更新于：2024-05-01

LOX-1

oxidized low density lipoprotein receptor 1

更新于：2024-05-01

基本信息

别名

C-type lectin domain family 8 member A、CLEC8A、hLOX-1

+ [11]

简介

Receptor that mediates the recognition, internalization and degradation of oxidatively modified low density lipoprotein (oxLDL) by vascular endothelial cells. OxLDL is a marker of atherosclerosis that induces vascular endothelial cell activation and dysfunction, resulting in pro-inflammatory responses, pro-oxidative conditions and apoptosis. Its association with oxLDL induces the activation of NF-kappa-B through an increased production of intracellular reactive oxygen and a variety of pro-atherogenic cellular responses including a reduction of nitric oxide (NO) release, monocyte adhesion and apoptosis. In addition to binding oxLDL, it acts as a receptor for the HSP70 protein involved in antigen cross-presentation to naive T-cells in dendritic cells, thereby participating in cell-mediated antigen cross-presentation. Also involved in inflammatory process, by acting as a leukocyte-adhesion molecule at the vascular interface in endotoxin-induced inflammation. Also acts as a receptor for advanced glycation end (AGE) products, activated platelets, monocytes, apoptotic cells and both Gram-negative and Gram-positive bacteria. (Microbial infection) May serve as a receptor for adhesin A variant 3 (nadA) of N.meningitidis.

关联

项与 LOX-1 相关的药物

Orticumab

靶点

LOX-1

作用机制

LOX-1抑制剂

在研机构

Abcentra LLC [+1]

原研机构

BioInvent International AB

在研适应症

主动脉瓣钙化 [+5]

非在研适应症

冠心病 [+1]

最高研发阶段临床2期

首次获批国家/地区-

首次获批日期1800-01-20

MEDI-6570

靶点

LOX-1

作用机制

LOX-1抑制剂

在研机构

原研机构

在研适应症

非在研适应症

最高研发阶段临床2期

首次获批国家/地区-

首次获批日期1800-01-20

项与 LOX-1 相关的临床试验

NCT05912218 / Not yet recruiting临床2期

REducing Diabetic macrovascUlar Complications duE to Peripheral Arterial Disease- REDUCE-PAD

This is a Phase IIa, multi-centre study conducted at 3 sites in Singapore (SGH and NUHS, KTPH). 70 patients with diabetes mellitus (DM) and peripheral arterial disease (PAD) will be randomised in a ratio 1:1 to receive normal saline control or MEDI6570 400mg by monthly subcutaneous injection for 9 months.

开始日期2023-06-15

申办/合作机构

National Heart Centre Singapore

[+3]

NCT04610892 / Completed临床2期

A Phase IIB, Randomized, Double Blinded, Placebo Controlled, Parallel Group Study to Evaluate the Efficacy and Safety of MEDI6570 in Participants With a Prior Myocardial Infarction and Persistent Inflammation

A Phase IIB Parallel group Study to Evaluate the Efficacy and Safety of MEDI6570 in Participants with a Prior Myocardial Infarction.

开始日期2020-11-04

申办/合作机构

AstraZeneca PLC

[+1]

NCT03654313 / Completed临床1期

A Phase 1 Randomized, Blinded, Placebo-controlled Study to Evaluate the Safety and Pharmacokinetics of Single and Multiple Ascending Doses of MEDI6570 in Subjects With Type 2 Diabetes Mellitus.

To evaluate the safety, tolerability, PK and immunogenicity of single and multiple ascending doses of MEDI6570 in subjects with Type 2 Diabetes Mellitus

开始日期2018-09-28

申办/合作机构

MedImmune LLC

100 项与 LOX-1 相关的临床结果

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100 项与 LOX-1 相关的转化医学

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0 项与 LOX-1 相关的专利（医药）

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2,070

项与 LOX-1 相关的文献（医药）

2024-02-10·Clinical biochemistry

The significance of PCSK-9's level and polymorphism in premature coronary artery disease: Relation to risk and severity.

