Therapeutic Antibodies for Treating Inflammatory Bowel Disease

用于治疗炎症性肠病的治疗性抗体

基本信息

批准号：
10255435
负责人：
Lauren J Schwimmer
金额：
$ 30.02万
依托单位：
ABALONE BIO, INC.
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-05-01 至 2023-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10255435
关键词：
Abdomen Abscess Address Adverse effects Affect Agonist Alleles Anemia Animal Model Anti-Inflammatory Agents Antibodies Antibody Affinity Antibody Formation Antiinflammatory Effect Biological Biological Assay Biophysics Blood Blood - brain barrier anatomy Blood coagulation Body Weight decreased CNR1 gene CNR2 gene Cannabinoids Cardiovascular system Cells Cellular Assay Chemicals Chronic Chronic Disease Clinical Clinical Trials Cognitive Colon Crohn&apos s disease Dehydration Development Diarrhea Disease Disease model Engineering Etiology Exclusion Eye Fatigue Feces Fever Fissure in Ano Fistula G-Protein-Coupled Receptors GTP-Binding Protein alpha Subunits, Gs Health Hemorrhage Histologic Human Immune Immunomodulators Inflammation Inflammatory Inflammatory Bowel Diseases Interleukin-10 Intestinal Fibrosis Intestinal Obstruction Intestines Knockout Mice Letters Life Link Liver Liver Fibrosis Malnutrition Marketing Mediating Modeling Mucous body substance Mus Operative Surgical Procedures Pain Patients Peripheral Pharmaceutical Preparations Phase Plasma Proteins Risk Safety Salvelinus Skin Small Business Innovation Research Grant Sodium Dextran Sulfate Specificity Stomach Symptoms T-Lymphocyte Testing Therapeutic Therapeutic antibodies Time Toxic Megacolon Toxic effect Ulcer Ulcerative Colitis Variant Vermont Work abalone base blood-brain barrier penetration body system chronic pain colon cancer risk cross reactivity cytokine drug candidate experience experimental study immunoregulation in vivo in vivo Model indexing inflammatory disease of the intestine innovation joint inflammation liver inflammation liver injury loss of function macrophage mouse model nanobodies natural antibodies pre-clinical primary sclerosing cholangitis side effect small molecule therapeutic candidate treatment strategy

项目摘要

SUMMARY Abalone Bio will develop antibody (Ab) drugs that inhibit intestinal inflammation to treat inflammatory bowel disease (IBD). IBD comprises chronic, debilitating, idiopathic inflammatory diseases that result in severe dam- age to the gut wall, including Crohn's disease (CD) and ulcerative colitis (UC). The primary etiology is chronic inflammation, which causes pain, diarrhea, weight loss, fever, bleeding ulcers, fistulas, and abscesses in the abdomen and perianal region, and CD patients develop obstructive intestinal fibrosis that must be surgically removed. There is an unmet need for long-acting, broadly applicable disease-modifying, and pain-reliev- ing IBD therapies. There are currently immunomodulators effective as disease-modifying therapies; however, some patients do not respond to them, they have adverse side effects, and their efficacies wane over time. To address this need, we used our proprietary Ab discovery platform to identify first-of-their-kind Ab agonists for a G protein-coupled receptor (GPCR), the cannabinoid receptor CB2. CB2 has immunomodulatory functions in many diseases that affect several body systems. In humans, CB2 is constitutively expressed in immune cells, and its expression is broadly induced in IBD, including in the colon. Consistently, CB2 function has been firmly linked to IBD: (1) CB2-KO mice are more susceptible to IBD in disease models, and (2) a common partial loss- of-function CB2 allele has been associated with increased risk of IBD in humans. CB2 agonism has limited adverse effects, and it can suppress inflammation in the gut and elsewhere, and, in contrast to CB1 agonism, it is not psychoactive. Abalone’s CB2-specific agonist Abs have many advantages over small-mole- cule CB2 agonist drug candidates, including CNS exclusion and high specificity, which minimize CB1 activation. Furthermore, Abs are natural proteins; thus, they are unlikely to have unexpected adverse effects due to chem- ical by-products. We will test the hypothesis that Abalone’s CB2 agonist Abs are feasible pre-clinical IBD thera- peutic candidates with anti-inflammatory effects. Our three major aims are (1) to engineer, produce, and char- acterize CB2 agonist Ab variants based on previously isolated and characterized agonist hits; (2) to eval- uate the anti-inflammatory activity of these CB2 agonist Abs on human immune cells; and (3) to assess the effects of the top CB2 agonist Abs in two complementary IBD mouse models. Successful completion of this Phase I project will validate this strategy for the treatment of IBD and will pave the way for further devel- opment of these Ab drugs. Although this SBIR application focuses on IBD, Abalone’s CB2 agonist Ab drugs are applicable to other inflammatory, chronic pain, and fibrotic diseases. Compared with small-molecule drugs, bio- logics have an excellent safety record, which supports development and approval for clinical trials and increased odds of marketing.

概括 Abalone Bio将开发抑制肠道炎症的抗体（Ab）药物以治疗炎症性肠病 IBD 疾病（IBD）包括导致严重损害的慢性、衰弱性、特发性炎症性疾病。年龄对肠壁的影响，包括克罗恩病（CD）和溃疡性结肠炎（UC），其主要病因是慢性的。炎症，导致疼痛、腹泻、体重减轻、发烧、溃疡出血、瘘管和脓肿腹部和肛周区域，CD 患者会出现阻塞性肠纤维化，必须进行手术对长效、广泛适用的疾病缓解和缓解的需求尚未得到满足。然而，目前有一些免疫调节剂可有效缓解疾病；有些患者对它们没有反应，它们会产生不良副作用，而且它们的疗效会随着时间的推移而减弱。为了满足这一需求，我们使用我们专有的 Ab 发现平台来识别首个 Ab 激动剂，用于 G蛋白偶联受体（GPCR），即大麻素受体CB2，具有免疫调节功能。在许多影响人体多个系统的疾病中，CB2 在免疫细胞中持续表达， CB2 的功能在 IBD 中广泛诱导，包括在结肠中。与 IBD 相关：(1) CB2-KO 小鼠在疾病模型中更容易患 IBD，以及 (2) 常见的部分缺失- 功能丧失的 CB2 等位基因与人类 IBD 风险增加有关，CB2 激动作用有限。不良反应，并且与 CB1 相比，它可以抑制肠道和其他部位的炎症鲍鱼的 CB2 特异性激动剂 Abs 比小分子抗体具有许多优势。 cule CB2 激动剂候选药物，包括 CNS 排斥和高特异性，可最大限度地减少 CB1 激活。此外，抗体是天然蛋白质；因此，它们不太可能因化学作用而产生意想不到的副作用。我们将检验鲍鱼的 CB2 激动剂 Abs 是可行的临床前 IBD 治疗的假设。我们的三个主要目标是（1）设计、生产和表征。根据先前分离和表征的激动剂命中（2）来表征 CB2 激动剂抗体变体；评估这些 CB2 激动剂 Abs 对人体免疫细胞的抗炎活性；以及 (3) 评估顶级 CB2 激动剂 Abs 在两个互补 IBD 小鼠模型中的作用成功完成。该第一阶段项目将验证这一治疗 IBD 的策略，并为进一步开发铺平道路。尽管本次 SBIR 申请的重点是 IBD，但 Abalone 的 CB2 激动剂 Ab 药物是与小分子药物相比，生物制剂适用于其他炎症、慢性疼痛和纤维化疾病。逻辑具有出色的安全记录，支持临床试验的开发和批准，并增加营销的几率。