Cd79b Expression in B Cell Chronic Lymphocytic Leukemia: Its Implication for Minimal Residual Disease Detection
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Molecules with Specificity for Cd45 and Cd79 Moleküle Mit Cd45- Und Cd79-Spezifizität Molécules Présentant Une Spécificité Vis-À-Vis De Cd45 Et Cd79
(19) *EP003169704B1* (11) EP 3 169 704 B1 (12) EUROPEAN PATENT SPECIFICATION (45) Date of publication and mention (51) Int Cl.: of the grant of the patent: C07K 16/28 (2006.01) 29.07.2020 Bulletin 2020/31 (86) International application number: (21) Application number: 15738655.8 PCT/EP2015/066368 (22) Date of filing: 16.07.2015 (87) International publication number: WO 2016/009029 (21.01.2016 Gazette 2016/03) (54) MOLECULES WITH SPECIFICITY FOR CD45 AND CD79 MOLEKÜLE MIT CD45- UND CD79-SPEZIFIZITÄT MOLÉCULES PRÉSENTANT UNE SPÉCIFICITÉ VIS-À-VIS DE CD45 ET CD79 (84) Designated Contracting States: • WRIGHT, Michael John AL AT BE BG CH CY CZ DE DK EE ES FI FR GB Slough GR HR HU IE IS IT LI LT LU LV MC MK MT NL NO Berkshire SL1 3WE (GB) PL PT RO RS SE SI SK SM TR • TYSON, Kerry Designated Extension States: Slough BA ME Berkshire SL1 3WE (GB) Designated Validation States: MA (74) Representative: UCB Intellectual Property c/o UCB Celltech (30) Priority: 16.07.2014 GB 201412659 IP Department 208 Bath Road (43) Date of publication of application: Slough, Berkshire SL1 3WE (GB) 24.05.2017 Bulletin 2017/21 (56) References cited: (73) Proprietor: UCB Biopharma SRL WO-A1-2011/025904 WO-A1-2013/085893 1070 Brussels (BE) • GOLD ET AL.: "The B Cell Antigen Receptor (72) Inventors: Activates the AKT/Glycogegn Synthase Kinase-3 • FINNEY, Helene Margaret Signalling Pathway via Phosphatydilinositol Slough 3-Kinase", J. IMMUNOLOGY, vol. 163, 1999, Berkshire SL1 3WE (GB) pages 1894-1905, XP002745175, • RAPECKI, Stephen Edward Slough Berkshire SL1 3WE (GB) Note: Within nine months of the publication of the mention of the grant of the European patent in the European Patent Bulletin, any person may give notice to the European Patent Office of opposition to that patent, in accordance with the Implementing Regulations. -
ORIGINAL ARTICLE Flow Cytometric Protein Expression Profiling As a Systematic Approach for Developing Disease-Specific Assays
Leukemia (2006) 20, 2102–2110 & 2006 Nature Publishing Group All rights reserved 0887-6924/06 $30.00 www.nature.com/leu ORIGINAL ARTICLE Flow cytometric protein expression profiling as a systematic approach for developing disease-specific assays: identification of a chronic lymphocytic leukaemia-specific assay for use in rituximab-containing regimens AC Rawstron, R de Tute, AS Jack and P Hillmen Haematological Malignancy Diagnostic Service (HMDS), Leeds Teaching Hospitals, Leeds, UK Depletion of disease below the levels detected by sensitive sustained remissions only occur in patients achieving an MRD- minimal residual disease (MRD) assays is associated with negative complete response.12 Therefore MRD is increasingly prolonged survival in chronic lymphocytic leukaemia (CLL). being used as an end point for therapeutic trials, and several Flow cytometric MRD assays are now sufficiently sensitive and rapid to guide the duration of therapy in CLL, but generally rely studies are now using the assessment of MRD to define the on assessment of CD20 expression, which cannot be accurately duration of therapy. measured during and after therapeutic approaches containing Approaches using allele-specific oligonucleotide polymerase rituximab. The aim of this study was to use analytical software chain reaction (ASO-PCR) to the immunoglobulin gene of the developed for microarray analysis to provide a systematic B-CLL cell are generally accepted to show the highest sensitivity approach for MRD flow assay development. Samples from CLL for MRD detection. However, more recent four-colour ap- patients (n ¼ 49), normal controls (n ¼ 21) and other B-lympho- proaches show sensitivities nearing that of ASO-PCR6,11,13 with proliferative disorders (n ¼ 12) were assessed with a panel of 66 antibodies. -
ROR1/CD19 Receptor Complex Promotes Growth of Mantle Cell Lymphoma Cells Independently of the B Cell Receptor–BTK Signaling Pathway † Qian Zhang,* Hong Y
