Chronic obstructive pulmonary disease (COPD) is complicated by malnutrition in 20-70% of cases. In COPD, low fat-free mass is associated with a higher risk of morbidity and mortality. L-citrulline is a non-protein amino acid that has a direct effect on muscle protein synthesis. Oral supplementation with L-citrulline (10 g/day) in malnourished patients has shown to increase fat-free mass. The effects of L-citrulline supplementation in malnourished COPD patients are unknown.
The main objective of this prospective, single-centre, randomised, double-blind, placebo-controlled study will be to determine the impact of 45 days of nutritional supplementation with L-citrulline (10 g/day) on lean body mass (fat-free mass index (in kg.m-2) measured by bioelectrical impedance analysis) in malnourished patients (BMI < 20 kg/m2 if < 70 years old or < 22 kg/m2 if ≥ 70 years old) with COPD at stages 3-4 of the GOLD classification.

开始日期2024-01-25

申办/合作机构

Grenoble University Hospital

NCT05722860 / Recruiting临床1期IIT

Effect of Oral L-Citrulline on the Peripheral and Central Endothelial Function in Young and Older Adults

The effect of L-Citrulline is well studied in relation to muscle strength, exhaustion, exercise performance, and endothelial function in health and disease. This study will extend current body of knowledge and will investigate the effect of L-Citrulline on brain vascular function.

开始日期2024-01-03

申办/合作机构

University of Oklahoma

NCT05259904 / Recruiting临床2期IIT

Study to Improve dEployment Related Asthma by Using L-citrulline Supplementation (SEALS)

Service men and women returning from deployment are significantly more likely to develop asthma and severe respiratory symptoms from airway obstruction. Why this happens is not well known, but exposure to diesel, burn pits, biomass smoke, and sandstorms are thought to play a role. Ultimately, patients with deployment related asthma develop a complex airway disease that does not respond well to standard asthma medications. Therefore, it is imperative that safe and affordable treatments that could improve quality of life and symptoms are studied.
It has been previously shown that adult patients with poorly controlled asthma have an abnormal regulation of an amino acid called L-arginine and airway nitric oxide (FeNO), a gaseous molecule normally produced in the airways of healthy people. In healthy people, nitric oxide is present in amounts that help keep the airways open. However, in some patients with asthma, nitric oxide and L-arginine are often low. The investigators' preliminary data in obese asthmatics show that L-citrulline, which is an amino acid that can be metabolized into L-arginine, improved lung function and asthma control, while increasing the levels of FeNO. This is potentially shifting the paradigm in how investigators think of asthma management, as rising FeNO is often thought of being a bad sign. Based on this, the study investigators hypothesize that an L-citrulline-based drug strategy will normalize nitric oxide metabolism, suppress oxidative inflammatory responses and improve airway function in obese patients with asthma. The study proposal presents a clinical trial approach to treat deployment related asthma patients using L-citrulline as an add-on therapy to improve asthma control. If this confirms the investigators' previous study results, the investigators will be in route for developing the only precision-based therapy available to treat this asthma phenotype. These study results will potentially show that L-citrulline is a safe, tolerable medication that can make a significant impact on the respiratory health of a large segment of our active and veteran population at a reasonable cost.

开始日期2023-03-08

申办/合作机构

University of Colorado Denver

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100 项与 L-Citrulline 相关的临床结果

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100 项与 L-Citrulline 相关的转化医学

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100 项与 L-Citrulline 相关的专利（医药）

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项与 L-Citrulline 相关的文献（医药）

2024-02-20·Journal of inherited metabolic disease

Impact of citrulline substitution on clinical outcome after liver transplantation in carbamoyl phosphate synthetase 1 and ornithine transcarbamylase deficiency.

Article

作者: Denise Aldrian ; Birgit Waldner ; Georg F Vogel ; Areeg H El-Gharbawy ; Patrick McKiernan ; Jerard Vockley ; Yuval E Landau ; Fuad Al Mutairi ; Karolina M Stepien ; Anne Mei-Kwun Kwok ; Yılmaz Yıldız ; Tomas Honzik ; Silvie Kelifova ; Carolyn Ellaway ; Allan M Lund ; Mari Mori ; Sarah C Grünert ; Sabine Scholl-Bürgi ; Thomas Zöggeler ; Rupert Oberhuber ; Stefan Schneeberger ; Thomas Müller ; Daniela Karall

Carbamoyl phosphate synthetase 1 (CPS1) and ornithine transcarbamylase (OTC) deficiencies are rare urea cycle disorders, which can lead to life-threatening hyperammonemia. Liver transplantation (LT) provides a cure and offers an alternative to medical treatment and life-long dietary restrictions with permanent impending risk of hyperammonemia. Nevertheless, in most patients, metabolic aberrations persist after LT, especially low plasma citrulline levels, with questionable clinical impact. So far, little is known about these alterations and there is no consensus, whether l-citrulline substitution after LT improves patients' symptoms and outcomes. In this multicentre, retrospective, observational study of 24 patients who underwent LT for CPS1 (n = 11) or OTC (n = 13) deficiency, 25% did not receive l-citrulline or arginine substitution. Correlation analysis revealed no correlation between substitution dosage and citrulline levels (CPS1, p = 0.8 and OTC, p = 1). Arginine levels after liver transplantation were normal after LT independent of citrulline substitution. Native liver survival had no impact on mental impairment (p = 0.67). Regression analysis showed no correlation between l-citrulline substitution and failure to thrive (p = 0.611) or neurological outcome (p = 0.701). Peak ammonia had a significant effect on mental impairment (p = 0.017). Peak plasma ammonia levels correlate with mental impairment after LT in CPS1 and OTC deficiency. Growth and intellectual impairment after LT are not significantly associated with l-citrulline substitution.

2024-01-17·Life sciences

Anti-obesity and anti-diabetic effects of L-citrulline are sex-dependent.

