Toll-like receptor-mediated inflammatory disease therapy / Pfizer, Opsona - LARVOL DELTA

CD21 primes extrafollicular differentiation of autoreactive B cells in a TLR7-driven lupus model. (PubMed, Sci Immunol) - "Time-resolved analyses revealed a Toll-like receptor 7 (TLR7)-dependent early escape of peripheral tolerance and a pre-ASC division program...Continuous complement receptor 2 (CR2/CD21)-complement C3d and CD21-complement iC3b engagement triggered receptor down-regulation before proliferation. We reveal CD21 as an initiator of TLR7-dependent autoimmune EF proliferation and target for suppressing autoreactivity."

Journal • Immunology • Infectious Disease • Inflammatory Arthritis • Lupus • Systemic Lupus Erythematosus • CD21 • ITGAX • TLR7

Toll-like receptor 7/8 agonist stimulation rapidly skews the antibody repertoire of B cells in non-human primates. (PubMed, Front Immunol) - "The identified expanded lineages, induced by the TLR7/8 agonist, exhibited λ chain bias and divergent antibodies across individuals, and primarily originated from highly mutated antibodies, likely corresponding to memory/effector-like B cells. Our findings demonstrate that the TLR7/8 agonist rapidly induces a divergent expansion of B cells, establishing an immune foundation supporting vaccine responses and offering new insights into the dynamic B cell modulation."

IO biomarker • Journal

Bank1 deficiency reshapes the gut microbiota of lupus mice towards an anti-inflammatory composition. (PubMed, Front Immunol) - "The B-cell scaffold protein with ankyrin repeats (BANK1) regulates Toll-like receptor-7 (TLR7) signaling in B cells and its absence ameliorates lupus...In vitro stimulation either with P. distasonis or via TLR9 allowed for the differentiation of IL-10 producing B cells which, in vivo, differentially accumulated in the Peyer´s patches of Bank1-deficient lupus mice. Finally, the blood microbiome of lupus patients was found to be devoid of P. distasonis, whereas healthy controls exhibited the bacterium, thereby supporting the protective role of P. distasonis in the disease."

Journal • Preclinical • Immunology • Inflammatory Arthritis • Lupus • Systemic Lupus Erythematosus • IL10 • TLR9

Pre-Vaccination Immune Profiles and Responsiveness to Innate Stimuli Predict Reactogenicity and Antibody Magnitude Following mRNA Vaccination. (PubMed, Vaccines (Basel)) - "The pre-vaccination assessment of innate immune function and resting states can be used to fit models potentially predictive of immunogenicity and reactogenicity to BNT162b2 vaccination. Pre-vaccination DC states may influence reactogenicity, while the response to RNA may impact antibody responses. Our data suggest that pre-vaccination assessment offers insights into the innate mechanisms driving mRNA vaccine responses and has predictive potential."

Journal • Infectious Disease • Novel Coronavirus Disease • CDK1

Synovial immune cells exhibit a type I IFN gene signature in ACPA-negative rheumatoid arthritis (EULAR 2025) - "Here, we assessed the frequency of dendritic cell populations and their capacity to produce pro-inflammatory cytokines upon Toll-Like Receptor stimulation... In this study, we demonstrate a distinct type I IFN gene response signature in immune cells within the synovial joint, but not in peripheral blood, of patients with ACPA- RA. The lack of difference in the levels of IFNs suggest that IFN priming might occur either in a local niche in the synovial joint or in the lymph nodes, or even at a different disease stage. These findings provide a foundation for future research to explore the initiation of type I IFN responses and their role in the pathogenesis of ACPA- RA."

