FPR1

导读：G 蛋白偶联受体（GPCR, G protein-coupled receptor）是细胞表面的膜蛋白家族，在人体及多种动物体内广泛存在。GPCR 参与多种疾病的发生机制，如癌症、神经疾病、代谢疾病、免疫疾病和炎症等。因此，GPCR是药物开发的重要靶点。然而，由于跨膜蛋白自身的特性，GPCR靶向药物（尤其是抗体）开发的最大挑战在于抗原的可及性，在体外很难获得具有生物活性的全长GPCR蛋白。 今天的文章，菌菌总结了GPCR抗体开发的潜力和难点，包括GPCR抗体的应用前景、早期开发流程与面临的技术挑战。我们还汇总了当前的GPCR免疫原类型及优劣势，包括表达目标抗原的全细胞或细胞膜、VLP嵌合抗原、纯化后的抗原、DNA、以及最新技术驱动下的mRNA免疫原。 GPCR是最大的蛋白质超家族之一，由800多个家族成员组成。这类受体的结构特点是具有七个跨膜结构域。GPCR激动剂能够诱导其构象变化，激活其与下游信号蛋白（以异三聚体G蛋白为主）的结合。GPCR家族蛋白作用于多种细胞通路。据早期文献报道，约40%的上市药物通过GPCR介导其效应。 GPCR的化学特性、结构、信号和药理学有助于靶向药物的开发。2012年的诺贝尔化学奖授予了Brian Kobilka和Robert Lefkowitz，以表彰他们关于“G蛋白偶联受体功能方面的重要发现”。 根据既往报道，超过200个GPCR靶点在临床前或临床研究中显示出特异性抗体开发的可行性，涵盖多疾病领域，如肿瘤、代谢疾病、炎症、呼吸道疾病、感染性疾病等。目前，FDA已批准3种靶向GPCR或GPCR相关配体的单克隆抗体用于非肿瘤适应症，分别为莫格利珠单抗（mogamulizumab, C-C 趋化因子受体4(CCR4)）、erenumab（抗降钙素基因相关肽(CGRP)1型受体）和eptinezumab（CGRP）。 其他在研的GPCR抗体靶点包括但不限于C-C趋化因子受体7 (CCR7)、CCR5、C-X-C基序趋化因子受体2（CXCR2）、CXCR4、C-X3-C 趋化因子受体1（CX3CR1）、补体5a受体（C5aR）、G蛋白偶联受体（GPR20）、GPR56、β1-肾上腺素受体、胃泌素/胆囊收缩素B型受体（CCKBR）、趋化因子样受体1 （CMKLR1）、甲酰基肽受体1（FPR1）、胰高血糖素受体（GCGR）、蛋白酶激活受体4（PAR4）、富含亮氨酸重复单位的G蛋白偶联受体（LGR5）。 抗体类药物的早期开发流程一般为抗原选择、抗原制备、动物免疫、抗体筛选和测序，以获得特异性抗体序列，随后进行抗体改造、体外试验、动物试验和临床试验验证。 2.1 GPCR抗原的选择和制备 抗原发挥免疫原的作用，刺激宿主动物产生特异性抗体，随后通过一定的筛选手段进行鉴别。抗原的选择和制备是抗体开发的重要环节。 目前，GPCR常用的免疫原种类包括：纯化的抗原、全细胞、细胞膜组分、病毒样颗粒（VLP）、合成多肽、DNA和mRNA。GPCR抗原的制备是一大技术难题，不同种类抗原的制备方式、免疫原性和特异性存在很大差异。 2.2 动物免疫与GPCR抗体筛选 目标抗原制备完成后，下一步是进行动物免疫。常规单克隆抗体通常选择鼠、兔、羊等作为宿主动物进行抗原免疫；而纳米抗体（也称单域抗体）、重链抗体的筛选以羊驼或鲨鱼为代表。动物免疫的其他关键点包括宿主动物的年龄、抗原用量、注射方式和部位等。 随着传统单克隆抗体、双特异性抗体、抗体偶联药物、纳米抗体的发展，抗体筛选技术也趋于成熟，包括杂交瘤技术、B细胞筛选技术、噬菌体展示技术、酵母展示技术等。我们可以通过以上方法得到抗体序列，包括可变区域的互补决定区（CDR）。 GPCR抗体的开发同样面临技术上的挑战，主要在于GPCR特异性抗原或抗原表位的可及性，及其与GPCR生物学的相关性。 当前虽存在多种类型的抗原用于抗体的筛选，然而或多或少存在缺陷与不足。全细胞抗原、膜组分和VLP存在其他背景抗原的干扰，免疫原性和特异性差；纯化抗原较难制备；多肽类抗原完整性差；DNA抗原细胞核内递送困难、抗原表达水平低且依赖佐剂。 依托mRNA这一近年趋向成熟的技术平台（核苷酸修饰和递送技术等不断优化），能够在目标宿主内表达天然有活性的GPCR蛋白。mRNA作为免疫原的独特优势，有望在GPCR抗体筛选中发挥有效作用，加速GPCR抗体成药的研发进程。 参考文献 [1] Hutchings CJ, Koglin M, Olson WC, Marshall FH. Opportunities for therapeutic antibodies directed at G-protein-coupled receptors. Nat Rev Drug Discov. 2017 Sep;16(9):787-810. doi: 10.1038/nrd.2017.91. [2] Gulezian E, Crivello C, Bednenko J, Zafra C, Zhang Y, Colussi P, Hussain S. Membrane protein production and formulation for drug discovery. Trends Pharmacol Sci. 2021 Aug;42(8):657-674. doi: 10.1016/j.tips.2021.05.006. [3] Hutchings CJ. A review of antibody-based therapeutics targeting G protein-coupled receptors: an update. Expert Opin Biol Ther. 2020 Aug;20(8):925-935. doi: 10.1080/14712598.2020.1745770.[4] High P, Carmon KS. G protein-coupled receptor-targeting antibody-drug conjugates: Current status and future directions. Cancer Lett. 2023 Jun 28;564:216191. doi: 10.1016/j.canlet.2023.216191. 内容来源于网络，如有侵权，请联系删除。