Article

作者: Fatemeh Bagheripour ; Sajad Jeddi ; Khosrow Kashfi ; Asghar Ghasemi

AIMS:

Anti-diabetic and anti-obesity effects of L-citrulline (Cit) have been reported in male rats. This study determined sex differences in response to Cit in Wistar rats.

MAIN METHODS:

Type 2 diabetes (T2D) was induced using a high-fat diet followed by low-dose of streptozotocin (30 mg/kg) injection. Male and female Wistar rats were divided into 4 groups (n = 6/group): Control, control+Cit, T2D, and T2D + Cit. Cit (4 g/L in drinking water) was administered for 8 weeks. Obesity indices were recorded, serum fasting glucose and lipid profile were measured, and glucose and pyruvate tolerance tests were performed during the Cit intervention. White (WAT) and brown (BAT) adipose tissues were weighted, and the adiposity index was calculated at the end of the study.

KEY FINDINGS:

Cit was more effective in decreasing fasting glucose (18 % vs. 11 %, P = 0.0100), triglyceride (20 % vs. 14 %, P = 0.0173), and total cholesterol (16 % vs. 11 %, P = 0.0200) as well as decreasing gluconeogenesis and improving glucose tolerance, in females compared to male rats with T2D. Following Cit administration, decreases in WAT weight (16 % vs. 14 % for gonadal, 21 % vs. 16 % for inguinal, and 18 % vs. 13 % for retroperitoneal weight, all P < 0.0001) and increases in BAT weight (58 % vs. 19 %, for interscapular and 10 % vs. 7 % for axillary, all P < 0.0001) were higher in females than male rats with T2D. The decrease in adiposity index was also higher (11 % vs. 9 %, P = 0.0007) in females.

SIGNIFICANCE:

The anti-obesity and anti-diabetic effects of Cit in rats are sex-dependent, with Cit being more effective in female than male rats.

2024-01-01·Biomolecules & therapeutics

Effect of Various Pathological Conditions on Nitric Oxide Level and L-Citrulline Uptake in Motor Neuron-Like (NSC-34) Cell Lines.

Article

作者: Shashi Gautam ; Sana Latif ; Young-Sook Kang

Amyotrophic lateral sclerosis (ALS) is a fatal motor neuron disorder that causes progressive paralysis. L-Citrulline is a non-essential neutral amino acid produced by L-arginine via nitric oxide synthase (NOS). According to previous studies, the pathogenesis of ALS entails glutamate toxicity, oxidative stress, protein misfolding, and neurofilament disruption. In addition, L-citrulline prevents neuronal cell death in brain ischemia; therefore, we investigated the change in the transport of L-citrulline under various pathological conditions in a cell line model of ALS. We examined the uptake of [¹⁴C]L-citrulline in wild-type (hSOD1wt/WT) and mutant NSC-34/ SOD1^G93A (MT) cell lines. The cell viability was determined via MTT assay. A transport study was performed to determine the uptake of [¹⁴C]L-citrulline. Quantitative real-time polymerase chain reaction (qRT-PCR) analysis was performed to determine the expression levels of rat large neutral amino acid transported 1 (rLAT1) in ALS cell lines. Nitric oxide (NO) assay was performed using Griess reagent. L-Citrulline had a restorative effect on glutamate induced cell death, and increased [¹⁴C]L-citrulline uptake and mRNA levels of the large neutral amino acid transporter (LAT1) in the glutamate-treated ALS disease model (MT). NO levels increased significantly when MT cells were pretreated with glutamate for 24 h and restored by co-treatment with L-citrulline. Co-treatment of MT cells with L-arginine, an NO donor, increased NO levels. NSC-34 cells exposed to high glucose conditions showed a significant increase in [¹⁴C]L-citrulline uptake and LAT1 mRNA expression levels, which were restored to normal levels upon co-treatment with unlabeled L-citrulline. In contrast, exposure of the MT cell line to tumor necrosis factor alpha, lipopolysaccharides, and hypertonic condition decreased the uptake significantly which was restored to the normal level by co-treating with unlabeled L-citrulline. L-Citrulline can restore NO levels and cellular uptake in ALS-affected cells with glutamate cytotoxicity, pro-inflammatory cytokines, or other pathological states, suggesting that L-citrulline supplementation in ALS may play a key role in providing neuroprotection.

项与 L-Citrulline 相关的新闻（医药）

2023-10-05

·PRNewswire

Bizz Energy Is a Clean, Mean Way to Beat the Modern Midday Slump

The Energy Drink Formula Unleashes Unique Levels of Energy Whilst Avoiding Sugar Crashes and Unhealthy Ingredients FORT LAUDERDALE, Fla., Oct. 5, 2023 /PRNewswire/ -- The modern, remote-first work world may not have a consistent nine-to-five rhythm anymore. But that doesn't change the fact that people are still putting a lot of time into working their jobs. The Bureau of Labor Statistics reports that the average American worker clocks in at just over eight hours of labor per day (8.01, to be precise). That means, no matter when those work hours take place, they're going to extend over a significant portion of an individual's daily schedule. It also means it will involve a slump in energy and productivity at some point along the way. "Midday slumps may not always happen in the early afternoon anymore," says Gavin Jacono, founder of Bizz Energy, "But they happen at some point — and on a regular basis. If you start work at four in the morning, chances are you're going to lag after breakfast or in the late morning. If you start at noon, you'll feel tired before dinner." Northwestern Medicine points out that the biggest reason for this energy slump is that it's a predictable part of every individual's circadian cycle. However, the medical site adds that things like sleep disorders, stress, and even poor eating habits can also contribute to a slowdown in the middle of the workday. When that happens, many people turn to energy drinks as a solution — but Jacono points out that traditional energy drink formulas don't really solve the problem. "Those classic formulas use sugar, high fructose corn syrup, or aspartame. They give you a quick boost, but it's often followed by a crash — usually before your work day ends, which only means you're kicking the productivity issue down the road. And your body has to work through all of those unhealthy chemicals and additives, too. That's why we created Bizz Energy. To turn unhealthy, short-term energy drinks into healthy, long-term productivity and health solutions." Bizz Energy replaces unwanted ingredients with healthy alternatives. Each 12 oz can contains a clean shot of 200 mg of caffeine along with a punchy nutritional combination called the SuperTurk® blend. This includes an innovative soluble form of Turkesterone along with creatine, essential amino acids, L-citrulline, L-theanine, L-carnitine, niacin, and biotin. The result of this revolutionary combination is an energy drink that doubles as a nutritional supplement. It helps boost energy without a sugar crash while also stimulating metabolism and helping build muscle and strength. This makes it a clean, mean way to beat a midday slump — no matter when it might take place. About Bizz Energy Bizz Energy was founded by Gavin Jacono. The fitness and nutrition fanatic hails from New York City and is obsessed with boxing, weightlifting, and soccer. As an aspiring 17-year-old entrepreneur, Jacono launched Bizz Energy as a way to create the ultimate energy drink he had always wanted to fuel his athletic pursuits. Along with a potent dose of caffeine, the Bizz Energy formula taps into a unique form of soluble Turkesterone. It is delicious, clean, and effective. Learn more at bizzenergy.com. Media Contact: Gavin Jacono 516-637-8701 [email protected] SOURCE Bizz Energy