Article

作者: Marwa A Gaber ; Omnia H M Omar ; Abdel-Raheim M A Meki ; Ahmed Y Nassar ; Ayman K M Hassan ; Marwan S Mahmoud

BACKGROUND:

Proprotein convertase subtilisin/kexin type 9 (PCSK-9) is a circulating protein that plays an important role in lipid metabolism and is linked to inflammation, which has implications for atherosclerosis and its severe cardiac effects. We studied the potential association of the PCSK-9 gene single nucleotide polymorphism (SNP), Oxidized low-density lipoprotein receptor 1- (OLR-1), and caspase-3 serum levels with the risk and severity of premature coronary artery disease (PCAD). The potential contribution of PCSK-9 serum level to the severity of PCAD patients was also assessed.

METHOD:

This case-control study included 120 PCAD patients (age < 45), and 60 age matched healthy controls. Serum PCSK-9 and caspase-3 levels and clinical characteristics were recorded. SYNTAX score was calculated to estimate the severity of the coronary artery lesions. The SNP rs2483205 of the PCSK-9 gene and the rs11053646 of the OLR-1gene were genotyped in all participants.

RESULTS:

Serum PCSK-9 levels were higher in PCAD patients and were significantly different among the three SYNTAX score groups (SS ≤ 12, 12 < SS ≤ 21.5, and SS > 21.5). The diagnostic cutoff values of PCSK-9 and caspase-3 levels for PCAD were > 3.2 ng/mL for both, yielding an area under the curve (AUC) of 0.98 and 0.92, sensitivity of 85 %, 98 %, and specificity of 99.5 %, 93 % for PCSK-9 and caspase-3, respectively. The genotypes TT + CT vs. CC of PCSK-9's rs2483205 SNP presented a higher risk for PCAD and higher SYNTAX scores. Furthermore, the rs11053646 SNP of OLR-1 presented the CG genotype as more risky and having higher SYNTAX scores.

CONCLUSION:

Circulating PCSK9 and caspase-3 concentrations were higher in PCAD patients and were associated with CAD severity. The SNPs of PCSK-9 (rs2483205) and OLR-1 (rs11053646) were associated with PCAD and its severity.

2024-01-24·Bone research

Transcriptional reprogramming during human osteoclast differentiation identifies regulators of osteoclast activity.

Article

作者: Morten S Hansen ; Kaja Madsen ; Maria Price ; Kent Søe ; Yasunori Omata ; Mario M Zaiss ; Caroline M Gorvin ; Morten Frost ; Alexander Rauch

Enhanced osteoclastogenesis and osteoclast activity contribute to the development of osteoporosis, which is characterized by increased bone resorption and inadequate bone formation. As novel antiosteoporotic therapeutics are needed, understanding the genetic regulation of human osteoclastogenesis could help identify potential treatment targets. This study aimed to provide an overview of transcriptional reprogramming during human osteoclast differentiation. Osteoclasts were differentiated from CD14⁺ monocytes from eight female donors. RNA sequencing during differentiation revealed 8 980 differentially expressed genes grouped into eight temporal patterns conserved across donors. These patterns revealed distinct molecular functions associated with postmenopausal osteoporosis susceptibility genes based on RNA from iliac crest biopsies and bone mineral density SNPs. Network analyses revealed mutual dependencies between temporal expression patterns and provided insight into subtype-specific transcriptional networks. The donor-specific expression patterns revealed genes at the monocyte stage, such as filamin B (FLNB) and oxidized low-density lipoprotein receptor 1 (OLR1, encoding LOX-1), that are predictive of the resorptive activity of mature osteoclasts. The expression of differentially expressed G-protein coupled receptors was strong during osteoclast differentiation, and these receptors are associated with bone mineral density SNPs, suggesting that they play a pivotal role in osteoclast differentiation and activity. The regulatory effects of three differentially expressed G-protein coupled receptors were exemplified by in vitro pharmacological modulation of complement 5 A receptor 1 (C5AR1), somatostatin receptor 2 (SSTR2), and free fatty acid receptor 4 (FFAR4/GPR120). Activating C5AR1 enhanced osteoclast formation, while activating SSTR2 decreased the resorptive activity of mature osteoclasts, and activating FFAR4 decreased both the number and resorptive activity of mature osteoclasts. In conclusion, we report the occurrence of transcriptional reprogramming during human osteoclast differentiation and identified SSTR2 and FFAR4 as antiresorptive G-protein coupled receptors and FLNB and LOX-1 as potential molecular markers of osteoclast activity. These data can help future investigations identify molecular regulators of osteoclast differentiation and activity and provide the basis for novel antiosteoporotic targets.

