A CD40L-targeting protein reduces autoantibodies and improves disease activity in patients with autoimmunity

2019 ◽  
Vol 11 (489) ◽  
pp. eaar6584 ◽  
Author(s):  
Jodi L. Karnell ◽  
Marius Albulescu ◽  
Stacey Drabic ◽  
Liangwei Wang ◽  
Rachel Moate ◽  
...  
Keyword(s):  
B Cells ◽  
Disease Activity ◽  
Plasma Cell ◽  
Cell Activation ◽  
Phase 1 ◽  
Clinical Results ◽  
Gene Signature ◽  
Induce Platelet Aggregation ◽  
Humoral Immune ◽  
Dose Dependent

The CD40/CD40L axis plays a central role in the generation of humoral immune responses and is an attractive target for treating autoimmune diseases in the clinic. Here, we report the generation and clinical results of a CD40L binding protein, VIB4920, which lacks an Fc domain, therefore avoiding platelet-related safety issues observed with earlier monoclonal antibody therapeutics that targeted CD40L. VIB4920 blocked downstream CD40 signaling events, resulting in inhibition of human B cell activation and plasma cell differentiation, and did not induce platelet aggregation in preclinical studies. In a phase 1 study in healthy volunteers, VIB4920 suppressed antigen-specific IgG in a dose-dependent fashion after priming and boosting with the T-dependent antigen, KLH. Furthermore, VIB4920 significantly reduced circulating Ki67+ dividing B cells, class-switched memory B cells, and a plasma cell gene signature after immunization. In a phase 1b proof-of-concept study in patients with rheumatoid arthritis, VIB4920 significantly decreased disease activity, achieving low disease activity or clinical remission in more than 50% of patients in the two higher-dose groups. Dose-dependent decreases in rheumatoid factor autoantibodies and Vectra DA biomarker score provide additional evidence that VIB4920 effectively blocked the CD40/CD40L pathway. VIB4920 demonstrated a good overall safety profile in both clinical studies. Together, these data demonstrate the potential of VIB4920 to significantly affect autoimmune disease and humoral immune activation and to support further evaluation of this molecule in inflammatory conditions.

scholarly journals Clinical Results with a B Cell Activating Anti-CD73 Antibody for the Immunotherapy of COVID-19

2021 ◽  
Author(s):  
Richard A. Miller ◽  
Pramod Guru ◽  
Philippe Bauer ◽  
Jorge Robles ◽  
Christian Tomaszewski ◽  
...  
Keyword(s):  
B Cells ◽  
Viral Infections ◽  
Phase 1 ◽  
Lymphocyte Activation ◽  
Clinical Results ◽  
Hospitalized Patients ◽  
Double Blind ◽  
Humoral Immune ◽  
Novel Approach ◽  
Rapid Generation

ABSTRACTRobust polyclonal humoral immune responses have the potential to generate a diverse set of antibodies to neutralize and eliminate viruses such as SARS-CoV-2 and protect against transmission, re-infection and the evolution of variants that evade immunity. CD73 is present on subsets of human B and T cells where it plays a role in lymphocyte activation and migration. CD73 also functions as an ectoenzyme that converts AMP into immunosuppressive adenosine. We have developed a humanized anti-CD73 antibody, mupadolimab (CPI-006), that blocks CD73 enzymatic activity and activates CD73POS B cells, thereby inducing differentiation into plasmablasts, immunoglobulin class switching, and antibody secretion independent of the adenosine modulatory activity. These effects suggest mupadolimab may enhance the magnitude, diversity, and duration of anti-viral responses in patients with COVID-19. This hypothesis was tested in a dose escalation phase 1 trial in 29 hospitalized patients with COVID-19. Single doses of 0.3 mg/kg – 5 mg/kg mupadolimab were well tolerated with no drug related adverse events. Doses greater than 0.3 mg/kg resulted in rapid generation of IgG and IgM to SARS-CoV-2 significantly above titers measured in convalescent controls, with elevated IgG titers sustained for more than 6 months beyond presentation of symptoms. Based on these findings, a randomized double-blind, placebo-controlled Phase 3 study in hospitalized patients was initiated. The primary endpoint was proportion of patients alive and free from respiratory failure within 28 days. This trial was discontinued early during the period of waning COVID-19 incidence after enrolling 40 patients. Although underpowered, results from this trial suggest improvement in the primary and key secondary endpoints in patients treated with single doses of 2 mg/kg and 1 mg/kg compared to placebo. The presumed mechanism of action, stimulation of B cells, may represent a novel approach to immunotherapy of COVID-19 and other viral infections.