2023-08-04

·PRNewswire

Bizz Energy Clears Minds and Sharpens Focus

The Clean, Zero-Sugar Energy Drink Is Good For More Than Just Physical Performance. It Boosts Brain Function, Too. FORT LAUDERDALE, Fla., Aug. 4, 2023 /PRNewswire/ -- Bizz Energy is a revolutionary new zero-sugar energy drink designed to boost performance through natural ingredients without the use of harmful chemicals or additives. While this is primarily focused on physical activities, the energy supplement's ingredients can also deliver some helpful benefits for the brain. "I designed Bizz Energy to clear my mind as well as boost my physical performance," explains company founder Gavin Jacono. "Sometimes you need to do more than run faster, lift more, or stay awake longer. Sometimes you need that sharp focus that helps you deliver at work or in school." Bizz Energy helps with cognitive function through multiple natural ingredients. For instance, creatine is a safe brain and body amino acid that has been connected to short-term memory improvement when administered orally. L-citrulline has clearly demonstrated benefits for brain function, as well. L-Theanine relieves stress disorders, improves mood, and helps with sleep. Another ingredient with the potential to help with cognition is Turkesterone. While this popular supplement is currently trending in the sports and fitness world for its physical benefits, there are also suggestions that it could aid mental health by helping cope with stress and fatigue. "Including Turkesterone was a big deal for us," says Jacono. "I knew we wanted it in there, but it's a plant-based steroid, so it isn't water-soluble. We invested in extensive research and testing and were able to develop a method to solubilize Turkesterone — it's one of the most unique things about our product." From carefully selected amino acids to soluble Turkesterone, Bizz Energy is packed with natural ingredients designed to deliver a critical dose of energy when needed. The innovative combination of natural ingredients doesn't just apply to physical performance, either. It can be a game-changer when it comes to cognitive function, too, helping to sharpen the mind and create clear focus. About Bizz Energy Bizz Energy was founded by Gavin Jacono. The fitness and nutrition fanatic hails from New York City and is obsessed with boxing, weightlifting, and soccer. As an aspiring 17-year-old entrepreneur, Jacono launched Bizz Energy as a way to create the ultimate energy drink he had always wanted to fuel his athletic pursuits. Along with a potent dose of caffeine, the Bizz Energy formula taps into a unique form of soluble Turkesterone. It is delicious, clean, and effective. Learn more at bizzenergy.com. Media Contact: Gavin Jacono 516-637-8701 [email protected] SOURCE Bizz Energy

