Characterization of Antibodies Direct against the Idiotypic VK3 Chain of HCV-Related Type-II Mixed Cryoglobulinemia and B-Cell Proliferations

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 4988-4988
Author(s):  
Valli De Re ◽  
Maria Paola Simula ◽  
Alessandro Pavan ◽  
Dolores Marin ◽  
Laura Caggiari ◽  
...  
Keyword(s):  
Monoclonal Antibodies ◽  
B Cells ◽  
Western Blot ◽  
B Cell ◽  
Rheumatoid Factor ◽  
Light Chain ◽  
B Cell Lymphoma ◽  
Type Ii ◽  
Cell Proliferations

Abstract Autoimmune type-II cryoglobulinemia (MC) is sustained by clonal/oligoclonal B-cell populations such the disease may be considered an “indolent B-cell lymphoma (NHL) “ and may favor overt NHL development. HCV-antigen driven mechanism induces B-cell proliferations. Clonal B-cells demonstrate a restricted used of variable genes to construct the B-cell receptor (BCR) and a homology between BCR functional regions and autoimmune rheumatoid factor (RF) activity. We underline the BCR unique repertoire with frequent rheumatoid factor activity also in other autoimmune disorders associated to NHL development as Sjogren’s syndrome and rheumatoid arthritis. All together these BCRs are characterized by their high degree of idiotypic (Id) cross reactivity. Particularly the K chain V3-20/15 is frequently found in subject with positive HCV antibody. Id is a clonamarker expressedby B cells, thus is an ideal target for immunotherapy. The evidence of few Id presented in the NHL subgroup above reported constitute the rational for the development of antibodies and recombinant proteins that use shared Id among different NHL. Five monoclonal antibodies have been produced in our laboratory toward the VK3-20 region of a subject HCV+ with NHL. Epitopes recognized has been performed using epitope excision approach. A fine determination of the antibodies activities toward specific amino acids, possibly common to different individuals, are in progress. Monoclonal antibodies reactivity has been tested in vitro in ELISA, western blot and cytofluorimetry. Apoptosis and SyK/ERK phosphorylation pathways induced following BCR cross-linking of antiId murine IgG will be performed. All the antibodies were reactive in Elisa against the VK3-Ig light chain. Two of these antibodies showed a reactivity against the light chain of cryoprecipitated immunocomplexes from several patients in western blot, and by cytofluorimter they recognised two lymphoma B-cell lines.

scholarly journals Antigenic modulation limits the efficacy of anti-CD20 antibodies: implications for antibody selection

Blood ◽  
2010 ◽  
Vol 115 (25) ◽  
pp. 5191-5201 ◽  
Author(s):  
Stephen A. Beers ◽  
Ruth R. French ◽  
H. T. Claude Chan ◽  
Sean H. Lim ◽  
Timothy C. Jarrett ◽  
...  
Keyword(s):  
B Cells ◽  
B Cell ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Type I ◽  
Type Ii ◽  
Antigenic Modulation ◽  
Lymphatic Leukemia ◽  
Human B Cells ◽  
Anti Cd20

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.

scholarly journals Monoclonal antibodies to the 140,000 mol wt glycoprotein of B lymphocyte membranes (CR2 receptor) initiates proliferation of B cells in vitro

Blood ◽  
1985 ◽  
Vol 66 (4) ◽  
pp. 824-829
Author(s):  
BS Wilson ◽  
JL Platt ◽  
NE Kay
Keyword(s):  
Monoclonal Antibodies ◽  
B Cells ◽  
B Cell ◽  
Peripheral Blood ◽  
B Lymphocyte ◽  
Human Peripheral Blood ◽  
Raji Cell ◽  
Lymphoid Cells ◽  
Humoral Immune

