meera ramanujam - Academia.edu (original) (raw)

Papers by meera ramanujam

Research paper thumbnail of II-06 Therapeutic blockade of immune complex-mediated glomerulonephritis by highly selective inhibition of bruton’s tyrosine kinase

Lupus Science & Medicine, 2016

Background Lupus nephritis (LN) is a potentially dangerous end organ pathology that affects upwar... more Background Lupus nephritis (LN) is a potentially dangerous end organ pathology that affects upwards of 50% of patients with systemic lupus erythematosus (SLE). Classical treatments for this condition have targeted the adaptive immune response and/or autoantibodies, rather than the inflammatory process itself. Besides its role in B cell development, Bruton’s tyrosine kinase (BTK) is important for Fc receptor signalling and macrophage polarisation. Furthermore, increasing evidence points to the role of the innate immune system, and particularly macrophages, in the pathogenesis of lupus nephritis. Materials and methods In this study, we investigated the effects of a novel, highly selective and potent BTK inhibitor, BI-BTK-1, in an inducible model of LN in which female 129/SvJ mice receive nephrotoxic serum (NTS) containing anti-glomerular antibodies. Mice were treated once daily with vehicle alone or BI-BTK-1 (0.3–10 mg/kg, n = 16/group), either prophylactically or therapeutically. Res...

Research paper thumbnail of BTK inhibition ameliorates renal, skin, and brain disease in a spontaneous murine model of systemic lupus erythematosus

Journal of Immunology, 2018

Systemic lupus erythematosus (SLE) can affect multiple different organ systems, including the kid... more Systemic lupus erythematosus (SLE) can affect multiple different organ systems, including the kidneys (lupus nephritis, LN), brain (neuropsychiatric SLE, NPSLE), and skin (cutaneous lupus, CLE). B cells and macrophages are implicated in the pathogenesis of these disease manifestations. We have previously shown the importance of Bruton’s tyrosine kinase (BTK), an enzyme important in B cell and macrophage signaling, in reversing disease in a model of immune nephritis induced by the passive transfer of nephrotoxic antibodies. To extend our findings to a more severe type of nephritis more similar to human disease and examine the effects of BTK inhibition on extra-renal lupus manifestations, we treated a spontaneous model of lupus, MRL/lpr mice, with the novel BTK inhibitor, BI-BTK-1. Early treatment with BI-BTK-1 normalized proteinuria (p MRL/lpr mice develop brain and skin disease that model the pathology of NPSLE and CLE, respectively. Early BI-BTK-1 treatment significantly improved c...

Research paper thumbnail of Epicutaneous Staphylococcus aureus induces IL-36 to enhance IgE production and ensuing allergic disease

Journal of Clinical Investigation, 2021

Boehringer Ingelheim, which is developing therapeutics targeting IL-36R inhibition in patients wi... more Boehringer Ingelheim, which is developing therapeutics targeting IL-36R inhibition in patients with atopic dermatitis and other inflammatory conditions. LSM is a full-time employee of Janssen Pharmaceuticals and holds Johnson & Johnson stock. LSM received prior grant support from AstraZeneca, Pfizer, Boehringer Ingelheim, Regeneron Pharmaceuticals, and Moderna Therapeutics, was a paid consultant for Armirall and Janssen Research and Development, was on the scientific advisory board of Integrated Biotherapeutics, and is a shareholder of Noveome Biotherapeutics, which are all developing therapeutics against infections (including S. aureus and other pathogens) and/or inflammatory conditions.

Research paper thumbnail of IL36 is a critical upstream amplifier of neutrophilic lung inflammation in mice

Communications Biology, 2021

IL-36, which belongs to the IL-1 superfamily, is increasingly linked to neutrophilic inflammation... more IL-36, which belongs to the IL-1 superfamily, is increasingly linked to neutrophilic inflammation. Here, we combined in vivo and in vitro approaches using primary mouse and human cells, as well as, acute and chronic mouse models of lung inflammation to provide mechanistic insight into the intercellular signaling pathways and mechanisms through which IL-36 promotes lung inflammation. IL-36 receptor deficient mice exposed to cigarette smoke or cigarette smoke and H1N1 influenza virus had attenuated lung inflammation compared with wild-type controls. We identified neutrophils as a source of IL-36 and show that IL-36 is a key upstream amplifier of lung inflammation by promoting activation of neutrophils, macrophages and fibroblasts through cooperation with GM-CSF and the viral mimic poly(I:C). Our data implicate IL-36, independent of other IL-1 family members, as a key upstream amplifier of neutrophilic lung inflammation, providing a rationale for targeting IL-36 to improve treatment of...

Research paper thumbnail of Transcriptional insights into pathogenesis of cutaneous systemic sclerosis using pathway driven meta-analysis assisted by machine learning methods

PLOS ONE, 2020

Pathophysiology of systemic sclerosis (SSc, Scleroderma), an autoimmune rheumatic disease, compri... more Pathophysiology of systemic sclerosis (SSc, Scleroderma), an autoimmune rheumatic disease, comprises of mechanisms that drive vasculopathy, inflammation and fibrosis. Understanding of the disease and associated clinical heterogeneity has advanced considerably in the past decade, highlighting the necessity of more specific targeted therapy. While many of the recent trials in SSc failed to meet the primary end points that predominantly relied on changes in modified Rodnan skin scores (MRSS), sub-group analysis, especially those focused on the basal skin transcriptomic data have provided insights into patient subsets that respond to therapies. These findings suggest that deeper understanding of the molecular changes in pathways is very important to define disease drivers in various patient subgroups. In view of these challenges, we performed meta-analysis on 9 public available SSc microarray studies using a novel pathway pivoted approach combining consensus clustering and machine learn...