2023-06-16

·生物制品圈

甾体类化合物ADC梳理：Ambrx/再生元/Abbvie/映恩

近年来，随着多款抗体-药物偶联物(ADC)的批准以及多个ADC实体在临床开发中取得可喜进展，人们对ADC的研发兴趣大增[1]。通过将生物活性分子(Payload)连接到具有靶向性的抗体，ADC可将Payload靶向递送至与疾病相关的细胞/组织，同时最大限度地减少其在全身的分布，降低毒副作用，提高Payload的治疗窗口[2]。基于ADC的作用优势，ADC技术在除肿瘤以外的许多其他疾病领域都有潜在的应用，并且这种应用扩展的例子越来越频繁地出现在科学文献及专利中。甾(zai)体类药物(Steroid)，分子母体结构中都含有环戊烷骈多氢菲（cyclopentano-perhydrophenanthrene）碳骨架，此骨架又称甾核（steroid nucleus），通常用于治疗与多种疾病相关的炎症。然而，这些药物也会引起肌肉骨骼、内分泌和胃肠道副作用以及其他毒性，限制它们的治疗效用(尤其是长期服用时)。基于以上甾体类药物的使用情况，将甾体类药物引入到抗体中构建新型ADC，作用于目的免疫细胞，以此减少全身性副作用同时保持甾体类药物的抗炎活性，成为一大潜力研究领域[3]。甾体类化合物 01 早期甾类化合物ADC构建--Dexa-AbhEsel追述到2002年，格罗宁根大学药物探索研究所Maaike Everts博士较早利用糖皮质激素(Glucocorticoid)构建ADC[4, 5]。在慢性炎症性疾病中，内皮细胞在白细胞募集中起着重要作用，因此其成为药物干预的一个极具吸引力的靶点，抑制内皮细胞活化和随之而来的白细胞浸润可改善慢性炎症性疾病的治疗效果。Maaike Everts博士以靶向E-选择素(E-selectin)的抗体与地塞米松(Dexamethasone)构建Dexa-AbhEsel (羧基+伯胺随机偶联[6]，DAR=2.3)，可选择性地与TNF-α刺激的内皮细胞结合，而不与静息态的内皮细胞结合；Dexa-AbhEsel经过细胞内吞在溶酶体内降解后，酯键水解释放出具有药理学活性的Dexa，能够下调促炎基因IL-8的表达(图1)。该项研究表明使用Dexa-AbhEsel可选择性地将抗炎药物递送到活化的内皮细胞中，为后续药物开发提供指导。图1. Dexa-AbhEsel的构建及其对促炎基因IL-8的影响 02 丹麦Cytoguide公司--Anti-CD163-Dexa ADC除了E-Selectin外，CD-163 (Hemoglobin Scavenger Receptor，血红蛋白清道夫受体)靶点也被用来开发含Glucocorticoid的ADC。2012年，丹麦Cytoguide公司开发出一种新的可生物降解的靶向CD163的ADC，可特异性地将Dexa靶向递送至巨噬细胞中的CD163 (图2)[7]。在Dexa末端21位-OH上引入琥珀酸形成Dexa-hemisuccinate，对其末端羧基进行活化引入NHS酯构建Drug-Linker：Dexa-hemisuccinate-NHS，提高后续偶联效率；将其与抗体室温孵育(pH 8.3, PBS, ~15 Min)，与伯胺进行随机偶联(主要是赖氨酸)，所构建的ADC-Anti-CD163-Dexa的DAR值为4 (图2左)，偶联后对CD163表现出高亲和力，说明该种随机偶联的方式对其亲和力没有过多的影响。体外研究和体内研究表明，Anti-CD163-Dexa具有很强的抗炎作用，可使脂多糖诱导的肿瘤坏死因子分泌减少(图2中、右)。Anti-CD163-Dexa中地塞米松的效力是非偶联地塞米松的~50倍。与地塞米松的强烈全身作用相反，等效剂量的Anti-CD163-Dexa没有这些副作用：胸腺淋巴细胞凋亡、体重减轻和内源性皮质醇水平的抑制。综上所述，该研究表明ADC是抗炎巨噬细胞定向治疗的未来方法。同时也说明CD163是抗炎药物递送的极佳靶点。图2. ADC-Anti-CD163-Dexa的构建及其抗炎活性的评价 03 Merck联合Ambrx，基于新型焦磷酸二酯Linker开发系列ADC为探究ADC在肿瘤学适应症之外的应用，Merck和Ambrx公司强强联合，发现了一种新型焦磷酸二酯Linker。作为小分子，含有该种焦磷酸二酯的Drug-Linker具有很好的水溶性、出色的血浆稳定性以及在溶酶体环境中快速释放有效载荷等特点，可实现Glucocorticoid的靶向递送(图3)[8]，因此利用该种新型Linker开发了一系列靶向CD70[8-10]和CD74[11]的新型ADC药物。图3. 含有焦磷酸二酯ADC的作用机制Merck & Ambrx公司研究人员于2016年在JACS上公布了利用新型焦磷酸二酯Linker构建位点特异性ADC的方法[8]；同年，在Biocojugate Chemistry上发文对焦磷酸二酯Linker进行优化，引入组织蛋白酶B (Cathepsin B, CatB)敏感的VC二肽接头[9]；针对以上研究内容分别于2015年和2017年公布了关于该类型ADC的专利-WO2015153401[12]和WO2017062271[13, 14]；2018年，两家公司的研究人员又在Biocojugate Chemistry上发文优化焦磷酸二酯Linker，构建新型ADC[11]。接下作者将简要介绍该系列ADC的构建工作。CD70[15]是一种在免疫细胞中特异性表达的受体，同时也在多种人类癌症中异常表达。目前针对该靶点ADC药物的开发多集中于肿瘤学领域[16]，但针对免疫细胞进行ADC的开发较少。基于CD70在肿瘤ADC文献中作为靶点的先例，以其相对应的抗体做为模式抗体进行概念验证，引入Glucocorticoid并测试特定细胞系对Glucocorticoid的反应情况。Merck & Ambrx公司研究人员以anti-hCD70抗体-2h5[17]进行模式反应，利用基因密码子扩增技术[18]将非天然氨基酸(para-azido-phenylalanine, pAF[19])引入到2h5抗体CH1 (HA114)中，替换原有的丙氨酸，使其与含有环辛炔结构的Linker-Drug发生无铜催化的叠氮炔基环加成反应[20]构建含有Dexa的系列ADC (图4)，其DAR值均大于1.8；同时也显示出高单体含量(>98%)，并且发现纯化后残留的Linker-Drug小于1%。图4. 无铜催化的SPAAC构建含有糖皮质激素的ADCDrug涉及地塞米松、布地奈德和氟替卡松。对于地塞米松和布地奈德而言，其与Linker连接的位点为21位；对于氟替卡松而言，其与Linker连接的位点为11位的羟基，且二者中间还存在亚甲基(1-37)，在无亚甲基存在的情况下，所构建的ADC (1-33)无法将所带药物完全转化为Free的形式释放，怀疑是11位空间位阻所致。通过上述两种ADC简单代谢过程的研究认为该类ADC发挥作用机制涉及两种酶：一种用于切割焦磷酸二酯键(例如磷酸酶)，另一种用于水解剩余的末端磷酸集团并释放free形式的药物。对于含有不同磷酸基团的Linker-Drug，含有单磷酸的在溶酶体裂解液中缓慢释放药物，含有双磷酸的在溶酶体裂解液中快速释放药物；因此，在后续ADC研究主要以不含苯环的焦磷酸二酯Linker作为主要的研究对象。