Articles de revues : « Anti-CD20 monoclonal antibodie »

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&NA;. « Anti-CD20 monoclonal antibody/thalidomide ». Reactions Weekly &NA;, n^o 855 (juin 2001) : 7. http://dx.doi.org/10.2165/00128415-200108550-00016.

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Beers, Stephen A., Ruth R. French, H. T. Claude Chan, Sean H. Lim, Timothy C. Jarrett, Regina Mora Vidal, Sahan S. Wijayaweera et al. « Antigenic modulation limits the efficacy of anti-CD20 antibodies : implications for antibody selection ». Blood 115, n^o 25 (24 juin 2010) : 5191–201. http://dx.doi.org/10.1182/blood-2010-01-263533.

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Abstract Rituximab, a monoclonal antibody that targets CD20 on B cells, is now central to the treatment of a variety of malignant and autoimmune disorders. Despite this success, a substantial proportion of B-cell lymphomas are unresponsive or develop resistance, hence more potent anti-CD20 monoclonal antibodies (mAbs) are continuously being sought. Here we demonstrate that type II (tositumomab-like) anti-CD20 mAbs are 5 times more potent than type I (rituximab-like) reagents in depleting human CD20 Tg B cells, despite both operating exclusively via activatory Fcγ receptor–expressing macrophages. Much of this disparity in performance is attributable to type I mAb-mediated internalization of CD20 by B cells, leading to reduced macrophage recruitment and the degradation of CD20/mAb complexes, shortening mAb half-life. Importantly, human B cells from healthy donors and most cases of chronic lymphatic leukemia and mantle cell lymphoma, showed rapid CD20 internalization that paralleled that seen in the Tg mouse B cells, whereas most follicular lymphoma and diffuse large B-cell lymphoma cells were far more resistant to CD20 loss. We postulate that differences in CD20 modulation may play a central role in determining the relative efficacy of rituximab in treating these diseases and strengthen the case for focusing on type II anti-CD20 mAb in the clinic.

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van Oers, Marinus H. J. « CD20 antibodies : type II to tango ? » Blood 119, n^o 22 (31 mai 2012) : 5061–63. http://dx.doi.org/10.1182/blood-2012-04-420711.

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Although the chimeric anti-CD20 monoclonal antibody (mAb) rituximab has revolutionized the treatment of B-cell non-Hodgkin lymphoma (NHL), still many patients relapse and an increasing number become refractory to rituximab-containing therapy. This has initiated intense research to develop more potent anti-CD20 antibodies.

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Uchida, Junji, Yasuhito Hamaguchi, Julie A. Oliver, Jeffrey V. Ravetch, Jonathan C. Poe, Karen M. Haas et Thomas F. Tedder. « The Innate Mononuclear Phagocyte Network Depletes B Lymphocytes through Fc Receptor–dependent Mechanisms during Anti-CD20 Antibody Immunotherapy ». Journal of Experimental Medicine 199, n^o 12 (21 juin 2004) : 1659–69. http://dx.doi.org/10.1084/jem.20040119.

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Anti-CD20 antibody immunotherapy effectively treats non-Hodgkin's lymphoma and autoimmune disease. However, the cellular and molecular pathways for B cell depletion remain undefined because human mechanistic studies are limited. Proposed mechanisms include antibody-, effector cell–, and complement-dependent cytotoxicity, the disruption of CD20 signaling pathways, and the induction of apoptosis. To identify the mechanisms for B cell depletion in vivo, a new mouse model for anti-CD20 immunotherapy was developed using a panel of twelve mouse anti–mouse CD20 monoclonal antibodies representing all four immunoglobulin G isotypes. Anti-CD20 antibodies rapidly depleted the vast majority of circulating and tissue B cells in an isotype-restricted manner that was completely dependent on effector cell Fc receptor expression. B cell depletion used both FcγRI- and FcγRIII-dependent pathways, whereas B cells were not eliminated in FcR common γ chain–deficient mice. Monocytes were the dominant effector cells for B cell depletion, with no demonstrable role for T or natural killer cells. Although most anti-CD20 antibodies activated complement in vitro, B cell depletion was completely effective in mice with genetic deficiencies in C3, C4, or C1q complement components. That the innate monocyte network depletes B cells through FcγR-dependent pathways during anti-CD20 immunotherapy has important clinical implications for anti-CD20 and other antibody-based therapies.

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Pejcic, Ivica, et Svetislav Vrbic. « Application of anti-CD20 monoclonal antibodies in the treatment of lymphoproliferative diseases ». Archive of Oncology 17, n^o 3-4 (2009) : 65–67. http://dx.doi.org/10.2298/aoo0904065p.

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Out of numerous studied monoclonal antibodies, only a few reached the stage of clinical application. The CD20 molecule, non-glycolysed phospholipoprotein (usually termed B1), belonging to the tetraspan (TM4SF) family, 35-37 kD, is characteristic for all mature B lymphocytes, including CLL cells. The CD20 receptors, characteristic for 'B' lymphoproliferative diseases, have been demonstrated to be a good target for therapeutic effects to be achieved. Rituximab is a chimeric anti-CD20 IgG1 monoclonal antibody, with the sequences of the human constant region and sequences of the murine variable region. It is specifically bound to the B-lymphocyte CD20 antigen. The mechanism of all rituximab antitumor activity has not been established, but ADCC and CDC are believed to be the principal, with possible complementary effects. Therapeutic use of anti-CD20 monoclonal antibodies has demonstrated a significant benefit in the patients with 'B' CD20 positive lymphoproliferative diseases. Rituximab is today a golden standard for the comparation with other treatment modalities, increasingly in combination with chemotherapy.

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Casan, J. M. L., J. Wong, M. J. Northcott et S. Opat. « Anti-CD20 monoclonal antibodies : reviewing a revolution ». Human Vaccines & ; Immunotherapeutics 14, n^o 12 (6 septembre 2018) : 2820–41. http://dx.doi.org/10.1080/21645515.2018.1508624.

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Moreno Torres, Irene, et Antonio García-Merino. « Anti-CD20 monoclonal antibodies in multiple sclerosis ». Expert Review of Neurotherapeutics 17, n^o 4 (21 octobre 2016) : 359–71. http://dx.doi.org/10.1080/14737175.2017.1245616.

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Taylor, Ronald P., et Margaret A. Lindorfer. « Immunotherapeutic mechanisms of anti-CD20 monoclonal antibodies ». Current Opinion in Immunology 20, n^o 4 (août 2008) : 444–49. http://dx.doi.org/10.1016/j.coi.2008.05.011.

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Avivi, Irit, Dina Stroopinsky et Tamar Katz. « Anti-CD20 monoclonal antibodies : Beyond B-cells ». Blood Reviews 27, n^o 5 (septembre 2013) : 217–23. http://dx.doi.org/10.1016/j.blre.2013.07.002.

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Habermann, Thomas M. « Antibody Therapy in Aggressive Lymphomas ». Hematology 2007, n^o 1 (1 janvier 2007) : 257–64. http://dx.doi.org/10.1182/asheducation-2007.1.257.

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AbstractThe aggressive lymphomas are potentially curable. The natural history of certain aggressive lymphomas has been altered by monoclonal antibody therapy. Targeted monoclonal antibody therapy to the CD20 antigen has altered the outcome of patients with diffuse large B-cell lymphoma in patients of all ages. Anti-CD20–based radioimmunoconjugates are being evaluated as radioimmunotherapy approaches in patients who have relapsed and in stem cell transplant settings. Antibody-directed therapy to the B-cell–specific antigen CD22 are ongoing. New approaches include different CD20 antibodies and an antibody to the CD40 antigen, which is a member of the tumor necrosis factor (TNF) receptor family, which is expressed on B-cells. Antibody therapy has been incorporated into CHOP (cyclophosphamide, adriamycin, vincristine, prednisone) therapy and other regimens such as EPOCH (etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin) and HyperCVAD (cyclophosphamide, vincristine, adriamycin, dexamethasone). Single-agent anti-CD20 therapy is active in the post-transplantation lymphoproliferative disorders. T-cell antibodies are under evaluation in a number of T-cell lymphoproliferative disorders. Targeted therapy has changed the natural history of a number of aggressive non-Hodgkin lymphomas. This review will describe the contributions of antibody therapies to the treatment of these diseases.