Gene Signature • Immune cell • IO biomarker • Immunology • Inflammatory Arthritis • Psoriatic Arthritis • Rheumatoid Arthritis • Rheumatology • Seronegative Spondyloarthropathies • CD4 • CDK1 • CXCL13 • HLA-DRB1

Design of a peptide-based vaccine against human respiratory syncytial virus using a reverse vaccinology approach: evaluation of immunogenicity, antigenicity, allergenicity, and toxicity. (PubMed, Front Immunol) - "Attempts to develop an hRSV vaccine have faced safety and efficacy challenges, with only three FDA-approved vaccines (Moderna's Mresvia, Pfizer's Abrysvo, and GSK's Arexvy) available...We then characterized its kinetic properties, evaluated its structural integrity, and analyzed its interactions with Toll-like receptors (TLRs) using molecular docking, modeling, and refinement with AlphaFold3 and ClusPro...This study presents a promising peptide-based vaccine candidate against hRSV that can effectively engage the immune system, showing strong immunogenicity and antigenicity. Future in vitro and in vivo studies are essential to evaluate the ability of the multi-epitope vaccine candidate to stimulate both humoral and cell-mediated immune responses and to assess its efficacy and safety profile."

Journal • Infectious Disease • Respiratory Diseases • Respiratory Syncytial Virus Infections • IFNG • IL2 • TLR1 • TLR4

LYMPHOCYTE, NK CELL AND MITOCHONDRIAL GENE DYSREGULATION PATTERNS SEPARATE PATIENTS WITH NEUROPSYCHIATRIC SYSTEMIC LUPUS ERYTHEMATOSUS INTO DISTINCT SUBGROUPS WITH DIFFERENTIAL ANTICIPATED RESPONSE TO TARGETED THERAPIES (EULAR 2024) - "Drugs annotated to the cytotoxic/NK cell network included pegaptanib, a selective vascular endothelial growth factor (VEGF) antagonist, while many anticonvulsants such as zonisamide, lamotrigine, and oxcarbazepine showed potential for counteracting the transcriptomic signature associated with the B cell module. Druggability analysis for the mitochondrial cluster module revealed potential for the centrally acting angiotensin-converting enzyme inhibitor captopril, the mammalian target of rapamycin (mTOR) inhibitor everolimus, the proteasome inhibitor bortezomib, the toll-like receptor 5 (TLR5) agonist entolimod, and the spleen tyrosine kinase (SYK) inhibitor fostamatinib. In silico prediction algorithms demonstrated a greater anticipated response to anifrolumab and calcineurin inhibitors for the active CNS subgroup with B cell, T cell, cytotoxic/NK cell, and mitochondrial gene downregulation compared with the patient subgroup of mixed dysregulation patterns. In this..."

Clinical • IO biomarker • Immunology • Inflammatory Arthritis • Lupus • Metabolic Disorders • Psychiatry • Systemic Lupus Erythematosus • SYK

BANK1 SIGNALLING SHAPES THE GUT MICROBIOTA COMPOSITION BY CONTROLLING THE GUT MUCOSAL B CELL RESPONSE IN A TLR7-MEDIATED LUPUS MODEL (EULAR 2024) - "The B-cell scaffold protein with ankyrin repeats ( Bank1 ) regulates Toll-like receptor-7 (TLR7) signalling in B cells and it has been genetically associated with human lupus and its absence correlated with a less severe disease in mice... Lupus derived gut affectation was characterised by using two TLR7-mediated models of the disease by topical application of the TLR7 agonist Imiquimod (IMQ) or the transgenic expression of the Tlr7 gene... The absence of Bank1 predisposed to differential microbiota and differences in the numbers of IL-10+ B cells in the gut, together with reduced autoimmune inflammation. Changes in the humoral and cellular IgA response, may pave the way for the gut-activated IgA+ plasma cells to act peripherally and regulate autoimmunity. These results highlight the complex crosstalk between genes and environmental factors that modulate autoimmune inflammation."

