IL-31RA

靶向蛋白降解（TPD）是一种新兴的治疗疾病的药物模式，可通过重定向细胞中的蛋白质循环系统来破坏致病蛋白质。蛋白降解靶向嵌合体（PROTAC）和分子胶（molecular glues）是两类重要的靶向蛋白降解剂：PROTAC是一种双功能化合物，由两个独立的部分组成，可分别结合靶标和E3连接酶。PROTAC分子能将泛素连接酶招募到目标蛋白附近，给目标蛋白打上泛素标签，使其被蛋白酶体降解；分子胶可以将两个原本没有相互作用的蛋白拉到一起，使得两个蛋白质在结合后降解、稳定或激活，进而改变其蛋白质-蛋白质相互作用（PPI）。2月21日，英国邓迪大学生命科学学院靶向蛋白降解研究中心与奥地利科学院CeMM分子医学研究中心合作在Nature发表最新成果，揭示了一类全新的靶向蛋白降解（TPD）分子——分子内二价胶（intramolecular bivalent glues，IBG），这类分子的降解模式结合了PROTAC和分子胶的特性，能够实现低皮摩尔效力的降解，有望开启新一代的TPD治疗模式。来源：Nature总体来说，研究人员通过正交遗传筛选、生物物理表征和结构重构，研究了BRD2和BRD4的双功能降解物（即IBGs）的作用机制，发现它们不像PROTAC那样在反式（trans）中连接靶标和连接酶，而是在顺式（cis）中同时连接靶标蛋白的两个相邻区域。所造成的结构改变使得靶标蛋白BRD4被E3连接酶DCAF11或DCAF16所识别，从而标记该蛋白质以供降解。通过对BRD4-IBG1-DCAF16三元复合物的结构解析，研究人员得以改良并设计出具低皮摩尔效力的降解剂。具体来说，目前indisulam、E7820等分子胶都含有芳基磺胺，它们可招募cullin RING E3泛素连接酶（CRL）底物受体DCAF15，来定向降解RNA结合蛋白RBM39。最近的一项专利描述了一种类似PROTAC的降解剂（称为IBG1，如图1所示)，它是由E7820和JQ1（一种BET溴结构域抑制剂）连接、优化而来的，既可以招募DCAF15，又能结合溴结构域（BRD），是一种双功能分子。理论上，IBG1可以通过招募DCAF15来降解BRD。但研究人员发现，IBG1可以在不依赖于DCAF15的情况下完成对BRD2和BRD4的降解。图1. IBG1可降解BRD2和BRD4且不依赖于DCAF15所以为了确定IBG1活性所需的因素，研究人员通过正交试验，发现了IBG1诱导的BRD2和BRD4降解是依赖于CRL4–DCAF16的。图2. IBG1诱导的BRD2和BRD4降解依赖于CRL4–DCAF16接下来，研究人员在体外表征了DCAF16、BRD4和IBG1之间可能的相互作用，结果显示，IBG1增强了DCAF16对BRD4的亲和力。图3. IBG1增强了BRD4 和 DCAF16 的串联溴结构域区域之间的内在相互作用为了深入了解IBG1诱导BRD4降解的分子机制，研究人员通过低温电镜，解析了BRD4Tandem、IBG1、DCAF16–DDB1(ΔBPB)–DDA1之间形成的三元配合物的结构。结果发现，IBG1能同时结合两个BRD4溴结构域，并将BRD4结合到DCAF16上。图4. IBG1双价结合两个BRD4溴结构域至此，研究人员做出假设，具有两个高亲和力溴域配体的双功能化合物，应该更有效地稳定降解能力强的溴域构象，从而有可能产生更有效的、基于DCAF16的降解剂。于是研究人员合成了一批化合物。通过合理改进第一代的IBG1，他们得到了第二代IBG3。IBG3在个位皮摩尔浓度下的降解活性，表明这种新型降解剂可以达到比迄今为止报道的任何PROTAC更高的效率。如图5所示，IBG4是最近报道的一种BRD4降解剂，由吡唑并嘧啶部分组成，通过短刚性接头连接到JQ1。IBG4与IBG1在结构上存在差异，但两种化合物都具有相同的分子内胶机制。此外，研究人员通过实验发现，IBG1是通过CRL4-DCAF16发挥作用的，而IBG4是通过CRL4-DCAF11发挥作用的。图5. IBG4是一种DCAF11依赖性的分子内二价胶降解剂总之，研究人员发现，结构不同的BET降解剂趋同于一种共同的新作用机制：两个结构域的分子内二聚化，以修饰蛋白质表面，并调节PPI。大约60-80%的人类蛋白质具有至少两个不同的结构域，因此有可能通过分子内二价胶接进行靶向降解。这一新发现引入了一种新的靶向蛋白质降解模式，该模式通过桥接顺式蛋白质结构域来增强与E3连接酶的表面互补性，从而实现高效的泛素化和降解。论文通讯作者Georg Winter博士表示：“这种方法为开发可用于对抗癌症等疾病的药物开辟了全新的可能性，有可能治疗许多以前无法治疗的疾病。”参考资料：Oliver Hsia et al. Targeted protein degradation via intramolecular bivalent glues. Nature（2024）医药魔方Pro新靶点 新技术 新疗法商务合作：13502093012媒体合作：15895423126Copyright © 2024 PHARMCUBE. All Rights Reserved.欢迎转发分享及合理引用，引用时请在显要位置标明文章来源；如需转载，请给微信公众号后台留言或发送消息，并注明公众号名称及ID。免责申明：本微信文章中的信息仅供一般参考之用，不可直接作为决策内容，医药魔方不对任何主体因使用本文内容而导致的任何损失承担责任。