Several mouse monoclonal IgG antibodies (AB1, AB2, AB3, and AB5) were developed that reacted with a 140,000 mol wt glycoprotein on the surface of cultured RAJI B lymphoid cells. The antibodies reacted with purified normal human peripheral blood B cells and CLL Ig+ B cells and showed specific germinal center and mantle zone staining in tissue sections of secondary lymphoid organs. Immunodepletion studies using 125I surface-labeled Raji cell membrane antigens demonstrated that the antigen identified by AB5 is the same 140,000 mol wt glycoprotein detected by anti-B2 that has recently been shown to react with the C3d fragment or CR2 receptor. (Iida et al: J Exp Med 158:1021, 1983). Addition of the AB series and anti-B2 monoclonal antibodies to cultures of purified human peripheral blood B cells resulted in the uptake of 3H- thymidine at two to six times background control levels provided that irradiated autologous T cells were added to the culture. Stimulation was not evoked by other monoclonal antibodies to B cell surface molecules (ie, B1, BA-1, BA-2, and HLA-DR). Pepsin-generated F(ab')2 fragments of anti-CR2 antibodies were essentially as effective as the intact IgG molecule in stimulating B cells. Induction of B cell proliferation by antibody binding to CR2 suggests that the C3d receptor may have an integral role in regulation of humoral immune response.

scholarly journals P09.01 Adoptive cell therapy of hematological malignancies using cytokine-induced killer cells retargeted with monoclonal antibodies

2020 ◽  
Vol 8 (Suppl 2) ◽  
pp. A51.2-A52
Author(s):  
A Dalla Pietà ◽  
E Cappuzzello ◽  
P Palmerini ◽  
R Sommaggio ◽  
G Astori ◽  
...  
Keyword(s):  
Monoclonal Antibodies ◽  
Cell Therapy ◽  
B Cell ◽  
Cell Lymphoma ◽  
Adoptive Cell Therapy ◽  
B Cell Lymphoma ◽  
Clinical Grade ◽  
Cik Cells

BackgroundCytokine-Induced Killer (CIK) cells are a population of effector cells that represents a promising tool for adoptive cell therapy. They are easily expandable ex-vivo, safe, and exert cytotoxicity against a broad range of tumor histotypes.1 We recently reported that they have a relevant expression of FcγRIIIa (CD16a), which can be exploited in combination with clinical-grade monoclonal antibodies (mAbs) to redirect their cytotoxicity in an antigen-specific manner, to improve their antitumor activity.2 Indeed, the engagement of CD16a on CIK cells leads to a potent antibody-dependent cell-mediated cytotoxicity (ADCC) against ovarian cancer both in vitro and in vivo. Based on this observation, we investigated whether CIK cells can be specifically retargeted against B-cell malignancies by combination with anti-CD20 mAbs, namely Rituximab® (RTX) and Obinutuzumab® (OBI).Materials and MethodsCIK cells were obtained from peripheral blood mononuclear cells of healthy donors, and stimulated in vitro with IFN-γ, CD3 mAb and IL-2 for 14 days; fresh IL-2 was provided every 3–4 days. CIK cell phenotype was analyzed by multicolor flow cytometry; cytotoxic activity was assessed by calcein AM-release assay against B-cell lines, primary samples and patient-derived xenografts (PDX) obtained from B-cell lymphoma patients after written informed consent.ResultsThe combination with both RTX and OBI significantly increased specific CIK cells lysis against several CD20-expressing lymphoma B cell lines, primary tumors from B-cell lymphoma patients and an established PDX, compared to the combination with a control mAb (cetuximab, CTX). NK-depletion demonstrated that the mAb-mediated cytotoxicity is accountable to the CIK cells fraction within the bulk population since no difference in the lytic activity was detectd in the absence of NK cells. In addition, these results are further supported by in vivo preliminary experiments where the treatment with CIK cells in combination with OBI extensively reduced the growth of PDX and increased mice survival, compared to CIK cells or OBI administered alone.ConclusionsHere we proved that CIK cells can be retargeted with clinical-grade mAbs against CD20-expressing lymphomas. These data indicate that the combination of CIK cells with mAbs can represent a novel approach for the treatment of haematological malignancies.ReferencesFranceschetti M, Pievani A, Borleri G, Vago L, Fleischhauer K, Golay J, et al. Cytokine-induced killer cells are terminally differentiated activated CD8 cytotoxic T-EMRA lymphocytes. Exp Hematol 2009;37:616–28.Cappuzzello E, Tosi A, Zanovello P, Sommaggio R, Rosato A. Retargeting cytokine-induced killer cell activity by CD16 engagement with clinical-grade antibodies. Oncoimmunology 2016 Aug;5(8):e1199311.The research leading to these results has received funding from Fondazione AIRC under IG 2018 - ID. 21354 project - P.I. Rosato AntonioDisclosure InformationA. Dalla Pietà: None. E. Cappuzzello: None. P. Palmerini: None. R. Sommaggio: None. G. Astori: None. K. Chieregato: None. O. Perbellini: None. M. Tisi: None. C. Visco: None. M. Ruggeri: None. A. Rosato: None.