2024-01-22·Nature communications

LOX-1 acts as an N⁶-methyladenosine-regulated receptor for Helicobacter pylori by binding to the bacterial catalase.

Article

作者: Judeng Zeng ; Chuan Xie ; Ziheng Huang ; Chi H Cho ; Hung Chan ; Qing Li ; Hassan Ashktorab ; Duane T Smoot ; Sunny H Wong ; Jun Yu ; Wei Gong ; Cong Liang ; Hongzhi Xu ; Huarong Chen ; Xiaodong Liu ; Justin C Y Wu ; Margaret Ip ; Tony Gin ; Lin Zhang ; Matthew T V Chan ; Wei Hu ; William K K Wu

The role of N⁶-methyladenosine (m⁶A) modification of host mRNA during bacterial infection is unclear. Here, we show that Helicobacter pylori infection upregulates host m⁶A methylases and increases m⁶A levels in gastric epithelial cells. Reducing m⁶A methylase activity via hemizygotic deletion of methylase-encoding gene Mettl3 in mice, or via small interfering RNAs targeting m⁶A methylases, enhances H. pylori colonization. We identify LOX-1 mRNA as a key m⁶A-regulated target during H. pylori infection. m⁶A modification destabilizes LOX-1 mRNA and reduces LOX-1 protein levels. LOX-1 acts as a membrane receptor for H. pylori catalase and contributes to bacterial adhesion. Pharmacological inhibition of LOX-1, or genetic ablation of Lox-1, reduces H. pylori colonization. Moreover, deletion of the bacterial catalase gene decreases adhesion of H. pylori to human gastric sections. Our results indicate that m⁶A modification of host LOX-1 mRNA contributes to protection against H. pylori infection by downregulating LOX-1 and thus reducing H. pylori adhesion.