2022年，美国、欧盟和日本获批新药数量48种，其中12种药物具有新型MOA，包括五款小分子、五款抗体、一款双特异性融合蛋白和一款多肽。小分子中，一些停滞不前的领域出现了新的靶点，如治疗心肌病的MYH7和治疗慢性咳嗽的P2RX3。而吉利德的HIV药物Lenacapavir是12款药物中唯一一款靶向非人类蛋白的药物，其靶点是HIV-1的衣壳蛋白。以下详细说下几款生物药：01Sutimlimab（Enjaymo®）Sutimlimab是赛诺菲子公司Bioverativ开发的补体C1s lgG4人源化单抗，2022年2月获批，用于减少患有冷凝集素病（CAD）的成年人因溶血而导致的红细胞输注需求，是首个也是唯一一个被批准用于CAD患者的疗法。补体系统有3种不同的激活途径：经典途径、凝集素途径和替代途径。Sutimlimab通过选择性靶向C1s来抑制经典途径，防止补体免疫球蛋白沉积在红细胞表面，从而防止溶血，而补体介导的溶血是CAD患者红细胞溶解的根本原因。获批是基于关键性3期临床CARDINAL试验结果，研究针对有近期输血史的 CAD 患者（n=24）。大多数患者（54%）达到了综合主要终点标准，其中63%的患者实现了血红蛋白≥12g/dL或至少增加2g/dL；71%的患者在第5周后仍然没有输血；92%（n=22）的患者没有使用其他CAD相关治疗。Enjaymo的美国上市价格为每瓶1800美元。02Spesolimab（SPEVIGO®）Spesolimab是勃林格殷格翰开发的IL-36R单抗药物，2022年9月2日获FDA批准上市，用于泛发性脓疱型银屑病（GPP）的治疗，这是首个获FDA批准的成人GPP疗法。这是一种新型的人源化选择性抗体，可阻断IL-36R的激活，该受体是免疫系统内信号通路的一个关键部分，参与GPP等自身免疫性疾病的发病过程。此前，勃林格殷格翰在今年的AAD年会上公布了最新关键性II期EffisayilTM 1临床数据，该研究为期12周（n=52）。结果显示，在使用spesolimab与安慰剂治疗后的第一周内，对比安慰剂组（6%），spesolimab组54%患者脓疱亚评分为0。spesolimab组43%患者的GPPGA总分是0或1，安慰剂组11%。治疗效果持续了12周，84.4%的患者在12周的试验期后没有明显的脓包，81.3%的患者皮肤清晰/基本清晰。公开资料显示，目前全球仅5款IL-36R单抗在研，两款国内的处于临床I期。03SNemolizumab（Mitchga®）Nemolizumab是由中外开发的IL-31RA单抗，2022年3月在日本获批上市，是全球首个上市的IL-31靶向药，这代表着IL-31正式入局AD领域，并且从目前的在研情况来看，Nemolizumab之后的几年都将是AD领域唯一一款IL-31靶向药。该药主要用于特应性皮炎相关瘙痒，可竞争性地与IL-31RA结合，从而抑制IL-31与受体的结合以及随后进入细胞的信号传导，抑制瘙痒。此前III期的数据表明，Nemolizumab治疗16周后，视觉模拟量表（VAS）评分相对基线的变化率，对比安慰剂下降的21.4%，试验组显著下降42.8%。04Faricimab(Vabysmo®)Faricimab是罗氏开发的VEGF-A/ANG-2双抗，于2022年1月获FDA批准上市，用于治疗新生血管性或“湿性”年龄相关性黄斑变性（nAMD）和糖尿病黄斑水肿（DME）。它是首个专为眼睛设计的lgG1双抗，用罗氏的CrossMAb技术开发，抗体的Fc端采用了Knob-in-Hole的设计，并进行Fc突变，以减少与FcγR和FcRn受体的结合。Ang-2和VEGF-A通过使血管不稳定，导致形成新的渗漏血管并增加炎症进而导致视力丧失，通过同时阻断Ang-2和VEGF-A这两个通路，Faricimab可稳定血管，阻止nAMD等眼部疾病的发展。给药方式采用玻璃体注射，其优势在于，像Eylea、雷珠单抗等药物基本都是1个月给药一次直至病情稳定后再2-3个月给药，而Faricimab可以做到4个月给药一次且保证疗效。05Relatlimab/Nivolumab(Opdualag®)2022年3月，美国FDA批准BMS的抗LAG-3抗体药物relatlimab与抗PD-1抗体Opdivo联用疗法上市，治疗不可切除或转移性黑色素瘤患者。这是近10年来，美国FDA批准的首个靶向新免疫检查点蛋白的免疫疗法。相比于其他免疫检查点联合治疗，PD-1和LAG-3在活化T细胞上的共表达，有助于其信号及化学物质向免疫突触的快速运输，从而表现出对T细胞信号转导更强的协同抑制作用。PD-1和LAG-3的联合使用还可以避免如PD-1的单个检查点封锁会导致的LAG-3和CTLA-4以及其他检查点途径的补偿性诱导，从而避免形成反馈环所导致的单一用药的疗效减退。批准是基于2/3期RELATIVITY-047的研究结果，比较了Opdualag (n=355) 与纳武利尤单抗单药(n=359) 的疗效和安全性。相比单药治疗，Opdualag中位PFS延长了一倍以上，分别为10.1个月（95%  [CI]: 6.4-15.7）和4.6个月（95% CI: 3.4-5.6）；（[HR] 0.75; 95% CI: 0.62-0.92,P=0.0055）。06Tebentafusp（KIMMTRAK®）Tebentafusp是Immunocore开发的TCR-scFv融合蛋白，TCR部分靶向gp100，scFv部分靶向CD3以募集T细胞，scFv融合到TCR的β链上。 用于治疗HLA-A*02：01阳性的不可切除或转移性葡萄膜黑色素瘤（mUM）成年患者，是全球首个获批的TCR疗法。此前公布的III期临床数据显示，Kimmtrak作为一线治疗，患者死亡风险降低49%（HR=0.51，95% CI：0.37, 0.71，p<0.0001）。Kimmtrak组的中位总生存期为21.7个月，活性对照组为16.0个月。安全性上，治疗相关不良事件具有可控性。Kimmtrak于去年1月获批，2022年首年销额达1.41亿美元，今年Q1销额0.52亿美元。截止目前，Immunocore的股价相较去年产品上市前已上涨超200%。细胞系产品查询投稿丨商务合作加入交流群往期推荐双抗ADC全球在研格局2023年美国最昂贵药物TOP102023，Biotech的下半场——现金为王，产品为金点击下方“药研网”，关注更多精彩内容