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Florou, Despoina, Maria Katsara, Jack Feehan, Efthimios Dardiotis et Vasso Apostolopoulos. « Anti-CD20 Agents for Multiple Sclerosis : Spotlight on Ocrelizumab and Ofatumumab ». Brain Sciences 10, n^o 10 (20 octobre 2020) : 758. http://dx.doi.org/10.3390/brainsci10100758.

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Until recently, in the pathogenesis of Multiple Sclerosis (MS), the contribution of B cells has been largely underestimated, and the disease was considered a T-cell-mediated disorder. However, newer evidence shows that B cells play a crucial role in the pathogenesis of MS via antigen-driven autoantibody responses and through the cross regulation of T-helper cells. As B cells express the surface molecule CD20 at all points of differentiation, it provides a specific target for monoclonal antibodies, and the development and clinical testing of anti-CD20 antibody treatments for MS have been successful. After some observations, some small clinical trials found positive effects for the first anti-CD20 therapeutic rituximab in MS; newer agents have been specifically evaluated, resulting in the development of ocrelizumab and ofatumumab. Ocrelizumab, a humanized anti-CD20 monoclonal antibody, was approved in March 2017 by the Food and Drug Administration (FDA) and is also the first proven therapy to reduce disability progression in primary progressive MS. This is particularly significant considering that disease-modifying treatment options are few for both primary and secondary progressive MS. Ofatumumab, a fully human anti-CD20 monoclonal antibody, that binds a distinct epitope, has been further investigated in phase 3 trials for relapsing forms of MS. In this review, we discuss in detail these two anti-CD20 agents and their advent for treatment of MS.

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Lin, WeiYu, Qian Gong, Dhaya Seshasayee, Zhoughua Lin, Qinglin Ou, Shiming Ye, Eric Suto et al. « Anti-BR3 antibodies – a new class of B cell immunotherapies combining cellular depletion and survival blockade (131.25) ». Journal of Immunology 178, n^o 1_Supplement (1 avril 2007) : S242. http://dx.doi.org/10.4049/jimmunol.178.supp.131.25.

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Abstract Pathogenic B lymphocytes removal through therapy with depleting monoclonal antibodies results in clinical benefit in both oncology and immunological indications. Incomplete rates of clinical response and the realization that B cell depletion following immunotherapy is incomplete fuels the need for better therapies. BAFF/BLyS signaling through its BAFFR/BR3 receptor have a critical role on B cell proliferation and survival in the mouse and to some extent in non-human primates and humans. In order to combine B cell depletion with the blockade of BAFF mediated B cell survival, we generated depleting, BAFF-blocking, non-agonistic anti-BR3 monoclonal antibodies. The results from this study indicate that in mice anti-BR3 monoclonal antibody reduces B cells to a higher degree when compared to anti-CD20 or BAFF-blockade through BR3-Fc. Anti-BR3 depletes B cells with a slower kinetics than anti-CD20 but showed high B cell depletion and a decrease in bone marrow plasma cells which was not seen with anti-CD20. Anti-BR3 treatment of NZB/W lupus mouse model results in significant survival benefit and reduction of established nephritic clinical symptoms indicating potential therapeutically value for human disease. In conclusion, in vivo comparison in mice of anti-BR3 antibodies with other B cell immunotherapies (anti-CD20 and BR3-Fc) shows characteristics in B cell subset reduction that can guide translation to treatment of human disease. This work was supported by Genentech Inc.

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Leonard, John P. « Targeting CD20 in Follicular NHL : Novel Anti-CD20 Therapies, Antibody Engineering, and the Use of Radioimmunoconjugates ». Hematology 2005, n^o 1 (1 janvier 2005) : 335–39. http://dx.doi.org/10.1182/asheducation-2005.1.335.

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Abstract Rituximab (chimeric anti-CD20 monoclonal antibody) is widely employed in the treatment of patients with B cell non-Hodgkin lymphoma (NHL). This agent has activity in both indolent and aggressive disease, alone and in combination with chemotherapy. Unfortunately, however, many patients develop resistant disease. Ongoing efforts to improve outcomes include changes in dose and schedule, as well as the use of other biologic agents or antibodies that may enhance activity when administered together with rituximab. A relatively new focus is the development of engineered anti-CD20 antibodies that are optimized for their capability to mediate antibody-mediated cellular cytotoxicity (ADCC) or complement-dependent cytotoxicity (CDC). Human or humanized structures have also been employed to potentially improve these attributes, as well as to improve on pharmacokinetics and immunogenicity. Other studies in NHL have clearly demonstrated that radiolabeled anti-CD20 antibodies (such as I-131 tositumomab and Y-90 ibritumomab tiuxetan) may be useful in relapsed and refractory disease, and have potential utility as part of initial treatment as well. Further studies of these modified anti-CD20 antibodies are ongoing in order to optimize their use for maximal clinical benefit.

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Österborg, Anders. « Ofatumumab, a human anti-CD20 monoclonal antibody ». Expert Opinion on Biological Therapy 10, n^o 3 (29 janvier 2010) : 439–49. http://dx.doi.org/10.1517/14712590903586239.

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Smida, Michal, Veronika Kozlova, Viera Vakulova, Aneta Ledererova, Michael Doubek, Jiri Mayer et Sarka Pospisilova. « Cellular Mechanisms Regulating CD20 As a Target of Monoclonal Antibody Therapy in B-Lymphoid Malignancies ». Blood 128, n^o 22 (2 décembre 2016) : 3968. http://dx.doi.org/10.1182/blood.v128.22.3968.3968.

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Abstract Standard treatment of B-lymphoid malignancies nowadays still relies on the administration of monoclonal antibodies (mAbs), with CD20 antigen being the prime target. Although initially effective, repeated cycles of anti-CD20 monoclonal antibody therapy often result in the loss of CD20 on the surface of malignant B cells and consequently in therapy resistance. In spite of the widespread use of CD20 monoclonal antibodies, the exact mechanisms regulating CD20 expression stay largely unrevealed and it mainly remains unclear whether they can be exploited pharmacologically to modulate expression of CD20 in the clinic. Interestingly, application of CD20 mAbs on various B-cell lines in vitro triggers active CD20 signaling within the cells. This signal transmission results in rapid CD20 downregulation at the surface accompanied by dramatically reduced CD20 transcription. Contrary to the prompt initial downmodulation of CD20 transcription, it takes several days upon mAb removal until CD20 transcriptional gene activity and thereafter CD20 surface levels are restored back to normal. To further study cellular mechanisms responsible for regulating CD20 expression, we have mimicked the situation in patients in an in vitro setting by repeated chronic treatments of diverse B-cell lines with gradually increasing doses of clinically used anti-CD20 monoclonal antibodies Rituximab, Ofatumumab and Obinutuzumab. Thereby, we managed to generate permanently resistant lines that no more respond to additional administration of any of the anti-CD20 mAbs. Notably, these cells have permanently strongly downregulated CD20 expression, both on the cell surface as well as already on the level of mRNA gene transcription. In addition, we have utilized the state-of-the-art CRISPR/Cas9 system to fully knock out CD20 gene in B-cell lymphoma (Ramos) and CLL (MEC1) cell lines. As expected, these cells are totally resistant to CD20 monoclonal antibodies. CD20 was originally proposed to function as a calcium channel and to contribute to B-cell receptor signaling, however the exact function of CD20 remains largely elusive yet. Using both experimental systems, we demonstrate that B cells with the loss of CD20 have fairly normal B-cell receptor signaling with no signs of any large defect. Specifically, activation of major signaling proteins like SYK, AKT, ERK, PLCgamma or p38 upon BCR stimulation was equal in CD20 depleted cells when compared to normal cells. Also calcium flux in response to BCR triggering seems to be normal in CD20-deficient cells, thus suggesting that CD20 is dispensable for proper B-cell receptor signaling. Next, we have performed RNA sequencing on these cells in order to better understand intracellular changes on a more global level that are imposed by the deletion or chronic downmodulation of CD20. We have compared the expression of individual genes and gene sets in cells upon CD20 removal and have performed the differential gene set enrichment analysis that will be presented. In summary, analysis of mechanisms regulating CD20 expression and/or function is critically needed for identification of potential novel drug targets that might be applied in the clinic to control CD20 persistence and thereby improve the outcome of anti-CD20 monoclonal antibody therapy. This research has been financially supported by the Ministry of Education, Youth and Sports of the Czech Republic under the project CEITEC 2020 (LQ1601) and by the research grant AZV-MZ-CR 15-33561AA-4/2015 and grant MUNI/A/1028/2015. Disclosures No relevant conflicts of interest to declare.

