作者: Friedman, Scott L ; Yu, Richard C ; Bhattacharya, Dipankar ; Gopireddy, Raghavender Reddy ; Sen, Swastik ; Takeuchi, Toshi ; Schwartz, Monica A ; Schwimmer, Lauren J

Fibrotic diseases, often fueled by chronic inflammation, represent a major unmet medical need. A critical driver of this process is the activation of macrophages, which secrete pro-inflammatory cytokines and chemokines, leading to immune cell recruitment and collagen deposition by myofibroblasts. Agonizing the cannabinoid receptor 2 (CB2), expressed on macrophages, offers a potential therapeutic avenue to suppress this activation. Despite widespread interest in CB2 modulation, challenges remain in the development of small-molecule agonists, including insufficient specificity and poor drug-like properties. Antibodies are highly specific with favorable pharmacokinetics and bioavailability, but G-protein coupled receptor (GPCR) agonist antibodies have been difficult to discover. Herein, the first-in-class CB2 agonist antibodies, AB120 and AB150, are presented. These antibodies are CB2 specific, G-α biased, and effectively decrease the expression of macrophage activation markers and key pro-inflammatory cytokines, including IL-6, IL-1β and TNF-α. Furthermore, treatment of ex vivo human precision-cut liver slice with CB2 agonist antibodies both reduces inflammatory markers and decreases collagen expression reinforcing their potential as antifibrotic agents. Thus, these novel CB2-specific agonist antibodies may be effective for a range of fibrotic and inflammatory conditions driven by chronic macrophage activation and demonstrating the potential of GPCR antibody agonists to drug this challenging class of targets. SIGNIFICANCE STATEMENT: Fibrotic diseases, which are typically driven by chronic inflammation lack effective treatments. CB2 agonism modulates macrophage activation to reduce pro-inflammatory cytokines suggesting a novel therapeutic avenue, but small-molecule CB2 agonists have faced substantial limitations due to off-target effects. Herein, two novel CB2-specific agonist antibodies with potent anti-inflammatory and antifibrotic effects in vitro and in a human ex vivo liver fibrosis model are presented. These antibodies provide a promising new therapeutic strategy and highlight the advantages of antibodies as GPCR agonist drugs.

2022-12-01·Clinical and translational medicine

Genetically encoded tools for in vivo G‐protein‐coupled receptor agonist detection at cellular resolution

Review

作者: Kayla E. Kroning ; Wenjing Wang

Abstract:

G‐protein‐coupled receptors (GPCRs) are the most abundant receptor type in the human body and are responsible for regulating many physiological processes, such as sensation, cognition, muscle contraction and metabolism. Further, GPCRs are widely expressed in the brain where their agonists make up a large number of neurotransmitters and neuromodulators. Due to the importance of GPCRs in human physiology, genetically encoded sensors have been engineered to detect GPCR agonists at cellular resolution in vivo. These sensors can be placed into two main categories: those that offer real‐time information on the signalling dynamics of GPCR agonists and those that integrate the GPCR agonist signal into a permanent, quantifiable mark that can be used to detect GPCR agonist localisation in a large brain area. In this review, we discuss the various designs of real‐time and integration sensors, their advantages and limitations, and some in vivo applications. We also discuss the potential of using real‐time and integrator sensors together to identify neuronal circuits affected by endogenous GPCR agonists and perform detailed characterisations of the spatiotemporal dynamics of GPCR agonist release in those circuits. By using these sensors together, the overall knowledge of GPCR‐mediated signalling can be expanded.

2020-12-08·Proceedings of the National Academy of Sciences of the United States of America1区 · 综合性期刊

Chemical mutagenesis of a GPCR ligand: Detoxifying “inflammo-attraction” to direct therapeutic stem cell migration

1区 · 综合性期刊

Article

作者: Chen, Justin ; Wenger, David A ; Fang, Xiao ; Hamblin, Milton H ; Xu, Yan ; An, Jing ; Wang, Juan ; Feng, Yongmei ; Wakeman, Dustin R ; Seyfried, Thomas N ; Huang, Ziwei ; Zhang, Runquan ; Sidman, Richard L ; Gonzalez, Rodolfo ; Duggineni, Srinivas ; Han, Edward B ; Snyder, Evan Y ; Yan, Maocai ; Zhu, Yinsong ; Lee, Jean-Pyo ; Niles, Walter L

A transplanted stem cell's engagement with a pathologic niche is the first step in its restoring homeostasis to that site. Inflammatory chemokines are constitutively produced in such a niche; their binding to receptors on the stem cell helps direct that cell's "pathotropism." Neural stem cells (NSCs), which express CXCR4, migrate to sites of CNS injury or degeneration in part because astrocytes and vasculature produce the inflammatory chemokine CXCL12. Binding of CXCL12 to CXCR4 (a G protein-coupled receptor, GPCR) triggers repair processes within the NSC. Although a tool directing NSCs to where needed has been long-sought, one would not inject this chemokine in vivo because undesirable inflammation also follows CXCL12-CXCR4 coupling. Alternatively, we chemically "mutated" CXCL12, creating a CXCR4 agonist that contained a strong pure binding motif linked to a signaling motif devoid of sequences responsible for synthetic functions. This synthetic dual-moity CXCR4 agonist not only elicited more extensive and persistent human NSC migration and distribution than did native CXCL 12, but induced no host inflammation (or other adverse effects); rather, there was predominantly reparative gene expression. When co-administered with transplanted human induced pluripotent stem cell-derived hNSCs in a mouse model of a prototypical neurodegenerative disease, the agonist enhanced migration, dissemination, and integration of donor-derived cells into the diseased cerebral cortex (including as electrophysiologically-active cortical neurons) where their secreted cross-corrective enzyme mediated a therapeutic impact unachieved by cells alone. Such a "designer" cytokine receptor-agonist peptide illustrates that treatments can be controlled and optimized by exploiting fundamental stem cell properties (e.g., "inflammo-attraction").

100 项与 GPCR agonist(4e Therapeutics, Inc.) 相关的药物交易

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