项与 LOX-1 相关的新闻（医药）

2023-04-20

·佰傲谷BioValley

脂肪相关巨噬细胞(ATM)：特征与功能

脂肪细胞(AT)中，脂肪相关巨噬细胞(AT-M)，在脂肪细胞代谢功能受累的状态下，在脂质稳态中也具有重要的适应功能。AT代谢损害的不良后果可能是未能维持局部脂质平衡，并对AT以外的免疫细胞产生长期影响。在喂食正常饮食的小鼠的AT中，嗜酸性粒细胞、ILC2细胞和低炎症状态的巨噬细胞占主导地位。AT-M的特征、分布和表达在肥胖环境中，巨噬细胞通过局部增殖和CCR2依赖的单核细胞被募集以及增加组织驻留比例。随着肥胖程度的增加，CD11c+ AT-M的比例增加。从二分法理论上来说，随着CD11c表达比例增加，AT-M也会从M2样表型向促炎的M1样表型转变。CD206则是M2样巨噬细胞的特征标记物。但实际上，• 例如在糖尿病患者中，其CD206+ CD11c- AT-M也会产生IL-6和IL-8等促炎细胞因子。• 此外，CD11c+CD206+AT-M较单一CD11c+或CD206+ AT-M有更高的炎性细胞因子表达。从功能分类来说，AT-M还包括：● 驻留型AT-M，主要包括PVM(表达CD206、CD163、LYVE1和TIM4)和NPVM(高表达Fcrls、Cd74 和Ear2，低表达LYVE1)。CD206+ CD11c- AT-M中主要是PVM；而IM属于CD206- CD11c+亚群；LAM则位于CD206+ CD11c+亚群中。● 具有脂质清除功能的脂质相关巨噬细胞(LAM)；● 表达胶原蛋白形式的促纤维化巨噬细胞亚群；● 即时炎症巨噬细胞：高表达CCL3L1、TNF和CXCL3；● 交感神经元相关巨噬细胞 (SAM)：SAMs比较特殊，其位于小鼠AT和人类交感神经节的交感神经束上，以依赖脑源性神经营养因子(BDNF)的方式维持AT神经支配。● CLS相关AT-M，等等。➤ 驻留AT-M显示出抗炎表型并促进对代谢有利的米色脂肪组织的发育。在脂肪环境中，LAM逐渐累积。PVM和NPVM的丰度相对减少，会被转录重新连接，通过脂质处理相关基因表达增加的特征，表现出类似BM衍生的LAMs的特征。➤ 促纤维化巨噬细胞亚群则可以通过Ly6a等编码干细胞抗原表达来导致AT的纤维化，在炎症环境下造成肌成纤维细胞过度沉积胶原蛋白，降低AT可塑性。➤ 此外，生物信息学分析表明，单核细胞可以在“瘦子”的AT(lean AT)中分化为PVM，而“胖子”的AT(obesity AT)主要提供缺氧和炎症环境，也可能有利于单核细胞向IMs的产生转变，作为PVM过渡到LAMs。➤ SAM的β2肾上腺素能受体(b2AR)表达高于一般AT-M亚群。b2AR介导的信号能维持AT-M处于抗炎状态，不过也有研究发现骨髓细胞特异性b2AR消融不会影响肥胖AT炎症。➤ 此外，b2AR信号可能触发部分AT-M亚群分泌乙酰胆碱分泌，称为胆碱能脂肪巨噬细胞，驱动皮下AT产热。CLS相关AT-M在肥胖AT中，CD11c+ AT-M聚集在受损或垂死的脂肪细胞周围的一种冠状结构(CLSs)中。这种冠状结构是炎症组织的圆形复合体，可视为脂肪组织中的炎症表现。Nat Immunol (2023).CLS相关的AT-M中存在脂质的代谢适应机制，富含与溶酶体生物发生和功能相关的基因(Lamp2、Acp5、CTSK、NPC1)和脂代谢相关基因(LPL、Lipa、FABP4、Fabp5、PPARG、ANGPTL4、Pnpla2)。因此，在一些研究中，这些细胞被视为LAMs。CLS相关AT-M还表达脂质处理和新陈代谢所需的其他因子，包括高水平表达脂肪酸转运蛋白CD36和其他清道夫受体，如CLEC7A和OLR1。CLS AT-M的另一个显著特征是其表达脂质受体TREM2，TREM2是触发髓系细胞表达的受体之一。研究表明，ATM中的许多中性脂质不与Perilipin 2共存，而Perilipin 2与脂滴的磷脂层有关。