Published September 18, 2019, doi:10.4049/jimmunol.1801327 Cutting Edge: ROR1/CD19 Receptor Complex Promotes Growth of Mantle Cell Lymphoma Cells Independently of the B Cell Receptor–BTK Signaling Pathway † Qian Zhang,* Hong Y. Wang,* Xiaobin Liu,* Selene Nunez-Cruz,* Mowafaqx Jillab, Olga Melnikov,† Kavindra Nath,‡ Jerry Glickson,‡ and Mariusz A. Wasik*,†, Inhibitors of Bruton tyrosine kinase (BTK), a kinase these mechanisms is of uttermost importance in design- downstream of BCR, display remarkable activity in a ing an appropriate therapeutic strategy to counteract the subset of mantle cell lymphoma (MCL) patients, but reprogramming. the drug resistance remains a considerable challenge. In ROR1 belongs to the receptor tyrosine kinase-like orphan this study, we demonstrate that aberrant expression of receptor (ROR) family and displays very restricted expression ROR1 (receptor tyrosine kinase-like orphan receptor 1), in normal tissues (11, 12). ROR1 is aberrantly expressed in seen in a large subset of MCL, results in BCR/BTK– various malignancies, including small lymphocytic lymphoma/ independent signaling and growth of MCL cells. ROR1 chronic lymphocytic leukemia (SLL/CLL) and MCL. ROR1 forms a functional complex with CD19 to persistently activates signaling molecules, such as RAC-1 and contractin activate the key cell signaling pathways PI3K–AKT and (13, 14), to promote cell proliferation, survival, and migration MEK–ERK in the BCR/BTK–independent manner. (13–15). CD19 is a B cell–specific receptor capable of stimu- lating the growth of malignant B cells (16). In normal This study demonstrates that ROR1/CD19 complex B lymphocytes, it is activated by SRC family kinases and effectively substitutes for BCR–BTK signaling to SYK, both downstream of BCR (17). -
B Cell Checkpoints in Autoimmune Rheumatic Diseases
REVIEWS B cell checkpoints in autoimmune rheumatic diseases Samuel J. S. Rubin1,2,3, Michelle S. Bloom1,2,3 and William H. Robinson1,2,3* Abstract | B cells have important functions in the pathogenesis of autoimmune diseases, including autoimmune rheumatic diseases. In addition to producing autoantibodies, B cells contribute to autoimmunity by serving as professional antigen- presenting cells (APCs), producing cytokines, and through additional mechanisms. B cell activation and effector functions are regulated by immune checkpoints, including both activating and inhibitory checkpoint receptors that contribute to the regulation of B cell tolerance, activation, antigen presentation, T cell help, class switching, antibody production and cytokine production. The various activating checkpoint receptors include B cell activating receptors that engage with cognate receptors on T cells or other cells, as well as Toll-like receptors that can provide dual stimulation to B cells via co- engagement with the B cell receptor. Furthermore, various inhibitory checkpoint receptors, including B cell inhibitory receptors, have important functions in regulating B cell development, activation and effector functions. Therapeutically targeting B cell checkpoints represents a promising strategy for the treatment of a variety of autoimmune rheumatic diseases. Antibody- dependent B cells are multifunctional lymphocytes that contribute that serve as precursors to and thereby give rise to acti- cell- mediated cytotoxicity to the pathogenesis of autoimmune diseases -
Molecular Design, Optimization and Genomic Integration of Chimeric B
bioRxiv preprint doi: https://doi.org/10.1101/516369; this version posted June 5, 2019. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-NC 4.0 International license. 1 Molecular design, optimization and genomic integration of chimeric B cell 2 receptors in murine B cells 3 4 Theresa Pesch1, Lucia Bonati1, William Kelton1, Cristina Parola1,2, Roy A Ehling1, Lucia 5 Csepregi1, Daisuke Kitamura3, Sai T ReDDy1,* 6 7 1 Department of Biosystems Science and Engineering, ETH Zürich, Basel 4058, Switzerland 8 2 Life Science Graduate School, Systems Biology, ETH Zürich, University of Zurich, Zurich 8057, 9 Switzerland 10 3 Research Institute for Biomedical Sciences, Tokyo University of Science, Noda, Japan 11 *To whom corresponDence shoulD be aDDresseD. Tel: +41 61 387 33 68; Email: [email protected] 12 Key worDs: B cells, synthetic antigen receptor, cellular engineering, genome eDiting, cellular 13 immunotherapy, CRISPR-Cas9 14 15 Abstract 16 Immune cell therapies baseD on the integration of synthetic antigen receptors proviDe 17 a powerful strategy for the treatment of Diverse Diseases, most notably retargeting 18 T cells engineereD to express chimeric antigen receptors (CAR) for cancer therapy. In 19 aDDition to T lymphocytes, B lymphocytes may also represent valuable immune cells 20 that can be engineereD for therapeutic purposes such as protein replacement therapy 21 or recombinant antiboDy proDuction. In this article, we report a promising concept for 22 the molecular Design, optimization anD genomic integration of a novel class of 23 synthetic antigen receptors, chimeric B cell receptors (CBCR). -
