Plozalizumab

趋化因子系统参与调节细胞迁移、粘附、定位和细胞间相互作用，作用于肿瘤细胞和免疫细胞调节二者细胞活动，高度参与肿瘤的发展过程。根据肿瘤发生过程中所处的阶段、免疫细胞的活化状态、效应与调控反应间的平衡以及趋化因子受体在效应靶细胞和调节性靶细胞上的相对表达，趋化因子会表现出促肿瘤和抗肿瘤两种效应，甚至同一趋化因子作用于不同细胞，具有两种截然相反的效应。 一、促瘤趋化因子 1. CCL2：通过CCL2-CCR2轴募集肿瘤相关免疫抑制细胞；介导肿瘤与肿瘤相关巨噬细胞（TAM）相互作用，提高肿瘤干细胞特性、转移能力和治疗抵抗。 2. CXCL1/CXCL8：通过CXCL1/CXCL8-CXCR2轴募集肿瘤相关免疫抑制细胞。 3. CXCL12：通过CXCR4-CXCL12轴促进TAM分化为血管周围TAM细胞，提高血管通透性，使肿瘤细胞向血管内浸润；实体瘤增加骨髓基质细胞中CXCL12的表达，导致表达CXCR4的髓样细胞积聚，影响免疫细胞的发育成熟，CXCR4-CXCL12轴参与Treg向骨髓的迁移。 4. CCR4：在肿瘤微环境（TME）中募集调节性T细胞（Treg）。 5. CCR6：促进Treg细胞在TME原位增殖。 6. CCR8：在TME内DC细胞附近募集Treg，并通过抗原识别使Treg具有免疫抑制作用；通过CCR8-CCL1轴增加Foxp3表达维持Treg细胞的免疫抑制能力。 7. CCR4+Th2、CCR6+Th17、CXCR3+Th1、CXCR5+Tfh，以上4类趋化因子受体分别在不同细胞中的表达，与Treg抑制功能有一定相关性。 二、抗瘤趋化因子 1. XCL1：通过XCL1-XCR1轴介导cDC1细胞向肿瘤募集，促进cDC1与CD8+T细胞相互作用，促使T细胞扩增和获得效应器功能。 2. CXCL11：其表达与髓源性抑制细胞（MDSCs）的丰度和CD8+T细胞浸润程度成反比。 3. CCR7：介导cDC1和cDC2细胞从肿瘤向TDLN迁移，启动T细胞的效应功能。 4.  CCL21：介导T细胞和DC细胞向肿瘤引流淋巴结（TDLN）募集，其表达减少会影响免疫细胞群定位，最终可能导致T细胞活性降低。 5. CX3CR1：CD8+T细胞接收到CX3CR1信号才能发挥抗肿瘤作用。 三、双效趋化因子 1. CCR5：CCR5-CCL5轴介导cDC1向肿瘤募集，能同时募集Treg细胞和CD8+T细胞；调控TAM表型和功能，介导肿瘤与TAM相互作用，提高肿瘤肝细胞性、转移能力、治疗抵抗 2. CXCR3：CXCR3-CXCL9/CXCL10轴也能同时募集Treg和CD8+T细胞；使干细胞样TCF-1+细胞向cDC1细胞募集、在TME中重激活和通过接触IL-2获得效应器功能；调控免疫效应细胞在肿瘤附近的定位。 四、药物开发 一些趋化因子的研究进入了临床阶段，但总体而言疗效不显著。 1. CXCR3-CXCL9/10/11：IFN-γ是该趋化因子轴的主要驱动因素，联用可以增加效应细胞浸润；瘤内注射CXCL9/10/11等配体或者表达配体的溶瘤病毒，增加效应细胞浸润。 3. CXCR4：使用其拮抗剂 AMD3100， BL-8040可以促进肿瘤的T细胞浸润。 4. CCR4-CCL22/17：用于阻断该轴介导的Treg募集的策略，包括阻断抗体、siRNAs和拮抗剂： （1）CCR4抗体：mogamulizumab (KW-0761)是一种人源化、糖工程IgG1κ单克隆抗体，通过ADCC靶向表达CCR4的细胞。临床试验结果显示它可以消除淋巴瘤中Treg的积累。 （2）CCR4小分子抑制剂：FLX475和RPT193，FLX475联合派姆单抗治疗晚期或转移性癌症的1/2期临床试验(NCT03674567)最近已经完成，但尚未被报道；此外GSK 的(GSK2239633) 和AstraZeneca的(AZD-1678，AZD-2098) 也是CCR4的小分子抑制剂。 5. CCL2-CCR2：阻断CCL2-CCR2，可以抑制MDSCs的浸润： （1）抗CCR2抗体：MLN1202，治疗骨转移（NCT01015560）。 （2）CCR2小分子抑制剂：PF-04136309，联合白蛋白-紫杉醇/吉西他滨治疗中期静态PDA患者的1b期试验显示，外周血中炎症性单核细胞(IM)减少，而没有在骨髓中积累。但与标准化疗相比，CCR2抑制也会导致肺毒性增加。在另一项1b期试验中PF-04136309和叶酸，不同的标准化疗方案（边缘可切除和局部晚期胰腺癌），是安全的，减少单核细胞从骨髓，TAM浸润原发肿瘤，导致高于预期的客观反应率（49%）。 （3）CCR2拮抗剂：CCX872 ，用于治疗胰腺癌，总生存率提高（18个月时29%Vs18.6%）。 6. CCR5：CCR5拮抗剂Maraviroc，在体外模型中将巨噬细胞重新极化为免疫活性表型。目前还在招募的临床试验是卒中后认知障碍：NCT04966429 Safety and Efficacy of Maraviroc in Post-stroke Cognitive Impairment Phase2 7. CXCR1/CXCR2-CXCL8：阻断该轴，抑制肿瘤生长： （1）CXCR1/2抑制剂：Reparixin是一种临床级抑制剂，可在体外抑制乳腺癌的生长。 （2）CXCR1/2的小分子拮抗剂：包括SCH479833和SCH527123，在乳腺癌、CRC、自发性结肠癌肝转移和黑色素瘤的异种移植模型中具有抗肿瘤活性。 （3）CXCL8阻断抗体：ABX-CXCL8，在异种移植模型中抑制黑色素瘤的生长。 总体如麻省总医院Andrew D. Luster教授所言，趋化因子和趋化因子受体很难作为治疗靶点进行开发... Even if chemokines and chemokine receptors represent difficult therapeutic targets, they might help todissect cellular components critical for induction and maintenance of pro- and anti-tumorigenic immune cell states. 参考文献 Hanahan, D. et al. Hallmarks of cancer: the next generation. Cell. 2011; 144: 646-674. Hua, Y. et al. Tumors vs. chronic wounds: an immune cell’sperspective. Front. Immunol.    2019; 10: 2178.  Villablanca et al, Tumor-mediated liver X receptor-alpha activation inhibits CC chemokine receptor-7expression on dendritic cells and dampens antitumor responses. Nat. Med.  2010; 16: 98–105. Binnewies, M. et al, Unleashing type-2 dendritic cells to drive protective antitumor CD4(+)    T cell immunity. Cell. 2019; 177: 556–571.e16. Griffith, J.W. et al. Chemokines and chemokinereceptors: positioning cells for host defense    and immunity. Annu. Rev. 2014; 32: 659-702. Karan Kohli et al，Key chemokines direct migration of immune cells in solid tumors，Cancer Gene Ther . 2022;29(1):10-21. 本周好文推荐 如需转载请联系佰傲谷并在醒目位置注明出处 · · · · · · · ·