这说明AT-M中的脂肪储存在脂质囊泡而非脂滴中，这与动脉粥样硬化斑块中的巨噬细胞(又称泡沫细胞)正相反。CD9+ AT-M小鼠模型单细胞分析显示，在饮食诱导或遗传性肥胖的小鼠中，存在一个独特的ATM亚群聚集，其特征是表达CD9+ Tetraspanin(四次跨膜蛋白)。CD9+AT-M可能属于被代谢激活的AT-M，似乎与CD11c+ATM有一定重叠，主要定位于CLSs和具有脂质清除功能的脂质相关巨噬细胞(LAM)中。CD9+ AT-M群体表达与细胞内小泡和溶酶体途径相关的基因(CD63、Lamp2等)表达、骨桥蛋白和脂代谢相关的信号(LPL、CD36、TREM2等)相关，并可作为细胞内脂质积聚的标志。AT-M对炎症和脂质稳态的调节代谢激活的AT-M具有促炎特征。同时，AT-M可以响应食物中脂肪的摄入并通过溶酶体代谢、脂肪分解和脂质储存吸收和处理脂质，以调控脂肪的储存。其表现为：➤ 巨噬细胞中编码NOX2的基因Cybb如果失活，会导致死亡脂肪细胞积聚并加重其胰岛素抵抗。➤ 此外，AT-M能够诱导转录因子EB(TFEB)，通过上调生长分化因子15(GDF15)来实现对肥胖、脂肪炎症和胰岛素抵抗的保护作用。➤ ATM在肥胖状态下也可能通过胶原蛋白沉积促进纤维化，这是一种适应不良的功能，可能会增加AT的刚度。➤ 巨噬细胞上的α4整合素与脂肪细胞上VCAM-1的相互作用，与巨噬细胞表达并调节的层粘连蛋白相关蛋白Netrin 1共同作用，使得招募的AT-M在脂质环境中储存。血管周围间充质基质细胞和内皮细胞也在肥胖状态下的AT中表达更多的炎性特征，并可能有助于巨噬细胞的募集。➤ CD9+ AT-M则通过表达高水平的CCL2、IL1a和TNF，当其过继转移到瘦AT后会触发其转变出类似肥胖AT环境中的炎症特征。➤ 但同时，与血管相邻的驻留AT-M(如PVM)具有稳态功能并支持血管完整性。骨髓细胞特异性NF-κB调节剂A20的缺失能增强CD206+ AT-M的积累，通过驻留AT-M中的膳食脂肪酸代谢升高，从而降低肥胖和胰岛素抵抗的水平。因此，肥胖中的AT-M表型在维持脂质稳态方面具有适应性作用。在TREM2缺乏的情况下，肥胖患者LAM亚群和CLSs的产生比例下降，伴随着AT功能障碍，脂肪细胞肥大，血脂异常，加剧HFD诱导的体重增加和全身糖耐量降低，但是不影响本身的系统代谢。TREM2过表达同样加剧了高脂食物诱导的肥胖、脂肪细胞肥大和胰岛素抵抗。➤ TIM4+ LYVE1+ 驻留AT-M还表达胆固醇输出子ABCA1，其表达与调节循环中的脂质浓度有关。TIM4则是其溶酶体激活所必需的，以应对高脂肪饮食，并介导餐后高密度脂蛋白胆固醇的释放。小结总而言之，在微环境依赖的情况下(lean AT或者obesity AT)，AT-M可能不仅通过促进AT炎症而产生有害影响，而且可能通过补偿脂肪细胞的受抑代谢功能来适应AT的动态平衡。抑制CCR2依赖性的巨噬细胞募集可以防止肥胖相关的AT炎症、胰岛素抵抗、肝骨病和代谢综合征，但对脂肪细胞大小没有影响。相关阅读：肥胖导致的几类炎症性疾病肥胖引起慢性疼痛；居家办公不忘坚持锻炼！肥胖引起炎性疼痛的免疫学基础（控制体重，健康生活！）巨噬细胞极化与炎症性疾病（过敏性哮喘、糖尿病、肥胖、动脉粥样硬化、自身免疫病）参考文献：1.Chavakis, T., Alexaki, V.I. & Ferrante, A.W. Macrophage function in adipose tissue homeostasis and metabolic inflammation. Nat Immunol (2023). https://doi.org/10.1038/s41590-023-01479-0近期热门视频更多精彩视频，尽在佰傲谷视频号，欢迎关注~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﹀‍‍ 点亮在看，传递信息♥