Research paper thumbnail of Safety, pharmacokinetics and pharmacodynamics of BI 705564, a highly selective, covalent inhibitor of Bruton's tyrosine kinase, in Phase I clinical trials in healthy volunteers

British Journal of Clinical Pharmacology, 2020

To evaluate the safety, pharmacokinetics and pharmacodynamics of single- and multiple-rising dose... more To evaluate the safety, pharmacokinetics and pharmacodynamics of single- and multiple-rising doses (SRDs/MRDs) of BI 705564 and establish proof of mechanism (PoM). BI 705564 was studied in two placebo-controlled, Phase I clinical trials testing SRDs (1-160 mg) and MRDs (1-80 mg) of BI 705564 over 14 days in male healthy volunteers. Blood samples were analysed for BI 705564 plasma concentration, Bruton's tyrosine kinase (BTK) target occupancy (TO) and CD69 expression in B cells stimulated ex vivo. A sub-study was conducted in allergic, otherwise healthy, MRD participants. Safety was assessed in both studies. All doses of BI 705564 were well tolerated. Geometric mean BI 705564 plasma terminal half-life ranged from 10.1 hours to 16.9 hours across tested doses, with no relevant accumulation after multiple dosing. Doses ≥20 mg resulted in ≥85% average TO that was maintained for ≥48 hours after single-dose administration. Functional effects of BTK signalling were demonstrated by dose-dependent inhibition of CD69 expression. In allergic participants, BI 705564 treatment showed a trend in wheal size reduction in a skin prick test and complete inhibition of basophil activation. Mild bleeding-related adverse events were observed with BI 705564; bleeding time increased in 1/12 participants (8.3%) who received placebo vs 26/48 (54%) treated with BI 705564. BI 705564 showed efficient target engagement through durable TO and inhibition of ex vivo B-cell activation, and PoM through effects on allergic skin responses. Mild bleeding-related adverse events were likely related to inhibition of platelet aggregation by BTK inhibition.

Research paper thumbnail of BTK inhibition modulates multiple immune cell populations involved in the pathogenesis of immune mediated nephritis

Clinical Immunology, 2021

et al., BTK inhibition modulates multiple immune cell populations involved in the pathogenesis of... more et al., BTK inhibition modulates multiple immune cell populations involved in the pathogenesis of immune mediated nephritis, Clinical Immunology (2020),

Research paper thumbnail of Gut T cell–independent IgA responses to commensal bacteria require engagement of the TACI receptor on B cells

Science Immunology, 2020

Signaling by the B cell–activating receptor TACI drives T cell–independent IgA responses to gut c... more Signaling by the B cell–activating receptor TACI drives T cell–independent IgA responses to gut commensal bacteria.

Research paper thumbnail of P014 Identification of Crohn’s disease immunopathotypes

Journal of Crohn's and Colitis, 2020

Background Crohn’s disease (CD) is a chronic inflammatory gastrointestinal condition, with global... more Background Crohn’s disease (CD) is a chronic inflammatory gastrointestinal condition, with globally increasing incidence. Patients with CD suffer from a loss of tolerance towards their commensal microbiota causing an aberrant immune response, occurring in a protracted relapse and remission cycle. Although a variety of frontline therapies is currently available, including targeted therapies such as biologic drugs, 30–40% of CD patients still require surgery to manage the disease. At present, the immunobiology of CD is not fully understood. However, differences in immune responses between patients might play an important role in diverse treatment responses. The aim of this study was to identify differences in peripheral and local immune responses of CD to understand differences in disease behaviour and treatment outcome. Methods Peripheral blood mononuclear cells and plasma were isolated from whole blood of a cross-sectional CD patient cohort (nCD = 12) and normal controls (NC, nNC = ...

Research paper thumbnail of 32 Safety, pharmacokinetics and pharmacodynamics of BI 705564, a covalent inhibitor of brutons tyrosine kinase in phase 1 clinical trials in healthy volunteers

Research paper thumbnail of Effects of BI 655064, an antagonistic anti-CD40 antibody, on clinical and biomarker variables in patients with active rheumatoid arthritis: a randomised, double-blind, placebo-controlled, phase IIa study

Annals of the Rheumatic Diseases, 2019

ObjectiveTo evaluate the safety, efficacy and therapeutic mechanism of BI 655064, an antagonistic... more ObjectiveTo evaluate the safety, efficacy and therapeutic mechanism of BI 655064, an antagonistic anti-CD40 monoclonal antibody, in patients with rheumatoid arthritis (RA) and an inadequate response to methotrexate (MTX-IR).MethodsIn total, 67 patients were randomised to receive weekly subcutaneous doses of 120 mg BI 655064 (n=44) or placebo (n=23) for 12 weeks. The primary endpoint was the proportion of patients who achieved 20% improvement in American College of Rheumatology criteria (ACR20) at week 12. Safety was assessed in patients who received at least one dose of study drug.ResultsAt week 12, the primary endpoint was not met, with 68.2% of patients treated with BI 655064 achieving an ACR20 vs 45.5% with placebo (p=0.064); using Bayesian analysis, the posterior probability of seeing a difference greater than 35% was 42.9%. BI 655064 was associated with greater changes in CD40–CD40L pathway-related markers, including reductions in inflammatory and bone resorption markers (inter...

