Therapeutic Antibodies for Treating Inflammatory Bowel Disease

用于治疗炎症性肠病的治疗性抗体

• 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
• 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' 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

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.

总结 鲍鱼生物将开发抑制肠道炎症的抗体（Ab）药物，以治疗炎症性肠病 疾病（IBD）。IBD包括慢性、衰弱性、特发性炎性疾病，其导致严重的损害， 年龄对肠壁的影响，包括克罗恩病（CD）和溃疡性结肠炎（UC）。主要病因是慢性的 炎症，引起疼痛，腹泻，体重减轻，发烧，出血性溃疡，瘘管和脓肿， 腹部和肛周区域，CD患者发生梗阻性肠纤维化，必须手术治疗。 删除.对长效、广泛适用的疾病缓解和疼痛缓解的需求尚未得到满足， IBD治疗。目前存在有效作为疾病修饰疗法的免疫调节剂;然而， 有些病人对它们没有反应，它们有副作用，它们的效力随着时间的推移而减弱。到 为了满足这一需求，我们使用我们专有的Ab发现平台来识别第一种Ab激动剂， G蛋白偶联受体（GPCR），大麻素受体CB 2。CB 2具有免疫调节功能， 许多疾病会影响几个身体系统。在人类中，CB 2在免疫细胞中组成型表达， 并且其表达在IBD中广泛诱导，包括在结肠中。因此，CB 2功能已被牢固地 与IBD相关：（1）CB 2-KO小鼠在疾病模型中对IBD更易感，和（2）常见的部分缺失- 功能缺失的CB 2等位基因与人类IBD风险增加相关。CB 2激动作用有限 副作用，它可以抑制肠道和其他地方的炎症，与CB 1相反， 激动，它不是精神活性的。鲍鱼的CB 2特异性激动剂Ab与小分子- cule CB 2激动剂候选药物，包括CNS排斥和高特异性，最大限度地减少CB 1激活。 此外，Ab是天然蛋白质;因此，它们不太可能由于化学修饰而具有意想不到的不良反应。 化学副产品。我们将检验Abalone的CB 2激动剂Ab是可行的临床前IBD治疗的假设。 具有抗炎作用的候选药物。我们的三个主要目标是（1）工程，生产，和字符- 基于先前分离和表征的激动剂命中物的actin CB 2激动剂Ab变体;（2）评估- 评估这些CB 2激动剂Ab对人免疫细胞的抗炎活性;以及（3）评估 顶级CB 2激动剂Abs在两种互补IBD小鼠模型中的作用。成功完成 该I期项目的研究将验证该治疗IBD的策略，并为进一步开发IBD铺平道路。 这些Ab药物的作用。虽然SBIR的应用主要针对IBD，但Abalone的CB 2激动剂Ab药物 适用于其它炎症、慢性疼痛和纤维化疾病。与小分子药物相比， 逻辑具有良好的安全记录，支持临床试验的开发和批准， 营销的机会。