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GÖNCÜOĞLU, Cansu, Kübra Nur ÖKSÜZOĞLU et Aygin BAYRAKTAR EKİNCİOĞLU. « Infusion-Related Reactions with Anti-CD20 Monoclonal Antibody Treatments in Multiple Sclerosis : Traditional Review ». Journal of Literature Pharmacy Sciences 11, n^o 3 (2022) : 231–40. http://dx.doi.org/10.5336/pharmsci.2022-92927.

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Lim, S. H., S. A. Beers, R. R. French, P. W. M. Johnson, M. J. Glennie et M. S. Cragg. « Anti-CD20 monoclonal antibodies : historical and future perspectives ». Haematologica 95, n^o 1 (22 septembre 2009) : 135–43. http://dx.doi.org/10.3324/haematol.2008.001628.

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Glennie, Martin J., Ruth R. French, Mark S. Cragg et Ronald P. Taylor. « Mechanisms of killing by anti-CD20 monoclonal antibodies ». Molecular Immunology 44, n^o 16 (septembre 2007) : 3823–37. http://dx.doi.org/10.1016/j.molimm.2007.06.151.

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Jain, Preetesh, et Susan O'Brien. « Anti-CD20 monoclonal antibodies in chronic lymphocytic leukemia ». Expert Opinion on Biological Therapy 13, n^o 2 (21 décembre 2012) : 169–82. http://dx.doi.org/10.1517/14712598.2012.735655.

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Tacke, Sabine, Rittika Chunder, Verena Schropp, Eduard Urich et Stefanie Kuerten. « Effects of a Fully Humanized Type II Anti-CD20 Monoclonal Antibody on Peripheral and CNS B Cells in a Transgenic Mouse Model of Multiple Sclerosis ». International Journal of Molecular Sciences 23, n^o 6 (15 mars 2022) : 3172. http://dx.doi.org/10.3390/ijms23063172.

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Successful therapy with anti-CD20 monoclonal antibodies (mAbs) has reinforced the key role of B cells in the immunopathology of multiple sclerosis (MS). This study aimed to determine the effects of a novel class of anti-CD20 mAbs on vascular and extravascular central nervous system (CNS)-infiltrating B cells in experimental autoimmune encephalomyelitis (EAE), an animal model of MS. Male hCD20xhIgR3 mice and wild-type C57BL/6 (B6) mice were immunized with human myelin oligodendrocyte glycoprotein (MOG)1–125 to induce EAE. While hCD20xhIgR3 mice were injected intravenously with an anti-human CD20 mAb (5 mg/kg) (rituximab (a type I anti-CD20 mAb) or obinutuzumab (a type II anti-CD20 mAb), B6 mice received the anti-mouse CD20 antibody 18B12. Neither mAb affected clinical disease or serum antibody levels. Obinutuzumab and rituximab had an impact on splenic and CNS-infiltrated B cells with slightly differential depletion efficacy. Additionally, obinutuzumab had beneficial effects on spinal cord myelination. B cell depletion rates in the 18B12/B6 model were comparable with those observed in obinutuzumab-treated hCD20xhIgR3 mice. Our results demonstrate the usefulness of anti-CD20 mAbs for the modulation of B cell-driven peripheral immune response and CNS pathology, with type II antibodies potentially being superior to type I in the depletion of tissue-infiltrating B cells.

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Sharman, Jeff P. « Targeting CD20 : teaching an old dog new tricks ». Hematology 2019, n^o 1 (6 décembre 2019) : 273–78. http://dx.doi.org/10.1182/hematology.2019000031.

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Abstract Rituximab was the first monoclonal antibody used for the treatment of a malignancy. In the 22 years since initial approval, it has become a vital component of therapy for a multitude of B-cell malignancies. Within the last several years, however, there has been a robust development of novel agents targeting CD20, including second generation anti-CD20 antibodies, biosimilar antibodies, and subcutaneous formulations that have been approved. The era of passive immunotherapy is now yielding to therapeutic approaches that actively engage the immune system. Emerging approaches leverage immunomodulatory drugs or novel checkpoint inhibitors to enhance CD20 therapy. Recent data sets on bispecific CD3/CD20 antibodies demonstrate exciting early findings, and CD20-directed chimeric antigen receptor T-cell therapies are now entering clinical trials. Anti-CD20 therapies are a vital component of the treatment of B-cell malignancies, and there is a dynamic therapeutic environment with multiple new data sets reviewed here.

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Alduaij, Waleed, et Tim M. Illidge. « The future of anti-CD20 monoclonal antibodies : are we making progress ? » Blood 117, n^o 11 (17 mars 2011) : 2993–3001. http://dx.doi.org/10.1182/blood-2010-07-298356.

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AbstractThe anti-CD20 monoclonal antibody (mAb) rituximab has revolutionized the treatment of B-cell malignancies. This unprecedented success has not only substantially changed the mindset of the clinical community about the ability of mAb to improve outcomes but has catalyzed the interest in the pharmaceutical industry to develop the next generation of anti-CD20 mAbs. Since the introduction of rituximab 15 years ago, we have learned much about the potential mechanisms underlying the therapeutic efficacy of anti-CD20 mAbs. In parallel, many novel anti-CD20 mAbs have entered the clinic, each designed with modifications to structure aimed at further improving efficacy. On review of the newer generation of anti-CD20 mAbs entering clinical trials, it appears that the link between the novel mechanistic insights and the development of these next-generation anti-CD20 mAbs is unclear. As we move into an era of personalized medicine, it will become increasingly important for us to develop closer links between the emerging mechanistic insights and the clinical development, to further enhance the potency of anti-CD20 mAbs beyond that achieved with rituximab.

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Stein, Rhona, Pankaj Gupta, Xiaochuan Chen, Thomas M. Cardillo, Richard R. Furman, Susan Chen, Chien-Hsing Chang et David M. Goldenberg. « Therapy of B-cell malignancies by anti–HLA-DR humanized monoclonal antibody, IMMU-114, is mediated through hyperactivation of ERK and JNK MAP kinase signaling pathways ». Blood 115, n^o 25 (24 juin 2010) : 5180–90. http://dx.doi.org/10.1182/blood-2009-06-228288.

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Abstract A humanized IgG4 anti–HLA-DR monoclonal antibody (IMMU-114), engineered to avoid side effects associated with complement activation, was examined for binding and cytotoxicity on leukemia, lymphoma, and multiple myeloma cell lines and chronic lymphocytic leukemia (CLL) patient specimens, followed by evaluation of the effects of IMMU-114 on extracellular signal-regulated kinase (ERK) and c-Jun N-terminal kinase (JNK) signaling pathways. HLA-DR was expressed on the majority of these cells at markedly higher levels than CD20, CD22, and CD74. IMMU-114 was toxic to mantle cell lymphoma, CLL, acute lymphoblastic leukemia, hairy cell leukemia, non-Hodgkin lymphoma (including rituximab-resistant), and multiple myeloma cell lines, and also patient CLL cells. IMMU-114 induced disease-free survival in tumor-bearing SCID mice with early-stage disease and in models that are relatively resistant to anti-CD20 monoclonal antibodies. Despite positive staining, acute myelogenous leukemic cells were not killed by IMMU-114. The ability of IMMU-114 to induce activation of ERK and JNK signaling correlated with cytotoxicity and differentiates the mechanism of action of IMMU-114 from monoclonal antibodies against CD20 and CD74. Thus, antigen expression is not sufficient for cytotoxicity; antibody-induced hyperactivation of ERK and JNK mitogen activated protein kinase signaling pathways are also required.