Research paper thumbnail of BTK inhibition ameliorates kidney disease in spontaneous lupus nephritis

Clinical Immunology, 2018

Lupus nephritis is a common disease manifestation of SLE, in which immune complex deposition and ... more Lupus nephritis is a common disease manifestation of SLE, in which immune complex deposition and macrophage activation are important contributors to disease pathogenesis. Bruton's tyrosine kinase (BTK) plays an important role in both B cell and FcgammaR mediated myeloid cell activation. In the current study, we examined the efficacy of BI-BTK-1, a recently described irreversible BTK inhibitor, in the classical NZB×NZW F1 (NZB/W) and MRL/lpr spontaneous mouse models of SLE. NZB/W mice were randomly assigned to a treatment (0.3 mg/kg, 1 mg/kg, 3 mg/kg and 10 mg/kg) or control group and began treatment at 22 weeks of age. The experimental setup was similar in MRL/lpr mice, but with a single treated (10 mg/kg, beginning at 8-9 weeks of age) and control group. A separate experiment was performed in the MRL/lpr strain to assess the ability of BI-BTK-1 to reverse established kidney disease. Early treatment with BI-BTK-1 significantly protected NZB/W and MRL/lpr mice from the development of proteinuria, correlating with significant renal histological protection, decreased anti-DNA titers, and increased

Research paper thumbnail of Human Secretory IgM Emerges from Plasma Cells Clonally Related to Gut Memory B Cells and Targets Highly Diverse Commensals

Immunity, Jul 18, 2017

Secretory immunoglobulin A (SIgA) enhances host-microbiota symbiosis, whereas SIgM remains poorly... more Secretory immunoglobulin A (SIgA) enhances host-microbiota symbiosis, whereas SIgM remains poorly understood. We found that gut IgM+ plasma cells (PCs) were more abundant in humans than mice and clonally related to a large repertoire of memory IgM+ B cells disseminated throughout the intestine but rare in systemic lymphoid organs. In addition to sharing a gut-specific gene signature with memory IgA+ B cells, memory IgM+ B cells were related to some IgA+ clonotypes and switched to IgA in response to T cell-independent or T cell-dependent signals. These signals induced abundant IgM which, together with SIgM from clonally affiliated PCs, recognized mucus-embedded commensals. Bacteria recognized by human SIgM were dually coated by SIgA and showed increased richness and diversity compared to IgA-only-coated or uncoated bacteria. Thus, SIgM may emerge from pre-existing memory rather than newly activated naive IgM+ B cells and could help SIgA to anchor highly diverse commensal communities ...

Research paper thumbnail of OP0164 Blockade of Immune Complex-Mediated Glomerulonephritis by Highly Selective Inhibition of Bruton's Tyrosine Kinase

Annals of the Rheumatic Diseases, 2016

relative to baseline, CMR with T2 mapping was performed again. Despite BUN levels and weight meas... more relative to baseline, CMR with T2 mapping was performed again. Despite BUN levels and weight measurements showing no signs of end-stage renal disease, T2 signals were elevated and the myocardium thickened significantly to produce a prominent left ventricular hypertrophy upon MRI analysis. In addition, expression of IL-10, IL-2, IL-6, CXCL1, and TNF-α was significantly up-regulated in the serum of these mice. Histopathological examination revealed robust infiltrates in cardiac tissue with significant fibrosis. While immunohistochemical staining showed little to no detection of B-cells, neutrophils, or macrophages, IL-17 and CD3+ T-cells were observed in cardiac infiltrates. Conclusions: Our results demonstrate that myocarditis is associated with proinflammatory cytokine expression and LN disease progression in NZM2410 mice prior to end-stage renal disease. Consequently, our data establish CMR as a novel non-invasive technique to explore the contribution of SLE-mediated inflammation on CVD and to develop therapeutic strategies to pharmacologically inhibit cardiac damage. Future work will identify biomarkers associated with cardiac damage and will further develop CMR with quantitative T2 mapping as a clinical tool to assess CVD in patients with SLE.

Research paper thumbnail of FRI0231 Treatment with BI 655064 (Antagonistic Anti-CD40 Antibody) Modulates Biomarkers Associated with Rheumatoid Arthritis (RA): Table 1

Annals of the Rheumatic Diseases, 2016

Background: Co-stimulation through the CD40-CD40L axis has been implicated in the pathogenesis of... more Background: Co-stimulation through the CD40-CD40L axis has been implicated in the pathogenesis of RA including T cell mediated responses, B cell driven autoantibodies, adhesion molecule expression, synovial hyperplasia, and pannus formation, in addition to the secretion of proinflammatory cytokines and MMPs. Circulating CD40L levels are elevated in RA patients versus healthy controls. BI 655064 is a humanized antagonistic anti-CD40 monoclonal antibody which blocks the CD40/ CD40L interaction in in vitro CD40L induced B cell and APC activation assays with IC50 of <1nM. Objectives: To characterize the effect of BI 655064 on cellular and protein biomarkers in RA patients with prior inadequate response to a stable dose MTX ≥15 mg over a 12 wk period of treatment. Methods: In this double-blinded, randomized trial RA patients were treated with either 120 mg BI 655064 or placebo q1w for 12 wks as add-on to MTX. Inclusion criteria were ≥6 swollen and ≥6 tender joints, CRP >8 mg/L or ESR>28 mm/1h. The primary efficacy endpoint was ACR20 response at wk 12.Select biomarkers were assessed in whole blood and serum pre and post treatment with BI 655064. Results: Treatment with BI 655064 resulted in minimal changes in median %CD19+ B cell population but larger median decreases in select %CD95+ activated B cell subsets, specifically class switched (CD19+IgD-CD27+CD95+), pre-switched (CD19+IgD+CD27+CD95+) and double negative (CD19+IgD-CD27-CD95+) cells and decreases in autoantibodies (IgG-RF and IgA-RF), total IgG and IgM levels in RA patients vs placebo at 12 wks. Median decreases in IL-6 levels (important for B cell and monocyte differentiation) and select bone resorption biomarkers (MMP-3 and RANKL) were also observed in the BI 655064 treated patients vs placebo through 12 wks. Baseline levels of IgG RF, IgM RF, TNFa and COMP correlated with improvement in swollen joint counts at 12 wks and IgA RF levels correlated with improvement in DAS-28 CRP scores at 12 wks in patients treated with BI 655064.