EBV Transformation of Tonsil Germinal Centre B Cells Carrying Functionally Inactivated IgV Gene.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 3248-3248
Author(s):  
Sridhar Chaganti ◽  
Noelia Begue Pastor ◽  
Mark T. Drayson ◽  
Andy I. Bell ◽  
Alan B. Rickinson
Keyword(s):  
B Cells ◽  
B Cell ◽  
Somatic Hypermutation ◽  
B Cell Lymphoma ◽  
Affinity Maturation ◽  
Germinal Centre ◽  
Chain Gene ◽  
Lymphoid Tissues ◽  
Memory B Cell

Abstract Somatic hypermutation of immunoglobulin (Ig) gene sequences in the germinal centres of lymphoid tissues is necessary for affinity maturation of B cell responses to antigen challenge. This process generates a few clones with improved affinity that are selected into B cell memory and many clones with other non favourable Ig mutations, including some cells with functionally inactivated Ig gene that normally die by apoptosis. It is postulated that infection with Epstein-Barr virus (EBV), a B lymphotropic agent linked to several types of B cell lymphoma, can rescue germinal centre cells with unfavourable mutations. This creates a pool of infected cells at greater risk of developing into lymphomas. In the present work, CD38+ germinal centre B cells were separated from tonsil by negative selection for IgD and CD39. Peripheral blood naïve and memory B cell subpopulations were FACS sorted as IgD+, CD27− and IgD−, CD27+ fractions respectively. These cells were infected with EBV (B95.8 strain) in vitro and seeded at limiting dilutions onto fibroblast feeders. EBV transformed lymphoblastoid cell lines (LCLs) from such cultures were analysed for surface Ig phenotype. Naïve B cell transformants were consistently IgM+, IgD+. Memory B cell transformants were IgM+ in some cases but more frequently IgG+ or IgA+. Germinal centre transformants showed the same spectrum of surface Ig phenotypes as memory cell transformants but in addition we identified six germinal centre derived LCLs which were consistently surface Ig negative. Sequencing from these lines confirmed that in at least three cases EBV had rescued cells with functionally inactivated Ig heavy chain gene.

Pathologic Co-Expression and Physical Interaction of c-MYC and BCL6 in B-Cell Lymphomas.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 2-2 ◽  
Author(s):  
Masumichi Saito ◽  
Ryan T. Phan ◽  
Herbert C. Morse ◽  
Laura Pasqualucci ◽  
Riccardo Dalla-Favera
Keyword(s):  
B Cells ◽  
B Cell ◽  
Cell Lymphoma ◽  
Somatic Hypermutation ◽  
B Cell Lymphoma ◽  
Transgenic Animals ◽  
Primary Lymphoma ◽  
Physical Interaction

