CLBS-03

Regeneron Pharmaceuticals already has a presence in immunology, but nothing in its portfolio or pipeline addresses inflammatory bowel disorders nor does the drugmaker have any cell therapies. The company is checking off both boxes by striking up an alliance with Sonoma Biotherapeutics, a startup working in a hot area of immunology and inflammation drug research. Sonoma develops therapies based on regulatory T cells, or Tregs. These cells suppress immune responses, and the biotech is developing therapies that leverage that capability as a way of treating autoimmune diseases. According to deal terms announced Tuesday, Regeneron is paying South San Francisco-based Sonoma $75 million up front, which includes a $30 million equity investment in the startup. The first two disease targets for the new partners are ulcerative colitis and Crohn’s disease. Tregs are like the police officers of the immune system, says Sonoma co-founder and CEO Jeff Bluestone. In autoimmune diseases, effector T cells mistakenly attack healthy tissue. Tregs shut down these rogue responses and restore the immune system to a healthy balance. Sonoma’s therapies are autologous, meaning they come from the patient. After those cells are harvested, they’re engineered in a lab to go after the right target. The engineered cells are multiplied, then infused back into the patient. Autologous cell therapies have already been validated in cancer. CAR T-therapies are made by harvesting and engineering a patient’s T cells. Regeneron has capabilities that can contribute to the development of Treg cell therapies. The company’s VelociSuite platform uses mice to discover and develop human antibodies and T cell receptors that address disease targets of interest. The tech platform was used to develop antibodies for its cancer immunotherapy research. Bluestone said the Regeneron technology can be used to rapidly identify receptors and antibodies, enabling the partners to then engineer the receptors that guide the engineered Treg to its target and activate it gets there. “In our business, the most important thing is the target,” Bluestone said. “It’s got to be right target. It’s got to very specific to the disease.” The field of Treg research is building momentum. Sangamo Therapeutics has reached Phase 1 testing with a Treg for kidney transplants. Organ transplant patients must receive anti-rejection therapies that circulate systemically. Sangamo’s Treg is engineered with a chimeric antigen receptor that targets an antigen specific to the kidneys, Sangamo Chief Scientific Officer Jason Fontenot told MedCity News in an interview during the J.P. Morgan Health Care Conference in January. “The innovation here and why we’re so excited is you can target the immune response only to a specific tissue,” he said. The potential of Tregs has sparked research and