In the era of precision medicine, digital technologies and artificial intelligence, drug discovery and development face unprecedented opportunities for product and business model innovation, ...fundamentally changing the traditional approach of how drugs are discovered, developed and marketed. Critical to this transformation is the adoption of new technologies in the drug development process, catalyzing the transition from serendipity-driven to data-driven medicine. This paradigm shift comes with a need for both translation and precision, leading to a modern Translational Precision Medicine approach to drug discovery and development. Key components of Translational Precision Medicine are multi-omics profiling, digital biomarkers, model-based data integration, artificial intelligence, biomarker-guided trial designs and patient-centric companion diagnostics. In this review, we summarize and critically discuss the potential and challenges of Translational Precision Medicine from a cross-industry perspective.
Lymphocyte exit from lymph nodes and their recirculation into blood is controlled by the sphingolipid sphingosine 1-phosphate (S1P). The cellular receptor mediating lymphocyte exit is S1P(1), one of ...five S1P receptors. Nonselective agonists for S1P receptors lead to blood lymphocyte count reduction. The effects of selective S1P(1) agonists on blood lymphocyte count and their impact in models of lymphocyte-mediated tissue inflammation have been less investigated. We describe here the general pharmacology of ponesimod, (Z,Z)-5-3-chloro-4-((2R)-2,3-dihydroxy-propoxy)-benzylidene-2-propylimino-3-o-tolyl-thiazolidin-4-one, a new, potent, and orally active selective S1P(1) agonist. Ponesimod activated S1P(1)-mediated signal transduction with high potency (EC(50) of 5.7 nM) and selectivity. Oral administration of ponesimod to rats led to a dose-dependent decrease of blood lymphocyte count. After discontinuation of dosing, blood lymphocyte count returned to baseline within 48 h. Ponesimod prevented edema formation, inflammatory cell accumulation, and cytokine release in the skin of mice with delayed-type hypersensitivity. Ponesimod also prevented the increase in paw volume and joint inflammation in rats with adjuvant-induced arthritis. These data show that selective activation of S1P(1) using ponesimod leads to blood lymphocyte count reduction and efficacy in models of lymphocyte-mediated tissue inflammation. Immunomodulation with a rapidly reversible S1P(1)-selective agonist may represent a new therapeutic approach in lymphocyte-mediated autoimmune diseases.
In the present study, we investigated the therapeutic potential of a selective S1P1 receptor modulator, ponesimod, to protect and reverse autoimmune diabetes in non-obese diabetic (NOD) mice. ...Ponesimod was administered orally to NOD mice starting at 6, 10, 13 and 16 weeks of age up to 35 weeks of age or to NOD mice showing recent onset diabetes. Peripheral blood and spleen B and T cell counts were significantly reduced after ponesimod administration. In pancreatic lymph nodes, B lymphocytes were increased and expressed a transitional 1-like phenotype. Chronic oral ponesimod treatment efficiently prevented autoimmune diabetes in 6, 10 and 16 week-old pre-diabetic NOD mice. Treatment withdrawal led to synchronized disease relapse. Ponesimod did not inhibit the differentiation of autoreactive T cells as assessed by adoptive transfer of lymphocytes from treated disease-free NOD mice. In addition, it did not affect the migration, proliferation and activation of transgenic BDC2.5 cells into the target tissue. However, ponesimod inhibited spreading of the T cell responses to islet-specific glucose-6-phosphatase catalytic subunit-related protein (IGRP). Treatment of diabetic NOD mice with ponesimod induced disease remission. However, here again, upon treatment cessation, the disease rapidly recurred. This recurrence was effectively prevented by combination treatment with a CD3 antibody leading to the restoration of self-tolerance. In conclusion, treatment with a selective S1P1 modulator in combination with CD3 antibody represents a promising therapeutic approach for the treatment of autoimmune diabetes.
Background
The NLRP3 inflammasome drives release of pro‐inflammatory cytokines including interleukin (IL)‐1β and IL‐18 and is a potential target for ulcerative colitis (UC). Selnoflast (RO7486967) is ...an orally active, potent, selective and reversible small molecule NLRP3 inhibitor. We conducted a randomized, placebo‐controlled Phase 1b study to assess the safety, tolerability, pharmacokinetics (PK) and pharmacodynamics (PD) of selnoflast.
