PMX 53 / Teva - LARVOL DELTA

PTX3 Deficiency Aggravates Periodontitis by the Complement C5a-C5aR1 Axis. (PubMed, J Dent Res) - "Inhibition of C5a signaling with PMX53 or NLRP3 inflammasome with MCC950 significantly alleviated these adverse effects...In vitro studies showed that PTX3 deficiency promoted C5a conversion and release in monocytes, thereby activating the NLRP3 inflammasome via the C5a-C5aR1 axis-mediated mitogen-activated protein kinase and nuclear factor κB signaling in an inflammatory environment. In conclusion, these data elucidate the link between PTX3 in regulating complement activation and periodontitis progression, providing a potential target for innate immune-based therapy of periodontitis."

Journal • Dental Disorders • Inflammation • Osteoporosis • Periodontitis • NLRP3 • PTX3

Autoantibodies cause nociceptive sensitization in a mouse model of degenerative osteoarthritis. (PubMed, Pain) - "Monosodium iodoacetate-injected joints demonstrate elevated levels of complement component 5a (C5a) and C5a receptor blockade using intra-articular PMX-53-reduced sensitization. These data suggest that MIA-treated mice and patients with OA generate pronociceptive antibodies, and further support the pronociceptive autoimmunity hypothesis for the transition from tissue injury to chronic musculoskeletal pain."

Journal • Preclinical • Immunology • Musculoskeletal Diseases • Musculoskeletal Pain • Orthopedics • Osteoarthritis • Pain • Rheumatology

The activation of complement C5a-C5aR1 axis in astrocytes facilitates the neuropathogenesis due to EV-A71 infection by upregulating CXCL1. (PubMed, J Virol) - "Notably, EV-A71 infection led to activation of the C5a-C5aR1 axis in U87-MG cells, and knockdown (siC5aR1) or blockade (PMX53) of C5aR1 significantly suppressed EV-A71-induced astrocyte activation and proinflammatory cytokine (e.g., CXCL1) production...In addition, neutralizing CXCL1 significantly alleviates the neuropathogenesis caused by EV-A71 infection. Thus, inhibiting the C5a-C5aR1 axis has emerged as a potential therapeutic strategy to mitigate neural damage caused by EV-A71 infection."

Journal • CNS Disorders • Infectious Disease • Inflammation • CXCL1 • IL6

Dysregulated complement activation during acute myocardial infarction leads to endothelial glycocalyx degradation and endothelial dysfunction via the C5a:C5a-Receptor1 axis. (PubMed, Front Immunol) - "Endothelial cells were stimulated with C5a or patient sera (with/without C5a-receptor1 antagonist "PMX53") and the nanomechanical properties of eGC quantified using the atomic force microscopy (AFM)-based nanoindentation technique...This study demonstrates that dysregulated C5a activation during AMI results in eGC damage with subsequent endothelial dysfunction and reduced NO bioavailability, indicating progressively developing vascular inflammation. This could be prevented by antagonizing C5aR1, highlighting the role of the C5a:C5a-Receptor1 axis in vascular inflammation development and endothelial dysfunction in AMI, offering new therapeutic approaches for future investigations."

Journal • Cardiovascular • Inflammation • Myocardial Infarction • RAC1 • RHOA

An herbal formula Shenlian decoction upregulates M1/M2 macrophage proportion in hepatocellular carcinoma by suppressing complement cascade. (PubMed, Biomed Pharmacother) - "The suggested mechanism was demonstrated by application of C5aR1 inhibitor, PMX-53 in mouse HCC model...SLD could suppress the C5 secretion in hepatoma cells via inhibition of AMPK/p38 signaling. We suggested that SLD is a potential herbal therapy for the treatment of HCC by alleviating immune-suppressive status."

Journal • Gastrointestinal Cancer • Hepatocellular Cancer • Liver Cancer • Oncology • Solid Tumor • C5AR1 • CTNNB1 • MET

Blockade of C5aR1 resets M1 via gut microbiota-mediated PFKM stabilization in a TLR5-dependent manner. (PubMed, Cell Death Dis) - "Therefore, in this study, genetic deletion of C5ar1 or pharmacological inhibition of C5aR1 with anti-C5aR1 Ab or PMX-53 in the presence or absence of deletion Abs were utilized to verify if and how C5aR1 inhibition regulated TAMs polarization via affecting gut microbiota composition...Our data revealed that high levels of C5aR1 in TAMs predicted poor prognosis. In summary, our study suggested that C5aR1 inhibition reduced CRC growth via resetting M1 by AKT2 activation-mediated PFKM stabilization in a TLR5-dependent manner, which relied on IL-22-regulated gut flora."