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bioRxiv preprint doi: https://doi.org/10.1101/801530; this version posted October 13, 2019. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-NC 4.0 International license. An integrated multi-omic single cell atlas to redefine human B cell memory David R. Glass,1,2,5 Albert G. Tsai,2,5 John Paul Oliveria,2,3 Felix J. Hartmann,2 Samuel C. Kimmey,2,4 Ariel A. Calderon,1,2 Luciene Borges,2 Sean C. Bendall1,2,6,* 1Immunology Graduate Program, Stanford University, Stanford, CA, 94305, USA 2Department of Pathology, Stanford University, Stanford, CA, 94305, USA 3Department of Medicine, Division of Respirology, McMaster University, Hamilton, ON, L8S4K1, Canada 4Department of Developmental Biology, Stanford, University, Stanford CA, 94305, USA 5Co-first author 6Lead Author *Correspondence: [email protected] bioRxiv preprint doi: https://doi.org/10.1101/801530; this version posted October 13, 2019. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-NC 4.0 International license. Abstract: To evaluate the impact of heterogeneous B cells in health and disease, comprehensive profiling is needed at a single cell resolution. We developed a highly- multiplexed screen to quantify the co-expression of 351 surface molecules on low numbers of primary cells. We identified dozens of differentially expressed molecules and aligned their variance with B cell isotype usage, metabolism, biosynthesis activity, and signaling response. -
Immunotherapies Shape the Treatment Landscape for Hematologic Malignancies Jane De Lartigue, Phd
Feature Immunotherapies shape the treatment landscape for hematologic malignancies Jane de Lartigue, PhD he treatment landscape for hematologic of TIL therapy has been predominantly limited to malignancies is evolving faster than ever melanoma.1,3,4 before, with a range of available therapeutic Most recently, there has been a substantial buzz Toptions that is now almost as diverse as this group around the idea of genetically engineering T cells of tumors. Immunotherapy in particular is front and before they are reintroduced into the patient, to center in the battle to control these diseases. Here, increase their anti-tumor efficacy and minimize we describe the latest promising developments. damage to healthy tissue. This is achieved either by manipulating the antigen binding portion of the Exploiting T cells T-cell receptor to alter its specificity (TCR T cells) The treatment landscape for hematologic malig- or by generating artificial fusion receptors known as nancies is diverse, but one particular type of therapy chimeric antigen receptors (CAR T cells; Figure 1). has led the charge in improving patient outcomes. The former is limited by the need for the TCR to be Several features of hematologic malignancies may genetically matched to the patient’s immune type, make them particularly amenable to immunother- whereas the latter is more flexible in this regard and apy, including the fact that they are derived from has proved most successful. corrupt immune cells and come into constant con- CARs are formed by fusing part of the single- tact with other immune cells within the hemato- chain variable fragment of a monoclonal antibody poietic environment in which they reside. -
New Additions to Antibody Panels in the Characterisation of Chronic Lymphoproliferative Disorders J Clin Pathol: First Published As on 1 March 2002
