Preclinical Pharmacokinetics of Complement C5a Receptor Antagonists PMX53 and PMX205 in Mice

Kumar, Vinod; Lee, John D.; Clark, Richard J.; Noakes, Peter G.; Taylor, Stephen M.; Woodruff, Trent M.

doi:10.1021/acsomega.9b03735

Cited by 67 publications

(72 citation statements)

References 47 publications

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“…Furthermore, we point to a promising therapeutic strategy since PMX53, a potent C5aR1 antagonist, completely blocked shedding of C5aR1-positive MVs ( Figure 8 ). The pharmacological profile of PMX53 have been extensively studied in several animal models including mice ( 54 ) and rats ( 55 ). Also in humans, oral and topical administration was found to be safe and well-tolerated and successfully completed phase I clinical trials ( 33 ).…”

Section: Discussionmentioning

confidence: 99%

Complement C5a Induces Pro-inflammatory Microvesicle Shedding in Severely Injured Patients

et al. 2020

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Initially underestimated as platelet dust, extracellular vesicles are continuously gaining interest in the field of inflammation. Various studies addressing inflammatory diseases have shown that microvesicles (MVs) originating from different cell types are systemic transport vehicles carrying distinct cargoes to modulate immune responses. In this study, we focused on the clinical setting of multiple trauma, which is characterized by activation and dysfunction of both, the fluid-phase and the cellular component of innate immunity. Given the sensitivity of neutrophils for the complement anaphylatoxin C5a, we hypothesized that increased C5a production induces alterations in MV shedding of neutrophils resulting in neutrophil dysfunction that fuels posttraumatic inflammation. In a mono-centered prospective clinical study with polytraumatized patients, we found significantly increased granulocyte-derived MVs containing the C5a receptor (C5aR1, CD88) on their surface. This finding was accompanied by a concomitant loss of C5aR1 on granulocytes indicative of an impaired cellular chemotactic and pro-inflammatory neutrophil functions. 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. Mechanistic analyses revealed that the interaction between C5aR1 signaling and the small GTPase Arf6 acts as a molecular switch for MV shedding. When neutrophil derived, C5a-induced MV were exposed to a complex ex vivo whole blood model significant pro-inflammatory properties (NADPH activity, ROS and MPO generation) of the MVs became evident. 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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Section: Discussionmentioning

confidence: 99%

Complement C5a Induces Pro-inflammatory Microvesicle Shedding in Severely Injured Patients

et al. 2020

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“…In this study, we showed the e cacy of the combined therapy C5aRA and hiPSC-NS/PCs transplantation for SCI in SCID-Beige mice. However, in order to apply this treatment in a clinical setting, it is necessary to perform further studies using C5aRA, which has already been clinically applied, instead of PMX205 that is not approved for marketing [16]. For example, CCX168 has completed phase trials [50] and is one of the most advanced C5aRA in clinical development.…”

Section: Discussionmentioning

confidence: 99%

“…Consequently, C5aR antagonist (C5aRA) could be a target as a treatment for in ammatory reaction after SCI. Among C5aRA, PMX205 (hydrocinnamate-(OPdChaWR)) is often used in the eld of CNS disease experiment because PMX205 is able to penetrate blood-brain barrier and blood-spinal cord barrier [15,16], and it has been shown that PMX205 administration after SCI suppresses in ammatory cytokines and macrophage in ltration into the lesion, decreases secondary damage, and improves the recovery of locomotor function [17]. These studies indicate that administration of C5aRA can inhibit the in ammatory reaction during the acute phase of SCI and prepare the injured microenvironment for receiving transplanted NS/PCs.…”

Section: Introductionmentioning

confidence: 99%

Administration of C5a Receptor Antagonist Improves the Efficacy of Human iPSCS-derived NS/PC Transplantation in the Acute Phase Of spinal Cord Injury

