Enabling translational studies and clinical entry plan in gastro-intestinal inflammatory diseases and cancers for human GPR35 antagonist lead molecules.

ThirtyFiveBio已经对GPR35信号如何促进胃肠道炎性化生和癌症生物学产生了世界领先的理解。近年来，免疫治疗药物，如检查点抑制剂，已经显著提高了一些癌症患者的生存能力。然而，大多数患者对这些新疗法仍然没有足够的反应。这是因为肿瘤能够设置多种屏障来防止免疫系统的攻击，而目前批准的治疗方法并没有解决其中的许多障碍。其次，尽管有一系列治疗胃肠道炎症性疾病的选择，但10%-30%的患者对最初的治疗没有反应，23%-46%的患者随着时间的推移失去反应。迫切需要一个紧急的游戏规则改变者。癌症是一个重大的医疗挑战：它是全球主要的死亡原因之一，2020年有1000万人死亡，2021年每年新诊断病例1700万例，年总经济成本约9300亿GB。仅在英国，每年就有35万新的癌症病例。在英国，癌症造成的总经济负担是惊人的76亿英镑。炎症性疾病可导致几种疾病，这些疾病共同代表着全球残疾和死亡的主要原因，如心血管疾病、癌症、糖尿病、慢性肾脏疾病、非酒精性脂肪性肝病以及自身免疫性和神经退行性疾病。炎症性肠病是最常见的自身免疫性疾病之一。在英国，约有30万人受到IBD的影响，NHS每年花费10亿GB(约3352 GB/年每名患者)。在这个项目中，ThirtyFiveBio将开发强大的人类-GPR35活性拮抗剂，其特性与表达人类靶标的啮齿动物模型的剂量相称。随后验证/指导ThirtyFiveBio公司先进的小分子人类GPR35拮抗剂的部署，用于通过临床前研究确定的疾病的临床应用。这将指导和加快人-GPR35拮抗剂对患者的研究进展。

ThirtyFiveBio has developed a world-leading understanding of how GPR35-signalling promotes gastrointestinal inflammatory metaplasia and cancer disease biology.In recent years, immunotherapy agents, such as checkpoint inhibitors, have led to dramatic survival benefits in some cancer patients. However, the majority of patients still do not respond adequately to these new treatments. This is because tumours are able to put up multiple barriers to prevent immune system attack and many of these are not addressed by currently approved therapies. Secondly, despite an array of options for inflammatory disorders of the gastrointestinal tract, 10%-30% of patients don't respond to initial treatments and 23%-46% lose response over-time. There's a significant need for an emergent game-changer.Cancer represents a significant healthcare challenge: it's one of the leading causes of death worldwide with 10m deaths in 2020, 17m new cases diagnosed per annum and a total annual economic cost of ~£930bn in 2021\. In the UK alone there are \>350,000 new cases of cancer a year. The total economic burden of cancer in the UK is a staggering ~£7.6bn.Inflammatory disorders can lead to several diseases that collectively represent the leading causes of disability and mortality worldwide, such as cardiovascular disease, cancer, diabetes mellitus, chronic kidney disease, non-alcoholic fatty liver disease and autoimmune and neurodegenerative disorders. Inflammatory bowel disease (IBD) is one of the most common autoimmune diseases. In the UK, ~300,000 people are affected by IBD, costing the NHS ~£1bn/year (~£3,352/year cost/patient).In this project, ThirtyFiveBio will develop potent human-GPR35-active antagonists with properties commensurate with dosing to rodent models of disease expressing the human target. Subsequently validating/guiding deployment of ThirtyFiveBio's advanced small-molecule human-GPR35-antagonists towards clinical applications in diseases identified through preclinical studies. This will guide and accelerate progress of human-GPR35 antagonists to patients.