Characterization of Pharmacologic and Pharmacokinetic Properties of CCX168, a Potent and Selective Orally Administered Complement 5a Receptor Inhibitor, Based on Preclinical Evaluation and Randomized Phase 1 Clinical Study

Bekker, Pirow; Dairaghi, Daniel J.; Seitz, Lisa; Leleti, Manmohan R.; Wang, Yu; Ertl, Linda; Baumgart, Trageen; Shugarts, Sarah; Lohr, Lisa; Dang, Ton; Miao, Shichang; Zeng, Yibin; Fan, Pingchen; Zhang, Penglie; Johnson, Daniel E.; Powers, Jay P.; Jaén, Juan C.; Charo, Israel F.; Schall, Thomas J.

doi:10.1371/journal.pone.0164646

Cited by 116 publications

(110 citation statements)

References 30 publications

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“…Here we demonstrated that inhibition of C5a receptor attenuates the up-regulation of activated Mac-1 on APS IgG-stimulated neutrophils ( Figure 4D). These data are consistent with previous studies demonstrating that C5a receptor contributes to up-regulation of Mac-1 (32,33).…”

Section: Discussionsupporting

confidence: 94%

Increased Adhesive Potential of Antiphospholipid Syndrome Neutrophils Mediated by β2 Integrin Mac‐1

Sule

Kelley

Gockman

et al. 2019

Arthritis & Rheumatology

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Objective While the role of antiphospholipid antibodies in activating endothelial cells has been extensively studied, the impact of these antibodies on the adhesive potential of leukocytes has received less attention. This study was undertaken to investigate the extent to which antiphospholipid syndrome (APS) neutrophils adhere to resting endothelial cells under physiologic flow conditions and the surface molecules required for that adhesion. Methods Patients with primary APS (n = 43), patients with a history of venous thrombosis but negative test results for antiphospholipid antibodies (n = 11), and healthy controls (n = 38) were studied. Cells were introduced into a flow chamber and perfused across resting human umbilical vein endothelial cells (HUVECs). Surface adhesion molecules were quantified by flow cytometry. Neutrophil extracellular trap release (NETosis) was assessed in neutrophil‐HUVEC cocultures. Results Upon perfusion of anticoagulated blood through the flow chamber, APS neutrophils demonstrated increased adhesion as compared to control neutrophils under conditions representative of either venous (n = 8; P < 0.05) or arterial (n = 15; P < 0.0001) flow. At the same time, APS neutrophils were characterized by up‐regulation of CD64, CEACAM1, β2‐glycoprotein I, and activated Mac‐1 on their surface (n = 12–18; P < 0.05 for all markers). Exposing control neutrophils to APS plasma or APS IgG resulted in increased neutrophil adhesion (n = 10–11; P < 0.0001) and surface marker up‐regulation as compared to controls. A monoclonal antibody specific for activated Mac‐1 reduced the adhesion of APS neutrophils in the flow‐chamber assay (P < 0.01). The same monoclonal antibody reduced NETosis in neutrophil–HUVEC cocultures (P < 0.01). Conclusion APS neutrophils demonstrate increased adhesive potential, which is dependent upon the activated form of Mac‐1. In patients, this could lower the threshold for neutrophil–endothelium interactions, NETosis, and possibly thrombotic events.

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Section: Discussionsupporting

confidence: 94%

Increased Adhesive Potential of Antiphospholipid Syndrome Neutrophils Mediated by β2 Integrin Mac‐1

Sule

Kelley

Gockman

et al. 2019

Arthritis & Rheumatology

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“…However, the selective C5aR1 antagonist PMX53 [43] ablated the C5a-induced CD11b expression on monocytes. This indicates that C5a-mediated induction of CD11b in human monocytes is wholly dependent upon C5aR1 signaling, similar to that described for human neutrophils [44].…”

Section: (A) (B)supporting

confidence: 72%

“…5. This indicates that C5a-mediated induction of CD11b in human monocytes is wholly dependent upon C5aR1 signaling, similar to that described for human neutrophils [44]. The blood samples from healthy donors were preincubated with eritoran, eculizumab (Eculiz.…”

Section: Discussionmentioning

confidence: 63%

Complement component 5 does not interfere with physiological hemostasis but is essential forEscherichia coli-induced coagulation accompanied by Toll-like receptor 4