Identification and stratification of systemic lupus erythematosus patients into two transcriptionally distinct clusters based on IFN-I signature

Lupus ◽  
2021 ◽  
pp. 096120332199010
Author(s):  
Vineeta Shobha ◽  
Anu Mohan ◽  
AV Malini ◽  
Puneet Chopra ◽  
Preethi Karunanithi ◽  
...  
Keyword(s):  
Systemic Lupus Erythematosus ◽  
Disease Activity ◽  
Lupus Erythematosus ◽  
Time Course ◽  
Cell Activation ◽  
Immune Cell ◽  
Gene Signature ◽  
Systemic Lupus ◽  
Auto Antibody ◽  
Activation Status

Objective Despite the significant advancement in the understanding of the pathophysiology of systemic lupus erythematosus (SLE) variable clinical response to newer therapies remain a major concern, especially for patients with lupus nephritis and neuropsychiatric systemic lupus erythematosus (NPSLE). We performed this study with an objective to comprehensively characterize Indian SLE patients with renal and neuropsychiatric manifestation with respect to their gene signature, cytokine profile and immune cell phenotypes. Methods We characterized 68 Indian SLE subjects with diverse clinical profiles and disease activity and tried to identify differentially expressed genes and enriched pathways. To understand the temporal profile, same patients were followed at 6 and 12-months intervals. Additionally, auto-antibody profile, levels of various chemokines, cytokines and the proportion of different immune cells and their activation status were captured in these subjects. Results Multiple IFN-related pathways were enriched with significant increase in IFN-I gene signature in SLE patients as compared to normal healthy volunteers (NHV). We identified two transcriptionally distinct clusters within the same cohort of SLE patients with differential immune cell activation status, auto-antibody as well as plasma chemokines and cytokines profile. Conclusions Identification of two distinct clusters of patients based on IFN-I signature provided new insights into the heterogeneity of underlying disease pathogenesis of Indian SLE cohort. Importantly, patient within those clusters retain their distinct expression dynamics of IFN-I signature over the time course of one year despite change in disease activity. This study will guide clinicians and researchers while designing future clinical trials on Indian SLE cohort.

scholarly journals Complement receptors regulate differentiation of bone marrow plasma cell precursors expressing transcription factors Blimp-1 and XBP-1

2005 ◽  
Vol 201 (6) ◽  
pp. 993-1005 ◽  
Author(s):  
Dominique Gatto ◽  
Thomas Pfister ◽  
Andrea Jegerlehner ◽  
Stephen W. Martin ◽  
Manfred Kopf ◽  
...  
Keyword(s):  
Bone Marrow ◽  
B Cells ◽  
B Cell ◽  
Plasma Cell ◽  
Cell Activation ◽  
Plasma Cells ◽  
Antibody Responses ◽  
Complement Receptors ◽  
Essentially Normal ◽  
Bone Marrow Plasma

Humoral immune responses are thought to be enhanced by complement-mediated recruitment of the CD21–CD19–CD81 coreceptor complex into the B cell antigen receptor (BCR) complex, which lowers the threshold of B cell activation and increases the survival and proliferative capacity of responding B cells. To investigate the role of the CD21–CD35 complement receptors in the generation of B cell memory, we analyzed the response against viral particles derived from the bacteriophage Qβ in mice deficient in CD21–CD35 (Cr2−/−). Despite highly efficient induction of early antibody responses and germinal center (GC) reactions to immunization with Qβ, Cr2−/− mice exhibited impaired antibody persistence paralleled by a strongly reduced development of bone marrow plasma cells. Surprisingly, antigen-specific memory B cells were essentially normal in these mice. In the absence of CD21-mediated costimulation, Qβ-specific post-GC B cells failed to induce the transcriptional regulators Blimp-1 and XBP-1 driving plasma cell differentiation, and the antiapoptotic protein Bcl-2, which resulted in failure to generate the precursor population of long-lived plasma cells residing in the bone marrow. These results suggest that complement receptors maintain antibody responses by delivery of differentiation and survival signals to precursors of bone marrow plasma cells.

scholarly journals SWAP-70 deficiency causes high-affinity plasma cell generation despite impaired germinal center formation