Gut Microbiota • IO biomarker • Immunology • Inflammatory Arthritis • Inflammatory Bowel Disease • Lupus • Systemic Lupus Erythematosus • IL10 • TLR7

Does COVID -19 vaccine induce BASCULE syndrome? (EADV-Sp 2024) - " Bilastine 20 mg twice daily was started and she achieved nearly complete resolution of pruritus while taking the drug, but recurred when the dose was halved...Both may trigger Toll-like receptors 7/8 inducing type 1 interferons production and others proinflammatory cytokines... The pathogeneses of BASCULE syndrome remains unknown. An exaggerated response to decreased arterial oxygen saturation due to venous pooling induced by orthostatism appears to be the trigger of erythrocyanosis and Bier anemic spots, while urticaria-like eruption may result from mast-cell degranulation in response to hypoxia. SARS-COV2 infection has been associated with a variety of skin lesions, including pernio-like changes (“COVID-toes”) and peripheral acrocyanosis."

Cardiovascular • Dermatology • Hematological Disorders • Immunology • Infectious Disease • Novel Coronavirus Disease • Pain • Pediatrics • Pruritus • Respiratory Diseases • Thrombosis • Urticaria • CRP

B cell, T cell, cytotoxic/NK cell, and mitochondrial gene dysregulation patterns separate neuropsychiatric systemic lupus erythematosus patients into two distinct subgroups with differential anticipated response to targeted therapies (LUPUS 2024) - "Drugs annotated to the cytotoxic/NK cell network included pegaptanib, a selective vascular endothelial growth factor (VEGF) antagonist, while many anticonvulsants such as zonisamide, lamotrigine, and oxcarbazepine showed potential for counteracting the transcriptomic signature associated with the B cell module. Druggability analysis for the mitochondrial cluster module revealed potential for the centrally acting angiotensin-converting enzyme inhibitor captopril, the mammalian target of rapamycin (mTOR) inhibitor everolimus, the proteasome inhibitor bortezomib, the toll-like receptor 5 (TLR5) agonist entolimod, and the spleen tyrosine kinase (SYK) inhibitor fostamatinib. In silico prediction algorithms demonstrated a greater anticipated response to anifrolumab and calcineurin inhibitors for the active CNS subgroup with B cell, T cell, cytotoxic/NK cell, and mitochondrial gene downregulation compared with the patient subgroup of mixed dysregulation patterns (figure 1B)...."

Clinical • IO biomarker • Immunology • Inflammatory Arthritis • Lupus • Systemic Lupus Erythematosus • SYK

Gonadal androgens are associated with decreased type I interferon production by plasmacytoid dendritic cells and increased IgG titres to BNT162b2 following co-vaccination with live attenuated influenza vaccine in adolescents. (PubMed, Front Immunol) - "Plasmacytoid dendritic cells (pDCs) are the primary cell type responsible for IFN-I production, and female pDCs produce more IFN-I than male pDCs since the upstream pattern recognition receptor Toll-like receptor 7 (TLR7) is encoded by X chromosome and is biallelically expressed by up to 30% of female immune cells. Also unexpectedly, we observed that co-vaccination with live attenuated influenza vaccine boosted the magnitude of IgG responses to BNT162b2. Together, these data support a model where systemic IFN-I increases vaccine-mediated immune responses, yet for vaccines with intracellular stages, modulation of the local IFN-I response may alter antigen longevity and consequently improve vaccine-driven immunity."

Journal • Infectious Disease • Influenza • Novel Coronavirus Disease • Respiratory Diseases • TLR7

Molecular characterisation of lupus low disease activity state (LLDAS) and DORIS remission by whole-blood transcriptome-based pathways in a pan-European systemic lupus erythematosus cohort. (PubMed, Ann Rheum Dis) - "We demonstrated for the first time molecular signalling pathways distinguishing LLDAS/remission from active SLE. LLDAS/remission was associated with reversal of biological processes related to SLE pathogenesis and specific clinical manifestations. DEP clustering by remission better grouped patients compared with LLDAS, substantiating remission as the ultimate treatment goal in SLE; however, the lack of substantial pathway differentiation between the two states justifies LLDAS as an acceptable goal from a biological perspective."