180 REVIEW New additions to antibody panels in the characterisation of chronic lymphoproliferative disorders J Clin Pathol: first published as on 1 March 2002. Downloaded from E Matutes ............................................................................................................................. J Clin Pathol 2002;55:180–183 Advances in flow cytometry techniques and the In addition to the panel of monoclonal antibod- availability of monoclonal antibodies that detect key ies routinely used in the past decade,2 and recom- mended in 1994 by the general haematology task functional molecules on lymphocytes have contributed force of the British Committee for Standards in greatly to a more precise diagnosis of the chronic Haematology,3 several others have been shown to lymphoproliferative disorders. In addition to the provide relevant diagnostic and/or prognostic information, and could be incorporated into the diagnostic value, the expression of certain markers such panel of markers in a routine practice. The as p53 or CD38 provides relevant prognostic characteristics of these monoclonal antibodies information to the clinician. Beyond their diagnostic and and the molecules that they recognise, in addition to their relevance for the characterisation of the prognostic value, immunological markers play a major chronic lymphoproliferative disorders, are de- role in the detection of minimal residual disease, scribed below enabling the clinician to estimate more accurately the response to chemotherapy. Those monoclonal MONOCLONAL ANTIBODIES TO CD79B CD79 is a heterodimeric molecule comprising two antibodies that are relevant to the characterisation of the polypeptide chains: the α-chain or mb1 (CD79a) chronic lymphoproliferative disorders and that could be and the β-chain or B29 (CD79b). CD79b is incorporated in a routine practice are discussed. -
B-Cell Development, Activation, and Differentiation
B-Cell Development, Activation, and Differentiation Sarah Holstein, MD, PhD Nov 13, 2014 Lymphoid tissues • Primary – Bone marrow – Thymus • Secondary – Lymph nodes – Spleen – Tonsils – Lymphoid tissue within GI and respiratory tracts Overview of B cell development • B cells are generated in the bone marrow • Takes 1-2 weeks to develop from hematopoietic stem cells to mature B cells • Sequence of expression of cell surface receptor and adhesion molecules which allows for differentiation of B cells, proliferation at various stages, and movement within the bone marrow microenvironment • Immature B cell leaves the bone marrow and undergoes further differentiation • Immune system must create a repertoire of receptors capable of recognizing a large array of antigens while at the same time eliminating self-reactive B cells Overview of B cell development • Early B cell development constitutes the steps that lead to B cell commitment and expression of surface immunoglobulin, production of mature B cells • Mature B cells leave the bone marrow and migrate to secondary lymphoid tissues • B cells then interact with exogenous antigen and/or T helper cells = antigen- dependent phase Overview of B cells Hematopoiesis • Hematopoietic stem cells (HSCs) source of all blood cells • Blood-forming cells first found in the yolk sac (primarily primitive rbc production) • HSCs arise in distal aorta ~3-4 weeks • HSCs migrate to the liver (primary site of hematopoiesis after 6 wks gestation) • Bone marrow hematopoiesis starts ~5 months of gestation Role of bone -
Novel Immunotherapies in Lymphoid Malignancies
REVIEWS Novel immunotherapies in lymphoid malignancies Connie Lee Batlevi1, Eri Matsuki1, Renier J. Brentjens2 and Anas Younes1 Abstract | The success of the anti‑CD20 monoclonal antibody rituximab in the treatment of lymphoid malignancies provided proof-of-principle for exploiting the immune system therapeutically. Since the FDA approval of rituximab in 1997, several novel strategies that harness the ability of T cells to target cancer cells have emerged. Reflecting on the promising clinical efficacy of these novel immunotherapy approaches, the FDA has recently granted ‘breakthrough’ designation to three novel treatments with distinct mechanisms. First, chimeric antigen receptor (CAR)-T‑cell therapy is promising for the treatment of adult and paediatric relapsed and/or refractory acute lymphoblastic leukaemia (ALL). Second, blinatumomab, a bispecific T‑cell engager (BiTE®) antibody, is now approved for the treatment of adults with Philadelphia-chromosome- negative relapsed and/or refractory B‑precursor ALL. Finally, the monoclonal antibody nivolumab, which targets the PD‑1 immune-checkpoint receptor with high affinity, is used for the treatment of