GILZ (Glucocorticoid-Induced Leucine Zipper) mRNA表达水平是糖皮质激素受体(Glucocorticoid Receptor, GR)富集的主要指征，多用于糖皮质激素对受体刺激程度的表征，在此利用该参数来评估所构建ADC的活性。利用含不同数目磷酸基团的ADC处理CD70+ 786-O细胞，含有焦磷酸二酯结构的ADC的活性强于含有单磷酸的ADC，说明该类ADC在细胞中的活性与其在溶酶体中的裂解能力有关(图5左上)；利用该方法构建的ADC处理CD70+ 786-O细胞，1-37与氟替卡松丙酸脂作用相当，1-33因无法释放游离的药物而完全无活性(图5左下)，以上数据说明该类型ADC的作用依赖于其Linker-Drug的构成。相较于对照组ADC (α-RSV)，实验组ADC (α-hCD70, 除1-33外)均表现良好的细胞活性(图5右)。图5. 该类型ADC的细胞活性：α-hCD70(实验组)和α-RSV (对照组)针对此类型ADC中所用Linker发挥药效的作用机制JACS仅给出了推测，并未进行详细的研究。为了能够更广泛应用此类Linker，Merck & Ambrx科研人员对其进行优化，开发了一款新型焦磷酸二酯桥接的CatB敏感的Linker，用以实现糖皮质激素的靶向递送[9]。该种Linker含有缬氨酸-瓜氨酸(Valine-Citrulline, VC)结构，用于CatB的特异性识别；同时，该Linker还含有自降解的PAB结构。该种ADC进入体内经CatB裂解和PAB自发丢失后，将产生含有单磷酸的布地奈德，然后末端磷酸可以被磷酸酶裂解以释放游离的布地奈德(图6上)。这种Linker-Drug设计策略以溶解度增强的方式掺入CatB敏感的二肽和糖皮质激素类固醇，在确保高DAR值的同时减少疏水性导致的聚集问题。与JACS中ADC的构建方法一致，将构建好的两种ADCs (aCD70-8a/b)处理CD70+ 786-O细胞，利用RT-qPCR测量GILZ mRNA表达水平以评估该类型ADC活性，实验结果表明aCD70-8a/b可使GILZ mRNA表达水平以剂量依赖性的方式显著表达，且EC50值与布地奈德相似(图6下)。相较于对照ADC (aRSV)，aCD70-8a/b可实现靶向递送，活性作用与Linker-Drug在溶酶体环境中被切割的能力相关。图6. 含有布地奈德载荷ADC的构建及其载荷释放机制基于上述Linker-Drug的技术优势，Merck & Ambrx公司于2015公布专利-WO2015153401[12]，2017年公布专利-WO2017062271[13]。作者对两篇专利中所提及的内容进行简单梳理(表1)，供大家参考学习，具体内容请参考专利。表1. 专利WO2015153401和WO2017062271内容的简单梳理两篇专利关于所构建ADC的活性评价方式与前述文献中记载的一致。两篇专利的内容大致相似，WO2015153401的首次公开日为2015年10月8日，WO2017062271优先权日为2015年10月6日，因此WO2015153401不能作为现有技术评价WO2017062271的创造性。除了上述提及的Drug外，2018年Merck & Ambrx公司研究人员利用氟替卡松丙酸酯(Fluticasone Propionate)作为有效载荷构建靶向CD74的ADC (图7)[11]。对Anti-CD74-flu449作用机制研究表明，组织培养上清液中游离有效载荷的积累是活性的主要驱动因素；此外，将该ADC施用于人CD74转基因小鼠未能激活脾脏B细胞中的糖皮质激素受体靶基因，研究人员认为产生这种现象的主要原因是有效载荷的渗透性。基于以上事实，设计合成大量的氟替卡松丙酸酯衍生物评估其在不同pH条件下的渗透性，确保Drug在中性pH有较低的渗透性，在pH5-6时拥有适中的渗透性使其可以从溶酶体中逃逸出来，最终选取Compound A构建新型ADC：anti-CD74-AXC496。虽然anti-CD74-AXC496的活性没有Anti-CD74-flu449优秀，但作者更倾向于其产生的细胞特异性靶向递送，为降低该类型药物的毒副作用提供帮助。Anti-CD74-AXC496 (DAR=1.5)的活性低于Anti-CD74-flu449 (DAR=1.9)也有可能是其DAR较低的原因，后续若作者再提高其DAR值可能会消除这种活性较低的问题。图7. 构建抗CD74 ADC靶向递送糖皮质激素及其活性评价 04 再生元：GC-ADCs 广泛的专利布局再生元(Regeneron Pharmaceuticals, Inc.,)是一家美国生物技术公司，成立于1988年。该公司最初专注于神经营养因子及其再生能力而得名，后来又扩展到细胞因子、酪氨酸激酶受体等领域，其正在开发的商业化药物和候选产品旨在帮助患有眼疾、过敏性和炎症性疾病、癌症、心血管和代谢性疾病、疼痛、传染病和罕见疾病的患者。针对ADC领域，Regeneron利用甾体药物及其衍生物构建了一系列抗体-甾体药物偶联物(Antibody-Glucocorticoid Conjugates (GC-ADCs))[4-7]，采用微生物转谷氨酰胺酶(Microbial Transglutaminase, MTGase)有效地将含有伯胺的底物与去糖基化(Q295)或非糖基化(N297Q、N297A)抗体结合，从而构建DAR值为2/4的ADC (图8a、b)[8, 9]；此外，加入LLQG肽标签(Q-标签)还可以在Q295以外的所需位置引入Payload (图8c)。通过该方法将Payload引入到抗体的Fc，最大限度地降低Payload对抗体亲和力(特异性)的影响；也可根据实验要求使用分支Linker在引入Payload的同时引入亲水性基团[10]，降低偶联物的疏水性，改善ADME性质。图8. 利用MTG对抗体进行位点特异性偶联[8, 9]Regeneron主要利用含有Q295、Q297反应位点的抗体构建GC-ADC，利用MTGase将含有氨基的底物(N3-PEG3-NH2)引入到目的抗体中，通过环张力驱动的叠氮炔基环加成反应(Strain-Promoted Azide−Alkyne Cycloaddition, SPAAC[11])进行位点特异性的偶联，获得DAR值为4的偶联物(图9)，改善甾体类药物的口服生物利用度(F)，降低肝脏首过效应，减少单独应用时所产生的副作用[4]。图9. Regeneron GC-ADC的构建方法接下来作者将以长表格的形式解析Regeneron在GC-ADC领域的专利/文章，重点介绍其Linker-Payload的组成(表2)。表2. GC-ADC相关专利内容的简要解析专利WO2018089373引申出的GC-ADC (Anti-PRLR Ab-PEG3-Triazole-Suc-PEG4-vc-PABC-P3/P12)活性数据已发表在Journal of Medicinal Chemistry上[4]。