2023-04-17

·BioSpace

Magnetic Resonance Imaging Evaluation of Mineralocorticoid Receptor Antagonism in Diabetic Atherosclerosis (MAGMA) trial Presented at NKF Spring Clinical Meetings

AUSTIN, Texas, April 14, 2023 /PRNewswire/ -- The main results of the Magnetic Resonance Imaging Evaluation of Mineralocorticoid Receptor Antagonism in Diabetic Atherosclerosis (MAGMA) trial, a National Heart, Lung, and Blood Institute (NHLBI) sponsored trial were presented. Although the results of the trial are not final, they offer valuable information for patients using the generic drug Spironolactone. This drug therapy activates white cells and reduces tissue damage as well as reduces proteins that would normally be considered inflammatory. The results from this study will be presented at the National Kidney Foundation's (NKF) NKF Spring Clinical Meetings during the "late-breaking presentations" at the largest multidisciplinary gathering of kidney care professionals in North America from April 11-15 in Austin, Texas. My message to patients is to consider using Spironolactone as their generic drug choice if they can. QUOTE FROM RESEARCHER "My message to patients is to consider using Spironolactone as their generic drug choice if they can for appropriate indications. We want to consider using this drug in high-risk patients with diabetes and atherosclerosis, because the benefit of the drug might extend not only to preventing heart failure and kidney disease progression but potentially other benefits," explained Sanjay Rajagopalan, MD, FACC, FAHA, Chief of the Division of Cardiovascular Medicine and Chief Academic and Scientific Officer of UH Harrington Heart & Vascular Institute; Herman K. Hellerstein, MD, Chair in Cardiovascular Research and a professor at the Case Western Reserve University School of Medicine. "Having a drug that works on these systems in a connective manner is a big benefit to a patient, and this drug happens to be one of those." Highlights of the interim results include: Results: Seventy-nine patients were randomized at 4 sites in US and Canada to Spironolactone (n=37) vs placebo (n=42) for 12 months, after a 2-week single-blind placebo lead-in period and 4-week dose escalation phase. Mean age was 64±8 years; HbA1c 7.3±1.3%; eGFR 44 ml/min/1.73m2; baseline systolic BP 132 ±19 mmHg. The results demonstrated a marked reduction in thoracic plaque volume (Percent change in wall volume) response to Spironolactone at the end of 12 months compared to placebo. These changes were accompanied by changes in left ventricular mass and fibrosis. Spironolactone treatment did not change clinic systolic blood pressure but did cause a statistically significant change in 24-hour mean systolic and diastolic blood pressures compared to baseline and versus placebo respectively. Spironolactone also reduced LV wall mass and a measure of LV fibrosis (native T1 values). Plasma proteomic analysis revealed significant downregulation of a number of pathways involved in immune activation/inflammation, leukocyte activation, proliferation and pathways involved in cytokine stimulation. The top 2 molecules downregulated were DDR2, and oxidized LDL receptor-1 (LOX-1) involved in collagen synthesis and inflammation respectively. Additional top downregulated proteins included known Aldosterone targets such as Sodium/potassium-transporting ATPase subunit beta-3 and Adenylyl cyclase-associated protein 1. Data are mean ± SD. Change was defined as the value at 12 months minus the value at baseline. †p < 0.05; †††p < 0.001 Thousands of kidney care professionals will attend the Spring Clinical Meetings in-person and virtually. Hundreds of the latest studies and kidney care advances will be unveiled. NKF Spring Clinical Meetings For the past 31 years, nephrology healthcare professionals from across the country have come to NKF's Spring Clinical Meetings to learn about the newest developments related to all aspects of nephrology practice; network with colleagues; and present their research findings. The NKF Spring Clinical Meetings are designed for meaningful change in the multidisciplinary healthcare teams' skills, performance, and patient health outcomes. It is the only conference of its kind that focuses on translating science into practice for the entire healthcare team. About Kidney Disease In the United States, more than 37 million adults are estimated to have kidney disease, also known as chronic kidney disease (CKD)—and approximately 90 percent don't know they have it. About 1 in 3 adults in the U.S. are at risk for kidney disease. Risk factors for kidney disease include: diabetes, high blood pressure, heart disease, obesity, and family history. People of Black or African American, Hispanic or Latino, American Indian or Alaska Native, Asian American, or Native Hawaiian or Other Pacific Islander descent are at increased risk for developing the disease. Black or African American people are about four times as likely as White people to have kidney failure. Hispanics experience kidney failure at about double the rate of White people. NKF Professional Membership Healthcare professionals can join NKF to receive access to tools and resources for both patients and professionals, discounts on professional education, and access to a network of thousands of individuals who treat patients with kidney disease. Media Contacts:

临床结果临床研究AHA会议

2023-03-07

·药研网

CLL1：急性髓性白血病靶点研究进展

急性髓性白血病（AML）是成人患者中最常见和最致命的血液恶性肿瘤，大多数患者的预后很差。尽管现阶段免疫疗法在血液瘤和实体瘤领域发挥了重要作用，但由于缺乏高特异性的目标抗原和AML的异质性，免疫疗法在AML上的进展非常缓慢，AML目前的治疗手段仍以化疗和造血干细胞移植为主，亟需开发新方法以改善AML预后。01C型凝集素样分子-1（CLL-1）2004年，Bakker等人利用噬菌体展示技术首次确定了CLL-1，其在90％-95％的新发或复发AML病例中过表达，在正常组织中很少见。更重要的是，CLL-1在白血病干细胞（LSC）上表达。LSC具有无限期自我更新的能力，并产生大量具有CLL-1、CD123、CD44、CD96、CD90、CD32、CD25和TIM-3特定表型的子细胞，是白血病复发的最重要原因之一。由此，CLL-1很可能是治疗AML的理想靶标。CLL-1(CLEC12A, MICL, DCAL-2或CD371），属于C型凝集素样受体家族的第五组。编码CLL-1的人类基因映射到12p13，属于NKG2R、低密度脂蛋白受体-1（LOX-1）和β葡聚糖受体（BGR）在内的NK基因复合物，CLL-1与LOX-1和BGR高度同源（A）。CLL-1基因的大小约为31 kDa，编码275个氨基酸的多肽。胞外特征表明CLL-1是一个II型跨膜糖蛋白，由一个具有6个N-糖基化位点的细胞外碳水化合物识别域、一个跨膜区和一个细胞内NH2末端组成，序列为I/VXYXXL和YXXM（B）。[1]研究表明CLL-1配体是死亡细胞的尿酸晶体和细胞上的未知配体，来自死亡细胞或其他物质的配体引发ITAM的磷酸化和Syk信号的激活，促进ROS的生成，并通过含有CARD9、MALT1和Bcl-10的复合物激活NF-kB，进一步促进基因转录和趋化因子/细胞因子的释放，促进中性粒细胞的活化和炎症浸润。当尿酸钠盐（MSU）或死亡细胞上的未知配体与CLL-1结合，招募SHP-1和SHP-2来负向调节Syk信号时，炎症会消除或减轻。CLL-1中的YXXM是否能与PI3K的P85结合并激活下游信号，目前还不清楚。[1]吉满生物根据市场需求和研究现状，推出构建CLL-1过表达稳定细胞系和抗体的服务（详细数据见文末），可用于抗体筛选、表征、一致性评价, 充分满足药物研发的需求，助力抗体药物临床申报。（联系方式：18916119826）02研究进展目前，针对CLL-1的在研疗法以CAR-T为主，也有公司尝试双抗和ADC疗法，但目前没有太大进展。在美国，AML是导致白血病患者死亡人数最多的疾病，成人五年总生存率仅27%。2022年9月，Kite的KITE-222获FDA授予孤儿药称号。在国内，百暨基因的自体CLL-1 CAR-T疗法于去年12月获批临床，IIT期初步试验结果显示，入组的11名R/R AML的儿童患者，在接受给药后后，CAR-T细胞患儿体内快速、高效地扩增；ORR达81.8%（9/11），DCR达90.9%（10/11），10名患者均在一个月内即对BG1805产生积极响应。2022年7月，南开大学附属第一中心医院的研究人员在“Journal of Hematology & Oncology”上发表了CLL-1 CAR-T成人患者的I期试验结果。试验共招募10名R/R AML患者，所有患者均对最近的化疗耐药，在3天FC预处理后进行CAR-T细胞注输，剂量1–2×10(-6)。10名患者信息[2]安全性方面大多数患者在输液过程中出现发热，研究人员认为这与CRS无关（A）。