Journal • Immunology • Inflammatory Arthritis • Lupus • Musculoskeletal Diseases • Systemic Lupus Erythematosus • BTK • NLRC5 • NLRP3

Similarities and Differences in Peripheral Itch and Pain Pathways in Atopic Dermatitis. (PubMed, J Allergy Clin Immunol) - "These distinct yet reciprocal sensations share many similarities in the peripheral nervous system including common mediators (such as serotonin [5-HT], endothelin-1 [ET-1], interleukin-33 [IL-33], and thymic stromal lymphopoietin [TSLP]), receptors (such as members of the G protein-coupled receptor [GCPR] family and toll-like receptors [TLRs]), and ion channels for signal transduction (such as certain members of the transient receptor potential [TRP] cation channels)...Activation of mu-opioid receptors is known to alleviate pain but exacerbate itch. Understanding the connection between itch and pain mechanisms may offer new insights into the treatment of chronic pain and itch in atopic dermatitis."

Journal • Review • Atopic Dermatitis • Dermatitis • Dermatology • Immunology • Pain • CCL2 • EDN1 • IL33 • POSTN • TRPM3 • TSLP

Presence of MDSC associates with impaired antigen-specific T cell reactivity following COVID-19 vaccination in cirrhotic patients. (PubMed, Front Immunol) - "Immune phenotype and function in peripheral blood from 42 cirrhotic patients and 44 age-matched healthy controls were analysed after two doses of the mRNA-based COVID-19 vaccines [BNT162b2 (Pfizer BioNTech) or mRNA-1273 (Moderna)]...In addition, monocytic cells recovered from cirrhotic patients showed impaired expression of the antigen-presenting molecule HLA-DR and the co-stimulatory molecule CD86 upon Toll-like receptor (TLR) stimulation...Vaccine efficiency inversely correlated with levels of M-MDSC. These results implicate MDSC as mediators of immunosuppression, with ensuing deficiency of vaccine-specific T cell responses, in cirrhosis."

IO biomarker • Journal • Myeloid-derived suppressor cells • Fibrosis • Hepatology • Immunology • Infectious Disease • Novel Coronavirus Disease • CD86 • IL6

BASCULE syndrome after COVID -19 vaccination (EADV 2023) - "Bilastine 20 mg twice daily was started and she achieved nearly complete resolution of pruritus while taking the drug, but recurred when the dose was halved...Both may trigger Toll-like receptors 7/8 inducing type 1 interferons production and others proinflammatory cytokines... The pathogeneses of BASCULE syndrome remains unknown. An exaggerated response to decreased arterial oxygen saturation due to venous pooling induced by orthostatism appears to be the trigger of erythrocyanosis and Bier anemic spots, while urticaria-like eruption may result from mast-cell degranulation in response to hypoxia. SARS-COV2 infection has been associated with a variety of skin lesions, including pernio-like changes (“COVID-toes”) and peripheral acrocyanosis."

Cardiovascular • Dermatology • Hematological Disorders • Immunology • Infectious Disease • Novel Coronavirus Disease • Pain • Pediatrics • Pruritus • Respiratory Diseases • Thrombosis • Urticaria • CRP

Role of Innate Immunity in Allergic Contact Dermatitis: An Update. (PubMed, Int J Mol Sci) - "Pattern recognition receptors (PRRs) including toll-like receptors (TLRs) and nucleotide-binding oligomerization domain (NOD)-like receptors (NLRs) in innate immune cells recognize damage-associated molecular patterns (DAMPs) and cascade the signal to produce several cytokines and chemokines including tumor necrosis factor (TNF)-α, interferon (IFN)-α, IFN-γ, interleukin (IL)-1β, IL-4, IL-6, IL-12, IL-13, IL-17, IL-18, and IL-23. Here we discuss the recent findings showing the roles of the innate immune system in allergic contact dermatitis during the sensitization and elicitation phases."