Adiso to Utilize Noninvasive RNA Technology Developed by Geneoscopy as a Precision Immunology Measure in ADS051 Phase 2 IBD Trial ST. LOUIS, Mo. & CONCORD, Mass.--(BUSINESS WIRE)-- Geneoscopy, Inc., a life sciences company focused on developing noninvasive diagnostic and precision medicine tools for gastrointestinal health, and Adiso Therapeutics, Inc., a clinical-stage biotechnology company advancing novel medicines to treat inflammatory diseases, today announced a strategic collaboration to further treatment options available for patients with inflammatory bowel disease (IBD). The agreement allows Geneoscopy’s patented RNA biomarker technology to be used in conjunction with ADS051, a first-in-class, oral, gut-restricted, small molecule modulator of neutrophil trafficking and activation being developed by Adiso for the treatment of IBD. This press release features multimedia. View the full release here: “Utilizing our RNA biomarker platform to assess stool samples from IBD patients and categorize response to treatment with ADS051 is an exciting opportunity,” said Andrew Barnell, CEO of Geneoscopy. “Our technology shows significant promise to enhance IBD clinical trials by identifying patients likely to respond to a particular therapeutic and, through noninvasive methods, determining therapeutic effectiveness through the measurement of RNA expression profiles which signal mucosal healing in the colon.” “The addition of noninvasive stool-based RNA technology from Geneoscopy within our Phase 2 trial of ADS051 is a perfect complement to our neutrophil-targeted, gut-restricted, non-systemic therapy,” said Scott Megaffin, CEO of Adiso. “Employing precision immunology within our trial holds the potential to significantly advance our ability to provide IBD patients with a novel and highly differentiated treatment option that targets their specific needs.” As part of the Adiso ADS051 Phase 2 trial in patients with ulcerative colitis, Geneoscopy will prospectively assess stool-based transcriptome changes in patients treated with ADS051 to identify immunological markers that may predict individual response. Beyond its utility in identifying likely responders to therapy, preliminary research has also indicated that Geneoscopy’s RNA biomarker technology could provide a noninvasive method of determining clinical remission that is more accurate than traditional diagnostics such as fecal calprotectin. In subsequent clinical trials, Adiso will leverage the Geneoscopy biomarker panel to employ a precision immunology approach that uses stool-derived eukaryotic RNA (seRNA) to assess mucosal healing and predict patient response to therapy. This collaboration comes at a critical time for the estimated 3 million Americans living with IBD. Despite an increased focus on improving treatment and patient care, effective tools are lacking to inform therapy selection, and significant opportunities exist to advance and refine methods for disease monitoring. The Adiso ADS051 Phase 2 clinical study will be conducted globally and begin recruiting in 2024. About Geneoscopy, Inc. Geneoscopy Inc. is a life sciences company focused on developing