Journal • Colorectal Cancer • Gastrointestinal Cancer • Oncology • Solid Tumor • AKT2 • IL22 • PFKM • TLR5

Polystyrene microplastics induce kidney injury via gut barrier dysfunction and C5a/C5aR pathway activation. (PubMed, Environ Pollut) - "Further experiments using a C5aR inhibitor, PMX53, verified the vital role of renal C5a/C5aR pathway activation in the development of kidney injury induced by PS-MPs. Collectively, our results suggest that PS-MPs induce kidney injury in mice by impairing the gut barrier, increasing C5a levels, and ultimately activating the renal C5a/C5aR pathway, highlighting the crucial role of the gut-kidney axis in PS-MPs-induced kidney injury."

Journal • Chronic Kidney Disease • Gastrointestinal Disorder • Nephrology • Renal Disease

C5aR1 blockade reshapes immunosuppressive tumor microenvironment and synergizes with immune checkpoint blockade therapy in high-grade serous ovarian cancer. (PubMed, Oncoimmunology) - "Transcriptomic analyses of the xenografts delineated the mechanisms driving the immunomodulatory activity of PMX53, an orally bioavailable C5aR1 inhibitor...Furthermore, the combination of C5aR1 and PD-L1 was associated with specific molecular characteristics and matched clinical response annotations. Therefore, the abundance of C5aR1 could predict an inferior prognosis in HGSCs, and incorporating PD-L1 may serve as a novel predictive biomarker to guide therapeutic options."

Biomarker • Checkpoint block • Checkpoint inhibition • IO biomarker • Journal • Tumor microenvironment • Oncology • Ovarian Cancer • Ovarian Serous Adenocarcinoma • Solid Tumor

C5a-C5aR1 induces endoplasmic reticulum stress to accelerate vascular calcification via PERK-eIF2α-ATF4-CREB3L1 pathway. (PubMed, Cardiovasc Res) - "High level of C5a was associated with increased risk of VC, and it accelerated VC by activating the receptor C5aR1. PERK-eIF2α-ATF4-CREB3L1 pathway of endoplasmic reticulum stress was activated by C5a-C5aR1, hence promoting VSMCs osteogenic transdifferentiation. Targeting C5 or C5aR1 may be an appealing therapeutic target for VC."

Journal • Cardiovascular • Chronic Kidney Disease • Nephrology • Renal Disease • ATF4 • COL1A1 • CREB3L1

Blockade of C5aR1 alleviates liver inflammation and fibrosis in a mouse model of NASH by regulating TLR4 signaling and macrophage polarization. (PubMed, J Gastroenterol) - "Blockade of the C5a-C5aR1 axis reduces hepatic steatosis, inflammation, and fibrosis in NASH mice. Our data suggest that C5aR1 may be a potential target for drug development and therapeutic intervention of NASH."

IO biomarker • Journal • Preclinical • Fibrosis • Gastrointestinal Cancer • Hepatocellular Cancer • Hepatology • Immunology • Inflammation • Non-alcoholic Steatohepatitis • Oncology • Solid Tumor • IL1B • NF-κβ • NLRP3 • TGFB1 • TLR4 • TNFA

Valproic acid attenuates cellular senescence in diabetic kidney disease through the inhibition of complement C5a receptors. (PubMed, Sci Rep) - "Similar results were observed in diabetic mice treated with a C5aR1 inhibitor, PMX53...Collectively, these results for the first time demonstrated that complement C5a mediates cellular senescence in diabetic kidney disease. Cellular senescence has been implicated in the pathogenesis of diabetic kidney disease, thus therapies to inhibit cellular senescence such as complement inhibitors present as a novel therapeutic option to treat diabetic kidney disease."

Journal • Diabetes • Diabetic Nephropathy • Glomerulonephritis • Metabolic Disorders • Nephrology • Renal Disease

Investigating the Dynamic Binding Behavior of PMX53 Cooperating with Allosteric Antagonist NDT9513727 to C5a Anaphylatoxin Chemotactic Receptor 1 through Gaussian Accelerated Molecular Dynamics and Free-Energy Perturbation Simulations. (PubMed, ACS Chem Neurosci) - "Therefore, pose 2 (ΔG = -16.27 kcal/mol) is notably stable than pose 1 (ΔG = -9.78 kcal/mol) in the ternary complex. The identification of a novel binding mode of PMX53 and the detailed structural information of PMX53 interacting with a receptor obtained by GaMD simulations will be helpful in designing potent antagonists of C5aR1."