Hodgkin lymphoma following treatment failure with autologous-stem-cell transplantation and brentuximab vedotin. Herein, we review the background and development of these three distinct immunotherapy platforms, address the scientific advances in understanding the mechanism of action of each therapy, and assess the current clinical knowledge of their efficacy and safety. We also discuss future strategies to improve these immunotherapies through enhanced engineering, biomarker selection, and mechanism-based combination regimens. The concept of immunotherapy for treating cancer of cell-based therapy directed at TAAs expressed on the emerged almost a century ago; the graft-versus-tumour tumour-cell surface, typically CD19 in B‑cell malignan- effect following allogeneic haematopoietic-stem-cell cies (BOX 1). -
Chimeric Antigen Receptor T Cells Targeting Cd79b Show Efficacy in Lymphoma with Or Without Cotargeting CD19
Published OnlineFirst August 22, 2019; DOI: 10.1158/1078-0432.CCR-19-1337 Precision Medicine and Imaging Clinical Cancer Research Chimeric Antigen Receptor T Cells Targeting CD79b Show Efficacy in Lymphoma with or without Cotargeting CD19 Maria Ormhøj1,2, Irene Scarfo1, Maria L. Cabral1, Stefanie R. Bailey1, Selena J. Lorrey1, Amanda A. Bouffard1, Ana P. Castano1, Rebecca C. Larson1, Lauren S. Riley1, Andrea Schmidts1, Bryan D. Choi1, Rikke S. Andersen3, Oriane Cedile 4,6,7, Charlotte G. Nyvold4,6,7, Jacob H. Christensen5, Morten F. Gjerstorff3,8, Henrik J. Ditzel3,8, David M.Weinstock9,10,Torben Barington2,7, Matthew J. Frigault1,10, and Marcela V. Maus1,10 Abstract Purpose: T cells engineered to express a chimeric antigen Results: We demonstrate CAR79b antigen-specificrecog- receptor (CAR) against CD19 have recently been FDA nition and cytotoxicity against a panel of cell lines and approved for the treatment of relapsed or refractory large B- patient-derived xenograft models of MCL. Importantly, we cell lymphoma. Despite the success and curative potential of show that downregulation of CD19 does not influence CD19 CAR T cells, several reports describing disease relapse surface expression of CD79b and that anti-CD79b CAR due to antigen loss are now emerging. T cells alone or arranged in a dual-targeting format with Experimental Design: We developed a novel CAR construct a CD19 single-chain variable fragment (scFv) are able to þ À directed against CD79b, a critical receptor for successful B-cell recognize and eliminate CD19 ,CD19, and mixed þ À development that remains highly expressed in several sub- CD19 /CD19 B-cell lymphoma. -
The Diagnostic Value of CD123 in B-Cell Disorders with Hairy Or Villous Lymphocytes
Chronic Lymphoproliferative Disorders • Research Paper The diagnostic value of CD123 in B-cell disorders with hairy or villous lymphocytes [haematologica] 2004;89:303-308 ILARIA DEL GIUDICE ABSTRACT ESTELLA MATUTES RICARDO MORILLA Background and Objectives. CD123 is an antibody that identifies the α chain of the ALISON MORILLA human interleukin-3 receptor and is expressed in a variety of normal hematopoietic cells, KWASI OWUSU-ANKOMAH acute leukemia and hairy cell leukemia (HCL). The aim of the study was to investigate the FURHEEN RAFIQ diagnostic value of CD123 expression in B-cell disorders with circulating hairy and vil- ROGER A’HERN lous lymphocytes. JULIO DELGADO Design and Methods. We investigated the diagnostic value of CD123 expression in neo- MOHAMMED BADIE BAZERBASHI plastic cells from 59 patients with B-cell disorders with circulating hairy or villous lym- DANIEL CATOVSKY phocytes: HCL (n=24), the variant form of HCL (n=11) and splenic lymphoma with villous lymphocytes (SLVL) (n=24). Cells from 12 patients with chronic lymphocytic leukemia were used as controls. Immunophenotypic analysis was performed by flow cytometry on 77 samples from peripheral blood (n=48), bone marrow (n=25) and spleen cell suspensions (n=4). Results. Our findings show that cells from 95% of typical HCL express CD123 with strong to moderate intensity while this molecule is absent in circulating cells from most cases of HCL-variant (91%) and SLVL (97%). Interpretation and Conclusions. We conclude that CD123 is a useful new marker for distinguishing B-cell disorders with circulating villous lymphocytes as its expression is characteristic of typical HCL with high sensitivity and specificity.