diagnostic tests for gastrointestinal health. Leveraging its proprietary, patented stool-derived eukaryotic RNA (seRNA) biomarker platform, Geneoscopy’s mission is to empower patients and providers to transform gastrointestinal health through innovative diagnostics. Beyond colorectal cancer screening, Geneoscopy is developing diagnostic tests for treatment selection and therapy monitoring in other disease areas in partnership with leading universities and biopharmaceutical companies. For more information, visit and follow the company on LinkedIn. About Adiso Adiso is a clinical-stage biopharmaceutical company dedicated to improving the health of patients suffering from debilitating inflammatory diseases. This dedication is epitomized by our lead clinical candidates, which exemplify 'healthruption' (disruption in healthcare and drug development) with novel mechanisms of action and a distinct approach to the treatment of inflammatory diseases. ADS051, an oral, gut-restricted modulator of neutrophil trafficking and activation via inhibition of MRP2 and FPR1 for the treatment of ulcerative colitis; and ADS032, a dual NLRP1/NLRP3 inflammasome inhibitor initially being developed for inflammatory diseases of the lung. Adiso has built development programs upon a rich history of institutional and academic collaboration, including, the University of Massachusetts Chan Medical School, the Hudson Institute of Medical Sciences Centre for Innate Immunity and Infectious Diseases in Australia, the University of Edinburgh Centre for Inflammation Research and the University College Cork, Ireland, the APC Microbiome Institute. For more information, please visit or our LinkedIn page. About ADS051 ADS051 is a novel first-in-class, oral, gut-restricted, small molecule modulator of neutrophil trafficking and activation via MRP2 and FPR1 receptor inhibition. ADS051 is a locally acting targeted therapy that addresses the underlying pathophysiology of disease while sparing the peripheral role of neutrophil function. Unlike currently available therapies, ADS051 addresses neutrophil-mediated tissue damage, a hallmark of UC. UC is a form of IBD that causes inflammation and ulcers in the colon. Neutrophils are a type of white blood cell that plays a key role in the body's immune response. In UC, neutrophils are recruited to the colon in large numbers, where they release a variety of inflammatory mediators that cause tissue damage. ADS051 gut restriction, safety and tolerability after oral dosing has been demonstrated in a healthy subject Phase 1a clinical study. In a healthy volunteer Single Ascending Dose study and in a moderate to severe UC patient Phase 1b Multiple Ascending Dose study, oral doses of ADS051 were safe and well-tolerated and largely restricted to the gut with limited systemic exposure while demonstrating encouraging signals of pharmacologic activity and clinical benefit.