Abstract Deregulated expression of the proto-oncogenes BCL6 and c-MYC caused by chromosomal translocation or somatic hypermutation is common in non-Hodgkin B cell lymphoma derived from germinal center (GC) B cells, including diffuse large cell lymphoma (DLBCL) and Burkitt lymphoma (BL). Normal GC B cells express BCL6, whereas, surprisingly, they do not express c-MYC, suggesting that the expression of this oncogene in BL and DLBCL (20% of cases) is ectopic (Klein, U. et al. Proc Natl Acad Sci U S A100, 2639–2644, 2003). Here we report that c-MYC is absent in proliferating GC B cells because it is transcriptionally suppressed by BCL6, as demonstrated by the presence of specific BCL6 binding sites in the c-MYC promoter region and by chromatin immunoprecipitation experiments showing that BCL6 is bound to these sites in vivo. Thus, c-MYC escapes BCL6-mediated suppression in lymphoma leading to the co-expression of the two transcription factors, an event never observed in immunohistochemical and gene expression profile analysis of normal GC B cells. Surprisingly, co-immunoprecipitation experiments and in vitro binding experiments indicate that, when co-expressed, BCL6 and c-MYC are physically bound in a novel complex detectable in DLBCL and BL cell lines as well as in primary lymphoma cases. The formation of the BCL6/c-MYC complex has several significant functional consequences on the function of both c-MYC and BCL6: 1) a two fold, BCL6-binding dependent increase in c-MYC half-life, an event that has been shown to contribute to its oncogenic activation; 2) a synergistic increase in the ability of both BCL6 and c-MYC to suppress MIZ1-activated transcription of the p21CIP cell cycle arrest gene; 3) MYC-dependent inhibition of BCL6 acetylation by p300, an event that physiologically inactivates BCL6 via c-MYC-mediated recruitment of HDAC. Notably, the pathologic co-expression of c-MYC and BCL6 was shown to have pathologic consequences in vivo, since double transgenic BCL6/c-MYC mice display accelerated lymphoma development and the appearance of a novel GC-derived tumor phenotype not recognizable in single transgenic animals and containing the pathologic c-MYC/BCL6 complex. Thus, the pathologic co-expression and illegitimate physical interaction of BCL6 and c-MYC leads to an increase in the constitutive activity of both oncogenes. These results identify a novel mechanism of oncogenic function for BCL6 and c-MYC and a novel tumor-specific protein complex of potential therapeutic interest.

Potent B-Cell Depletion by IMGN529, a CD37-Targeting Antibody-Maytansinoid Conjugate for the Treatment of B-Cell Malignancies,

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 3726-3726
Author(s):  
Jutta Deckert ◽  
Sharon Chicklas ◽  
Yong Yi ◽  
Min Li ◽  
Jan Pinkas ◽  
...  
Keyword(s):  
T Cells ◽  
B Cells ◽  
B Cell ◽  
Whole Blood ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Cell Depletion ◽  
B Cell Depletion ◽  
B Cell Malignancies