利用该方法构建的GC-ADC (DAR≈4)与对照组(anti-Fel D1 Ab)相比，在抗原阳性细胞系中表现出有效的GR激活和超过其同类型Control GC-ADCs 100倍以上的选择性；此外，两种GC-ADCs (Payload为P3/P12)在混合抗原阳性和阴性细胞系中均表现出旁观者效应。虽然Regeneron在专利布局上做了很多关于GC-ADCs的工作，但其官网所显示的在研管线中并未涉及GC-ADCs，证明该类GC-ADCs的临床前研究仍有一些问题需要解决[12]。 05 Abbvie: 专利WO2017210471与ABBV-154 相较于Regeneron而言，Abbvie在GC-ADC领域的专利-WO2017210471[13]布局更早，优先权日为2016年6月2日。在GC-ADC制备过程中，对偶联物中的硫代琥珀酰亚胺进行开环处理，使其稳定性增加，降低其因逆迈克尔加成反应所致的副反应[14]。作者对专利WO2017210471进行简单梳理，详细信息请参考专利内容(表3)。表3. WO2017210471专利内容简单梳理基于专利中Biaryl基团的活性数据，Abbvie的工作人员对其进行进一步的结构优化，将原有的二苯甲烷更换成苄基哌嗪结构构建新型的Linker (mc-AA-PABC)-Payload，与抗TNF-α抗体-阿达木单抗(Adalimumab, ADA)[15]进行偶联，得到DAR为2或4的GC-ADC；对DAR值为4的GC-ADC进行水解开环处理，避免在血液循环过程中解偶联，使其稳定性增加，该GC-ADC被命名为ABBV-3373 (图10左上)[16]，其可选择性地将Payload递送至活化免疫细胞，从而提高整体抗炎功效，同时最大限度地减少对游离Payload的全身暴露。与全身给药的传统糖皮质激素相比，利用ABBV-3373递送可降低副作用的风险[17, 18]。目前，ABBV3373已完成临床二期实验(NCT03823391)[19]，该临床试验数据表明ABBV-3373在第12周时显示DAS28-CRP相对于基线的变化优于历史ADA参考值；受试患者接受ABBV-3373在DAS28-CRP方面比接受ADA治疗的患者在数值上有更大的改善(图10左下)。以上临床实验数据支持继续开发ABBV-3373用于治疗类风湿性关节炎(Rheumatoid Arthritis, RA)；与目前可用的疗法相比，它有可能取得更好的结果。图10. ABBV-3373结构及其临床数据、ABBV-154结构基于上述ABBV-3373良好的临床试验结果，ABBV-154在其基础上做了“细微修改(slightly modified)”-C21位引入磷酸集团(图10右)。目前，ABBV-154已进行多项临床研究，具体内容如下表4所示。表4. ABBV-154涉及的临床实验概览根据GlobalData的数据，ABBV-154用于治疗风湿性多肌痛(PMR)的II期临床试验具有75%的相变成功率(PTSR)，可以进入III期临床试验[20]。但是，据ENDPOINTS NEWS 2023年4月27日报道，Abbive出于对ABBV-154较高剂量获益-风险状况的担忧停止了ABBV-154的开发[21]。目前，ABBV-154在官网研发管线也已检索不到[22]。 06 映恩生物：DIMAC技术平台国内药企映恩生物(DualityBio)开发出具有全球知识产权的DIMAC (Duality Immune Modulating Antibody Conjugate，双重免疫调节抗体偶联物)技术平台[23]。DIMAC技术平台主要针对自身免疫疾病而开发，例如系统性红斑狼疮(Systemic lupus erythematosus, SLE)。该技术平台构建GC-ADCs所选用Payload的活性强于传统的激素类小分子，具有长效的特点；可以降低给药频次低，提高患者的用药依从性；此外，其具有高度靶点特异性，可最大限度地减少甾体类药物的全身副作用[24]。该平台技术专利-WO2022135332[25]于2022年6月30日公布，主要涉及一种甾体偶联物，作者将专利中的内容简要梳理如下表5所示。表5. WO2022135332专利内容简要梳理基于上述DIMAC技术，以及对疾病生物学和转化能力的深刻理解，DualityBio有两款该类GC-ADC药物在研-DB2304[26]和DB2306[27]，目前处于临床前研究阶段。此外，DualityBio DIMAC技术还涉及另一项专利WO2023040793[28]，有兴趣的朋友可以和Abbive的专利-WO2017210471进行对比阅读。免责声明：本文仅作信息交流之目的，文中观点不代表个人立场，亦不代表个人支持或反对文中观点。本文并非治疗方案推荐。如需获得治疗方案指导，请前往正规医院就诊。刍荛之作，若有纰漏/不足，欢迎各位批评指正(dyc21@mails.tsinghua.edu.cn)，谢谢！主要参考文献 1. Fuentes-Antrás, J., et al., Antibody-drug conjugates: in search of partners of choice. Trends Cancer, 2023. 9(4): p. 339-354.2. Fu, Z., et al., Antibody drug conjugate: the "biological missile" for targeted cancer therapy. Signal Transduct Target Ther, 2022. 7(1): p. 93.3. Dragovich, P.S., Antibody-Drug Conjugates for Immunology. J Med Chem, 2022. 65(6): p. 4496-4499.4. Han, A., et al., Development of Novel Glucocorticoids for Use in Antibody-Drug Conjugates for the Treatment of Inflammatory Diseases. J Med Chem, 2021. 64(16): p. 11958-11971.5. Han, A., W. Olson, and A.J. Murphy, Preparation of novel steroids and their protein-conjugates for the target-specific delivery of glucocorticoids. 2018, Regeneron Pharmaceuticals, Inc.6. Han, A., Steroids and antibody-conjugates thereof useful for target-specific delivery of glucocorticoids to cells. 2019, Regeneron Pharmaceuticals, Inc.7. Han, A., Traceless linkers and protein-conjugates thereof. 