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Journal: The Intracellular C5a-mtC5aR1 Axis Promotes Necroptosis in Dry Eye Through DRP1-Mediated Mitochondrial Dysfunction. (Pubmed Central) - Feb 18, 2026
The functional role of the intracellular C5a-mtC5aR1 axis was assessed through pharmacological inhibition (JPE-1375 and PMX-53) and analysis of downstream signaling (RIPK3/MLKL-mediated necroptosis, DRP1 activation, mitochondrial function, and inflammatory cytokine production)...Our findings identify the intracellular C5a-mtC5aR1-DRP1 axis as a novel regulatory mechanism driving necroptosis in DE. Targeting this pathway represents a potential therapeutic approach to reduce inflammation and corneal damage in DE.
- |||||||||| Soliris (eculizumab) / AstraZeneca, PMX 53 / Teva
Review, Journal: Research progress on the complement system in ischemia-reperfusion injury of organ transplantation. (Pubmed Central) - Jan 8, 2026
Advances in therapeutic research highlight the values of complement inhibitors, including anti-C5 agents (e.g., eculizumab) that mitigate delayed graft function (DGF) in kidney transplantation, C1 esterase inhibitors that attenuate IRI and antibody-mediated rejection (AMR), C5a receptor antagonists (e.g., PMX53) that extend graft survival in preclinical models, and soluble complement receptor 1 (sCR1) that alleviates multi-organ IRI. Future research should focus on optimizing organ-specific targeting strategies, validating the long-term efficacy and safety of these agents via clinical trials, and exploring synergistic immunomodulatory approaches to further improve transplantation outcomes.
- |||||||||| vigabatrin / Generic mfg., PMX 53 / Teva
Journal: Prenatal betamethasone-postnatal N-methyl-D-aspartic acid model of spasms: Update on mechanisms and treatments. (Pubmed Central) - Sep 16, 2025
FDA-approved therapies/medications, ACTH and vigabatrin, have limited efficacy and significant side effects, necessitating further research into better therapies...The C5a receptor antagonist PMX53 shows efficacy in males, suggesting inflammation may be a therapeutic target...Some therapies, like AQB-565, show promise in reducing seizures with fewer side effects. Our findings suggest that personalized, targeted treatments based on individual causes and sex differences could improve outcomes.
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Preclinical, Journal: Autoantibodies cause nociceptive sensitization in a mouse model of degenerative osteoarthritis. (Pubmed Central) - Jun 18, 2025
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.
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Journal: PTX3 Deficiency Aggravates Periodontitis by the Complement C5a-C5aR1 Axis. (Pubmed Central) - May 16, 2025
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 ?B 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.
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Journal: The activation of complement C5a-C5aR1 axis in astrocytes facilitates the neuropathogenesis due to EV-A71 infection by upregulating CXCL1. (Pubmed Central) - Jan 31, 2025
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.
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Biomarker, Journal, Checkpoint inhibition, Tumor microenvironment, PD(L)-1 Biomarker, IO biomarker, Checkpoint block: C5aR1 blockade reshapes immunosuppressive tumor microenvironment and synergizes with immune checkpoint blockade therapy in high-grade serous ovarian cancer. (Pubmed Central) - Oct 8, 2023
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.
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Journal: Valproic acid attenuates cellular senescence in diabetic kidney disease through the inhibition of complement C5a receptors. (Pubmed Central) - Nov 27, 2022
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.
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Journal: Regulatory relationship between macrophage autophagy and PVL-positive methicillin-resistant Staphylococcus aureus. (Pubmed Central) - Jun 9, 2022
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.
- |||||||||| Victoza (liraglutide) / Novo Nordisk
Journal, IO biomarker: HSP90-Mediates Liraglutide Preconditioning-Induced Cardioprotection by Inhibiting C5a and NF-κB. (Pubmed Central) - Apr 28, 2022
Hence, our study identifies complement C5a as a potential new target for the treatment and prevention of thrombosis. 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.
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PK/PD data, Preclinical, Journal: In Vivo Pharmacodynamic Method to Assess Complement C5a Receptor Antagonist Efficacy. (Pubmed Central) - Jan 26, 2022
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.
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Preclinical, Journal: C5aR1 Mediates the Progression of Inflammatory Responses in the Brain of Rats in the Early Stage after Ischemia and Reperfusion. (Pubmed Central) - Nov 16, 2021
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.
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Journal, Gene Expression Profile: C5a Activates a Pro-Inflammatory Gene Expression Profile in Human Gaucher iPSC-Derived Macrophages. (Pubmed Central) - Sep 29, 2021
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.
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Preclinical, Journal: C5a complement and cytokine signaling mediate the pronociceptive effects of complex regional pain syndrome patient IgM in fracture mice. (Pubmed Central) - May 20, 2021
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.