Blood ◽  
2008 ◽  
Vol 111 (5) ◽  
pp. 2714-2724 ◽  
Author(s):  
Laurence Quemeneur ◽  
Veronique Angeli ◽  
Michael Chopin ◽  
Rolf Jessberger
Keyword(s):  
B Cells ◽  
Plasma Cell ◽  
Cell Activation ◽  
Plasma Cells ◽  
Actin Binding ◽  
B Cell Activation ◽  
Interacting Protein ◽  
Memory Response ◽  
High Affinity

Germinal centers (GCs) are lymphoid tissue structures central to the generation of long-lived, high-affinity, antibody-forming B cells. However, induction, maintenance, and regulation of GCs are not sufficiently understood. The F-actin–binding, Rac-interacting protein SWAP-70 is strongly expressed in activated B cells like those in B follicles. Recent work suggests that SWAP-70 is involved in B-cell activation, migration, and homing. Therefore, we investigated the role of SWAP-70 in the T-dependent immune response, in GC formation, and in differentiation into plasma and memory B cells. Compared with wt, sheep red blood cell (SRBC)–, or NP-KLH–immunized SWAP-70−/− mice have strongly reduced numbers of GCs and GC-specific B cells. However, SWAP-70−/− NP-specific B cells accumulate outside of the B follicles, and SWAP-70−/− mice show more plasma cells in the red pulp and in the bone marrow, and increased NP-specific Ig and antibody-forming B cells. Yet the memory response is impaired. Thus, SWAP-70 deficiency uncouples GC formation from T-dependent antibody and long-lived plasma cell production and causes extrafollicular generation of high-affinity plasma cells, but does not adequately support the memory response.

Blinatumomab exposure and pharmacodynamic response in patients with non-Hodgkin lymphoma (NHL).

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 3051-3051 ◽  
Author(s):  
Youssef Hijazi ◽  
Matthias Klinger ◽  
Andrea Schub ◽  
Benjamin Wu ◽  
Min Zhu ◽  
...  
Keyword(s):  
T Cell ◽  
B Cells ◽  
B Cell ◽  
Phase 1 ◽  
Cell Depletion ◽  
B Cell Depletion ◽  
Dose Requirement ◽  
Time Curve ◽  
Cell Counts ◽  
Dose Dependent

3051 Background: Blinatumomab (AMG 103) is an investigational, bispecific, T cell engaging (BiTE) antibody targeting CD19-expressing B cells. We describe the exposure-pharmacodynamic (PD) response of blinatumomab in patients with NHL, using a quantitative pharmacology approach. Methods: In a phase 1 study, 76 patients with NHL received blinatumomab by continuous intravenous infusion (cIV) at doses of 0.5 to 90 μg/m2/d in 4- or 8-week cycles. Pharmacokinetics (PK) was determined. PD responses evaluated included lymphocytes and cytokines measured during treatment, and sum of the products of the greatest diameters of tumor size in lymph nodes (SPD) at the end of treatment. Blinatumomab concentration at steady state (Css) and the cumulative area under the concentration (AUCcum)–time curve over the period before the evaluation of SPD were used to evaluate the exposure-SPD relationship. Results: Blinatumomab showed linear PK. Early PD responses were characterized by B cell depletion, T cell redistribution, and transient cytokine release. Following cIV at doses from 0.5 to 90 μg/m2/d, B cells declined at a first-order rate with a dose-dependent rate constant, ranging from 0.16 to 1.0 h-1. Complete B cell depletion was achieved within 48 hours at doses ≥5 μg/m2/d. A dose-independent decrease in T cell counts was observed within 24 hours after dosing, and T cells returned to baseline within 2 weeks of treatment. Cytokine elevation occurred in some patients and was dose-dependent. Blinatumomab exposure-SPD relationship was best described by an inhibitory Emax model (E = E0-(Imax*C)/(IC50+C)). According to the model estimation, a 50% reduction in SPD would be achieved when Css is 2141 pg/mL and AUCcum is 1381 h*μg/L, equivalent to a blinatumomab dose of 54 µg/m2/d given over 27 days. Conclusions: B lymphocytes were completely depleted from the circulation at blinatumomab doses ≥5 μg/m2/d. Depletion was faster at higher doses. Higher blinatumomab Css and AUCcum were associated with better tumor reduction. Tissue accessibility may explain the higher dose requirement for SPD reduction versus peripheral B cell depletion. The PK/PD model has utility for the design of future studies of blinatumomab in NHL. Clinical trial information: NCT00274742.