Research paper thumbnail of Therapeutic targeting of macrophages in lupus nephritis

Discovery medicine, 2015

Systemic lupus erythematosus (SLE) is an autoimmune disease which results in multiple different e... more Systemic lupus erythematosus (SLE) is an autoimmune disease which results in multiple different end organ pathologies, including the kidney. Lupus nephritis (LN) is one of the most serious complications of SLE, and a leading cause of morbidity and mortality. Current treatment options are suboptimal, involving non-specific immunosuppression which exposes patients to potentially serious side effects with no guarantee of remission. More targeted therapeutic approaches may improve treatment results. Many studies have implicated macrophages as actively contributing to LN pathogenesis in both human and murine disease. Indeed, various studies have shown that depletion of macrophage populations, inhibition of macrophage recruitment, and disruption of inflammatory macrophage activation and polarization have significantly ameliorated nephritis in several different murine LN models. The current literature explores targeting macrophages by several different means, including the CSF-1/CSF-1R sig...

Research paper thumbnail of THU0407 Preclinical Characterization of a Highly Selective and Potent Antagonistic Anti-CD40 mAb

Annals of the Rheumatic Diseases, 2015

duration of the diseases was 44 [17-84] months. Before the treatment of the disease SLEDAI2K was ... more duration of the diseases was 44 [17-84] months. Before the treatment of the disease SLEDAI2K was 20 [15-27], the concentration of a-dsDNA was 61,5 [24,6-111] U/ml, C3 was 0,58 [0,49-0,76] g/l, C4 was 0,1 [0,08-0,15] g/l, the concentration of B-cells was 6,6 [3,5-14,7]%. Previous puls-therapy was not effective in 66% of patients who received the cyclophosphamide (CF) and high dosage of glucocorticoids (GC), in 34% of patients who received previous therapy with mycofemolate mofetil (MFM) and azathioprine (AZA). Only 1 course of RTM received 19 patients, 2 courses-5 patients, 3 courses-5 patients, 4 courses-3 patients. After the first course of RTM 30 patients received maintenance therapy with cytostatics and hydroxychloroquine: CF-10, AZA-1, MFM-4 patients and hydroxychloroquine received 5 patients. CF was changed to AZA in 3 patients after the 3 months of the therapy. 1 patient received combined therapy with CF and MFM. Results: During the long-term follow-up (12 [12-24] months, from 6 to 48 months) the repeated courses of rituximab were effective in 84% of patients (complete response in 56%, partial response in 28%) and were not effective in 16% of patients. The B-cell depletion was observed in 72% of patients during a month after the therapy with RTM. The mean time of B-cell recovery was 6 [1-12] months. The exacerbations were noticed in 25% of patients during 12 [6-21] months of follow-up. Reducing signs of skin manifestations occurred gradually with the following sequence: the most rapid effect was observed in subacute LE, generalized acute cutaneous LE, discoid LE and further in ulcerative vasculitis. Complete response was observed in 60% of patients during a month after the first course of anti-B-cell therapy. During the long-term follow-up we observed the improvements of disease activity by SLEDAI2K, concentrations of a-dsDNA and components of the complement, decreasing the daily dosage of glucocorticoids. Conclusions: Rituximab has demonstrated efficacy in different subtype of skin manifestations of lupus erythematosus refractory to standard treatment during long-term follow-up. We noticed gradually improvement of skin manifestations symptoms: the most rapid effect was observed in subacute LE, generalized acute cutaneous LE, discoid LE and further in ulcerative vasculitis.

Research paper thumbnail of Phoenix from the flames: Rediscovering the role of the CD40–CD40L pathway in systemic lupus erythematosus and lupus nephritis

Autoimmunity Reviews, 2020

This is a PDF file of an article that has undergone enhancements after acceptance, such as the ad... more This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

Research paper thumbnail of Identification and characterization of an antagonistic anti-mouse CD40 antibody

Journal of Immunology, 2016

Targeting CD40-CD40L interactions has been an interesting drug concept for the treatment of autoi... more Targeting CD40-CD40L interactions has been an interesting drug concept for the treatment of autoimmune diseases given this pathway’s role in the development of both humoral and cell mediated immune responses. While preclinical blockade of CD40L is well documented in various autoimmune animal models of disease, limited data exists for CD40 blockade due to lack of a truly antagonistic anti-mouse CD40 tool antibody (Ab). Here we describe the in vitro and in vivo characterization of a fully antagonistic anti-mouse CD40 monoclonal Ab (BI CD40-1); a chimeric rat Fv anti-mouse CD40 mAb engineered with a mouse IgG2a Fc containing mutations to abrogate Fcγ receptor binding. BI CD40-1 blocks molecular CD40-CD40L interactions (IC50 = 0.25 nM) and exhibits potent binding to CD40 expressed on mouse B cells (EC50 = 0.42 nM ± 0.08). In vitro profiling of BI CD40-1 using a mouse splenocyte proliferation assay confirmed potent antagonistic activity (IC50 = 0.27 nM ± 0.09) as well as absence of any a...

Research paper thumbnail of Therapeutic Blockade of Immune Complex-Mediated Glomerulonephritis by Highly Selective Inhibition of Bruton's Tyrosine Kinase

Scientific reports, May 19, 2016

Lupus nephritis (LN) is a potentially dangerous end organ pathology that affects upwards of 60% o... more Lupus nephritis (LN) is a potentially dangerous end organ pathology that affects upwards of 60% of lupus patients. Bruton's tyrosine kinase (BTK) is important for B cell development, Fc receptor signaling, and macrophage polarization. In this study, we investigated the effects of a novel, highly selective and potent BTK inhibitor, BI-BTK-1, in an inducible model of LN in which mice receive nephrotoxic serum (NTS) containing anti-glomerular antibodies. Mice were treated once daily with vehicle alone or BI-BTK-1, either prophylactically or therapeutically. When compared with control treated mice, NTS-challenged mice treated prophylactically with BI-BTK-1 exhibited significantly attenuated kidney disease, which was dose dependent. BI-BTK-1 treatment resulted in decreased infiltrating IBA-1+ cells, as well as C3 deposition within the kidney. RT-PCR on whole kidney RNA and serum profiling indicated that BTK inhibition significantly decreased levels of LN-relevant inflammatory cytokin...