2023, Regeneron Pharmaceuticals, Inc.8. Anami, Y. and K. Tsuchikama, Transglutaminase-Mediated Conjugations. Methods Mol Biol, 2020. 2078: p. 71-82.9. Dickgiesser, S., et al., Site-Specific Conjugation of Native Antibodies Using Engineered Microbial Transglutaminases. Bioconjug Chem, 2020. 31(4): p. 1070-1076.10. Han, A., Hydrophilic linkers for antibody drug conjugates. 2019, Regeneron Pharmaceuticals, Inc.11. Ramsubhag, R.R. and G.B. Dudley, Orthogonal dual-click diyne for CuAAC and/or SPAAC couplings. Organic & biomolecular chemistry, 2016. 14(22): p. 5028-5031.12. https://www.regeneron.com/pipeline-medicines/investigational-pipeline.13. McPherson, M.J., et al., Preparation of glucocorticoid receptor agonist and immunoconjugates thereof. 2017, AbbVie Inc.14. Huang, W., et al., Maleimide-thiol adducts stabilized through stretching. Nat Chem, 2019. 11(4): p. 310-319.15. Lu, X., et al., Efficacy and Safety of Adalimumab Biosimilars: Current Critical Clinical Data in Rheumatoid Arthritis. Front Immunol, 2021. 12: p. 638444.16. Hobson, A.D., et al., Discovery of ABBV-3373, an Anti-TNF Glucocorticoid Receptor Modulator Immunology Antibody Drug Conjugate. J Med Chem, 2022. 65(23): p. 15893-15934.17. Stoffel, B., et al., POS0365 anti-TNF glucocorticoid receptor modulator antibody drug conjugate for the treatment of autoimmune diseases. 2021, BMJ Publishing Group Ltd.18. D'Cunha, R., et al. ABBV-3373-A NOVEL IMMUNOLOGY ANTIBODY DRUG CONJUGATE: RESULTS FROM A FIRST-IN-HUMAN SINGLE ASCENDING DOSE STUDY IN HEALTHY SUBJECTS TO SUPPORT DOSE SELECTION FOR THE PROOF-OF-CONCEPT STUDY IN RHEUMATOID ARTHRITIS PATIENTS. in Clinical Pharmacology & Therapeutics. 2021. WILEY 111 RIVER ST, HOBOKEN 07030-5774, NJ USA.19. Buttgereit, F., et al., Efficacy and Safety of ABBV-3373, a Novel Anti-Tumor Necrosis Factor Glucocorticoid Receptor Modulator Antibody-Drug Conjugate, in Adults with Moderate-to-Severe Rheumatoid Arthritis Despite Methotrexate Therapy: A Randomized, Double-Blind, Active-Controlled Proof-of-Concept Phase IIa Trial. Arthritis Rheumatol, 2023. 75(6): p. 879-889.20. https://www.pharmaceutical-technology.com/data-insights/abbv-154-abbvie-polymyalgia-rheumatica-pmr-likelihood-of-approval/.21. https://endpts.com/abbvie-axes-two-candidates-as-company-revenue-drops-nearly-10/.22. https://www.abbvie.com/science/pipeline.html.23. https://www.dualitybiologics.com/approach.html?md=2.24. https://www.dualitybiologics.com/approach.html.25. Zhang, Y., et al., Steroid conjugate. 2022, Duality Biologics (Suzhou) Co., Ltd.26. Li, X., et al. DB-2304, a Novel anti-BDCA2 Monoclonal Antibody Drug Conjugate, Displayed Great Potency in Suppression of pDC Functions. in ARTHRITIS & RHEUMATOLOGY. 2022. WILEY 111 RIVER ST, HOBOKEN 07030-5774, NJ USA.27. Li, X., et al. DB-2306, a Novel Anti-TNF alpha Monoclonal Antibody Drug Conjugate, Is a Promising Novel Therapeutic Approach for Autoimmune Disease. in ARTHRITIS & RHEUMATOLOGY. 2022. WILEY 111 RIVER ST, HOBOKEN 07030-5774, NJ USA.28. Zhang, Y., et al., Anti-inflammatory compound and use thereof. 2023, Duality Biologics (Suzhou) Co., Ltd.