ZUG, Switzerland--( BUSINESS WIRE )--Galderma, the leading company solely dedicated to advancing the future of dermatology, today premiered the positive phase III results from the OLYMPIA 2 trial evaluating the efficacy, safety, pharmacokinetics and immunogenicity of nemolizumab compared with placebo in adult patients with prurigo nodularis. The results were presented as a late-breaking presentation at the 2023 American Academy of Dermatology (AAD) Annual Meeting by Dr. Shawn Kwatra, Associate Professor of Dermatology at the Johns Hopkins University School of Medicine. Galderma has an extensive presence at the meeting with further updates from its broad portfolio across Therapeutic Dermatology, Dermatological Skincare and Injectable Aesthetics. The phase III OLYMPIA 2 trial met all primary endpoints, showing nemolizumab monotherapy significantly improved pruritus (itch) and skin lesions compared with placebo in adult patients with moderate to severe prurigo nodularis. Results showed that: 56 percent of nemolizumab-treated patients achieved a response in itch intensity, as defined by an at least 4-point improvement in peak-pruritus numerical rating scale (PP-NRS) score, compared to 21 percent in the placebo group (p<0.0001) 38 percent of nemolizumab-treated patients reached treatment success in skin lesions, as defined by an investigator’s global assessment (IGA) score of 0 or 1, compared to 11 percent in the placebo group (p<0.0001) Key secondary endpoints showed rapid onset of action and significant improvements in itch and sleep disturbance (p<0.0001) as early as week 4: Over five times as many patients in the nemolizumab group vs placebo achieved significant and clinically meaningful improvement in itch intensity, as defined by a 4-point improvement in PP-NRS - (41.0% for nemolizumab vs 7.7% for placebo p<0.0001) Nearly four times as many patients in the nemolizumab group versus placebo achieved significant and clinically meaningful improvement in sleep disturbance as measured by a 4-point improvement in sleep disturbance numerical rating scale (SD-NRS) - (37.2% for nemolizumab vs 9.9% for placebo p<0.0001) The safety profile was consistent with the phase II trial results “ OLYMPIA 2 is a key piece of the largest phase III clinical development program ever undertaken in prurigo nodularis to date. On behalf of my co-investigators worldwide, I am honored and proud to present the study results to the scientific community in a late-breaking presentation. The results confirm the potential of this every four weeks injectable monoclonal antibody targeting the IL-31 receptor alpha, with rapidly acting effects on itch and sleep disturbance, and subsequent improvement of skin lesions.” SHAWN KWATRA, M.D. ASSOCIATE PROFESSOR OF DERMATOLOGY JOHN HOPKINS UNIVERSITY Further commitment to diversity in dermatology announced Also at the congress, Galderma shared an exciting update on the sponsorship of the Atlas initiative, in a highly anticipated booth session