On March 18th, Cell published online a research paper about a new mechanism involving the gut in regulating cholesterol metabolism. The researchers discovered a gut-derived hormone called Cholesin, which is triggered by cholesterol intake and produced within intestinal cells. Cholesin achieves inhibition of the PKA-ERK1/2 signaling pathway in the liver by binding to the GPR146 receptor there, thereby downregulating the cholesterol synthesis process regulated by SREBP2. This means that when the gut absorbs cholesterol, the Cholesin-GPR146 axis acts to suppress cholesterol production in the liver, helping to maintain stable blood cholesterol levels and combat hypercholesterolemia and atherosclerosis.  DOI: 10.1016/j.cell.2024.02.024To investigate the interaction between intestinal cholesterol absorption and hepatic cholesterol synthesis, the researchers designed experiments to induce mice to consume diets with varying cholesterol content (regular diet and high-cholesterol Western diet) and observed changes in cholesterol levels in the intestine and liver. Under a high-cholesterol diet, intestinal cholesterol content increased, accompanied by downregulated expression of the cholesterol biosynthesis marker HMGCR in the intestine, suggesting a negative feedback mechanism where absorbed cholesterol can influence its own synthesis. Against this backdrop, the researchers identified a new gut-derived hormone induced by cholesterol – Cholesin. Cholesin is triggered by cholesterol absorption mediated by NPC1L1, with its gene encoded in humans as C7orf50 and in mice as 3110082I17Rik. After secretion by intestinal cells, Cholesin binds to a specific orphan GPCR member, GPR146, and suppresses the PKA-ERK1/2 signaling pathway, reducing the hepatic cholesterol synthesis activity regulated by SREBP2. To further confirm the relationship between Cholesin and its receptor GPR146, researchers employed a variety of experimental approaches, including but not limited to binding assays on frozen tissue sections, genome-wide CRISPR-Cas9 screenings, and immunohistochemistry techniques. Ultimately, it was established that GPR146 is an effective receptor for Cholesin, and the interaction between Cholesin and GPR146 directly influences the regulation of cholesterol metabolism. Through CRISPR screenings, protein expression purification, and a range of experimental validations, Cholesin's mechanism of action was elucidated, and it was demonstrated that both the sole use of Cholesin and its combination with statin drugs significantly reduce total plasma cholesterol levels and alleviate atherosclerotic lesions. Moreover, Cholesin can also decrease body weight gain, lower triglyceride levels, and improve hepatic lipid accumulation and inflammation markers. About AtherosclerosisAtherosclerosis is a chronic inflammatory disease, primarily characterized by the accumulation of substantial amounts of cholesterol and other lipid substances on the vessel walls, forming plaques. These plaques gradually enlarge and can lead to the narrowing of the arterial lumen, impeding blood flow. Additionally, these plaques may become unstable and rupture, causing thrombosis, which in turn can trigger serious events such as myocardial infarction or stroke. Cholesterol is an essential lipid for the human body, involved in the construction of cell membranes, hormone synthesis, and various other physiological functions. However, when cholesterol levels in the blood are too high, especially when low-density lipoprotein cholesterol (LDL-C) concentrations are excessive, the risk for cardiovascular diseases increases, with the most notable being the onset and progression of atherosclerosis. Studies have shown that an excess of cholesterol, particularly oxidized LDL cholesterol, penetrating beneath endothelial cells, can trigger an inflammatory