Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of Single Rising Doses of BI 655088 Administered by Intravenous Infusion in Healthy Male Subjects (Single-blind, Partially Randomised Within Dose Groups, Placebo-controlled, Parallel Group Design)

Investigation of safety and tolerability of BI 655088 following intravenous infusion of single rising doses and exploration of the pharmacokinetics and pharmacodynamics of BI 655088 after single dosing

开始日期2016-03-16

申办/合作机构

Boehringer Ingelheim GmbH

100 项与 BI-655088 相关的临床结果

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100 项与 BI-655088 相关的转化医学

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100 项与 BI-655088 相关的专利（医药）

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项与 BI-655088 相关的文献（医药）

2021-07-01·Journal of the American Society of Nephrology1区 · 医学

Anti Human CX3CR1 VHH Molecule Attenuates Venous Neointimal Hyperplasia of Arteriovenous Fistula in Mouse Model

1区 · 医学

Article

作者: Wu, Chih-Cheng ; Misra, Sanjay ; Broadwater, John ; Vazquez-Padron, Roberto I ; Yang, Binxia ; Kilari, Sreenivasulu ; Sharma, Amit

Significance StatementFractalkine receptor 1 (CX3CR1) mediates macrophage infiltration into the vasculature. In this study, we used humanized mice knocked in with the human CX3CR1 gene and inhibited CX3CR1 signaling using a variable domains of camelid heavy-chain-only molecule (BI 655088) to test the hypothesis that blockade of CX3CR1 results in less of the venous neointimal hyperplasia formation that is associated with arteriovenous fistula (AVF) failure. We also used human samples removed from failed AVFs combined with cell culture experiments. Our results demonstrate a novel role for CX3CR1 in reducing venous stenosis formation in AVFs.BackgroundFractalkine receptor 1 (CX3CR1) mediates macrophage infiltration and accumulation, causing venous neointimal hyperplasia (VNH)/venous stenosis (VS) in arteriovenous fistula (AVF). The effect of blocking CX3CR1 using an anti–human variable VHH molecule (hCX3CR1 VHH, BI 655088) on VNH/VS was determined using a humanized mouse in which the human CX3CR1 (hCX3CR1) gene was knocked in (KI).MethodsWhole-transcriptomic RNA sequencing with bioinformatics analysis was used on human stenotic AVF samples, C57BL/6J, hCX3CR1 KI mice with AVF and CKD, and in in vitro experiments to identify the pathways involved in preventing VNH/VS formation after hCX3CR1 VHH administration.ResultsAccumulation of CX3CR1 and CD68 was significantly increased in stenotic human AVFs. In C57BL/6J mice with AVF, there was increased Cx3cr1, Cx3cl1, Cd68, and Tnf-α gene expression, and increased immunostaining of CX3CR1 and CD68. In hCX3CR1-KI mice treated with hCX3CR1 VHH molecule (KI-A), compared with vehicle controls (KI-V), there was increased lumen vessel area and patency, and decreased neointima in the AVF outflow veins. RNA-seq analysis identified TNF-α and NF-κB as potential targets of CX3CR1 inhibition. In KI-A–treated vessels compared with KI-V, there was decreased gene expression of Tnf-α, Mcp-1, and Il-1β; with reduction of Cx3cl1, NF-κB, and Cd68; decreased M1, Ly6C, smooth muscle cells, fibroblast-activated protein, fibronectin, and proliferation; and increased TUNEL and M2 staining. In cell culture, monocytes stimulated with PMA and treated with hCX3CR1 VHH had decreased TNF-α, CD68, proliferation, and migration.ConclusionsCX3CR1 blockade reduces VNH/VS formation by decreasing proinflammatory cues.

2020-07-01·Neuroscience3区 · 医学

Anti-mouse CX3CR1 Antibody Alleviates Cognitive Impairment, Neuronal Loss and Myelin Deficits in an Animal Model of Brain Ischemia

3区 · 医学

Article

作者: Zheng, Huiwen ; Zhang, Yanbo ; Du, Bingying ; Liang, Meng ; Fan, Cunxiu ; Zhang, Hailing ; Lian, Yongjie ; Bi, Xiaoying ; Lu, Xiaoyan ; Du, Zengkan

White matter lesions are common when global cerebral ischemia (GCI) occurs in the elderly, and cause damage to neurological and psychological functions. Remyelination often fails because of the limited recruitment of oligodendrocyte progenitor cells (OPCs) to the demyelinated site or the inefficient differentiation of OPCs to mature oligodendrocytes (OLs). The activation of microglia, the most important immune cells in the central nervous system, and subsequent inflammation have been implicated in myelination repair disorder. Little is known about the role of the Fractalkine/CX3CR1 signaling pathway, the key regulator of microglia activation, on myelin in microglia. In this study, a GCI animal model was generated through bilateral common carotid artery occlusion to induce ischemic inflammation and white matter damage; then, we downregulated CX3CR1 by intracerebroventricular administration of neutralizing antibody anti-FKR. Downregulation of CX3CR1 significantly reversed the depression-like behavior and cognitive impairment in GCI mice. Activation of microglia was inhibited, and the peripheral inflammatory responses were also ameliorated as revealed by decreased serum levels of IL-1β, IL-6 and TNF-α. CX3CR1 block substantially reversed demyelination in striatum, cortex and hippocampus and promoted differentiation and maturation of OPCs into mature OLs in the hippocampus. No effect was found on myelin in the corpus callosum. Besides, hippocampal neurons were protected by anti-FKR treatment after GCI. Collectively, our data demonstrated that downregulating of the Fractalkine/CX3CR1 signaling pathway had an anti-depressant and cognition-improvement effect by inhibiting microglia activation, promoting OPCs maturation and remyelination.

2020-01-01·mAbs2区 · 医学

VHH antibody targeting the chemokine receptor CX3CR1 inhibits progression of atherosclerosis

2区 · 医学

Article

作者: Li, Hua ; MacDougall, Margit ; Kerr, Steven ; Ahlberg, Jennifer ; Low, Sarah ; Berger, Valentina ; Waterman, Alisa ; Tibolla, Annette ; Webb, Deborah ; Broadwater, John ; Pantages, Lynn ; Kroe-Barrett, Rachel ; Jerath, Kavita ; Villalona, Jorge ; Dave, Rajvee ; Ververken, Cedric ; Fogal, Birgit ; Conrad, Rebecca ; Singh, Sanjaya ; Wu, Haixia ; Van Hoorick, Diane

CX3CR1 has been identified as a highly attractive target for several therapeutic interventions. Despite this potential, no potent antagonists, either small molecule or monoclonal antibody, have been identified. Here we describe the lead finding and engineering approach that lead to the identification of BI 655088, a potent biotherapeutic antagonist to CX3CR1. BI 655088 is a potent CX3CR1 antagonist that, upon therapeutic dosing, significantly inhibits plaque progression in the standard mouse model of atherosclerosis. BI 655088 represents a novel and highly selective biotherapeutic that could reduce inflammation in the atherosclerotic plaque when added to standard of care treatment including statins, which could result in a significant decrease in atherothrombotic events in patients with existing cardiovascular disease.

100 项与 BI-655088 相关的药物交易

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