focused on Diversity and Inclusion in Dermatology. The unique educational session explored how to diagnose dermatologic conditions in an array of skin tones, leveraging the renowned book and online gallery ‘ Full Spectrum of Dermatology: A Diverse and Inclusive Atlas’ , from the George Washington University School of Medicine. The event took place on Friday, March 17 and was hosted by editors of the Atlas, Dr. Adam Friedman and Dr. Misty Eleryan. As part of the Galderma sponsorship, copies of the Atlas book are being distributed throughout the AAD congress . Galderma is also proud to be providing an additional financial grant to pilot a pathway for other healthcare professionals to contribute to the online gallery. “ We are so pleased that we’re able to bring so much powerful new data to this year’s AAD congress. The data premiere from OLYMPIA 2 confirms the potential that nemolizumab is expected to improve outcomes for people with prurigo nodularis, which can have such a profound impact on the lives of those affected. Beyond this, our continued involvement and investment in the Atlas program demonstrates our commitment to address every skin need, with diversity and inclusion at the very heart of that promise.” BALDO SCASSELLATI SFORZOLINI, M.D., Ph.D. GLOBAL HEAD OF R&D GALDERMA Extensive updates from Galderma’s broad and innovative portfolio through posters and presentation sessions Galderma is the only pure-play dermatology category leader, with more than 40 years of heritage in dermatology. Its continued commitment to delivering science and innovation across a highly differentiated portfolio is reflected in its extensive presence at AAD. More details on Galderma’s scientific poster presentations can be found here . About the OLYMPIA 2 trial OLYMPIA 2 was a randomized, double-blind, placebo-controlled phase III clinical trial, to assess the efficacy and safety of nemolizumab monotherapy compared with placebo in patients at least 18 years of age with prurigo nodularis after a 16-week treatment period. The trial also assessed pharmacokinetics and immunogenicity of nemolizumab compared to placebo. OLYMPIA 2 included 274 patients with moderate-to-severe prurigo nodularis. About prurigo nodularis Prurigo nodularis is a debilitating, chronic skin condition with thick skin nodules covering large body areas and associated intense itch. 1,2,3 Prurigo nodularis affects an estimated 72 per 100,000 adults aged 18-64 years in the United States, primarily middle-aged women and disproportionately people of African descent. 