Journal

Complement activation contributes to subretinal fibrosis through the induction of epithelial-to-mesenchymal transition (EMT) in retinal pigment epithelial cells. (PubMed, J Neuroinflammation) - "Complement activation is critically involved in the development of subretinal fibrosis, partially through C5a-C5aR-mediated EMT in RPE cells. Targeting complement activation rather than C5a may be a novel approach for the management of macular fibrosis."

Journal • Age-related Macular Degeneration • Fibrosis • Immunology • Inflammation • Macular Degeneration • Ophthalmology • Retinal Disorders • Wet Age-related Macular Degeneration • CDH1 • FN1 • IL6 • SNAI2 • TGFB1 • VIM

High Throughput Screen Identifies Drugs That Rescue AMD Phenotype in iPSC Derived RPE Model of Macular Degeneration (ASGCT 2022) - "Receptor blockers Compstatin (C5aR1), PMX53 (C3aR1), and depleted sera for C5 and C3 were used to confirm the role of the complement pathway... C5a and C3a induced sub RPE deposits in iPSC-RPE were rescued by two drugs discovered from the high throughput screening. The AMD model helped us in dissecting out the cell autonomous role of RPE in disease pathogenesis. It also provides a platform to study the genotype-phenotype relation in AMD."

Age-related Macular Degeneration • Macular Degeneration • Ophthalmology • Retinal Disorders • APOE • ATG5 • EZR • RELA • VIM

Regulatory relationship between macrophage autophagy and PVL-positive methicillin-resistant Staphylococcus aureus. (PubMed, Immunobiology) - "The results showed that PVL-MRSA could induced the autophagy of macrophages, which in turn reduced the damage from macrophages, which were respectively alleviated by 3-MA and aggravated by rapamycin...Exogenous rPVL, particularly A-Luk S-PV, administrated into macrophages also caused the autophagy of macrophage, which was reversed by PMX53, a C5aR antagonist...In conclusion, this study indicated PVL-MRSA regulated macrophage autophagy, which in turns inhibit the phagocytosis of S. aureus by macrophage. This study may provide a potential target against S. aureus infection."

Journal • Infectious Disease • Pneumonia • Respiratory Diseases

Complement C5a induces the generation of neutrophil extracellular traps by inhibiting mitochondrial STAT3 to promote the development of arterial thrombosis. (PubMed, Thromb J) - "By inhibiting mitochondrial STAT3 to elicit Mito-ROS generation, C5a triggers the generation of NETs to promote the development of arterial thrombosis. Hence, our study identifies complement C5a as a potential new target for the treatment and prevention of thrombosis."

Journal • Cardiovascular • Hematological Disorders • Immunology • Inflammation • Myocardial Infarction • Thrombosis • STAT3

Effect of a C5a receptor antagonist on macrophage function in an intestinal transplant rat model. (PubMed, Transpl Immunol) - "Inhibition of C5a/C5aR1 signaling appears to regulate macrophage differentiation and suppress rejection in small intestine transplantation immunity."

Journal • Preclinical • Transplantation • IL1B • TNFA

In Vivo Pharmacodynamic Method to Assess Complement C5a Receptor Antagonist Efficacy. (PubMed, ACS Pharmacol Transl Sci) - "Pharmacokinetic analysis demonstrated rapid plasma distribution and elimination of both compounds, although PMX53 had a longer half-life, which allowed for the development of an accurate pharmacokinetic/pharmacodynamic model. Overall, our study developed a robust in vivo pharmacodynamic model for C5aR1 inhibitors in mice that may assist in preclinical translational studies of therapeutic drug candidates targeting C5a and its receptors."

Journal • PK/PD data • Preclinical • Immunology • Inflammation

HSP90-Mediates Liraglutide Preconditioning-Induced Cardioprotection by Inhibiting C5a and NF-κB. (PubMed, J Invest Surg) - "We previously showed that HSP90 is involved in postconditioning cardioprotection by inhibiting complement C5a. By contrast, PMX53, a C5a inhibitor, suppressed C5a activation, NF-κB signaling, and inflammation, and enhanced cardioprotection by LP. HSP90 markedly contributes to LP cardioprotection by inhibiting inflammatory responsesand C5a/NF-κB signaling , ultimately attenuating I/R-induced cardiomyocyte apoptosis by suppressing the proapoptotic factor Bax, and inducing the anti-apoptotic factor Bcl2."