Methods
Nineteen adults with previous diagnosis of UC and current active moderate to severe disease were randomized 2:1 to selnoflast or placebo for 7 days. A dose of 450 mg QD (once daily) was selected to achieve 90% IL‐1β inhibition in plasma and colon tissue. Consecutive blood, sigmoid colon biopsies and stool samples were analyzed for a variety of PD markers. Safety and PK were also evaluated.
Results
Selnoflast was well‐tolerated. Plasma concentrations increased rapidly after oral administration, reaching Tmax 1 h post‐dose. Mean plasma concentrations stayed above the IL‐1β IC90 level throughout the dosing interval (mean Ctrough on Day 1 and Day 5: 2.55 μg/mL and 2.66 μg/mL, respectively). At steady state, post‐dose selnoflast concentrations in sigmoid colon (5‐20 μg/g) were above the IC90. Production of IL‐1β was reduced in whole blood following ex vivo stimulation with lipopolysaccharide (LPS) (in the selnoflast arm). No changes were observed in plasma IL‐18 levels. There were no meaningful differences in the expression of an IL‐1‐related gene signature in sigmoid colon tissue, and no differences in the expression of stool biomarkers.
Conclusions
Selnoflast was safe and well‐tolerated. Selnoflast 450 mg QD achieved plasma and tissue exposure predicted to maintain IL‐1β IC90 over the dosing interval. However, PD biomarker results showed no robust differences between treatment arms, suggesting no major therapeutic effects are to be expected in UC. The limitations of this study are its small sample size and indirect assessment of the effect on IL‐1β in tissue.
Trial registration
ISRCTN16847938
Although selnoflast was well‐tolerated and reached sufficient plasma and tissue exposure to inhibit the NLRP3 inflammasome, there were no meaningful changes in sigmoid colon histology or markers of inflammation. No major therapeutic effect is expected in ulcerative colitis.
Summary
Granuloma is a typical feature of tuberculosis. We evaluated the chemotaxis of selected human leucocyte subsets induced by macrophages incubated with Mycobacterium tuberculosis (MT)‐derived ...products in vitro. The release of monocyte chemotactic protein 1 (MCP‐1) and interleukin‐8 (IL‐8) correlated with the specific induction of strong chemotaxis towards monocytes and polymorphonuclear leucocytes (PMNs). γδ and T helper type 1 (Th1) αβ lymphocytes were chemoattracted, while T‐resting, IL‐2‐activated and Th2 lymphocytes were unaffected. Activation with mycobacterium‐derived, phosphate‐containing components, modulated the chemokine receptor profile of γδ T lymphocytes as well as their pattern of cyto‐chemokine production, disclosing a potential for their active participation in granuloma formation. In particular, CXCR3 and IP‐10, which we found to be released by MT‐pulsed alveolar macrophages, seem to represent the receptor–counter‐receptor pair implicated in the chemotaxis of γδ lymphocytes. Immunohistochemical analysis and in situ hybridization revealed the in vivo presence of IL‐8, MCP‐1 and IL‐10 in lymph node and lung tuberculous granulomas. Our results underscore the role of MT extracts in the induction of macrophage‐derived chemokines responsible for the orchestrated recruitment of PMNs, monocytes, and Th1 and γδ T cells, as well as in the regulation of γδ function.
•The checkpoint molecule programmed death-ligand 1 (PD-L1) is expressed on human granulocytic MDSCs.•Targeting PD-L1 partially impairs MDSC-mediated T-cell suppression.•Collectively, these studies ...suggest a role for PD-L1 on human MDSCs and thereby expand the functionality of this immune checkpoint beyond T cells.
Myeloid-derived suppressor cells (MDSCs) are a heterogeneous cell population expanded in cancer, infection and autoimmunity capable of suppressing T-cell functions. Checkpoint inhibitors have emerged as a key therapeutic strategy in immune-oncology. While checkpoint molecules were initially associated with T cell functions, recent evidence suggests a broader expression and function in innate myeloid cells. Previous studies provided first evidence for a potential role for checkpoints on MDSCs, yet the human relevance remained poorly understood. Therefore, we investigated the expression and functional relevance of checkpoint molecules in human MDSC-T-cell interactions. Our studies demonstrate that programmed death-ligand 1 (PD-L1) is expressed on granulocytic MDSCs upon co-culture with T cells. Transwell experiments showed that cell-to-cell contact was required for MDSC-T-cell interactions and antibody blocking studies showed that targeting PD-L1 partially impaired MDSC-mediated T-cell suppression. Collectively, these studies suggest a role for PD-L1 in human MDSC function and thereby expand the functionality of this checkpoint beyond T cells, which could pave the way for further understanding and therapeutic targeting of PD-1/PD-L1 in innate immune-mediated diseases.