患者的发热几乎总是发生在输液后4-14天的范围内，这与中性粒细胞减少的时期相关（B）。所有患者均出现CRS（C,D）。其中6名患者和3患者分别接受皮质类固醇和托西珠单抗治疗后，CRS得到控制。没有CAR-T 细胞相关脑病综合征 (CRES)发生。所有患者都有严重的全血细胞减少症，9/10患者有3/4级粒细胞减少，7/10患者有3/4级贫血，7/10患者有3/4级血小板减少。患者2在输液获得PR后接受了挽救性造血干细胞移植（HSCT），2个月后因疾病进展而死亡。患者3和7尽管在治疗后获得CRi，但由于慢性粒细胞减少而死于严重感染。患者5因对治疗无反应（NR）和疾病快速进展而死亡。在6名输液后接受桥接性单倍体移植的患者中（G）。粒细胞、红细胞和血小板都正常植入，没有发生严重感染。因此，虽然输液后会出现严重的粒细胞缺乏症，但桥接移植可能会逆转这种毒性。A：注输后患者体温变化；B：注输后外周血中性粒细胞变化；C：注输前后外周血血清IL-6变化；D：注输前后CRP变化；E：不同时间CAR-T细胞与外周血T细胞比值；F：CR/CRi和NR患者CAR-T细胞峰值比较；G：注输后缓解持续时间和生存期；H：患者4,6骨髓涂片[2]疗效方面7/10（70%）的患者达到CR/CRi（G，H）。中位随访时间为173天，最后一次随访结束时有6名患者活着。6名患者在输液后的中位数20天（18-34天）进行了造血干细胞移植，4名（50%）在最后一次随访时仍处于CR。总结来说，该研究进一步证明了CLL-1在AML中的治疗潜力，虽然可能会出现严重的粒细胞减少，但CLL-1 CAR-T细胞可以为R/R AML患者提供在移植前达到CR/CRi的机会，这可能会降低复发的风险，延长患者的生存期。用心做好细胞，为更好的靶向药吉满生物科技（上海）有限公司，是位于上海浦东的一家以创新为驱动的工程化细胞系研发公司，基于自有的国内最大报告基因平台、慢病毒平台以及最迅速的药研网资讯平台，目前已构建出500余株现货单克隆细胞系产品，覆盖ROR1/DLL3/SLC39A6/TROP2/BCMA/BDCA/TREM2……200余新药热门靶点，其中有90余靶点开发有对应luciferase reporter方法，更有国内独家/首家CCR8, BDCA, TREM2和GAPR等luciferase的assay平台。CLEC12A(CLL-1)细胞系/抗体产品列表部分结果：GM-C19082：H_CLEC12A CHO-K1 Cell Line 使用Anti-CLEC12A hIgG1 Antibody流式验证结果GM-C27867：H_CLEC12A HEK-293 Cell Line使用Anti-CLEC12A hIgG1 Antibody流式验证结果吉满生物助力药物研发，紧随前沿靶点资讯，储备几百株现货细胞，覆盖GPCR、细胞因子、免疫检查点、TAA等多领域近200余个靶点。2020年底成立专业细胞系子品牌DDXCELL，同时已建立了DDXCELL现货查询小程序。截止当前已布局近200个热门靶向药靶点500余株细胞系，旨在助力、加速大分子早期研发，做到进口细胞的国产替代。同时可根据客户需求提供细胞系服务。细胞系现货查询请扫码👇参考：1. https://doi.org/10.1186/s13045-019-0726-52. https://doi.org/10.1186/s13045-022-01308-1

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