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Kadavakolan, Subhashini, Sonam Puri, Sandeep Sahay et Jitesh Joshi. « An update on newer monoclonal antibodies in lymphoma therapy ». Asian Journal of Oncology 02, n^o 01 (janvier 2016) : 003–7. http://dx.doi.org/10.4103/2454-6798.180581.

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AbstractIn 2014, an estimated 9.4% of all new cancers in the US were accounted to hematological cancers. Most of these cancers have a B-cell origin and on the cell surface express antigen CD20-known to restrict B-cells. Considering the intrinsic immune status of the patients receiving chemotherapy, monoclonal antibodies (mAbs) are designed to provide active or passive immunotherapy. Clinical success of rituximab-anti-CD20 mAb in the treatment of lymphoma has led to the development of newer generations of mAb to increase the anti-tumor activity. Hence, recent advances in lymphoma therapy are being built on the conventional prototype of anti-CD20 mAb-rituximab. Our review is an update on the advances in lymphoma therapy using mAb against CD20 including the second generation-ofatumumab, veltuzumab, ocrelizumab, and the third-generation mAbs-ocaratuzumab and obinutuzumab.

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Kapoor, Prashant, Patricia T. Greipp, William G. Morice, S. Vincent Rajkumar, Thomas E. Witzig et Philip R. Greipp. « Anti-CD20 monoclonal antibody therapy in multiple myeloma ». British Journal of Haematology 141, n^o 2 (avril 2008) : 135–48. http://dx.doi.org/10.1111/j.1365-2141.2008.07024.x.

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Friedberg, Jonathan W. « Flashback Foreword : Chimeric Anti-CD20 Monoclonal Antibody Therapy ». Journal of Clinical Oncology 41, n^o 2 (10 janvier 2023) : 151–52. http://dx.doi.org/10.1200/jco.22.02425.

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Sherman, Alexandra, Barry J. Byrne, David M. Markusic, Haiyan Jiang, Moanaro Biswas, Geoffrey L. Rogers et Roland W. Herzog. « Combination therapy for inhibitor reversal in haemophilia A using monoclonal anti-CD20 and rapamycin ». Thrombosis and Haemostasis 117, n^o 01 (2017) : 33–43. http://dx.doi.org/10.1160/th16-05-0404.

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SummaryDevelopment of antibodies (inhibitors) against coagulation factor VIII (FVIII) is a major complication of intravenous replacement therapy in haemophilia A (HA). Current immune tolerance induction (ITI) regimens are not universally effective. Rituximab, a B cell-depleting antibody against CD20, has shown mixed results for inhibitor reversal in patients. This study aims to develop a combinatorial therapy for inhibitor reversal in HA, using anti-murine CD20 (anti-mCD20) antibody and rapamycin, which targets both B and T cell responses. Additionally, it extensively characterises the role of the IgG backbone in B cell depletion by anti-CD20 antibodies. For this, inhibitors were generated in BALB/c-HA mice by weekly IV injection of FVIII. Subsequently, anti-mCD20 (18B12) with IgG2a or IgG1 backbone was injected IV in two doses three weeks apart and B cell depletion and recovery was characterised. Rapamycin was administered orally 3x/week (for 1 month) while continuing FVIII injections. Altering the IgG backbone of anti-mCD20 from IgG2a to IgG1 reduced overall depletion of B cells (including memory B cells), and marginal zone, B-10, and B-1b cells were specifically unaffected. While neither antibody was effective alone, in combination with rapamycin, anti-mCD20 IgG2a but not IgG1 was able to reverse inhibitors in HA mice. This regimen was particularly effective for starting titres of ∼10 BU. Although IgG1 anti-mCD20 spared potentially tolerogenic B cell subsets, IgG2a directed sustained hyporesponsiveness when administered in conjunction with rapamycin. This regimen represents a promising treatment for inhibitor reversal in HA, as both of these compounds have been extensively used in human patients.Supplementary Material to this article is available at www.thrombosis-online.com.

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Shan, Daming, Jeffrey A. Ledbetter et Oliver W. Press. « Apoptosis of Malignant Human B Cells by Ligation of CD20 With Monoclonal Antibodies ». Blood 91, n^o 5 (1 mars 1998) : 1644–52. http://dx.doi.org/10.1182/blood.v91.5.1644.

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Abstract CD20 is a nonglycosylated 33 to 37 kD phosphoprotein involved in B-cell signaling that subserves important functions in the regulation of B-cell proliferation and differentiation. In addition, this B-cell surface antigen has been shown recently to be an effective target for immunotherapy of B-cell malignancies using chimeric (mouse/human) or radiolabeled murine monoclonal anti-CD20 antibodies. In this report we show that extensive crosslinking of CD20 with murine anti-CD20 monoclonal antibodies (MoAbs) in the presence of either goat anti-mouse IgG or Fc receptor (FcR)-expressing cells directly inhibits B-cell proliferation, induces nuclear DNA fragmentation, and leads to cell death by apoptosis. The apoptotic effects of these MoAbs can be inhibited by chelation of extracellular or intracellular Ca2+ by EGTA or Bapta AM, indicating that anti-CD20–mediated apoptosis may be related to changes in Ca2+ concentration. These findings suggest that ligation of CD20 in vivo by anti-CD20 antibodies in the presence of FcR-expressing cells may initiate signal transduction events that induce elevation of [Ca2+]i and lead to apoptosis of malignant B cells, thereby contributing to the impressive tumor regressions observed in mouse models and clinical trials using anti-CD20 MoAbs.

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Shan, Daming, Jeffrey A. Ledbetter et Oliver W. Press. « Apoptosis of Malignant Human B Cells by Ligation of CD20 With Monoclonal Antibodies ». Blood 91, n^o 5 (1 mars 1998) : 1644–52. http://dx.doi.org/10.1182/blood.v91.5.1644.1644_1644_1652.

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CD20 is a nonglycosylated 33 to 37 kD phosphoprotein involved in B-cell signaling that subserves important functions in the regulation of B-cell proliferation and differentiation. In addition, this B-cell surface antigen has been shown recently to be an effective target for immunotherapy of B-cell malignancies using chimeric (mouse/human) or radiolabeled murine monoclonal anti-CD20 antibodies. In this report we show that extensive crosslinking of CD20 with murine anti-CD20 monoclonal antibodies (MoAbs) in the presence of either goat anti-mouse IgG or Fc receptor (FcR)-expressing cells directly inhibits B-cell proliferation, induces nuclear DNA fragmentation, and leads to cell death by apoptosis. The apoptotic effects of these MoAbs can be inhibited by chelation of extracellular or intracellular Ca2+ by EGTA or Bapta AM, indicating that anti-CD20–mediated apoptosis may be related to changes in Ca2+ concentration. These findings suggest that ligation of CD20 in vivo by anti-CD20 antibodies in the presence of FcR-expressing cells may initiate signal transduction events that induce elevation of [Ca2+]i and lead to apoptosis of malignant B cells, thereby contributing to the impressive tumor regressions observed in mouse models and clinical trials using anti-CD20 MoAbs.

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Weitzman, James, Monica Betancur, Laurent Boissel, Arthur P. Rabinowitz et Hans Klingemann. « Variable Contribution of Different Monocloncal Antibodies to NK Cell-Mediated ADCC Against Primary CLL Cells. » Blood 110, n^o 11 (16 novembre 2007) : 4715. http://dx.doi.org/10.1182/blood.v110.11.4715.4715.