Abstract Abstract 3726 CD37 is a B-cell surface antigen which is widely expressed on malignant B cells in non-Hodgkin's lymphoma (NHL) and chronic lymphocytic leukemia (CLL). In normal tissues CD37 expression is limited to blood cells and lymphoid tissues. This restricted expression profile makes CD37 an attractive therapeutic target for antibodies and antibody-drug conjugates. We developed a novel anti-CD37 antibody, K7153A, which provides a unique combination of functional properties: it demonstrated strong pro-apoptotic and direct cell killing activity against NHL cell lines and could mediate effector activity such as CDC and ADCC. The antibody-maytansinoid conjugate, IMGN529, was produced by conjugation of K7153A with the potent maytansinoid, DM1, via the non-cleavable linker, SMCC. The direct cytotoxic potency of the K7153A antibody was superior to that of the CD20-directed rituximab and was further enhanced with maytansinoid conjugation in IMGN529. In vivo, IMGN529 demonstrated better anti-tumor activity than the K7153A antibody in established subcutaneous follicular lymphoma (FL), diffuse large B-cell lymphoma (DLBCL), and CLL xenograft models in SCID mice. A single administration of IMGN529 showed similar or improved efficacy compared to anti-CD20 antibodies or standard chemotherapy where tested. Immunohistochemical (IHC) staining of formalin fixed paraffin-embedded (FFPE) NHL tissue sections was performed to evaluate CD37 expression. CD37 exhibited a similar prevalence to CD20 in subtypes of NHL such as FL, DLBCL, Burkitt's lymphoma (BL) and mantle cell lymphoma (MCL). B-cell depletion is an important measure of efficacy for targeted therapies, such as CD20-directed antibodies, in B-cell malignancies. CD37 expression in blood cells from healthy human donors was measured by quantitative flow cytometry in comparison to CD20. The greatest CD37 expression was found in B cells at approximately 77,000 antibodies bound per cell (ABC), which was similar to CD20 expression in B cells at 95,000 ABC. In other blood cell types CD37 staining was seen at low levels, about 2,000 – 5,000 ABC, in monocytes, NK cells and T cells. In vitro depletion experiments were performed with purified peripheral blood mononuclear cells (PBMCs) and with whole blood, both derived from several healthy donors. Cells were incubated for 1 hr with 10 μg/mL of either K7153A, IMGN529, CD37-targeting TRU-016, rituximab or the anti-CD52 antibody alemtuzumab, with cell depletion determined relative to counting beads by flow cytometry. The K7153A antibody and the IMGN529 conjugate efficiently and specifically depleted B-cells in a dose-dependent manner in the context of purified PBMCs and whole blood. With purified PBMCs, both K7153A and IMGN529 caused 50–60% depletion of B cells, with little to no depletion of T cells or monocytes. IMGN529 was more potent than rituximab, which led to 30–40% B-cell depletion, or TRU-016, which caused 20–30% B-cell depletion. IMGN529 also was more specific than alemtuzumab, which depleted T-cells and monocytes as well as B cells. With whole blood samples, both K7153A and IMGN529 resulted in 30–40% B-cell depletion with no effect on T cells, NK cells or monocytes. IMGN529 was again more potent than rituximab or TRU-016, which caused approximately 10% B-cell depletion, and was more specific than alemtuzumab, which depleted the majority of T cells in addition to 40% of B cells. IMGN529 embodies a unique B-cell targeted agent as it combines the intrinsic pro-apoptotic, CDC and ADCC activities of its anti-CD37 antibody component with the potent cytotoxic mechanism provided by the targeted delivery of its maytansinoid payload. It is highly active in vitro and in vivo against B-cell lymphoma and CLL cell lines. In addition, it mediates specific B-cell depletion in vitro that is greater than B-cell depletion by CD20-directed rituximab. Together, these findings indicate that IMGN529 is a promising therapeutic candidate for the treatment of B-cell malignancies. Disclosures: Deckert: ImmunoGen, Inc.: Employment. Chicklas:ImmunoGen, Inc.: Employment. Yi:ImmunoGen, Inc.: Employment. Li:ImmunoGen, Inc.: Employment. Pinkas:ImmunoGen, Inc.: Employment. Chittenden:ImmunoGen, Inc.: Employment. Lutz:ImmunoGen, Inc.: Employment. Park:ImmunoGen, Inc.: Employment.

Phase I/Ib Study of the Novel Immunotoxin MT-3724 in Relapsed/Refractory Non-Hodgkin's B-Cell Lymphoma (NHL)

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 5112-5112
Author(s):  
Paul A Hamlin ◽  
Catherine S. Diefenbach ◽  
David J. Valacer ◽  
Jack Higgins ◽  
Michelle A. Fanale
Keyword(s):  
B Cells ◽  
Phase I ◽  
B Cell ◽  
Board Of Directors ◽  
Research Funding ◽  
B Cell Lymphoma ◽  
Advisory Committees ◽  
Dose Cohort ◽  
Mixed Response