1,4 About nemolizumab Nemolizumab is an investigational drug and Galderma has not received approval for any indication in any country. Nemolizumab is a first-in-class investigational monoclonal antibody directed against the IL-31 receptor alpha that blocks signaling from IL-31. IL-31 is a neuroimmune cytokine that is recognized as driving multiple disease mechanisms in both prurigo nodularis and atopic dermatitis. With its unique role in directly stimulating sensory neurons related to itch and contributing to inflammation and barrier dysfunction, IL-31 is the bridge between the immune and nervous systems while also directly acting on structural cells in the skin. Nemolizumab was granted Breakthrough Therapy designation by the U.S. Food and Drug Administration (FDA) in December 2019 for the treatment of pruritus associated with prurigo nodularis, a status reconfirmed in February 2023. About Galderma Galderma is the pure-play dermatology category leader, present in approximately 90 countries. We deliver an innovative, science-based portfolio of premium flagship brands and services that span the full spectrum of the fast-growing dermatology market through Injectable Aesthetics, Dermatological Skincare and Therapeutic Dermatology. Since our foundation in 1981, we have dedicated our focus and passion to the human body’s largest organ – the skin – meeting individual consumer and patient needs with superior outcomes in partnership with healthcare professionals. Because we understand that the skin we’re in shapes our lives, we are advancing dermatology for every skin story. Galderma’s portfolio of flagship brands includes Restylane ® , Dysport ® , Azzalure ® , Alluzience ® and Sculptra ® in Injectable Aesthetics; Soolantra ® , Epiduo ® , Differin ® , Aklief ® , Epsolay ® , Twyneo ® , Oracea ® , Metvix ® , Benzac ® and Loceryl ® in Therapeutic Dermatology; and Cetaphil ® and Alastin ® in Dermo-cosmetics. For more information, visit www.galderma.com. References: 1 Williams KA, Roh YS, Brown I, et al. Pathophysiology, diagnosis, and pharmacological treatment of prurigo nodularis. Expert Rev Clin Pharmacol. 2021;14(1):67-77. doi:10.1080/17512433.2021.1852080 2 Elmariah S, Kim B, Berger T, et al. Practical approaches for diagnosis and management of prurigo nodularis: United States expert panel consensus. J Am Acad Dermatol. 2021;84(3):747-760. doi:10.1016/j.jaad.2020.07.025 3 Whang KA, Mahadevan V, Bakhshi PR, et al. Prevalence of prurigo nodularis in the United States. J Allergy Clin Immunol Pract. 2020;8(9):3240-3241. doi:10.1016/j.jaip.2020.05.051 4 Huang AH, Canner JK, Khanna R, Kang S, Kwatra SG. Real-world prevalence of prurigo nodularis and burden of associated diseases. J Invest Dermatol. 2020;140(2):480-483.e4. doi:10.1016/j.jid.2019.07.697