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Abstract Chronic Lymphocytic Leukemia (CLL) is characterized by the expression of the B-cell antigens CD19, 20 and 22, along with CD5 and CD23. These antigens make the malignant cells an ideal target for monoclonal antibody (mAb) therapy. Although the mechanism of action of mAbs is complex and not fully understood, one well-described action is antibody-dependent cellular cytotoxicity (ADCC). Binding of mAb to its target surface antigen initiates cytotoxicity through the interaction of the Fc portion of the mAb with the Fc receptor (FcR) on natural killer (NK) cells. This triggers release of perforin and granzymes from NK cells, and subsequent killing of the target cells. This study’s objectives were to measure ADCC of 4 different mAbs against primary CLL cells, and determine if cytotoxicity is dependent on antigen density. Methods: Mononuclear cells from 16 patients with untreated CLL were separated by density gradient separation and served as targets. The antigen density for CD20, 22 and 23 of each patient sample was quantified by flow cytometry. Effector cells for ADCC were NK-92 cells that do not express FcR, and a high affinity Fc receptor-expressing NK-92 variant (NK92.26.5) that also expresses inhibitory receptors (i.e. KIR). A fluourochrome-based flow cytometric assay determined ADCC by subtracting NK-92 induced cytotoxicity from NK-92.26.5 induced killing. Monoclonal antibodies tested were Rituximab (anti-CD20, Biogen/IDEC), Veltuzumab (anti-CD20, Immunomedics), Epratuzumab (anti-CD22, Immunomedics), and Lumiliximab (anti-CD23, Biogen/IDEC). Results: Mean ADCC of the four antibodies tested against 16 primary CLL cells were: 46.5% for Rituximab; 43.4% for Veltuzumab; 5.8% for Epratuzumab; 8.8% for Lumiliximab. Cytotoxicity of NK-92 and NK-92.26.5 against CLL cells without antibody ranged from 2–6%. Mean antigen density on the 16 CLL patient specimens were: CD20: 27,900 (range: 10,000–56,100); CD22: 820 (600–1300); CD23: 9870 (2340–14,800). Conclusions: We have developed a reliable in vitro assay to measure ADCC of mAbs against CLL cells. Our results indicate that ADCC contributes to cytotoxcity of CLL in vitro, and suggest that the magnitude of ADCC depends upon the surface antigen targeted. Anti-CD20 antibodies had significantly greater ADCC than the anti-CD22 and CD23 antibodies. This pattern was consistent in all patient cells tested. A similar pattern was observed with the surface antigen density on CLL cells tested, suggesting a correlation between cell surface antigen density and ADCC. Our results also suggest that resistance of primary CLL cells toward NK-mediated killing can be overcome by monoclonal antibodies even in the presence of inhibitory KIR expression on NK cells.

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Niederfellner, Gerhard J., Alfred Lammens, Manfred Schwaiger, Guy Georges, Kornelius Wiechmann, Andreas Franke, Wolfgang Schaefer et al. « Crystal Structure Analysis Reveals That the Novel Type II Anti-CD20 Antibody GA101 Interacts with a Similar Epitope as Rituximab and Ocrelizumab but in a Fundamentally Different Way. » Blood 114, n^o 22 (20 novembre 2009) : 3726. http://dx.doi.org/10.1182/blood.v114.22.3726.3726.

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Abstract Abstract 3726 Poster Board III-662 CD20 is a specific cell surface marker found on normal as well as malignant B cells. Rituximab, a monoclonal antibody directed against CD20, has a major impact on treatment of malignant lymphomas. Although all therapeutic CD20 antibodies are directed against the two relatively small extracellular loops of CD20, such antibodies can be classified into Type I CD20 antibodies like Rituximab, Ofatumumab or Ocrelizumab or Type II CD20 antibodies like the novel glycoengineered humanized CD20 antibody GA101 or the murine antibody Tositumumab. Type I and Type II antibodies differ significantly in their mode of action and mechanisms of killing malignant B-cells. The molecular basis of this is not understood. We use data from epitope mapping, X-ray crystallography, isothermal titration calorimetry, and point mutagenesis i) to accurately map the epitopes of different anti-CD20 antibodies, in particular GA101, and ii) to compare the molecular interactions involved in their binding. Although the epitope regions of these antibodies largely overlap, the crystal structure shows that GA101 binds CD20 in a completely different orientation from Rituximab, Ocrelizumab and Ofatumumab and that its binding also involves a larger surface area. In agreement with predictions based on the crystallographic data, point mutagenesis of single amino acid residues confirmed that exchanges at certain positions in CD20 affect binding of Rituximab and GA101 differently. Our data suggest that engagement of CD20 by these antibodies favors different conformations of CD20, which could form the molecular basis for the observed differences in cellular signals triggered by the respective antibodies. Disclosures: Niederfellner: Roche: Employment. Schwaiger:Roche: Employment. Georges:Roche: Employment. Wiechmann:Roche: Research Funding. Franke:Roche: Research Funding. Schaefer:Roche: Employment. Jenewein:Roche: Employment. Slootstra:Pepscan: Employment, Patents & Royalties. Moessner:Glycart: Employment, Equity Ownership, Patents & Royalties. Umana:Glycart: Employment, Equity Ownership, Patents & Royalties. Hopfner:Roche: Research Funding. Klein:Roche: Employment, Equity Ownership, Patents & Royalties.

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Gagez, Anne-Laure, et Guillaume Cartron. « New anti-CD20 monoclonal antibodies : which is the best ? » Leukemia & ; Lymphoma 56, n^o 1 (25 juin 2014) : 1–2. http://dx.doi.org/10.3109/10428194.2014.904513.

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Lina, Reslan, Stéphane Dalle, Jean-Louis Mestas, Cindy Tournebize et Charles Dumontet. « 69 : Chronic Lymphocytic Leukemia and anti-CD20 monoclonal antibodies ». Bulletin du Cancer 97, n^o 1 (mars 2010) : S60. http://dx.doi.org/10.1016/s0007-4551(15)31162-0.

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Schluenz, Lauren, Kate Jeffers et Joseph Kalis. « Compliance of protocol-driven hepatitis B serological screening in patients receiving anti-CD20 monoclonal antibody therapy. » Journal of Clinical Oncology 37, n^o 27_suppl (20 septembre 2019) : 261. http://dx.doi.org/10.1200/jco.2019.37.27_suppl.261.

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261 Background: The US Food and Drug Administration has issued a boxed warning for anti-CD20 monoclonal anti-bodies for the reactivation of Hepatitis B virus (HBV) infection. The National Comprehensive Cancer Network (NCCN) Non-Hodgkin Lymphoma and Infectious Diseases Society of America guidelines recommend routine serologic testing for all patients receiving anti-CD20 antibody therapy. NCCN specifies serologic screening of HBV surface antigen (HBsAg) and hepatitis B core antibody (HBcAb) should be completed prior to initiation of anti-CD20 therapy. In March 2018, UCHealth included HBV screening into the EHR oncology templates which include an anti-CD20 monoclonal antibody. The purpose of this study was to assess the impact of this template modification on compliance to guideline recommended screening for patients receiving anti-CD20 monoclonal antibody therapy. Methods: This was a retrospective chart review of patients who received an anti-CD20 monoclonal antibody for an oncologic indication between April 1, 2017 to November 30, 2017 (pre-template change) and April 1, 2018 to November 30, 2018 (post-template change) at any of the UCHealth Cancer Care and Hematology Centers. The primary objective was the composite compliance rate of HBsAg and HBcAb screening completed prior to receipt of treatment. Secondary objectives included compliance rate of each screening test, days between screening and treatment, screening for initial compared to relapse therapy, and rate of hepatitis C virus screening. Results: The addition HBV serologic screening to the EHR oncology templates containing an anti-CD20 agent improved screening compliance of HBsAg and HBcAb by 6.7% as a system (2017: 89.7% vs 2018: 96.4% [p = 0.133]). Secondary endpoints saw an increase in testing of each individual screening, testing for patients in the relapse setting, and HCV screening. Additionally, a reduction was seen in median days between screening and start of therapy (2017: 11 (4.5-30.3 IQR) vs 2018: 7 (2-14 IQR) [p = 0.008]). Conclusions: The addition of HBV serologic screening to EHR oncology templates increased compliance to guideline recommended screening for patients receiving anti-CD20 antibody therapy.