investment interest. London-based Quell Therapeutics raised $156 million in 2021 to continue development of a Treg therapy for liver transplant patients. The lead indication for Third Rock Ventures-backed Abata Therapeutics is multiple sclerosis. Sonoma’s internal research has produced three programs so far, the most advanced of which is combination drug. While the Treg component of this drug dampens inflammation, the fusion protein part of the therapy depletes and inactivates the effector T cells that are driving the autoimmune response. A Phase 1 test began late last year. A Sonoma Treg therapy for rheumatoid arthritis is approaching the clinic. Bluestone said the startup’s progress sparked partnership discussions in the past year, some of them with big players looking to enter the Treg space. Along the way, Bluestone said he had conversations with George Yancopoulos, the co-founder, president, and chief scientific officer of Regeneron. The two concluded that their respective companies could bring a synergistic approach to immune regulation. Bluestone said IBD makes sense for a drug research partnership. The applicability of Tregs in these disorders has been validated in preclinical studies, but the large size of the disease area makes it one Sonoma would likely be unable to pursue without a larger partner, Bluestone said. The agreement calls for both companies to share equally in the R&D costs of the Treg therapies. In addition to ulcerative colitis and Crohn’s disease, the deal covers two additional indications that remain undisclosed. Regeneron also has an option to pursue a fifth indications. Sonoma retains the rights to its internally developed programs. If the partnership yields any approved products, both companies will share equally in profits from sales. Regeneron has the option to lead late-stage development and commercialization of all potential products stemming from the pact, but Sonoma keeps rights to co-promote these products in the U.S. As the research progresses, Sonoma is eligible to receive a $45 million milestone payment. Bluestone said the Regeneron deal was not simply about money. The company closed a $265 million Series B financing in 2021, some of which was used to establish and R&D and manufacturing facility in Seattle. Sonoma still has enough money to last “a couple of years,” Bluestone said. The Regeneron partnership is not an exclusive one, but Sonoma is not looking for more partners. If the company does strike additional deals, they will likely be technology partnerships that bring automation or other advances that improve cell therapy manufacturing, Bluestone said. Photo by Sonoma Biotherapeutics