Journal • Review • Atopic Dermatitis • Contact Dermatitis • Dermatitis • Dermatology • Immunology • Oncology • IFNG • IL12A • IL13 • IL17A • IL18 • IL23A • IL4 • IL6 • NLRC5 • TNFA

Development of novel TLR7 agonist with synergistic antitumor activity with aPD1 and further optimization for short half-life to minimize systemic cytokine release syndrome (ACS-Fall 2023) - "Toll-like receptors (TLRs) recognize molecular patterns associated with pathogens or dead cancer cellsleading to innate immunity...Incombination with aPD1 in CT-26 tumor model, these agonists showed strong synergistic antitumoractivity using IV route. In order to limit the prolonged systemic cytokine release and ultimately to reducepotential tolerability issues, we have designed and evaluated new series of agonist with short half-lives.Structure-activity relationship studies leading to identification and characterization of these TLR7agonists in vitro and in vivo will be presented."

Cytokine release syndrome • Oncology

Identification of metabolically stable 1H-pyrazolo[4,3d]pyrimidine compounds as TLR7 agonists (ACS-Fall 2023) - "Toll-like receptors (TLRs) are a major part of the innate immune system and represent a class of pattern recognition receptors for the first line of the immune response...This compound showed robust induction of cytokines in female balb/c mice. Finally, we describe the development of SAR for the 1H-pyrazolo[4,3d]pyrimidine series to discover potent TLR7 agonists with acceptable ADME properties."

Oncology • TNFA

UN UPDATE OF A PHASE II EXPLORATORY STUDY OF OPN-305, A TOLL-LIKE RECEPTOR 2 (TLR-2) ANTIBODY, IN PATIENTS WITH LOWER RISK MYELODYSPLASTIC SYNDROMES WITH PRIOR HYPOMETHYLATING AGENT (HMA) THERAPY (EHA 2017) - "...Pts with isolated del(5q) should have received therapy with lenalidomide...If after 16 weeks of therapy, there was no response, azacitidine on a 3 day schedule, could be added to OPN-305...Treatment with OPN-305 in pts with previously treated lower-risk MDS was well tolerated with no significant toxicities and 53% ORR including 20% transfusion independence, and potential association between TLR2 levels and response"

P2 data • Biosimilar • Leukemia • Myelodysplastic Syndrome

TLR2 inhibition for cancer therapy, a novel approach with Tomaralimab a humanised IgG4 antibody (EORTC-NCI-AACR 2018) - P1/2; "...Toll-like receptors (TLRs) are a group of innate sensors that are key in the activation of immune responses...Opsona have developed a fully humanised monoclonal antibody Tomaralimab (OPN-305) against TLR2 that has potential as a novel clinical candidate in a range of cancers...Tomaralimab therapy was also assessed in recurrent paclitaxel-resistant ovarian cancer where it significantly delayed the regrowth of tumours via a decrease in intra-tumoural myeloid-derived suppressor cells (MDSCs)...In summary, Tomaralimabs beneficial effects in a range of animal models of solid organ tumours as well as in a clinical study of MDS suggests a potential broad applicability of this novel treatment through multiple mechanisms. To date, clinical benefit had been seen with Tomaralimab therapy in heavily pre-treated lower risk MDS patients that have failed HMA therapy."

Late-breaking abstract • Gastric Cancer • Gastrointestinal Cancer • Gynecologic Cancers • Melanoma • Myelodysplastic Syndrome • Oncology • Ovarian Cancer • Pancreatic Cancer

Intralesional SD-101 in combination with pembrolizumab in anti-PD-1 treatment naive head and neck squamous cell carcinoma: results from a multicenter, phase 2 trial. (PubMed, Clin Cancer Res) - "SD-101 combined with pembrolizumab induced objective responses, especially in HPV+ tumors, which were frequently associated with increased intratumoral inflammation and effector immune cell activity."