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Breakell, Thomas, Sabine Tacke, Verena Schropp, Henrik Zetterberg, Kaj Blennow, Eduard Urich et Stefanie Kuerten. « Obinutuzumab-Induced B Cell Depletion Reduces Spinal Cord Pathology in a CD20 Double Transgenic Mouse Model of Multiple Sclerosis ». International Journal of Molecular Sciences 21, n^o 18 (18 septembre 2020) : 6864. http://dx.doi.org/10.3390/ijms21186864.

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B cell-depleting therapies have recently proven to be clinically highly successful in the treatment of multiple sclerosis (MS). This study aimed to determine the effects of the novel type II anti-human CD20 (huCD20) monoclonal antibody (mAb) obinutuzumab (OBZ) on spinal cord degeneration in a B cell-dependent mouse model of MS. Double transgenic huCD20xHIGR3 (CD20dbtg) mice, which express human CD20, were immunised with the myelin fusion protein MP4 to induce experimental autoimmune encephalomyelitis (EAE). Both light and electron microscopy were used to assess myelination and axonal pathology in mice treated with OBZ during chronic EAE. Furthermore, the effects of the already established murine anti-CD20 antibody 18B12 were assessed in C57BL/6 wild-type (wt) mice. In both models (18B12/wt and OBZ/CD20dbtg) anti-CD20 treatment significantly diminished the extent of spinal cord pathology. While 18B12 treatment mainly reduced the extent of axonal pathology, a significant decrease in demyelination and increase in remyelination were additionally observed in OBZ-treated mice. Hence, the data suggest that OBZ could have neuroprotective effects on the CNS, setting the drug apart from the currently available type I anti-CD20 antibodies.

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Brando, Bruno, Arianna Gatti, Alfredo Maria Lurati et Paola M. L. Faggioli. « Monitoring anti-B cell immunotherapies in autoimmune diseases : Go with the flow. A Position Paper of the Italian Society for Clinical Cell Analysis (ISCCA) ». Beyond Rheumatology 1, n^o 2 (23 décembre 2019) : 52–62. http://dx.doi.org/10.4081/br.2019.26.

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During the past decades autoimmune diseases have been usually treated with immunosuppressive drugs mostly active on T-Cell mediated responses. Only in recent years, with our extended knowledge of the pathogenic mechanisms of autoreactive disorders and the tremendous development of new therapeutic monoclonal antibodies, anti-B-Cell therapies have emerged as a new option for treating autoimmune diseases. The rationale for this changeover from T-Cell to B-Cell targeted therapies resides in the recently accumulated evidence of the role of B-Cells in the pathogenesis of autoimmune diseases and in the generation of tissue damage. Targeting memory and effector BCells may then disrupt the production of pathogenic antibodies, counteract the role of B-Cells in sustaining antigen presentation to T-Cells and block the synthesis of B-Cell activation cytokines. The anti-CD20 monoclonal antibody Rituximab was first introduced more than 20 years ago for the treatment of CD20+ chronic B-lymphoproliferative disorders, and was then successfully experimented in the treatment of an ever-increasing spectrum of autoimmune diseases. Newer anti-CD20 monoclonal antibodies have been introduced more recently, which vary in their biological effects. The need for laboratory indicators that may help the rational usage and follow-up of anti-CD20 treatments has now emerged, due to the high variability of individual response, to the markedly different outcomes in the various diseases and to the controversial role of pathogenic autoantibodies as indicators of disease activity. Flow cytometric (FCM) analyses to identify and enumerate the B-cell functional subsets in the peripheral blood have been developed in recent years. They can be used to assess the degree and the persistence of memory B-Cell depletion, the quality and the timing of B-Cell reconstitution, along with the highly sensitive FCM counting technique needed for the detection of extremely low cell levels. The long-term aim of this innovative approach is to provide clinicians with a tool for a safer and more rational usage of anti-CD20 agents.

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Santos, Marcelo Antônio Oliveira, et Marinus de Moraes Lima. « CD20 role in pathophysiology of Hodgkin’s disease ». Revista da Associação Médica Brasileira 63, n^o 9 (2017) : 810–13. http://dx.doi.org/10.1590/1806-9282.63.09.810.

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Summary Hodgkin’s lymphoma (HL) is a tumor comprising non-malignant and malignant B-cells. Classical HL expresses CD15+ and CD30+ antigens, and 20 to 40% of patients are CD20+. This antigen is a ligand free protein present in B lymphocyte cells and its function is not well known. Some studies suggest that expression of CD20 may play a major role in Hodgkin’s disease pathophysiology and may affect the patients’ treatment prognosis, as well as relapse and refractory response. In the past few years, development of monoclonal anti-CD20 antibodies changed drastically the treatment for non-Hodgkin lymphomas in which CD20 is expressed. HL treatment is essentially composed of radiotherapy and chemotherapy; however, monoclonal anti-CD20 antibodies applicability is not well delimitated due to lack of information about clinical outcomes with anti-CD20 monotherapy or combined drug therapy using a classic regimen, as well as about CD20 pathophysiology mechanisms in B-cells tumors. The objective of our review is to discuss CD20 function in Hodgkin’s lymphoma development, its influence on disease evolution and outcomes, as well as its effects on therapeutics and patients’ prognostic.

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Golay, Josée, Rut Valgardsdottir, Gerta Musaraj, Damiano Giupponi, Orietta Spinelli et Martino Introna. « Human neutrophils express low levels of FcγRIIIA, which plays a role in PMN activation ». Blood 133, n^o 13 (28 mars 2019) : 1395–405. http://dx.doi.org/10.1182/blood-2018-07-864538.

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Abstract We have identified a rare healthy FcγRIIIB (CD16B)-null donor completely lacking FCGR3B RNA and protein expression and dissected the role of the different neutrophil Fcγ receptors in the response to therapeutic anti-CD20 monoclonal antibodies. We observed that polymorphonuclear neutrophils (PMNs) from FcγRIIIB wild-type (WT) individuals or the null donor were more effectively activated by chronic lymphocytic leukemia (CLL) B-cell targets opsonized with glycoengineered anti-CD20 antibodies compared with fully core-fucosylated anti-CD20 antibodies, suggesting the presence and role of FcγRIIIA (CD16A) on PMNs. Indeed, we demonstrated by reverse-transcription polymerase chain reaction, flow cytometry, and western blot analysis that PMNs from FcγRIIIB WT donors and the null individual express low levels of FcγRIIIA on their surfaces. FcγRIIIA is a functional and activating molecule on these cells, because anti-CD16 F(ab′)2 antibodies alone were able to activate highly purified PMNs from the FcγRIIIB-null donor. Use of blocking anti-CD16 and anti-CD32 antibodies showed that FcγRIIIA is also a major mediator of phagocytosis of CD20-opsonized beads by FcγRIIIB WT and null PMNs. In contrast, trogocytosis of antibody-opsonized CLL B cells by PMNs was mediated primarily by FcγRIIIB in WT PMNs and by FcγRIIA in null PMNs. We conclude that FcγRIIIA is an important player in PMN functions, whereas FcγRIIIB is dispensable for activation and phagocytosis. We discuss the clinical implications of these findings.

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Cheson, Bruce D. « Ofatumumab, a Novel Anti-CD20 Monoclonal Antibody for the Treatment of B-Cell Malignancies ». Journal of Clinical Oncology 28, n^o 21 (20 juillet 2010) : 3525–30. http://dx.doi.org/10.1200/jco.2010.27.9836.