Shibata¹,

Nagoshi²,

Kajikawa³

et al. 2020

Preprint

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Abstract Background: We previously reported the efficacy of human-induced pluripotent stem cells derived neural stem/progenitor cells (hiPSC-NS/PCs) transplantation for spinal cord injury (SCI) in the subacute phase. However, this procedure is not effective in the acute phase due to the inflammatory response occurring immediately after SCI, which negatively impacts transplanted cell survival. C5a, which is one of the complement components, is a powerful chemoattractant which recruits inflammatory cells through binding of the C5a receptor. We hypothesized that suppression of the inflammatory response immediately after SCI using a C5a receptor antagonist (C5aRA) as an immunosuppressant would improve the efficacy of hiPSC-NS/PCs transplantation for SCI in the acute phase.Methods: Immunodeficient SCID-Beige mice underwent contusion SCI at T10 and received C5aRA immediately after SCI. Inflammatory cytokines and inflammatory cells in the injured spinal cord tissue during the acute phase were quantified using quantitative PCR and flow-cytometry. Next, we randomly and blindly divided the SCI mice into 4 groups (PBS only, C5aRA only, PBS + transplantation (PBS+TP), C5aRA + transplantation (C5aRA+TP)). Immediately after SCI, C5aRA or PBS was injected intraperitoneally once a day for 4 consecutive days, and then, 5.0 × 105 hiPSC-NS/PCs were transplanted into the lesion epicenter on day 4 in the PBS+TP and C5aRA+TP groups. We evaluated cell survival rate, hindlimb motor function, and the differentiation profile of the graft hiPSC-NS/PCs.Results: C5aRA administration significantly reduced several inflammatory cytokines such as IL-1b, IL-6 and TNFα, as well as inflammatory cells after SCI. Within the transplantation groups, the C5aRA+TP group had better functional improvement as compared to the PBS only group. The C5aRA+TP group also had a significantly higher cell survival rate compared to the PBS+TP group. There were no significant differences in the differentiation profiles of grafted hiPSC-NS/PCs between the C5aRA+TP and PBS+TP groups.Conclusion: This study demonstrates that administration of C5aRA can suppress the inflammatory response during the acute phase of SCI, and also improve the survival rate of transplanted hiPSC-NS/PCs as well as enhance motor functional restoration. hiPSC-NS/PC transplantation with C5aRA is a promising treatment during the acute injury phase for SCI patients.

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“…For all experiments, tumors were measured with the use of calipers and volumes calculated by the ellipsoid estimation method as previously described (Taniguchi et al, 2014). For in vivo experiments involving PMX205 treatment, 10 mg/kg PMX205 (Tocris #5196, or synthesized and purified as previously described (Kumar et al, 2020)) was administered to mice orally flanking the irradiation doses. Vehicle control in these experiments refers to 20% ethanol/water.…”

Section: Methodsmentioning

confidence: 99%

“…PMX205 has been previously used in preclinical models and found to be a specific C5aR1 antagonist (Jain et al, 2013;Kumar et al, 2018Kumar et al, , 2020Lee et al, 2017;. Furthermore, PMX205 has been granted Food and Drug Administration (FDA) and European Medicines Agency (EMA) "orphan drug" approval allowing accelerated progression to clinical trials .…”

Section: C5ar1 As a Good Therapeutic Targetmentioning

confidence: 99%

Targeting C5aR1 Increases the Therapeutic Window of Radiotherapy

Olcina

Melemenidis

Nambiar

et al. 2020

Preprint

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Engaging innate immune pathways is emerging as a productive way of achieving durable anti-tumor responses. However, systemic administration of these therapies can result in toxicity, deemed to be particularly problematic when combined with current standard-of-care cytotoxic treatments such as radiotherapy. Increasing the therapeutic window of radiotherapy may be achieved by using targeted therapies, however, few pre-clinical studies investigate both tumor and normal tissue responses in detail. Here we show that targeting innate immune receptor C5aR1 improves tumor radiation response while reducing radiation-induced normal tissue toxicity, thereby increasing the therapeutic window. The potent and orally active C5aR1 inhibitor, PMX205, increases IL-10 secretion, which attenuates RelA phosphorylation and enhances apoptosis in tumor cells. Importantly, targeting C5aR1 improves tumor radiation response even in the presence of reduced CD8+ T-cell infiltration, suggesting that this is a good target even in tumors displaying features of T-cell deficiency or exclusion. Furthermore, we find that C5aR1 depletion results in decreased small intestinal histologic damage, crypt cell apoptosis and increased survival of mice following irradiation. Using a preclinical murine model allowing the simultaneous assessment of tumor and normal tissue radiation responses, we show that PMX205 treatment reduces histological and functional markers of small-bowel toxicity while affording a positive tumor response. Our data, therefore, suggest that targeting C5aR1 could be a promising approach for increasing the therapeutic window of radiotherapy.

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Preclinical Pharmacokinetics of Complement C5a Receptor Antagonists PMX53 and PMX205 in Mice

Cited by 67 publications

References 47 publications

Complement C5a Induces Pro-inflammatory Microvesicle Shedding in Severely Injured Patients

Complement C5a Induces Pro-inflammatory Microvesicle Shedding in Severely Injured Patients

Administration of C5a Receptor Antagonist Improves the Efficacy of Human iPSCS-derived NS/PC Transplantation in the Acute Phase Of spinal Cord Injury

Targeting C5aR1 Increases the Therapeutic Window of Radiotherapy

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