response through a complex series of biochemical processes. This stimulates smooth muscle cell migration and proliferation, causes macrophages to engulf lipids and become foam cells, forming what are called fatty streaks, which then evolve into mature atherosclerotic plaques. In addition to the abnormal accumulation of lipids, the state of imbalance between immune responses and their clearance is also believed to be primarily shaped by the migration and homeostasis of leukocytes, which are regulated by chemokines and their receptors. In recent years, new pro-inflammatory and anti-inflammatory pathways that link lipid biology with inflammation have been discovered, and gene expression profiling studies have revealed various factors involved in human coronary artery disease. Cardiovascular diseases are the leading cause of death globally, with an estimated 17.8 million people dying each year. Inflammation is considered to be one of the main driving forces in the development of atherosclerosis and is recognized as one of the major etiologies of cardiovascular disease. Despite the increasing body of research evidence over the past three decades showing that immune components play an indispensable role in the formation and chronicity of atherosclerosis, through a series of immunotherapeutic targets, the benefits and challenges brought about by targeting inflammation and the immune system in cardiovascular diseases have been demonstrated. DOI: 10.1038/s41569-021-00668-4DOI: 10.1038/nm.2538Using the diagram above as an example, chemokines and their receptors also play an important role in the pathogenesis of atherosclerosis. The process of leukocyte recruitment includes rolling, firm adhesion, lateral migration, and transendothelial migration, which are finely regulated by chemokines. On the one hand, soluble chemokines directly mediate the recruitment of leukocytes; on the other hand, chemokines immobilized by glycosaminoglycans (GAGs) on the surface of activated endothelial cells can trigger the docking of leukocytes through GPCRs and activate leukocyte integrins, thus achieving firm adhesion. The cell-specific and lesion stage-specific utilization of chemokines and their receptors underscores the robustness and complexity of the chemokine system, ensuring the formation of specific chemokine combinations at each stage of the lesion that attract specific subtypes of leukocytes. Synergistic effects among chemokines in the recruitment of leukocytes can lead to cooperative interactions, potentially mediating the process between leukocytes and atherosclerotic lesions. According to statistics from the Synapse database, as of now, there are more than 500 therapeutic drug pipelines globally, originating from over 400 institutions, encompassing over 200 targets, and involving 4095 clinical trials. The therapeutic drugs for this disease have a diverse range of Mechanisms of Action (MOA). At present, the primary therapeutic drugs for the treatment of atherosclerosis include statins, which function primarily by inhibiting the key enzyme in cholesterol biosynthesis—hydroxymethylglutaryl-coenzyme A (HMG-CoA) reductase. Examples include Lovastatin (Merck, approved in 1987), Fluvastatin (Novartis, approved in 1993), Atorvastatin (Pfizer, approved in 1996), Rosuvastatin (AstraZeneca, approved in 2002). P2Y12 receptor antagonists are another class of therapeutic drugs for atherosclerosis, acting by selectively blocking the function of the P2Y12 receptor to inhibit excessive activation and aggregation of platelets. This is crucial because platelets play a key role in the development of atherosclerosis and