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The availability of safe and effective monoclonal antibodies (mAbs) has dramatically altered treatment strategies for B-cell malignancies. Rituximab, a type I chimeric anti-CD20 mAb, not only has activity against a broad range of CD20-positive B-cell malignancies but also, when combined with chemotherapy or other biologic agents, has improved response rates; in addition, in certain situations, progression-free survival and even overall survival may be prolonged. Recently, other anti-CD20 mAbs have been developed to improve on the activity achieved with rituximab or to demonstrate efficacy in patients whose diseases are resistant to rituximab. The most extensively studied of these is ofatumumab, a type I human antibody that binds to a different epitope of CD20 than rituximab. Preclinical data suggest improved complement-dependent cytotoxicity and antibody-dependent cellular cytotoxicity compared with rituximab. In early clinical trials, ofatumumab demonstrated single-agent activity against chronic lymphocytic leukemia (CLL) and a number of histologies of B-cell non-Hodgkin's lymphomas. This antibody was recently approved by the US Food and Drug Administration for the treatment of CLL that is resistant to both fludarabine and alemtuzumab. Additional study is ongoing with ofatumumab in combination with chemotherapy and biologic agents to further enhance its efficacy. Ofatumumab offers another effective agent with which to improve the outcome of patients with B-cell malignancies.

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Faye, A., T. Van Den Abeele, M. Peuchmaur, A. Mathieu-Boue et E. Vilmer. « Anti-CD20 monoclonal antibody for post-transplant lymphoproliferative disorders ». Lancet 352, n^o 9136 (octobre 1998) : 1285. http://dx.doi.org/10.1016/s0140-6736(05)70493-1.

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Oflazoglu, Ezogelin, et Laurent P. Audoly. « Evolution of anti- CD20 monoclonal antibody therapeutics in oncology ». mAbs 2, n^o 1 (janvier 2010) : 14–19. http://dx.doi.org/10.4161/mabs.2.1.10789.

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Savchenko, Ya B., et S. A. Guseva. « Infusion intravenous IgG replacement therapy for hypogammaglobulinemia after anti-CD20 monoclonal antibodies at patients with non-hodgkin’s malignant lymphomas ». Infusion & ; Chemotherapy, n^o 3.1 (11 octobre 2020) : 66–67. http://dx.doi.org/10.32902/2663-0338-2020-3.1-55.

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Objective. Determining the risk of infectious complications in patients with non-hodgkin’s lymphomas (NМL) who received anti-CD20 monoclonal therapy and the effectiveness of intravenous immunoglobulin G (IgG) replacement therapy. Materials and methods. A prospective analysis of data of 37 persons with NML who were treated in the hematology clinic of the National Military Medical Clinical Center “Main Military Clinical Hospital” from January to December 2019. Statistical data processing was performed using computer programs Microsoft Office Excel (2007) and statistical processing package Statistica 6.0 using the procedure 2×2 Tables (YI/VI/Phil, McNemar, Fisher Exact) module Nonparametric Statistics, which uses the analysis of a four-cell conjugation table. Results and discussion. The mean age of patients was 56.5±1.4 years; 12 (32.43 %) were female patients. Baseline IgG levels before anti-CD20 monoclonal therapy were not determined in 17 (45.94 %) patients. Hypogammaglobulinemia was detected in 20 (54.05 %) subjects who were tested for IgG levels prior to anti-CD20 therapy. After administration of anti-CD20 monoclonal therapy, hypogammaglobulinemia worsened. There was an increase in severe infections after anti-CD20 therapy (from 9.4 to 40.7 %; p<0,001). An analysis of patient survival within 6 months of starting anti-CD20 monoclonal therapy revealed an increased mortality associated with an increase in age (hazard ratio (HR) 1.05; 95 % confidence interval (CI) 1.00-1.02; p<0.005), male (HR 1.12; 95 % CI 1.01-1.18; p<0.005), severe infectious complications (HR 5.18; 95 % CI 3.16-4,72; p<0.001). Only 10 (27.02 %) patients received IgG replacement therapy after anti-CD20 monoclonal therapy. Among these patients, a higher cumulative dose of immunoglobulin replacement therapy was associated with a reduced risk of serious infectious complications (HR 1.00; 95 % CI 0.98-1.02; p<0.005). Conclusions. Monitoring of IgG levels both before and after rituximab therapy may allow for earlier identification of risk for developing significant infection and identify patients who may benefit from IgG replacement, which may in turn help to avoid excess morbidity and mortality.

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Canninga-van Dijk, Marijke R., Hanneke M. van der Straaten, Rob Fijnheer, Cornelus J. Sanders, Jan G. van den Tweel et Leo F. Verdonck. « Anti-CD20 monoclonal antibody treatment in 6 patients with therapy-refractory chronic graft-versus-host disease ». Blood 104, n^o 8 (15 octobre 2004) : 2603–6. http://dx.doi.org/10.1182/blood-2004-05-1855.

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Abstract Chronic graft-versus-host disease (cGVHD) is an important determinant of long-term morbidity and mortality in allogeneic stem cell transplantation patients. Because cGVHD has clinical, histologic, and laboratory findings of autoimmune diseases and anti–B-cell therapy has shown efficacy in autoimmune diseases, we hypothesized that monoclonal anti-CD20 antibody therapy might improve patients with cGVHD. We treated 5 men and 1 woman with therapy-refractory extensive cGVHD with anti-CD20 monoclonal antibody. Intravenous infusion was given at a weekly dose of 375 mg/m2 for 4 weeks. In case of incomplete clinical response, additional courses of 4 weeks were given. Five patients responded to treatment with marked clinical, biochemical, and histologic improvement. One patient failed to respond. Anti-CD20 monoclonal antibody seems to be effective in cGVHD. A controlled trial is mandatory to confirm these results. The outcome of this study suggests a participating role of B cells in the pathogenesis of cGVHD.

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Sellebjerg, Finn, Morten Blinkenberg et Per Soelberg Sorensen. « Anti-CD20 Monoclonal Antibodies for Relapsing and Progressive Multiple Sclerosis ». CNS Drugs 34, n^o 3 (28 janvier 2020) : 269–80. http://dx.doi.org/10.1007/s40263-020-00704-w.

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Vandenbosch, K., M. A. Champagne, M. Gonthier, A. Moghrabi, M. F. Vachon et M. Duval. « Treatment of posttransplantation diabetes mellitus with anti-CD20 monoclonal antibodies ». Biology of Blood and Marrow Transplantation 11, n^o 2 (février 2005) : 64. http://dx.doi.org/10.1016/j.bbmt.2004.12.192.

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Mishima, Yuji, Yasuhito Terui, Yuko Mishima et Kiyohiko Hatake. « Anti-N-Terminal CD20 Monoclonal Antibody and L26 Dual Staining Identifies An Irreversible Resistant Mutant Genes ». Blood 116, n^o 21 (19 novembre 2010) : 4145. http://dx.doi.org/10.1182/blood.v116.21.4145.4145.