Abstract Background CD20 is selectively expressed on the surface of early pre-B-cells, remains throughout B-cell development, and is then lost from plasma cells. Because CD20 is present on the majority of B-cell lymphomas, anti-CD20 monoclonal antibody (MAb) therapy is widely employed in the treatment of NHL. However a majority of NHL patients eventually become refractory to CD20 MAb(s). Resistance mechanisms may include increased MAb catabolism, initial or post treatment selection of low CD20 expressing tumor cells, trogocytosis of surface CD20, failure of MAb effector mechanisms and/or impaired patient immune cell function. MT-3724 is a recombinant fusion protein consisting of a CD20 binding variable fragment (scFv) fused to the enzymatically active Shiga-like toxin-I A1 subunit (SLT-I A1). SLT-I A1 is an N-glycosidase that catalytically inactivates 60S ribosomal subunits causing inhibition of protein synthesis. Upon its scFv binding to cell surface CD20 in vitro, SLT-I A1 forces MT-3724 internalization which then routes in a predictable fashion to the cytosol and irreversibly inactivates the cell ribosomes triggering cell death. MT-3724 has been shown to specifically bind and kill CD20+ malignant human B-cells in vitro and non-human primate (NHP) B-cells in vivo. MT-3724 was tested for safety in healthy NHPs: 6 intravenous (IV) doses of MT-3724 were given over 12 days at doses of 50, 150, and 450 mcg/kg. There were no deaths or effects on serum chemistries in the NHP studies. The major observed toxicity (inappetence) resolved within 48 hours of last dose. There was a significant, dose-dependent NHP B-cell depletion by Day 3 at all doses. Given the preclinical activity and mechanism of action, a Phase I/Ib study of MT-3724 was initiated in NHL. Methods MT-3724 is being tested for safety and tolerability in a first-in-human, open label, ascending dose study (3 + 3 design) in sequential cohorts of 5, 10, 20 and 50 mcg/kg/dose. Eligible subjects who previously responded to a CD20 MAb containing therapy followed by relapse/recurrence of NHL receive 6 doses by 2 hour IV infusions over the first 12 days of a 28 day cycle (first cycle). With continued safety, tolerability and lack of tumor progression, subjects may receive up to 4 additional 6-dose cycles (21 days) with tumor assessments after cycles 2, 4 and 5. Dose escalation is based on < 33% dose limiting toxicities (DLTs) observed during the first 28 day cycle. Results Three NHL subjects (2 transformed DLBCL, 1 FL) have completed at least one cycle in the 5 mcg/kg/dose cohort with no protocol DLTs or infusion related reactions and are evaluable for safety. Non-DLTs included grade (Gr) 2-3 transient hyperglycemic episodes related to pre-infusion corticosteroid therapy (n=1); transient Gr 4 neutropenia, possibly related to MT-3724 during cycle 1, week 4 (n=1); Gr 4 hypercalcemia and acute kidney injury with Gr 3 hypophosphatemia during cycle 1, week 4 due to leukemic disease progression (n=1). Subject 1 completed 5 cycles of therapy, with a partial response achieved post cycle 2 sustained through cycle 5; Subject 3 had a mixed response (both subjects had transformed DLBCL). Three subjects have now initiated treatment in the 10 mcg/kg/dose cohort with updated data to be presented at the meeting. Conclusions MT-3724 at 5 mcg/kg/dose has been safely administered for up to 5 cycles in this first-in-human study in relapsed/refractory NHL subjects. Treatment with the 10 mcg/kg cohort has commenced with continuing dose ascension planned. There is early evidence of clinical activity. Disclosures Diefenbach: Gilead: Equity Ownership, Research Funding, Speakers Bureau; Jannsen Oncology: Consultancy; Idera: Consultancy; Immunogen: Consultancy; Incyte: Research Funding; Genentech: Research Funding; Celgene: Consultancy; Molecular Templates: Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding. Valacer:Molecular Templates: Employment. Higgins:Molecular Templates: Employment. Fanale:Merck: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Honoraria, Research Funding; Infinity: Membership on an entity's Board of Directors or advisory committees; Spectrum: Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Honoraria, Research Funding; Genentech: Research Funding; Medimmune: Research Funding; Novartis: Research Funding; Bayer: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Molecular Templates: Research Funding; ADC Therapeutics: Research Funding; Onyx: Research Funding; Gilead: Research Funding.