Clinical • Combination therapy • IO biomarker • Journal • P2 data • Head and Neck Cancer • Immunology • Inflammation • Oncology • Solid Tumor • Squamous Cell Carcinoma • Squamous Cell Carcinoma of Head and Neck

A RARE CASE OF PLEURODYNIA AFTER THE COVID-19 VACCINE (CHEST 2022) - "Patient was treated empirically for bacterial infection with ceftriaxone and azithromycin...One mechanism describes that lipid particles of SARS mRNA vaccines can induce inflammation by activating the NLR pyrin domain containing 3 inflammasome of mRNA which are recognized by toll like receptors and cytosolic inflammasome components leading to inflammation... As per current literature review there are no case reports about pleurodynia post COVID vaccination but pericarditis and myocarditis have been described. Further research studies are indicated to assess the cause and pathophysiology of pleurodynia post COVID vaccine. Physicians should have a high index of clinical suspicion for pleurodynia when assessing a patient with pleuritic chest pain with a recent history of COVID vaccination."

Clinical • Acute Coronary Syndrome • Atrial Fibrillation • Cardiovascular • Fatigue • Immunology • Infectious Disease • Inflammation • Musculoskeletal Pain • Novel Coronavirus Disease • Obesity • Otorhinolaryngology • Pain • Pulmonary Disease • Pulmonary Embolism • Respiratory Diseases

TRANSCRIPTOME PROFILING AND AUTOIMMUNITY-RELATED SEROLOGICAL MARKERS IDENTIFY TP53 and C3aR AS DRUG TARGETS IN NEUROPSYCHIATRIC SYSTEMIC LUPUS ERYTHEMATOSUS (EULAR 2022) - "Pathways included “Interferon signalling”, “TNF signalling” and “Toll-like Receptor Cascades”. Integrated multilevel omics analysis revealed a set of enriched pathways of potential interest for future drug investigation in CNS lupus, including BTK and C3aR inhibition, and B cell depletion."

IO biomarker • Immunology • Infectious Disease • Inflammatory Arthritis • Lupus • Movement Disorders • Ocular Inflammation • Oncology • Ophthalmology • Optic Neuritis • Psychiatry • Systemic Lupus Erythematosus • TP53

COVID-19 mRNA vaccines associated with MOG-Ab disease and transverse myelitis: Two case reports (AAN 2022) - "The association between CNS demyelinating syndromes and vaccination has been reported for many years. The proposed pathogenesis of CNS demyelinating syndromes after vaccines includes molecular mimicry, epitope spreading, bystander activation, polyclonal activation, effects of adjuvants, and depends on vaccine-related factors like type, dose, and route of administration. The adjuvanticity of COVID-19 vaccines is novel in that it involves Toll-like Receptor (TLR) 7 and 9 agonism, and several immune-mediated disorders have been linked to altered nucleic acid metabolism and processing that have stimulated TLR-7 and TLR-9 experimentally.While the risk of CNS demyelinating events is non-negligible, the incidence is very low."

Clinical • CNS Disorders • Gastrointestinal Disorder • Infectious Disease • Multiple Sclerosis • Neuromyelitis Optica Spectrum Disorder • Novel Coronavirus Disease • Ocular Inflammation • Oncology • Ophthalmology • Optic Neuritis • Rare Diseases • Respiratory Diseases • Solid Tumor • Urology • TLR7 • TLR9

Macrophage activation syndrome in a patient with adult-onset Still's disease following first COVID-19 vaccination with BNT162b2. (PubMed, BMC Rheumatol) - "To the best of our knowledge, this is the first case report of development of MAS in a patient with preexisting AOSD after vaccination in general, and SARS-CoV-2 vaccination in particular. The new mRNA vaccines have generally shown a reassuring safety profile, but it has been shown that nucleic acids in general, including mRNA can act as pathogen-associated molecular patterns that activate toll-like receptors with extensive production of pro-inflammatory cytokines and further activation of immune cells. Proving an interferon 1 response in our patient directly after vaccination, we think that in this particular case the vaccination might have acted as trigger for the development of MAS. Even if it remains difficult to establish causality in the case of rare adverse events, especially in patients with autoimmune or autoinflammatory conditions, these complications are important to monitor and register, but do not at all diminish the overwhelming positive benefit-risk ratio..."

Clinical • Journal • Immunology • Infectious Disease • Novel Coronavirus Disease • Respiratory Diseases