Research paper thumbnail of II-06 Therapeutic blockade of immune complex-mediated glomerulonephritis by highly selective inhibition of bruton’s tyrosine kinase

Lupus Science & Medicine, 2016

Background Lupus nephritis (LN) is a potentially dangerous end organ pathology that affects upwar... more Background Lupus nephritis (LN) is a potentially dangerous end organ pathology that affects upwards of 50% of patients with systemic lupus erythematosus (SLE). Classical treatments for this condition have targeted the adaptive immune response and/or autoantibodies, rather than the inflammatory process itself. Besides its role in B cell development, Bruton’s tyrosine kinase (BTK) is important for Fc receptor signalling and macrophage polarisation. Furthermore, increasing evidence points to the role of the innate immune system, and particularly macrophages, in the pathogenesis of lupus nephritis. Materials and methods In this study, we investigated the effects of a novel, highly selective and potent BTK inhibitor, BI-BTK-1, in an inducible model of LN in which female 129/SvJ mice receive nephrotoxic serum (NTS) containing anti-glomerular antibodies. Mice were treated once daily with vehicle alone or BI-BTK-1 (0.3–10 mg/kg, n = 16/group), either prophylactically or therapeutically. Res...

Research paper thumbnail of BTK inhibition ameliorates renal, skin, and brain disease in a spontaneous murine model of systemic lupus erythematosus

Journal of Immunology, 2018

Systemic lupus erythematosus (SLE) can affect multiple different organ systems, including the kid... more Systemic lupus erythematosus (SLE) can affect multiple different organ systems, including the kidneys (lupus nephritis, LN), brain (neuropsychiatric SLE, NPSLE), and skin (cutaneous lupus, CLE). B cells and macrophages are implicated in the pathogenesis of these disease manifestations. We have previously shown the importance of Bruton’s tyrosine kinase (BTK), an enzyme important in B cell and macrophage signaling, in reversing disease in a model of immune nephritis induced by the passive transfer of nephrotoxic antibodies. To extend our findings to a more severe type of nephritis more similar to human disease and examine the effects of BTK inhibition on extra-renal lupus manifestations, we treated a spontaneous model of lupus, MRL/lpr mice, with the novel BTK inhibitor, BI-BTK-1. Early treatment with BI-BTK-1 normalized proteinuria (p MRL/lpr mice develop brain and skin disease that model the pathology of NPSLE and CLE, respectively. Early BI-BTK-1 treatment significantly improved c...

Research paper thumbnail of Epicutaneous Staphylococcus aureus induces IL-36 to enhance IgE production and ensuing allergic disease

Journal of Clinical Investigation, 2021

Boehringer Ingelheim, which is developing therapeutics targeting IL-36R inhibition in patients wi... more Boehringer Ingelheim, which is developing therapeutics targeting IL-36R inhibition in patients with atopic dermatitis and other inflammatory conditions. LSM is a full-time employee of Janssen Pharmaceuticals and holds Johnson & Johnson stock. LSM received prior grant support from AstraZeneca, Pfizer, Boehringer Ingelheim, Regeneron Pharmaceuticals, and Moderna Therapeutics, was a paid consultant for Armirall and Janssen Research and Development, was on the scientific advisory board of Integrated Biotherapeutics, and is a shareholder of Noveome Biotherapeutics, which are all developing therapeutics against infections (including S. aureus and other pathogens) and/or inflammatory conditions.

Research paper thumbnail of IL36 is a critical upstream amplifier of neutrophilic lung inflammation in mice

Communications Biology, 2021

IL-36, which belongs to the IL-1 superfamily, is increasingly linked to neutrophilic inflammation... more IL-36, which belongs to the IL-1 superfamily, is increasingly linked to neutrophilic inflammation. Here, we combined in vivo and in vitro approaches using primary mouse and human cells, as well as, acute and chronic mouse models of lung inflammation to provide mechanistic insight into the intercellular signaling pathways and mechanisms through which IL-36 promotes lung inflammation. IL-36 receptor deficient mice exposed to cigarette smoke or cigarette smoke and H1N1 influenza virus had attenuated lung inflammation compared with wild-type controls. We identified neutrophils as a source of IL-36 and show that IL-36 is a key upstream amplifier of lung inflammation by promoting activation of neutrophils, macrophages and fibroblasts through cooperation with GM-CSF and the viral mimic poly(I:C). Our data implicate IL-36, independent of other IL-1 family members, as a key upstream amplifier of neutrophilic lung inflammation, providing a rationale for targeting IL-36 to improve treatment of...

Research paper thumbnail of Transcriptional insights into pathogenesis of cutaneous systemic sclerosis using pathway driven meta-analysis assisted by machine learning methods

PLOS ONE, 2020

Pathophysiology of systemic sclerosis (SSc, Scleroderma), an autoimmune rheumatic disease, compri... more Pathophysiology of systemic sclerosis (SSc, Scleroderma), an autoimmune rheumatic disease, comprises of mechanisms that drive vasculopathy, inflammation and fibrosis. Understanding of the disease and associated clinical heterogeneity has advanced considerably in the past decade, highlighting the necessity of more specific targeted therapy. While many of the recent trials in SSc failed to meet the primary end points that predominantly relied on changes in modified Rodnan skin scores (MRSS), sub-group analysis, especially those focused on the basal skin transcriptomic data have provided insights into patient subsets that respond to therapies. These findings suggest that deeper understanding of the molecular changes in pathways is very important to define disease drivers in various patient subgroups. In view of these challenges, we performed meta-analysis on 9 public available SSc microarray studies using a novel pathway pivoted approach combining consensus clustering and machine learn...