scholarly journals Phospholipase Cγ2 Contributes to Light-Chain Gene Activation and Receptor Editing

2007 ◽  
Vol 27 (17) ◽  
pp. 5957-5967 ◽  
Author(s):  
Li Bai ◽  
Yuhong Chen ◽  
Yinghong He ◽  
Xuezhi Dai ◽  
Xueyan Lin ◽  
...  
Keyword(s):  
B Cells ◽  
B Cell ◽  
Light Chain ◽  
Gene Activation ◽  
Chain Gene ◽  
Receptor Editing ◽  
Light Chain Gene ◽  
Transitional Type

ABSTRACT Phospholipase Cγ2 (PLCγ2) is critical for pre-B-cell receptor (pre-BCR) and BCR signaling. Current studies discovered that PLCγ2-deficient mice had reduced immunoglobulin λ (Igλ) light-chain usage throughout B-cell maturation stages, including transitional type 1 (T1), transitional type 2 (T2), and mature follicular B cells. The reduction of Igλ rearrangement by PLCγ2 deficiency was not due to specifically increased apoptosis or decreased proliferation of mutant Igλ+ B cells, as lack of PLCγ2 exerted a similar effect on apoptosis and proliferation of both Igλ+ and Igκ+ B cells. Moreover, PLCγ2-deficient IgHEL transgenic B cells exhibited an impairment of antigen-induced receptor editing among both the endogenous λ and κ loci in vitro and in vivo. Importantly, PLCγ2 deficiency impaired BCR-induced expression of IRF-4 and IRF-8, the two transcription factors critical for λ and κ light-chain rearrangements. Taken together, these data demonstrate that the PLCγ2 signaling pathway plays a role in activation of light-chain loci and contributes to receptor editing.

scholarly journals Anti-CD19 monoclonal antibodies for the treatment of relapsed or refractory B-cell malignancies: a narrative review with focus on diffuse large B-cell lymphoma

2021 ◽  
Author(s):  
Pier Luigi Zinzani ◽  
Giorgio Minotti
Keyword(s):  
Monoclonal Antibodies ◽  
B Cells ◽  
B Cell ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Cell Leukaemia ◽  
Antibody Drug Conjugate ◽  
B Cell Malignancies ◽  
Large B Cell Lymphoma ◽  
Large B Cell

Abstract Purpose CD19 is a cell surface protein that is found on both healthy and malignant B cells. Accordingly, it has become an important target for novel treatments for non-Hodgkin lymphomas and B-cell leukaemia. Three anti-CD19 monoclonal antibodies with distinct mechanisms of action have been developed for the treatment of B-cell malignancies. Methods We reviewed the preclinical and clinical data on the development of the newly approved anti-CD19 monoclonal antibodies blinatumomab, tafasitamab and loncastuximab tesirine, and consider their place in the treatment of relapsed or refractory B-cell malignancies. Results Blinatumomab is a bispecific T-cell engager that binds to both CD19 on B cells and CD3 on T cells, facilitating antibody-dependent cytotoxicity. Blinatumomab significantly prolongs overall survival in patients with relapsed or refractory B-cell acute lymphoblastic leukaemia, although cytokine release syndrome and severe neurotoxicity may necessitate discontinuation. Tafasitamab, which has modified anti-CD19 Fab and Fc regions, has significantly enhanced affinity for both CD19 and effector cell receptors compared with unmodified anti-CD19. In L-MIND, tafasitamab plus lenalidomide provided an overall response rate (ORR) of 57.5% in patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL) in patients non-transplant eligible. Loncastuximab tesirine is an antibody–drug conjugate that has been studied as monotherapy and in combination with ibrutinib in 3L + relapsed or refractory DLBCL. The ORR was 48.3% in a phase II trial of loncastuximab tesirine. The optimal place of anti-CD19 monoclonal antibodies in therapy has yet to be determined, but the prospect of improved outcomes for at least some patients with treatment-resistant B-cell malignancies appears likely, particularly in those with limited therapeutic options and poor prognosis.

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