Dok-3 plays a nonredundant role in negative regulation of B-cell activation

Blood ◽  
2007 ◽  
Vol 110 (1) ◽  
pp. 259-266 ◽  
Author(s):  
Chee-Hoe Ng ◽  
Shengli Xu ◽  
Kong-Peng Lam
Keyword(s):  
B Cells ◽  
B Cell ◽  
Cell Activation ◽  
Cell Receptor ◽  
Negative Regulation ◽  
Myelogenous Leukemia ◽  
Type I ◽  
B Cell Activation ◽  
Humoral Immune ◽  
Humoral Immune Responses

p62dok and Dok-3 are members of the Dok family of adaptors found in B cells, with the former cloned as a substrate of the p210bcr/abl oncoprotein in Ph + chronic myelogenous leukemia. A role for p62dok in FcγRIIB–mediated negative regulation of B-cell proliferation had been established previously. Here, we generated Dok-3−/− mice to assess the function of Dok-3 in B cells. Mice lacking Dok-3 have normal B-cell development but possess higher level of IgM antibodies in their sera. In comparison to wild-type mice, Dok-3−/− mice mounted significantly enhanced humoral immune responses to T cell–independent type I and II antigens. Dok-3–deficient B cells hyperproliferated, exhibited elevated level of calcium signaling as well as enhanced activation of NF-κB, JNK, and p38MAPK in response to B-cell receptor (BCR) engagement. In the absence of Dok-3, the localization of the inhibitory phosphatase SHIP-1 to the plasma membrane is intact while its phosphorylation is compromised, suggesting that Dok-3 could function to facilitate or sustain the activation of SHIP-1. The phenotype and responses of Dok-3−/− mice and B cells could be differentiated from those of the Dok-1−/− counterparts. Hence, we propose that Dok-3 plays a distinct and nonredundant role in the negative regulation of BCR signaling.

scholarly journals Cytoplasmic FOXO1 identifies a novel disease-activity associated B cell phenotype in SLE

2018 ◽  
Vol 5 (1) ◽  
pp. e000296 ◽  
Author(s):  
Molly K Hritzo Ahye ◽  
Amit Golding
Keyword(s):  
B Cells ◽  
Disease Activity ◽  
B Cell ◽  
Lupus Erythematosus ◽  
Cell Activation ◽  
Activity Index ◽  
Human Lymphocytes ◽  
Disease Activity Index ◽  
Memory B Cells ◽  
Cell Phenotype

Systemic lupus erythematosus (SLE) is a manifestation of hyperactivated lymphocytes and results, in part, from the loss of normal tolerance checkpoints. FOXO1 is a transcription factor involved at critical early and late B cell development checkpoints; however, its role in regulating peripheral B cell tolerance is not fully understood. We have applied our published approach for using imaging flow cytometry to study native FOXO1 localisation in human lymphocytes to peripheral blood samples from healthy individuals versus patients with SLE. We report, here, on dramatic cytoplasmic localisation of FOXO1 in two peripheral B cell SLE subsets: IgD-CD27+ (class-switched memory) B cells and IgD-CD27- (atypical memory) B cells. The latter, so-called ‘Double Negative’ (DN) B cells have previously been shown to be increased in SLE and enriched in autoreactive clones. Cytoplasmic-predominant FOXO1 (CytoFOX) B cells are significantly increased in patients with SLE as compared to healthy controls, and the levels of CytoFoOX DN B cells correlate directly with SLE disease activity. The highest abundance of CytoFox DN B cells was observed in African American females with SLE Disease Activity Index (SLEDAI)≥6. The phenotype of CytoFOX DN B cells in SLE includes uniquely low CD20 expression and high granularity/side scatter. As FOXO1 phosphorylation downstream of B cell receptor-dependent signalling is required for nuclear exclusion, CytoFOX B cells likely represent a high state of B cell activation with excess signalling and/or loss of phosphatase activity. We hypothesise that CytoFOX B cells in lupus represent a novel biomarker for the expansion of pathological, autoreactive B cells which may provide new insights into the pathophysiology of SLE.

scholarly journals The Toll-like Receptor Protein Rp105 Regulates Lipopolysaccharide Signaling in B Cells