Research paper thumbnail of Safety, pharmacokinetics and pharmacodynamics of BI 705564, a highly selective, covalent inhibitor of Bruton's tyrosine kinase, in Phase I clinical trials in healthy volunteers

British Journal of Clinical Pharmacology, 2020

To evaluate the safety, pharmacokinetics and pharmacodynamics of single- and multiple-rising dose... more To evaluate the safety, pharmacokinetics and pharmacodynamics of single- and multiple-rising doses (SRDs/MRDs) of BI 705564 and establish proof of mechanism (PoM). BI 705564 was studied in two placebo-controlled, Phase I clinical trials testing SRDs (1-160 mg) and MRDs (1-80 mg) of BI 705564 over 14 days in male healthy volunteers. Blood samples were analysed for BI 705564 plasma concentration, Bruton's tyrosine kinase (BTK) target occupancy (TO) and CD69 expression in B cells stimulated ex vivo. A sub-study was conducted in allergic, otherwise healthy, MRD participants. Safety was assessed in both studies. All doses of BI 705564 were well tolerated. Geometric mean BI 705564 plasma terminal half-life ranged from 10.1 hours to 16.9 hours across tested doses, with no relevant accumulation after multiple dosing. Doses ≥20 mg resulted in ≥85% average TO that was maintained for ≥48 hours after single-dose administration. Functional effects of BTK signalling were demonstrated by dose-dependent inhibition of CD69 expression. In allergic participants, BI 705564 treatment showed a trend in wheal size reduction in a skin prick test and complete inhibition of basophil activation. Mild bleeding-related adverse events were observed with BI 705564; bleeding time increased in 1/12 participants (8.3%) who received placebo vs 26/48 (54%) treated with BI 705564. BI 705564 showed efficient target engagement through durable TO and inhibition of ex vivo B-cell activation, and PoM through effects on allergic skin responses. Mild bleeding-related adverse events were likely related to inhibition of platelet aggregation by BTK inhibition.

Research paper thumbnail of BTK inhibition modulates multiple immune cell populations involved in the pathogenesis of immune mediated nephritis

Clinical Immunology, 2021

et al., BTK inhibition modulates multiple immune cell populations involved in the pathogenesis of... more et al., BTK inhibition modulates multiple immune cell populations involved in the pathogenesis of immune mediated nephritis, Clinical Immunology (2020),

Research paper thumbnail of Gut T cell–independent IgA responses to commensal bacteria require engagement of the TACI receptor on B cells

Science Immunology, 2020

Signaling by the B cell–activating receptor TACI drives T cell–independent IgA responses to gut c... more Signaling by the B cell–activating receptor TACI drives T cell–independent IgA responses to gut commensal bacteria.

Research paper thumbnail of P014 Identification of Crohn’s disease immunopathotypes

Journal of Crohn's and Colitis, 2020

Background Crohn’s disease (CD) is a chronic inflammatory gastrointestinal condition, with global... more Background Crohn’s disease (CD) is a chronic inflammatory gastrointestinal condition, with globally increasing incidence. Patients with CD suffer from a loss of tolerance towards their commensal microbiota causing an aberrant immune response, occurring in a protracted relapse and remission cycle. Although a variety of frontline therapies is currently available, including targeted therapies such as biologic drugs, 30–40% of CD patients still require surgery to manage the disease. At present, the immunobiology of CD is not fully understood. However, differences in immune responses between patients might play an important role in diverse treatment responses. The aim of this study was to identify differences in peripheral and local immune responses of CD to understand differences in disease behaviour and treatment outcome. Methods Peripheral blood mononuclear cells and plasma were isolated from whole blood of a cross-sectional CD patient cohort (nCD = 12) and normal controls (NC, nNC = ...

Research paper thumbnail of 32 Safety, pharmacokinetics and pharmacodynamics of BI 705564, a covalent inhibitor of brutons tyrosine kinase in phase 1 clinical trials in healthy volunteers

Research paper thumbnail of Effects of BI 655064, an antagonistic anti-CD40 antibody, on clinical and biomarker variables in patients with active rheumatoid arthritis: a randomised, double-blind, placebo-controlled, phase IIa study

Annals of the Rheumatic Diseases, 2019

ObjectiveTo evaluate the safety, efficacy and therapeutic mechanism of BI 655064, an antagonistic... more ObjectiveTo evaluate the safety, efficacy and therapeutic mechanism of BI 655064, an antagonistic anti-CD40 monoclonal antibody, in patients with rheumatoid arthritis (RA) and an inadequate response to methotrexate (MTX-IR).MethodsIn total, 67 patients were randomised to receive weekly subcutaneous doses of 120 mg BI 655064 (n=44) or placebo (n=23) for 12 weeks. The primary endpoint was the proportion of patients who achieved 20% improvement in American College of Rheumatology criteria (ACR20) at week 12. Safety was assessed in patients who received at least one dose of study drug.ResultsAt week 12, the primary endpoint was not met, with 68.2% of patients treated with BI 655064 achieving an ACR20 vs 45.5% with placebo (p=0.064); using Bayesian analysis, the posterior probability of seeing a difference greater than 35% was 42.9%. BI 655064 was associated with greater changes in CD40–CD40L pathway-related markers, including reductions in inflammatory and bone resorption markers (inter...

