Affiliations
                [a ]Amsterdam UMC, Vrije Universiteit Amsterdam, Department of Hematology, Cancer Center Amsterdam, Amsterdam, the Netherlands
                [b ]University Medical Center Utrecht, Laboratory of Translational Immunology, Utrecht, the Netherlands
                Author notes
                [∗ ]Corresponding author. Amsterdam UMC, Vrije Universiteit Amsterdam, Cancer Center Amsterdam, Department of Hematology, De Boelelaan 1117, 1081HV, Amsterdam, the Netherlands. n.vandedonk@ 123456amsterdamumc.nl
                Article
                Publisher ID: S2589-9090(19)30022-X Publisher ID: 100022
                DOI: 10.1016/j.jtauto.2019.100022
                PMC ID: 7388400
                PubMed ID: 32743508
                SO-VID: 51002e8e-4889-427a-afc3-efe7440d7c51
                Copyright © © 2019 The Author(s)
                License:

                This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).

                History
                Date received : 29 October 2019
                Date accepted : 4 November 2019
                Categories
                Subject: Research paper

                Keywords: antibody-mediated autoimmune disease,daratumumab,autoreactive,plasma cells,cd38
                Data availability:
                Keywords: antibody-mediated autoimmune disease, daratumumab, autoreactive, plasma cells, cd38

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