ADS051 was safe and well-tolerated at all doses with no safety signal observed Clinical remission was achieved in 22% of patients after only 28 days on drug CONCORD, Mass., Oct. 22, 2023 /PRNewswire/ -- Adiso Therapeutics, Inc., a clinical-stage biotechnology company committed to creating medicines that treat inflammatory diseases and improve the lives of patients and their families, today announced positive topline data from its Phase 1b multiple ascending dose (MAD) clinical trial evaluating ADS051 (BT051) in patients with moderate-to-severe ulcerative colitis (UC). The data were presented today at the American College of Gastroenterology (ACG) 2023 Annual Scientific Meeting being held October 20-25, in Vancouver, Canada. ADS051 is a first-in-class, oral, gut-restricted, small molecule modulator of neutrophil trafficking and activation via inhibition of MRP2 and FPR1. Unlike currently available therapies, ADS051 addresses neutrophil-mediated tissue damage, a hallmark of UC pathology. The randomized, double-blind, placebo-controlled, MAD Phase 1b study enrolled 24 moderately-to-severely active UC patients, all of whom completed the trial as planned over the 28-day treatment period (NCT05084261). ADS051 was found to be safe and well-tolerated at three dose levels (200, 800, and 3200 mg) administered orally, once daily for 28 days. PK data demonstrate that ADS051 was restricted to the gut with limited systemic exposure. On Day 28, for pooled ADS051 participants vs. pooled placebo participants, clinical remission was achieved in 22.2% vs. 0%, endoscopic improvement (investigator blinded, centrally-read) in 33.3% vs 0%, and endoscopic response (centrally-read) (UCEIS) was achieved in 50% vs. 17%. "We are very pleased with these positive results indicating that ADS051 clearly attained the objectives of this Phase 1b trial and may be an important therapeutic advancement as a safe and effective, once-daily oral therapy for patients with ulcerative colitis," said Scott Megaffin, Chief Executive Officer of Adiso. "ADS051 efficacy measures reveal encouraging signals of pharmacologic activity and clinical benefit versus placebo, after 28 days of treatment. Given these findings and a recently completed positive end-of-Phase 1 FDA interaction, we plan to advance ADS051 in a Phase 2 clinical study in early 2024." "Despite recent therapeutic advancements in the treatment of UC, there still remains a significant unmet need for safe and efficacious therapeutic options," said Jessica Allegretti, M.D., M.P.H Medical Director, Crohn's and Colitis Center, Brigham & Women's Hospital Boston and Associate Professor of Medicine, Harvard Medical School. "The results of this Phase 1b study demonstrate that not only is ADS051 safe and well-tolerated, it also may offer a potentially efficacious solution for patients with moderate-to-severe UC. I look forward to assessing this therapy further in a Phase 2 clinical study." The MAD clinical trial followed a healthy subject Phase 1a single ascending dose (SAD) study which demonstrated ADS051 was gut-restricted with minimal systemic drug exposure, with no dose-limiting toxicities or serious adverse events. One treatment-emergent adverse event was reported in 16.7% of patients in the pooled ADS051 group vs. 66.7% in the pooled placebo group. Safety and tolerability of the 3200-mg dose group were equivalent to the lower dose cohorts with substantially higher fecal concentrations of ADS051. The poster detailing these findings #P0172: ADS051, an Oral, Gut-Restricted, Small Molecule Neutrophil Modulator in Patients With Moderate-To-Severe Ulcerative Colitis: Results From a Multiple Ascending Dose Study, was presented at the ACG 2023 Annual Scientific Meeting, October 22, 2023, and will be available on the Company's website. About ADS051 ADS051 is a first-in-class, oral, gut-restricted, small molecule modulator of neutrophil trafficking and activation via MRP2 and FPR1 receptor inhibition. Unlike currently available therapies, ADS051 addresses neutrophil-mediated tissue damage, a hallmark of UC. UC is a chronic IBD that causes inflammation and ulcers in the colon. Neutrophils are a type of white blood cell that plays a key role in the body's immune response. In UC, neutrophils are recruited to the colon in large numbers, where they release a variety of inflammatory mediators that cause tissue damage. ADS051 gut restriction, safety and tolerability after oral dosing has been demonstrated in a healthy subject Phase 1a clinical study. About Adiso: Adiso is a clinical-stage biopharmaceutical company dedicated to improving the health of patients suffering from debilitating inflammatory diseases. This dedication is epitomized by our lead clinical candidates, which exemplify 'healthruption' (disruption in healthcare and drug development) with novel mechanisms of action and a distinct approach to the treatment of inflammatory diseases. ADS051, an oral, gut-restricted modulator of neutrophil trafficking and activation via inhibition of MRP2 and FPR1 for the treatment of ulcerative colitis; and ADS032, a dual NLRP1/NLRP3 inflammasome inhibitor initially being developed for inflammatory diseases of the lung. Adiso has built these development programs upon a rich history of institutional and academic collaboration, including, the University of Massachusetts Chan Medical School, the Hudson Institute of Medical Sciences Centre for Innate Immunity and Infectious Diseases in Australia, the University of Edinburgh Centre for Inflammation Research and the University College Cork, Ireland, the APC Microbiome Institute. For more information, please visit or our LinkedIn page. Contacts Argot Partners Media: Sarah Sutton/Liza Sullivan IR: Jason Finkelstein [email protected] 212.600.1902 SOURCE Adiso Therapeutics