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Clinical, Journal: Complement C5a Induces Pro-inflammatory Microvesicle Shedding in Severely Injured Patients. (Pubmed Central) - Apr 20, 2021
Furthermore, in vitro exposure of human neutrophils (from healthy volunteers) to C5a significantly increased MV shedding and C5aR1 loss on neutrophils, which could be blocked using the C5aR1 antagonist PMX53...C5a-induced MVs activated resting neutrophils and significantly induced IL-6 secretion. These data suggest a novel role of the C5a-C5aR1 axis: C5a-induced MV shedding from neutrophils results in decreased C5aR1 surface expression on the one hand, on the other hand it leads to profound inflammatory signals which likely are both key drivers of the neutrophil dysfunction which is regularly observed in patients suffering from multiple traumatic injuries.
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Preclinical, Journal: An Immunoregulatory Role for Complement Receptors in Murine Models of Breast Cancer. (Pubmed Central) - Jan 13, 2021
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.
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Journal: Inhibition of osteoclast activity by complement regulation with DF3016A, a novel small-molecular-weight C5aR inhibitor. (Pubmed Central) - Oct 27, 2020
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.
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Journal: Absence of the C5a Receptor C5aR2 Worsens Ischemic Tissue Injury by Increasing C5aR1-Mediated Neutrophil Infiltration. (Pubmed Central) - Oct 9, 2020
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.
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Preclinical, Journal: The C5a/C5aR1 axis promotes progression of renal tubulointerstitial fibrosis in a mouse model of renal ischemia/reperfusion injury. (Pubmed Central) - Sep 23, 2020
Thus, our results demonstrate a pathogenic role for C5aR1 in the progression of tubulointerstitial fibrosis following renal IR injury and support that C5aR1-mediated local inflammatory responses to hypoxic renal injury contribute to tubulointerstitial fibrosis through several cellular pathways, namely, promoting tubule injury, interstitial fibroblast proliferation and epithelial-to-mesenchymal transition of renal tubular epithelial cells. Our results also suggest the C5a-C5aR1 interaction is a therapeutic target for chronic post-ischemic fibrosis.
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Journal: Complement C5a Induces Renal Injury in Diabetic Kidney Disease Via Disruption in Mitochondrial Metabolic Agility. (Pubmed Central) - Jul 7, 2020
In vitro exposure of human renal proximal tubular epithelial cells to C5a led to altered mitochondrial respiratory function and reactive oxygen species generation. These studies provide evidence for a pivotal role of the C5a/C5aR1 axis in propagating renal injury in the development of DKD via disruption of mitochondrial agility, establishing a new immunometabolic signalling pathway in DKD.
- |||||||||| PMX 53 / Teva, PMX205 / Alsonex
PK/PD data, Preclinical, Journal: Preclinical Pharmacokinetics of Complement C5a Receptor Antagonists PMX53 and PMX205 in Mice. (Pubmed Central) - Feb 19, 2020
These results will be helpful in correlating the desired therapeutic effects of these C5aR1 antagonists with their pharmacokinetic profile. It also suggests that subcutaneous dosing of PMX205 may be an appropriate route of administration for future clinical testing in neurological disease.
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Preclinical, Journal: ACTH and PMX53 recover synaptic transcriptome alterations in a rat model of infantile spasms. (Pubmed Central) - Oct 4, 2019
Although IS alters expression of ~30% of the ARC genes in both sexes the transcriptomic effects are 3× more severe in males than their female counterparts, as indicated by the Weighted Pathway Regulation measure. Both treatments significantly restored the ARC neurotransmission transcriptome to the non-IS condition with PMX53 performing slightly better, as measured by the Pathway Restoration Efficiency, suggesting these treatments may reduce autistic traits often associated with IS.
- |||||||||| avacopan (CCX168) / Kissei, Galenica, ChemoCentryx, PMX 53 / Teva
Journal: Orthosteric and allosteric action of the C5a receptor antagonists. (Pubmed Central) - Aug 28, 2019
We also discuss critical structural features of C5aR in activation, including a novel conformation of helix 8. On the basis of our results, we suggest novel strategies for developing C5aR-targeting drugs.
- |||||||||| paclitaxel / generics
Journal: Complement C5a Fosters Squamous Carcinogenesis and Limits T Cell Response to Chemotherapy. (Pubmed Central) - Jun 15, 2019
Therapeutic inhibition of C5aR1 via the peptide antagonist PMX-53 improved efficacy of paclitaxel chemotherapy associated with increased presence and cytotoxic properties of CXCR3 effector memory CD8 T cells in carcinomas, dependent on both macrophage transcriptional programming and IFNγ. Together, these data identify C5aR1-dependent signaling as an important immunomodulatory program in neoplastic tissue tractable for combinatorial cancer immunotherapy.
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