2000 ◽  
Vol 192 (1) ◽  
pp. 23-30 ◽  
Author(s):  
Hirotaka Ogata ◽  
I-hsin Su ◽  
Kensuke Miyake ◽  
Yoshinori Nagai ◽  
Sachiko Akashi ◽  
...  
Keyword(s):  
B Cells ◽  
Immune Responses ◽  
B Cell ◽  
Neutralizing Antibodies ◽  
Cell Activation ◽  
Nuclear Factor Κb ◽  
Receptor Protein ◽  
B Cell Activation ◽  
Toll Like Receptor ◽  
Humoral Immune

The susceptibility to infections induced by Gram-negative bacteria is largely determined by innate immune responses to bacteria cell wall lipopolysaccharide (LPS). The stimulation of B cells by LPS enhances their antigen-presenting capacity and is accompanied by B cell proliferation and secretion of large quantities of LPS-neutralizing antibodies. Similar to macrophages and neutrophils, the LPS-induced activation of B cells is dependent on Toll-like receptor (TLR)4. Here, we demonstrate that the responses of B cells to LPS are also regulated by another TLR protein, RP105, which is predominantly expressed on mature B cells in mice and humans. The analysis of mice homozygous for the null mutation in the RP105 gene revealed impaired proliferative and humoral immune responses of RP105-deficient B cells to LPS. Using originally LPS-unresponsive Ba/F3 cells expressing exogenous TLR4 and RP105, we demonstrate the functional cooperation between TLR4 and RP105 in LPS-induced nuclear factor κB activation. These data suggest the existence of the TLR4–RP105 signaling module in the LPS-induced B cell activation.

scholarly journals Active Inhibition of Plasma Cell Development in Resting B Cells by Microphthalmia-associated Transcription Factor

2004 ◽  
Vol 200 (1) ◽  
pp. 115-122 ◽  
Author(s):  
Ling Lin ◽  
Andrea J. Gerth ◽  
Stanford L. Peng
Keyword(s):  
Transcription Factor ◽  
B Cells ◽  
B Cell ◽  
Plasma Cell ◽  
Cell Activation ◽  
Terminal Differentiation ◽  
B Cell Activation ◽  
Autoantibody Production ◽  
B Cell Homeostasis ◽  
Antibody Secretion

B cell terminal differentiation involves development into an antibody-secreting plasma cell, reflecting the concerted activation of proplasma cell transcriptional regulators, such as Blimp-1, IRF-4, and Xbp-1. Here, we show that the microphthalmia-associated transcription factor (Mitf) is highly expressed in naive B cells, where it antagonizes the process of terminal differentiation through the repression of IRF-4. Defective Mitf activity results in spontaneous B cell activation, antibody secretion, and autoantibody production. Conversely, ectopic Mitf expression suppresses the expression of IRF-4, the plasma cell marker CD138, and antibody secretion. Thus, Mitf regulates B cell homeostasis by suppressing the antibody-secreting fate.

scholarly journals BAFF-secreting neutrophils drive plasma cell responses during emergency granulopoiesis

2016 ◽  
Vol 213 (8) ◽  
pp. 1537-1553 ◽  
Author(s):  
Roham Parsa ◽  
Harald Lund ◽  
Anna-Maria Georgoudaki ◽  
Xing-Mei Zhang ◽  
André Ortlieb Guerreiro-Cacais ◽  
...  
Keyword(s):  
T Cell ◽  
B Cell ◽  
Plasma Cell ◽  
Cell Activation ◽  
Cell Function ◽  
Cell Formation ◽  
Dendritic Cell Activation ◽  
Humoral Immune ◽  
Cell Responses ◽  
The Impact

Prolonged infections or adjuvant usage can trigger emergency granulopoiesis (EG), leading to dysregulation in neutrophil blood counts. However, the impact of EG on T and B cell function remains largely unknown. In this study, to address this question, we used a mouse model of neutropenia and studied immune activation after adjuvant administration. The initial neutropenic state fostered an environment of increased dendritic cell activation and T cell–derived IL-17 production. Interestingly, neutropenic lysozyme 2–diphtheria toxin A mice exhibited striking EG and amplified neutrophil recruitment to the lymph nodes (LNs) that was dependent on IL-17–induced prostaglandin activity. The recruited neutrophils secreted a B cell–activating factor that highly accelerated plasma cell generation and antigen-specific antibody production. Reduction of neutrophil functions via granulocyte colony-stimulating factor neutralization significantly diminished plasma cell formation, directly linking EG with the humoral immune response. We conclude that neutrophils are capable of directly regulating T cell–dependent B cell responses in the LN.

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