IO biomarker • Journal • Immunology • Inflammation • Reperfusion Injury • BCL2 • HSP90AA1 • TNNI3

C5aR1 Mediates the Progression of Inflammatory Responses in the Brain of Rats in the Early Stage after Ischemia and Reperfusion. (PubMed, ACS Chem Neurosci) - "Here, we determined whether C5aR1 signaling was essential to the post-ischemic inflammation and brain injury and whether it is a valid target for therapeutic blockade by using soluble receptor antagonist PMX53 in the early stage after I/R injury...Thus, our results demonstrated a pathogenic role for C5aR1 in the progression of brain injury and inflammation response following I/R injury. Our study clearly demonstrated that C5aR1 inhibition might be an effective treatment strategy for ischemic stroke."

Journal • Preclinical • Cardiovascular • CNS Disorders • Immunology • Inflammation • Ischemic stroke • Oncology • Vascular Neurology • IL1B • IL6 • TLR4 • TNFA

C5a Activates a Pro-Inflammatory Gene Expression Profile in Human Gaucher iPSC-Derived Macrophages. (PubMed, Int J Mol Sci) - "PMX53, a C5aR1 blocker, reversed the enhanced GD macrophage TNF-α production, indicating that the observed effect was predominantly C5aR1-mediated...We found that rC5a-stimulated GD macrophages exhibit increased expression of genes involved in TNF-α inflammatory responses compared to rC5a-stimulated controls. Our results suggest that rC5a-induced inflammation in GD macrophages activates a unique immune response, supporting the potential use of inhibitors of the C5a-C5aR1 receptor axis to mitigate the chronic inflammatory abnormalities associated with GD."

Journal • Gaucher Disease • Genetic Disorders • Immunology • Inflammation • Metabolic Disorders • GBA • TNFA

An Immunoregulatory Role for Complement Receptors in Murine Models of Breast Cancer. (PubMed, Antibodies (Basel)) - "In contrast to prior studies in other tumor models, treatment with the selective C5aR1 antagonist PMX53 had no effect on tumor growth...These results support an immunoregulatory role for complement receptors in primary murine mammary carcinoma models. They also suggest that complement activation peptides can influence the anti-tumor response in different ways depending on the cancer type, the host immune response to the tumor and levels of endogenous complement activation within the tumor microenvironment."

Journal • Preclinical • Breast Cancer • Oncology • Solid Tumor • PCR

C5a complement and cytokine signaling mediate the pronociceptive effects of complex regional pain syndrome patient IgM in fracture mice. (PubMed, Pain) - "Intraplantar IgM injection caused nociceptive sensitization in muMT fracture mice with increased complement component C1q and inflammatory cytokine expression, and these IgM effects were blocked by a C5a receptor antagonist (PMX53) or a global cytokine inhibitor (pentoxifylline). Intrathecal injection of chronic (> 12 months duration) CRPS patient IgM (but not IgG) caused nociceptive sensitization in muMT fracture mice, but intraplantar injection of chronic CRPS IgM or IgG had no effect. We postulate that CRPS IgM antibodies bind to neoantigens in the fracture limb skin and corresponding spinal cord to activate C5a complement signaling in macrophages and microglia, evoking proinflammatory cytokine expression contributing to nociceptive sensitization in the injured limb."

Journal • Immunology • Musculoskeletal Diseases • Musculoskeletal Pain • Orthopedics • Pain

Inhibition of osteoclast activity by complement regulation with DF3016A, a novel small-molecular-weight C5aR inhibitor. (PubMed, Biomed Pharmacother) - "The impact of the peptidomimetic orthosteric C5aR antagonist (PMX-53), of two newly synthesized allosteric C5aR antagonists (DF2593A, DF3016A), and of C5aR down-regulation by specific siRNAs, were examined for regulation of osteoclastogenesis, using a well-validated in-vitro model starting from RAW264.7 precursor cells...Among the C5aR antagonists analyzed, DF3016A inhibited osteoclast degradation activity through inhibition of C5aR signal transduction and transcription. These data confirm the preclinical relevance of this novel therapeutic candidate."

Journal

Absence of the C5a Receptor C5aR2 Worsens Ischemic Tissue Injury by Increasing C5aR1-Mediated Neutrophil Infiltration. (PubMed, J Immunol) - "Inhibition of C5aR1 signaling in C5aR2 mice with PMX53 prevented neutrophil accumulation and reduced IR pathology, suggesting a key requirement for enhanced neutrophil C5aR1 activation in the absence of C5aR2 signaling...This is despite the potentially local pathogenic effects of C5aR2 in increasing intestinal proinflammatory cytokines and enhancing circulating neutrophil numbers in response to mobilizing signals. Our data therefore suggest that this balance between the dual pro- and anti-inflammatory roles of C5aR2 ultimately dictates disease outcomes."

Journal • Inflammatory Bowel Disease • Reperfusion Injury