抗体药物偶联物临床结果

100 项与 L-Citrulline 相关的药物交易

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外链

KEGG	Wiki	ATC	Drug Bank
D07706	L-Citrulline	-	-

研发状态

适应症	最高研发状态	国家/地区	公司
急性肺损伤	临床3期	奥地利更多	Asklepion Pharmaceuticals LLC 更多
呼吸功能不全	临床2期	美国更多	Asklepion Pharmaceuticals LLC 更多
肺性高血压	无进展	美国更多	Asklepion Pharmaceuticals LLC 更多
心房中隔缺损	无进展	美国更多	Asklepion Pharmaceuticals LLC 更多
心脏室间隔缺损	无进展	美国更多	Asklepion Pharmaceuticals LLC 更多

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临床结果

适应症

分期

评价

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研究	分期	人群特征	评价人数	分组	结果	评价	发布日期


NCT01386034 (Pubmed \| Clin Nutr)	临床3期	短肠综合征	9	Citrulline supplementation	膚鹹繭膚製夢蓋鹽憲衊(遞繭餘壓餘鏇簾鏇願繭) = 獵繭鹽獵鏇窪網構網壓範簾繭積遞衊艱鹽蓋窪 (齋築蓋簾膚鹹衊網簾遞 ) 更多	-	2019-12-01
				citrulline (Placebo)	膚鹹繭膚製夢蓋鹽憲衊(遞繭餘壓餘鏇簾鏇願繭) = 積範醖繭艱構膚鬱衊範範簾繭積遞衊艱鹽蓋窪 (齋築蓋簾膚鹹衊網簾遞 ) 更多
NCT04570384 (CTgov)	临床2期	低氧性呼吸衰竭 \| COVID-19 呼吸道感染 \| 新型冠状病毒感染	65	L-Citrulline (IV L-Citrulline (Turnobi) Arm)	餘襯壓蓋膚繭鹹醖艱積(鏇繭憲壓鏇鹽範鬱鑰壓) = 繭窪鏇鏇廠積簾鏇鏇網醖淵鏇範網鏇積憲積網 (製蓋繭觸壓網襯鬱餘夢, 餘蓋鬱築築淵窪淵簾築 ~ 積憲鹹蓋網淵築鹹壓鑰) 更多	-	2023-02-22
				Placebo (Placebo Arm)	餘襯壓蓋膚繭鹹醖艱積(鏇繭憲壓鏇鹽範鬱鑰壓) = 蓋醖鏇淵鬱蓋蓋艱夢艱醖淵鏇範網鏇積憲積網 (製蓋繭觸壓網襯鬱餘夢, 築衊艱選鹹膚淵憲衊衊 ~ 夢醖廠壓遞願製醖遞襯) 更多
NCT02314689 (CTgov)	临床1期	镰状细胞血症	4	Intravenous (IV) citrulline	蓋齋衊蓋憲餘構壓網築(顧鏇願襯觸淵膚鑰願顧) = 鏇蓋構淵鏇積獵膚鹹衊製簾淵獵積顧鹹鹽醖鬱 (繭醖憲積鬱觸蓋憲鬱餘, 範積憲齋願蓋觸觸遞構 ~ 膚壓鹹憲顧憲製醖構選)	-	2016-03-07
NCT02697240 (CTgov)	临床1期	血管闭塞危机 \| 急性胸部综合征	4	Intravenous citrulline	(製壓願網鹹鏇鹹築選構) = 廠鑰鏇鹽鏇衊窪獵簾艱艱壓觸夢鬱積鹽齋壓遞 (糧築網選鹹醖蓋夢廠顧, 蓋鹹夢鹽願網網膚鏇顧 ~ 夢淵製顧觸襯廠壓憲齋) 更多	-	2019-04-17
NCT01474863 (CTgov)	临床2期	脓毒症 \| 急性肺损伤	72	Low Dose Citrulline (Low Dose Citrulline)	壓鬱廠範選衊鹽構鏇齋(艱糧壓蓋餘簾糧築觸餘) = 鹹鬱構選鑰鹹鬱醖簾範鹽製鑰膚窪繭願築艱醖 (廠廠獵夢襯鏇淵築遞衊, 衊憲鏇糧襯顧構淵廠襯 ~ 鏇膚艱壓簾蓋壓築膚鹹) 更多	-	2017-06-05
				placebo (Placebo)	壓鬱廠範選衊鹽構鏇齋(艱糧壓蓋餘簾糧築觸餘) = 壓蓋構鬱艱鏇艱衊觸鹹鹽製鑰膚窪繭願築艱醖 (廠廠獵夢襯鏇淵築遞衊, 衊蓋鏇襯襯蓋築獵鏇齋 ~ 壓遞餘淵窪築繭願膚網) 更多
NCT01120964 (CTgov)	临床1/2期	房室间隔缺损 \| 心脏室间隔缺损 \| 心房中隔缺损	22	Intravenous L-Citrulline (Intravenous L-Citrulline)	鑰醖鑰餘糧獵鬱夢觸蓋(餘製積願襯鑰簾顧鑰顧) = 願糧壓顧鹽鑰製窪艱衊夢鹹衊獵夢蓋鑰鹽鏇構 (積鑰餘築廠憲獵築襯鑰, 蓋遞願鏇夢簾艱觸廠窪 ~ 選醖觸壓簾窪鑰範簾選) 更多	-	2022-06-21
				Placebo of Intravenous L-Citrulline (Placebo of Intravenous L-Citrulline)	鑰醖鑰餘糧獵鬱夢觸蓋(餘製積願襯鑰簾顧鑰顧) = 願淵鏇鏇範築窪糧網簾夢鹹衊獵夢蓋鑰鹽鏇構 (積鑰餘築廠憲獵築襯鑰, 醖獵醖網簾簾膚選簾醖 ~ 獵鬱蓋齋願鬱積鹹夢廠) 更多
Pubmed \| J Nutr	N/A	胎儿生长受限	-	L-Citrulline	醖夢餘齋壓鹹網淵網齋(糧憲範網繭膚範夢選衊) = 顧願繭衊鬱淵繭餘製醖簾鑰憲獵選簾觸壓獵簾 (膚願夢積鏇糧醖願淵夢 )	-	2016-03-01
				L-Citrulline	醖夢餘齋壓鹹網淵網齋(糧憲範網繭膚範夢選衊) = 鏇鏇齋網積餘餘憲繭鏇簾鑰憲獵選簾觸壓獵簾 (膚願夢積鏇糧醖願淵夢 )
NCT03542812 (Pubmed)	早期临床1期	支气管肺发育不良 \| 肺动脉高压	16	L-Citrulline	(壓願醖選構蓋襯憲簾選) = 餘繭築廠獵選鏇餘鏇蓋夢觸鹽網廠醖糧選鑰顧 (築鏇觸襯餘繭憲網簾範 ) 更多	-	2022-10-31