Chemokines constitute a constantly growing family of small inflammatory cytokines. They have been implied in many different diseases of the CNS including trauma, stroke and inflammation, e.g., ...multiple sclerosis. In this review we focus on the role of chemokines in infectious meningitis of bacterial or viral origin. In experimental bacterial meningitis induced by
Listeria monocytogeneses both CXC and CC chemokines namely MIP-1
α, MIP-1
β and MIP-2 are produced intrathecally by meningeal macrophages and leukocytes which infiltrate into the CNS. In patients with bacterial meningitis, IL-8, GRO
α, MCP-1, MIP-1
α and MIP-1
β are detectable in the CSF. These chemokines contribute to CSF mediated chemotaxis on neutrophils and PBMC in vitro. In viral meningitis IL-8, IP-10 and MCP-1 are identified in the CSF to be responsible for chemotactic activity on neutrophils, PBMC and activated T cells. Taken collectively these data indicate that the recruitment of leukocytes in infectious meningitis involves the intrathecal production of chemokines.
The chemokine receptor CXCR3 allows the selective recruitment of innate and adaptive inflammatory immune cells into inflamed tissue. CXCR3 ligands are secreted after exposure to pro-inflammatory ...cytokines. Upon binding to CXCR3 ligands, CXCR3 expressing T-lymphocytes migrate toward sites of inflammation and can promote tissue damage. Therefore, antagonizing this receptor may provide clinical benefits for patients suffering from autoimmune diseases characterized by high concentrations of CXCR3 ligands. Herein, we report the second part of our CXCR3 discovery program where we explored the benzimidazolo-thiazole core scaffold. The optimization of potency and the mitigation of an hERG liability are described. Further pharmacokinetic considerations led to the identification of the potent CXCR3 antagonist ACT-672125 (29). The compound showed good physicochemical properties and safety profile. In a proof-of-mechanism model of lung inflammation, ACT-672125 inhibited the recruitment of CXCR3 expressing T cells into the inflamed lung in a dose-dependent manner.
The chemokine receptor CXCR3 is a seven-transmembrane G-protein-coupled receptor (GPCR) involved in various pathologies, in particular autoimmune diseases. It is activated by the three chemokine ...ligands CXCL9, CXCL10, and CXCL11 and enables the recruitment of immune cell subsets leading to damage of inflamed tissues. Starting from a high-throughput screening hit, we describe the iterative optimization of a chemical series culminating in the discovery of the selective CXCR3 antagonist ACT-660602 (9j). The careful structural modifications during the lead optimization phase led to a compound with high biological potency in inhibiting cell migration together with improvements of the metabolic stability and hERG issue. In a LPS-induced lung inflammation model in mice, ACT-660602 led to significantly reduced recruitment of the CXCR3+ CD8+ T cell in the bronchoalveolar lavage compartment when administered orally at a dose of 30 mg/kg.
Immune checkpoints are regulators of immune cells and play key roles in the modulation of immune responses. The role of checkpoints in autoimmune disease is poorly understood but likely to be central ...since checkpoint inhibition during cancer treatment can cause autoimmunity. We generated a high‐dimensional single‐cell proteomics data set from PBMCs of healthy individuals and patients with ulcerative colitis (UC) by mass cytometry, enabling systems‐wide analyses of immune cell frequencies and cell type‐specific expression patterns of 12 immune checkpoints. Subtle but significant changes in immune cell frequencies and checkpoint expression were observed between UC patients on different treatment regimens and between patients and healthy controls. Most strikingly, UC patients showed a reduced number of peripheral NK‐cells and those cells showed an altered phenotype including increased TIGIT expression. Based on these results, we modulated NK‐cell function ex vivo through targeting of TIGIT pathway members. In summary, we describe a pattern of changes in immune cell abundance and checkpoint expression as a basis for UC patient stratification and we show modulation of a corresponding immune cell subset through checkpoint targeting. Our approach can be used for the identification of pathogenic immune cell subsets and guide target selection in autoimmunity and chronic inflammation.
High‐dimensional single‐cell proteomics identifies treatment‐specific patterns of immune cell type frequencies and immune checkpoint expression in peripheral blood of patients with ulcerative colitis. Phenotypic changes observed in the peripheral NK cell compartment possibly reflect the inflammatory state in the gut tissue and corresponding cells can be modulated through checkpoint targeting.
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