thrombosis, especially in the progression of cardiovascular diseases. Common drugs in this category include Clopidogrel (Sanofi, approved in 1997), Ticagrelor (AstraZeneca, approved in 2010), Cangrelor (CHIESI, approved in 2015). Additionally, in recent years, PCSK9 has emerged as a therapeutic candidate for the treatment of hypercholesterolemia and atherosclerosis-related diseases. The primary function of PCSK9 is to regulate the number of low-density lipoprotein cholesterol (LDL-C) receptors on the membrane of liver cells. When PCSK9 binds to LDL receptors, it leads to their degradation within lysosomes, thereby reducing the uptake and clearance of circulating LDL-C by the liver, resulting in elevated levels of LDL-C in the blood. Therapeutic drugs related to this mechanism include Evolocumab (Amgen, approved in 2015), Alirocumab (Sanofi, approved in 2015), Inclisiran (Novartis, approved in 2020). Factor Xa inhibitors are a class of drugs that specifically inhibit the activity of coagulation factor Xa (FXa). FXa plays a crucial role in the blood coagulation process, as it acts as a key enzyme in the coagulation cascade, facilitating the conversion of prothrombin to thrombin, which in turn catalyzes the transformation of fibrinogen into fibrin, leading to the formation of a stable clot. By binding to FXa and preventing its activity, Factor Xa inhibitors can effectively suppress the formation of thrombi and are widely used in clinical practice to prevent and treat various thrombotic diseases, such as deep vein thrombosis, pulmonary embolism, and stroke prevention in patients with atrial fibrillation. Therapeutic candidates in this category include Rivaroxaban (Bayer, approved in 2008), Edoxaban Tosylate (Daiichi Sankyo, approved in 2012), Apixaban (Bristol-Myers Squibb, approved in 2011). Additionally, SGLT2 inhibitors were initially developed for the treatment of type 2 diabetes by inhibiting the SGLT2 transporter protein in the renal proximal convoluted tubules, reducing the reabsorption of glucose and thereby promoting the excretion of glucose in the urine, leading to decreased blood glucose levels. In recent years, multiple large-scale clinical trials have revealed the significant therapeutic effect of SGLT2 inhibitors in reducing the risk of cardiovascular events, especially in patients with type 2 diabetes who have atherosclerotic cardiovascular diseases. Therapeutic candidates related to this include Tofogliflozin (Kowa, approved in 2014) and Ertugliflozin (Pfizer, approved in 2017). Besides the classical P2Y12 receptor, potential therapeutic targets within the GPCR family include AT1R, PAR-1R, CXCR4, CCR2, NIACR1, TBXA2R, PGI2R, ADRA1, and EP3. However, the progress in the drug pipeline related to these targets is not promising. Only Vorapaxar, a tricyclic compound derived from camptothecin that acts as a selective inhibitor on thrombin-activated receptor (PAR-1), has been approved for reducing the incidence of thrombotic cardiovascular events in patients with a history of myocardial infarction (MI) or peripheral artery disease (PAD). The first antibody drug candidate developed targeting an immunomodulatory factor associated with GPCRs for treating atherosclerosis is the humanized monoclonal antibody Plozalizumab, an antagonistic monoclonal antibody targeting CCR2 developed by Takeda Pharmaceutical in Japan. CCR2 plays a critical role in the migration of monocytes and macrophages to sites of inflammation. The recruitment of macrophages to the arterial wall is considered a key step in the development of atherosclerosis. The first nanobody drug candidate is BI-655088, targeting the CX3CR1 receptor.