Research paper thumbnail of BTK inhibition ameliorates kidney disease in spontaneous lupus nephritis

Clinical Immunology, 2018

Lupus nephritis is a common disease manifestation of SLE, in which immune complex deposition and ... more Lupus nephritis is a common disease manifestation of SLE, in which immune complex deposition and macrophage activation are important contributors to disease pathogenesis. Bruton's tyrosine kinase (BTK) plays an important role in both B cell and FcgammaR mediated myeloid cell activation. In the current study, we examined the efficacy of BI-BTK-1, a recently described irreversible BTK inhibitor, in the classical NZB×NZW F1 (NZB/W) and MRL/lpr spontaneous mouse models of SLE. NZB/W mice were randomly assigned to a treatment (0.3 mg/kg, 1 mg/kg, 3 mg/kg and 10 mg/kg) or control group and began treatment at 22 weeks of age. The experimental setup was similar in MRL/lpr mice, but with a single treated (10 mg/kg, beginning at 8-9 weeks of age) and control group. A separate experiment was performed in the MRL/lpr strain to assess the ability of BI-BTK-1 to reverse established kidney disease. Early treatment with BI-BTK-1 significantly protected NZB/W and MRL/lpr mice from the development of proteinuria, correlating with significant renal histological protection, decreased anti-DNA titers, and increased

Research paper thumbnail of Human Secretory IgM Emerges from Plasma Cells Clonally Related to Gut Memory B Cells and Targets Highly Diverse Commensals

Immunity, Jul 18, 2017

Secretory immunoglobulin A (SIgA) enhances host-microbiota symbiosis, whereas SIgM remains poorly... more Secretory immunoglobulin A (SIgA) enhances host-microbiota symbiosis, whereas SIgM remains poorly understood. We found that gut IgM+ plasma cells (PCs) were more abundant in humans than mice and clonally related to a large repertoire of memory IgM+ B cells disseminated throughout the intestine but rare in systemic lymphoid organs. In addition to sharing a gut-specific gene signature with memory IgA+ B cells, memory IgM+ B cells were related to some IgA+ clonotypes and switched to IgA in response to T cell-independent or T cell-dependent signals. These signals induced abundant IgM which, together with SIgM from clonally affiliated PCs, recognized mucus-embedded commensals. Bacteria recognized by human SIgM were dually coated by SIgA and showed increased richness and diversity compared to IgA-only-coated or uncoated bacteria. Thus, SIgM may emerge from pre-existing memory rather than newly activated naive IgM+ B cells and could help SIgA to anchor highly diverse commensal communities ...

Research paper thumbnail of OP0164 Blockade of Immune Complex-Mediated Glomerulonephritis by Highly Selective Inhibition of Bruton's Tyrosine Kinase

Annals of the Rheumatic Diseases, 2016

relative to baseline, CMR with T2 mapping was performed again. Despite BUN levels and weight meas... more relative to baseline, CMR with T2 mapping was performed again. Despite BUN levels and weight measurements showing no signs of end-stage renal disease, T2 signals were elevated and the myocardium thickened significantly to produce a prominent left ventricular hypertrophy upon MRI analysis. In addition, expression of IL-10, IL-2, IL-6, CXCL1, and TNF-α was significantly up-regulated in the serum of these mice. Histopathological examination revealed robust infiltrates in cardiac tissue with significant fibrosis. While immunohistochemical staining showed little to no detection of B-cells, neutrophils, or macrophages, IL-17 and CD3+ T-cells were observed in cardiac infiltrates. Conclusions: Our results demonstrate that myocarditis is associated with proinflammatory cytokine expression and LN disease progression in NZM2410 mice prior to end-stage renal disease. Consequently, our data establish CMR as a novel non-invasive technique to explore the contribution of SLE-mediated inflammation on CVD and to develop therapeutic strategies to pharmacologically inhibit cardiac damage. Future work will identify biomarkers associated with cardiac damage and will further develop CMR with quantitative T2 mapping as a clinical tool to assess CVD in patients with SLE.

Research paper thumbnail of FRI0231 Treatment with BI 655064 (Antagonistic Anti-CD40 Antibody) Modulates Biomarkers Associated with Rheumatoid Arthritis (RA): Table 1

Annals of the Rheumatic Diseases, 2016

Background: Co-stimulation through the CD40-CD40L axis has been implicated in the pathogenesis of... more Background: Co-stimulation through the CD40-CD40L axis has been implicated in the pathogenesis of RA including T cell mediated responses, B cell driven autoantibodies, adhesion molecule expression, synovial hyperplasia, and pannus formation, in addition to the secretion of proinflammatory cytokines and MMPs. Circulating CD40L levels are elevated in RA patients versus healthy controls. BI 655064 is a humanized antagonistic anti-CD40 monoclonal antibody which blocks the CD40/ CD40L interaction in in vitro CD40L induced B cell and APC activation assays with IC50 of <1nM. Objectives: To characterize the effect of BI 655064 on cellular and protein biomarkers in RA patients with prior inadequate response to a stable dose MTX ≥15 mg over a 12 wk period of treatment. Methods: In this double-blinded, randomized trial RA patients were treated with either 120 mg BI 655064 or placebo q1w for 12 wks as add-on to MTX. Inclusion criteria were ≥6 swollen and ≥6 tender joints, CRP >8 mg/L or ESR>28 mm/1h. The primary efficacy endpoint was ACR20 response at wk 12.Select biomarkers were assessed in whole blood and serum pre and post treatment with BI 655064. Results: Treatment with BI 655064 resulted in minimal changes in median %CD19+ B cell population but larger median decreases in select %CD95+ activated B cell subsets, specifically class switched (CD19+IgD-CD27+CD95+), pre-switched (CD19+IgD+CD27+CD95+) and double negative (CD19+IgD-CD27-CD95+) cells and decreases in autoantibodies (IgG-RF and IgA-RF), total IgG and IgM levels in RA patients vs placebo at 12 wks. Median decreases in IL-6 levels (important for B cell and monocyte differentiation) and select bone resorption biomarkers (MMP-3 and RANKL) were also observed in the BI 655064 treated patients vs placebo through 12 wks. Baseline levels of IgG RF, IgM RF, TNFa and COMP correlated with improvement in swollen joint counts at 12 wks and IgA RF levels correlated with improvement in DAS-28 CRP scores at 12 wks in patients treated with BI 655064.