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Abstract Abstract 4145 [Introduction] Recently, we reported that gene mutations of CD20 were involved in resistance to rituximab therapy, and we proposed that C-terminal deletion mutations of CD20 might be related to relapse/resistance after rituximab therapy. Many of these cases were diagnosed as CD20 negative by the immunohistochemical analysis using the L26 monoclonal antibody used routinely in most clinical laboratories. L26 recognizes the cytoplasmic region of CD20 molecules, but no more detailed information about its epitope had been reported. So, we could not distinguish whether protein expression of CD20 extremely decreased or whether the epitope of the antibody was lost by these mutations. To make this clear, we determined the binding site of L26 antibody on CD20 protein in the present study. In addition, we developed new antibodies that recognize amino acid sequence close to the amino terminal of CD20 molecule. Then we investigated clinical specimens with these antibodies together with L26 to elucidate characteristics of CD20 molecules having C-terminal mutations. [Methods] To determine the binding site of L26 antibody on CD20, we made a series of constructs of the CD20 molecules with deletion mutations in the C-terminal cytoplasmic domain and introduced them into retrovirus vectors. A CD20 negative multiple myeloma cell line, KMS12PE cells were then transformed, and we established six kinds of sub-lines with the various C-terminal deletion mutations of CD20 and used them for epitope-mapping. On the other hand, we screened the CD20 gene sequence of the clinical specimen of rituximab-resistant patients and identified several cases with the mutation in the C-terminal cytoplasm region. The immunochemistry using L26 and newly developed antibodies, as well as membrane expression of CD20 molecules using the rituximab were analyzed. [Results] The epitope analysis of L26 antibody using a series of CD20 deletion mutations revealed that L26 recognizes near the C-terminus of CD20 cytoplasmic region. These results showed that most of CD20 molecules with the C-terminal deletion mutation and frame-shift mutation could not be recognized by L26. The immunohistochemical analysis performed for clinical specimens revealed that the cells that were stained by antibodies recognizing N-terminal region of CD20 but not by L26 were indeed included in some rituximab-resistant cases. DNA sequencing analysis revealed that all these cases had mutated CD20 genes in its C-terminal cytoplasmic region. In addition, a cell-surface expression analysis using flowcytometry demonstrated that the cells having these mutations has reduced cell surface expression of CD20 compared with those of normal CD20. [Discussion] In this study, we determined the recognition site of L26 and demonstrated that L26 couldn't recognize CD20 with the resistant mutations. In contrast, newly developed antibodies against N-terminal region of CD20 could stain even these CD20 molecules. These results suggest that combination use of these antibodies and L26 enables to detect the onset of irreversible rituximab-resistant clones with the CD20 mutations. Disclosures: Hatake: Chugai Pharmaceutical Co., Ltd: Honoraria, Research Funding.

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Hu, Changyun, Heyuan Ding, F. Susan Wong et Li Wen. « Combined antibody therapy for type 1 diabetes (107.2) ». Journal of Immunology 186, n^o 1_Supplement (1 avril 2011) : 107.2. http://dx.doi.org/10.4049/jimmunol.186.supp.107.2.

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Abstract Studies have shown that oral tolerance is effective in treating different models of autoimmune diseases including type 1 diabetes (T1D). Both T and B cells play important roles in the development of T1D. Antibodies targeting either T or B cells have shown to be effective in treating T1D in both patients and NOD mice. However, individual antibodies are only effective in a proportion of those treated. Furthermore, the beneficial effects have not been long lasting. To test whether the combination of anti-CD20 and oral anti-CD3 treatment can improve the efficacy in prevention and reversal of T1D and prolong the beneficial effects, we treated a group of human CD20 transgenic NOD mice with anti-hCD20 monoclonal antibody and oral anti-CD3. The results suggested that anti-CD20 and anti-CD3 have synergistic effects in the diabetes prevention and reversal. Mechanistic studies have demonstrated that the combination treatment induced FoxP3+ Tregs and enhanced the regulatory function of Treg. A subset of IL-10+ CD4 T cells was also induced in peyer’s patches of the mice treated with combined therapy. Our preliminary study may provide a novel therapeutic approach to treating T1D.

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Bobrowicz, Malgorzata, Michal Dwojak, Kamil Bojarczuk, Magdalena Winiarska et Jakub Golab. « HDAC6 Inhibition Increases CD20 Level and Improves The Efficacy Of Anti-CD20 Monoclonal Antibodies ». Blood 122, n^o 21 (15 novembre 2013) : 4406. http://dx.doi.org/10.1182/blood.v122.21.4406.4406.

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Abstract CD20, an integrate membrane protein expressed on the surface of normal and malignant B-cells is widely used as a molecular target for monoclonal antibodies (mAbs) in the therapy of non-Hodgkin’s lymphomas and chronic lymphocytic leukemia (CLL). Accumulating evidence indicates that CD20 can be modulated at several levels, both transcriptional and posttranscriptional and its up-regulation would result in increased efficacy of anti-CD20 mAbs. CD20 antigen has been reported to be regulated epigenetically e.g. by histone deacetylases (HDACs). The results of our preliminary experiments show that use of non-selective HDAC inhibitors as well as blocking the activity of a single HDAC isoform - HDAC6 leads to up-regulation of CD20 protein in B-cell lymphoma cell lines and increase of the efficacy of therapy with anti-CD20 mAbs. Since HDAC6 is engaged mainly in the acetylation of non-histone substrates and the observed up-regulation of CD20 molecule does not seem to rely on transcriptional mechanisms we postulate that HDAC6 is engaged in processes of CD20 trafficking or/and degradation. CD20 being a membrane bound protein is most probably undergoing endocytosis. However, this process and the role of HDAC6 in its regulation has not been explored so far. The aim of this study was to understand how the inhibition of HDAC6 activity influences CD20 level in normal and malignant B-cells. We wanted to determine the mechanisms underlying this phenomena. This study required use of B-cell lymphoma cell lines as well as lymphocytes infected with Epstein-Barr virus and normal B- lymphocytes. Several HDAC pan-inhibitors and HDAC6 inhibitors were tested. To assess the membrane level of CD20 antigen, FITC-anti-CD20 staining was performed followed by cytometric analysis. The influence of HDACi on total level of CD20 protein was assessed in Western blotting. The complement-dependent cytotoxicity (CDC) assay was performed using rituximab and ofatumumab as well as human serum as a source of complement. Cell cytotoxicity was assessed by propidium iodide staining followed by cytometric analysis. The influence of HDAC inhibition on the transcription of CD20 was examined by qRT-PCR using SyBR Green and hydrolysis probes. The activity of CD20 promoter after inhibition of HDAC was assessed in Dual Luciferase Assay. The colocalisation of CD20 with other proteins that may influence its trafficking/degradation was assessed using immunocytochemistry with specific antibodies and observed under confocal microscope. The results of our study strongly suggest that combining HDACi with anti-CD20 antibodies can be an effective therapeutic modality for patients suffering from B-cell malignancies. Extensive experiments aiming at determining what factors are engaged in the regulation of CD20 by HDAC6 are planned. Disclosures: No relevant conflicts of interest to declare.

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Bobrowicz, Malgorzata, Michal Dwojak, Beata Pyrzynska, Joanna Stachura, Angelika Muchowicz, Elise Berthel, Nicole Dalla-Venezia et al. « HDAC6 inhibition upregulates CD20 levels and increases the efficacy of anti-CD20 monoclonal antibodies ». Blood 130, n^o 14 (5 octobre 2017) : 1628–38. http://dx.doi.org/10.1182/blood-2016-08-736066.

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Key Points HDAC6 inhibition represents a novel strategy to improve the efficacy of anti-CD20 mAbs. HDAC6 inhibition increases CD20 levels by enhancing CD20 protein synthesis without affecting the gene expression.

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James, Scott E., Nural N. Orgun, Thomas F. Tedder, Mark J. Shlomchik, Michael C. Jensen, Yukang Lin, Philip D. Greenberg et Oliver W. Press. « Antibody-mediated B-cell depletion before adoptive immunotherapy with T cells expressing CD20-specific chimeric T-cell receptors facilitates eradication of leukemia in immunocompetent mice ». Blood 114, n^o 27 (24 décembre 2009) : 5454–63. http://dx.doi.org/10.1182/blood-2009-08-232967.

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Abstract We have established a model of leukemia immunotherapy using T cells expressing chimeric T-cell receptors (cTCRs) targeting the CD20 molecule expressed on normal and neoplastic B cells. After transfer into human CD20 (hCD20) transgenic mice, cTCR+ T cells showed antigen-specific delayed egress from the lungs, concomitant with T-cell deletion. Few cTCR+ T cells reached the bone marrow (BM) in hCD20 transgenic mice, precluding effectiveness against leukemia. Anti-hCD20 antibody-mediated B-cell depletion before adoptive T-cell therapy permitted egress of mouse CD20-specific cTCR+ T cells from the lungs, enhanced T-cell survival, and promoted cTCR+ T cell–dependent elimination of established mouse CD20+ leukemia. Furthermore, CD20-specific cTCR+ T cells eliminated residual B cells refractory to depletion with monoclonal antibodies. These findings suggest that combination of antibody therapy that depletes antigen-expressing normal tissues with adoptive T-cell immunotherapy enhances the ability of cTCR+ T cells to survive and control tumors.

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