GHRELIN VACCINES FOR CONTROLLING OBESITY

用于控制肥胖的生长素释放肽疫苗

• 批准号: 7170457
• 负责人: VICTOR A RASO
• 金额: $ 37.49万
• 依托单位: BOSTON BIOTECHNOLOGY CORPORATION
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-08-10 至 2008-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7170457
• 关键词: Macaca fascicularis; abzyme; ghrelin; hormone inhibitor; immunotherapy; laboratory mouse; monoclonal antibody; obesity; vaccine development; weight control

DESCRIPTION (provided by applicant): Obesity has reached epidemic proportions in the United States and adversely affects the health of both adults and children. While dieting and exercise have had little effect on the overall problem, dramatic long-term weight loss has been achieved by gastric bypass surgery. The risk of complications and death limits this surgery to only the morbidly obese. However studies indicate that a concomitant marked suppression of plasma ghrelin levels is a likely physiologic basis for the effectiveness of this surgical procedure. Ghrelin is an octanoylated peptide that is produced by the empty stomach, enters the circulation and then passes into the brain to trigger a hunger response. This project uses actively and passively administered antibodies that can intercept ghrelin in the blood stream. Those antibodies will tightly bind to ghrelin or catalytically inactivate the hormone so that it cannot enter the brain and induce hunger. Thus by reducing ghrelin levels, immunotherapy should mimic the gastric bypass results of quelling hunger and controlling obesity. A vaccine therapeutic for obesity would have high commercial value. Mice and monkeys produced anti-ghrelin antibodies after immunization with the different ghrelin-based vaccines generated for this research. The monkeys are healthy and show no autoimmune disease even though ghrelin is a self-antigen. Mouse monoclonal antibodies were produced against native ghrelin and a ghrelin transition state analog. The later is designed to elicit catalytic antibodies which will inactivate ghrelin by cleaving its octanoyl ester. When mice were stimulated to secrete ghrelin by fasting overnight, they ate less food in the morning if injected i.p. with a monoclonal anti-ghrelin antibody versus saline. Ghrelin-specific, human, single chain antibodies have been obtained from a yeast recombinatoral display library. Safety of these novel immunotherapeutic agents will be tested in monkeys. Those human single chain antibodies can then be evaluated for suppressing hunger and reducing obesity in patients.

描述（由申请人提供）：肥胖症已达到美国的流行比例，并对成人和儿童的健康产生不利影响。虽然节食和运动对总体问题的影响很小，但胃旁路手术已经实现了巨大的长期体重减轻。并发症和死亡的风险限制了这项手术的肥胖。但是，研究表明，伴随的明显抑制血浆血浆素水平是该手术程序有效性的生理基础。 Ghrelin是一种由空腹产生的八酰胺肽，进入循环，然后进入大脑以触发饥饿反应。该项目使用积极，被动地施用的抗体，可以在血液中拦截生长素素。这些抗体将紧密结合与生长素蛋白或催化使激素失活，从而无法进入大脑并诱导饥饿感。因此，通过降低生长素素水平，免疫疗法应模仿胃旁路的结果，导致饥饿和控制肥胖的结果。肥胖症的疫苗治疗方法将具有很高的商业价值。小鼠和猴子与为这项研究产生的不同基于生长素蛋白的疫苗免疫后产生抗ghrelin抗体。这些猴子很健康，即使Ghrelin是自我抗原，也没有表现出自身免疫性疾病。小鼠单克隆抗体是针对天然生长素蛋白和生长素蛋白过渡态类似物产生的。后者旨在引起催化抗体，该抗体会通过切割其八烷酯来使生长素释放。当小鼠通过禁食过夜以分泌生长素素时，如果注射腹腔腹膜内食物，它们在早上吃的食物较少。与盐水与盐水的单克隆抗Ghrelin抗体。酵母重组显示库已获得生长素释放蛋白特异性的人类单链抗体。这些新型免疫治疗剂的安全性将在猴子中进行测试。然后可以评估那些人类的单链抗体，以抑制患者的饥饿和减少肥胖症。