Research paper thumbnail of Therapeutic targeting of macrophages in lupus nephritis

Discovery medicine, 2015

Systemic lupus erythematosus (SLE) is an autoimmune disease which results in multiple different e... more Systemic lupus erythematosus (SLE) is an autoimmune disease which results in multiple different end organ pathologies, including the kidney. Lupus nephritis (LN) is one of the most serious complications of SLE, and a leading cause of morbidity and mortality. Current treatment options are suboptimal, involving non-specific immunosuppression which exposes patients to potentially serious side effects with no guarantee of remission. More targeted therapeutic approaches may improve treatment results. Many studies have implicated macrophages as actively contributing to LN pathogenesis in both human and murine disease. Indeed, various studies have shown that depletion of macrophage populations, inhibition of macrophage recruitment, and disruption of inflammatory macrophage activation and polarization have significantly ameliorated nephritis in several different murine LN models. The current literature explores targeting macrophages by several different means, including the CSF-1/CSF-1R sig...

Research paper thumbnail of THU0407 Preclinical Characterization of a Highly Selective and Potent Antagonistic Anti-CD40 mAb

Annals of the Rheumatic Diseases, 2015

duration of the diseases was 44 [17-84] months. Before the treatment of the disease SLEDAI2K was ... more duration of the diseases was 44 [17-84] months. Before the treatment of the disease SLEDAI2K was 20 [15-27], the concentration of a-dsDNA was 61,5 [24,6-111] U/ml, C3 was 0,58 [0,49-0,76] g/l, C4 was 0,1 [0,08-0,15] g/l, the concentration of B-cells was 6,6 [3,5-14,7]%. Previous puls-therapy was not effective in 66% of patients who received the cyclophosphamide (CF) and high dosage of glucocorticoids (GC), in 34% of patients who received previous therapy with mycofemolate mofetil (MFM) and azathioprine (AZA). Only 1 course of RTM received 19 patients, 2 courses-5 patients, 3 courses-5 patients, 4 courses-3 patients. After the first course of RTM 30 patients received maintenance therapy with cytostatics and hydroxychloroquine: CF-10, AZA-1, MFM-4 patients and hydroxychloroquine received 5 patients. CF was changed to AZA in 3 patients after the 3 months of the therapy. 1 patient received combined therapy with CF and MFM. Results: During the long-term follow-up (12 [12-24] months, from 6 to 48 months) the repeated courses of rituximab were effective in 84% of patients (complete response in 56%, partial response in 28%) and were not effective in 16% of patients. The B-cell depletion was observed in 72% of patients during a month after the therapy with RTM. The mean time of B-cell recovery was 6 [1-12] months. The exacerbations were noticed in 25% of patients during 12 [6-21] months of follow-up. Reducing signs of skin manifestations occurred gradually with the following sequence: the most rapid effect was observed in subacute LE, generalized acute cutaneous LE, discoid LE and further in ulcerative vasculitis. Complete response was observed in 60% of patients during a month after the first course of anti-B-cell therapy. During the long-term follow-up we observed the improvements of disease activity by SLEDAI2K, concentrations of a-dsDNA and components of the complement, decreasing the daily dosage of glucocorticoids. Conclusions: Rituximab has demonstrated efficacy in different subtype of skin manifestations of lupus erythematosus refractory to standard treatment during long-term follow-up. We noticed gradually improvement of skin manifestations symptoms: the most rapid effect was observed in subacute LE, generalized acute cutaneous LE, discoid LE and further in ulcerative vasculitis.

Research paper thumbnail of Phoenix from the flames: Rediscovering the role of the CD40–CD40L pathway in systemic lupus erythematosus and lupus nephritis

Autoimmunity Reviews, 2020

This is a PDF file of an article that has undergone enhancements after acceptance, such as the ad... more This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

Research paper thumbnail of Identification and characterization of an antagonistic anti-mouse CD40 antibody

Journal of Immunology, 2016

Targeting CD40-CD40L interactions has been an interesting drug concept for the treatment of autoi... more Targeting CD40-CD40L interactions has been an interesting drug concept for the treatment of autoimmune diseases given this pathway’s role in the development of both humoral and cell mediated immune responses. While preclinical blockade of CD40L is well documented in various autoimmune animal models of disease, limited data exists for CD40 blockade due to lack of a truly antagonistic anti-mouse CD40 tool antibody (Ab). Here we describe the in vitro and in vivo characterization of a fully antagonistic anti-mouse CD40 monoclonal Ab (BI CD40-1); a chimeric rat Fv anti-mouse CD40 mAb engineered with a mouse IgG2a Fc containing mutations to abrogate Fcγ receptor binding. BI CD40-1 blocks molecular CD40-CD40L interactions (IC50 = 0.25 nM) and exhibits potent binding to CD40 expressed on mouse B cells (EC50 = 0.42 nM ± 0.08). In vitro profiling of BI CD40-1 using a mouse splenocyte proliferation assay confirmed potent antagonistic activity (IC50 = 0.27 nM ± 0.09) as well as absence of any a...

Research paper thumbnail of Therapeutic Blockade of Immune Complex-Mediated Glomerulonephritis by Highly Selective Inhibition of Bruton's Tyrosine Kinase

Scientific reports, May 19, 2016

Lupus nephritis (LN) is a potentially dangerous end organ pathology that affects upwards of 60% o... more Lupus nephritis (LN) is a potentially dangerous end organ pathology that affects upwards of 60% of lupus patients. Bruton's tyrosine kinase (BTK) is important for B cell development, Fc receptor signaling, and macrophage polarization. In this study, we investigated the effects of a novel, highly selective and potent BTK inhibitor, BI-BTK-1, in an inducible model of LN in which mice receive nephrotoxic serum (NTS) containing anti-glomerular antibodies. Mice were treated once daily with vehicle alone or BI-BTK-1, either prophylactically or therapeutically. When compared with control treated mice, NTS-challenged mice treated prophylactically with BI-BTK-1 exhibited significantly attenuated kidney disease, which was dose dependent. BI-BTK-1 treatment resulted in decreased infiltrating IBA-1+ cells, as well as C3 deposition within the kidney. RT-PCR on whole kidney RNA and serum profiling indicated that BTK inhibition significantly decreased levels of LN-relevant inflammatory cytokin...