Landsem

Fure

Ludviksen

et al. 2018

Clinical and Experimental Immunology

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Summary There is a close cross‐talk between complement, Toll‐like receptors (TLRs) and coagulation. The role of the central complement component 5 (C5) in physiological and pathophysiological hemostasis has not, however, been fully elucidated. This study examined the effects of C5 in normal hemostasis and in Escherichia coli‐induced coagulation and tissue factor (TF) up‐regulation. Fresh whole blood obtained from six healthy donors and one C5‐deficient individual (C5D) was anti‐coagulated with the thrombin inhibitor lepirudin. Blood was incubated with or without E. coli in the presence of the C5 inhibitor eculizumab, a blocking anti‐CD14 monoclonal antibody (anti‐CD14) or the TLR‐4 inhibitor eritoran. C5D blood was reconstituted with purified human C5. TF mRNA was measured by quantitative polymerase chain reaction (qPCR) and monocyte TF and CD11b surface expression by flow cytometry. Prothrombin fragment 1+2 (PTF1·2) in plasma and microparticles exposing TF (TF‐MP) was measured by enzyme‐linked immunosorbent assay (ELISA). Coagulation kinetics were analyzed by rotational thromboelastometry and platelet function by PFA‐200. Normal blood with eculizumab as well as C5D blood with or without reconstitution with C5 displayed completely normal biochemical hemostatic patterns. In contrast, E. coli‐induced TF mRNA and TF‐MP were significantly reduced by C5 inhibition. C5 inhibition combined with anti‐CD14 or eritoran completely inhibited the E. coli‐induced monocyte TF, TF‐MP and plasma PTF1·2. Addition of C5a alone did not induce TF expression on monocytes. In conclusion, C5 showed no impact on physiological hemostasis, but substantially contributed to E. coli‐induced procoagulant events, which were abolished by the combined inhibition of C5 and CD14 or TLR‐4.

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“…There is growing evidence to suggest the role of complement activation in glomerular disease in general. Avacopan, previously called CCX168, is an orally administered small-molecule C5aR antagonist that blocks the effects of C5a and prevented the development of GN induced by anti-myeloperoxidase antibodies in a murine model of ANCA associated vasculitis (AAV) [37]. Jayne et al [38] recently studied the drug as a potential steroid-sparing agent in the treatment of this disease.…”

Section: Current Therapy For Anca-positive Rpgnmentioning

confidence: 99%

Treatment of Rapidly Progressive Glomerulonephritis in the Elderly

Appel¹,

Lau²

2018

Blood Purif

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As the population worldwide ages, the epidemic of kidney disease will also increase. Anti-neutrophil cytoplasmic antibodies (ANCA) positive rapidly progressive positive glomerulonephritis (RPGN) is the most common etiology for biopsied patients among the very elderly. Its pathological features and clinical course are well described, though there is still debate about the mechanism of injury involved in individual patients. From very ancient times, the cornerstone of treatment historically has been high-dose cyclophosphamide and a lengthy course of high-dose corticosteroids. Although this regimen has diminished the immediate mortality rate of RPGN, its intermediate and long-term adverse effects are not insignificant. Attempts to minimize toxicity and improve efficacy have been made through the years to allow physicians some options for therapy. Lower cumulative cyclophosphamide regimens, shorter corticosteroid courses, and the introduction of rituximab have modified the armamentarium for treatment of ANCA positive RPGN. As progress is made in understanding the molecular pathogenesis of this disease, new targets will be found for potential therapeutic attack. The complement system is an area of active interest for all glomerular diseases at this time. Indeed, animal studies and preliminary human studies suggest that targeting the complement system can ameliorate the course of ANCA-positive RPGN. Hopefully, as the population ages, we will see more and safer therapeutic options to treat this once rapidly fatal disease.

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Characterization of Pharmacologic and Pharmacokinetic Properties of CCX168, a Potent and Selective Orally Administered Complement 5a Receptor Inhibitor, Based on Preclinical Evaluation and Randomized Phase 1 Clinical Study

Cited by 116 publications

References 30 publications

Increased Adhesive Potential of Antiphospholipid Syndrome Neutrophils Mediated by β2 Integrin Mac‐1

Increased Adhesive Potential of Antiphospholipid Syndrome Neutrophils Mediated by β2 Integrin Mac‐1

Complement component 5 does not interfere with physiological hemostasis but is essential forEscherichia coli-induced coagulation accompanied by Toll-like receptor 4

Treatment of Rapidly Progressive Glomerulonephritis in the Elderly

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