关注并星标CPHI制药在线       8月10日，GentiBio公告宣布与百时美施贵宝（BMS）达成合作，将共同开发新的工程化调节性T细胞（Treg）疗法，以重建炎症性肠病患者的免疫耐受并修复组织。此次合作将利用GentiBio特有的工程化Treg平台与BMS在细胞疗法和免疫学领域的经验，以开发可扩大规模、稳定、高选择性和持久的Tregs疗法。       这是继默克、礼来、强生和辉瑞后，又一大型公司押注Treg细胞疗法赛道。什么是Treg细胞疗法？它有哪些应用领域？为何深受资本青睐？       什么是Treg细胞疗法？       Treg 细胞是一种天然存在的T细胞亚群，能够负向调节机体免疫反应，通过诱导和维持对自身抗原的耐受性来维持体内免疫平衡。正常情况下，Treg细胞能抑制过度的免疫反应，从而预防自身免疫性疾病；而癌症发生时，Treg细胞经TCR介导的信号刺激活化后可分泌多种抑制性细胞因子，进而限制免疫系统对抗癌症的能力，让肿瘤细胞逃避免疫监视。在过去20年内，研究已经证实了Treg细胞在感染、肿瘤、器官移植、同种异体胎儿免疫相关疾病方面具有抑制各种途径的病理生理免疫应答的作用。       调节性T细胞可分为两类：天然Treg(n Treg)和获得性Treg(a Treg)，目前认为天然Treg来源于胸腺，主要通过细胞接触机制发挥抑制功能；获得性Treg是外周成熟T细胞在持续性抗原刺激及IL-10 、TGF-β等细胞因子条件下诱导产生，主要通过IL-10、TGF-b等可溶性细胞因子发挥作用。       Treg疗法的应用前景       1.自身免疫性疾病       Treg通过主动调节的方式，抑制存在于正常机体内潜在的自身反应性T细胞的活化与增殖，发挥免疫抑制和免疫稳态方面的特性，在自身免疫性疾病患者中发挥了重要作用。       当自身的免疫耐受出现问题（也称免疫耐受缺陷），免疫系统将会攻击自身组织，就会产生自身免疫性疾病。由于免疫反应和免疫耐受之间的平衡机制复杂，治疗这些疾病患者的进展缓慢。虽然小分子和生物治疗可以缓解症状，但它们往往是非特异性的，需长期服药。例如，严重系统性红斑狼疮的主要治疗方法是类固醇，它不能特异性地抑制炎症，具有公认的毒副作用。而 Treg细胞疗法，比传统的免疫抑制药物(如类固醇和环孢素)、生物制剂(如利妥昔单抗和贝利单抗)等有更大的特异性和更复杂的治疗效益，并可能通过恢复免疫耐受来治愈疾病。       2. 器官移植       器官移植是终末期器官衰竭患者的治疗选择。使用广谱免疫抑制药物会加速死亡，对移植有毒 性，不能预防慢性排斥反应。因此，建立对移植组织的临床耐受性以减少或消除免疫抑制是一个关键的研究目标。Treg细胞可以限制对外来抗原如同种异体抗原的免疫应答，刺激人体内的Treg细胞的恢复及再生，可使患者对于移植物的排异反应明显减少。输注Tregs可诱导移植耐受，从而避免长期使用毒 性免疫抑制剂导致发病率/死亡率增加。       3.Treg细胞与肿瘤治疗       肿瘤微环境在肿瘤的发生发展中起着非常重要的作用，免疫细胞可通过影响肿瘤微环境而影响肿瘤的进展。一方面，大部分免疫细胞可发挥抗肿瘤免疫作用。如辅助性T细胞和细胞毒 性T细胞。另一方面，Treg在肿瘤微环境中却扮演着相反的角色。Treg的免疫抑制作用既能防御人体发生自身免疫性疾病，又能促使肿瘤细胞发生免疫逃逸，间接加快了肿瘤细胞的增殖，增强了肿瘤细胞的浸润能力。研究表明，Treg细胞的数量与肿瘤的预后呈负相关。因此减少体内Treg细胞的数量，对肿瘤治疗至关重要。目前，此类药物也在研发中。       Treg疗法赛道升温       Treg疗法是一个备受关注的热门领域。德国默克（Merck KGaA）、武田（Takeda）、安进（Amgen）、礼来（Eli Lilly and Company）、Sangamo和其他一系列新兴生物技术公司已在这一领域布局。       2021年2月，默克公司以18.5亿美元收购了Pandion Pharmaceuticals及其针对Tregs治疗自身免疫性疾病的药物管线，此前其Treg疗法在溃疡性结肠炎的早期试验中显示出前景。2021年6月，ThirdRock以9500万美元推出了Abata Therapeutics。Abata希望利用Tregs治疗多发性硬化症。2021年8月4日，Sonoma Biotherapeutics宣布完成2.65亿美元B轮融资，用于推动其Treg治疗平台和新型效应T细胞（Teff）调节生物制剂进入临床，以治疗多种严重自身免疫和炎症性疾病；2021年8月11日，GentiBio宣布完成1.57亿美元A轮融资，用于推进1 型糖尿病功能性治疗和自身炎症项目等管线进入临床。2021年10月，Egle Therapeutics公司宣布完成4000万欧元（约4640万美元）的A轮融资，以开发靶向Treg的潜在first-in-class免疫疗法，用于治疗癌症和自身免疫性疾病。       综上可以感受到，Treg细胞疗法正逐步升温。有专家表示，现在的Treg已然是十年前的CAR-T，Treg细胞疗法的拐点要到了。在动物模型中，Treg已经被用于治疗红斑狼疮，免疫肾病，炎症性肠炎，风湿性关节炎等十数种自体免疫疾病和炎症，同时Treg在器官移植和移植物抗宿主病中也有显著效果。欧美正在开展的相关临床试验目前不低于三十个。不过关于Tregs的调控仍有许多问题需要探究，其潜在的靶点总体上仍不清楚。在肿瘤相关Tregs的调控方面，Tregs与TME中其他细胞类型的相互作用以及TME代谢异常对Tregs的影响有待进一步研究。因此，有必要进行进一步的基础研究，广泛了解Treg细胞的发育、维持和功能。       参考来源：       1. Femke Broere, Sergei G. Apasov, Michail V.T cell subsets and T cell-mediated immunity[J].Principles of Immunopharmacology.Dig. Dis. Sci. 2018 12;6312(12).       2. Collison LW, Workman CJ, Kuo TT, Boyd K.The inhibitory cytokine IL-35 contributes to regulatory T-cell function[J].Nature 2007 Nov 22;4507169(7169).       3. Mauro Di Pilato,et al.Targeting the CBM complex causes Tregcells to prime tumours for immune checkpoint therapy.Nature (2019) .       智药研习社8月培训会报名来源：CPHI制药在线声明：本文仅代表作者观点，并不代表制药在线立场。本网站内容仅出于传递更多信息之目的。如需转载，请务必注明文章来源和作者。投稿邮箱：Kelly.Xiao@imsinoexpo.com▼更多制药资讯，请关注CPHI制药在线▼点击阅读原文，进入智药研习社~