GHRELIN VACCINES FOR CONTROLLING OBESITY

用于控制肥胖的生长素释放肽疫苗

• 批准号: 6935665
• 负责人: VICTOR A RASO
• 金额: $ 7.41万
• 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 2005-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6935665
• 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）：肥胖在美国已达到流行病的程度，对成人和儿童的健康产生不利影响。虽然节食和运动对整体问题影响不大，但胃绕道手术已经实现了显着的长期减肥效果。由于并发症和死亡的风险，这种手术仅限于病态肥胖者。然而研究表明，血浆生长素释放肽水平的显着抑制可能是该手术有效性的生理基础。生长素释放肽是一种辛酰化肽，由空腹产生，进入循环系统，然后进入大脑引发饥饿反应。该项目使用主动和被动施用的抗体来拦截血流中的生长素释放肽。这些抗体将与生长素释放肽紧密结合或催化灭活激素，使其无法进入大脑并引起饥饿。因此，通过降低生长素释放肽水平，免疫疗法应该模仿胃绕道手术消除饥饿和控制肥胖的结果。治疗肥胖症的疫苗具有很高的商业价值。小鼠和猴子在使用本研究中产生的不同基于生长素释放肽的疫苗免疫后产生了抗生长素释放肽抗体。尽管生长素释放肽是一种自身抗原，但这些猴子很健康，没有表现出自身免疫性疾病。针对天然生长素释放肽和生长素释放肽过渡态类似物产生小鼠单克隆抗体。后者旨在引发催化抗体，该抗体将通过裂解其辛酰酯来灭活生长素释放肽。当小鼠通过过夜禁食刺激分泌生长素释放肽时，如果腹腔注射，它们早上吃的食物会减少。使用单克隆抗生长素释放肽抗体与盐水。生长素释放肽特异性人类单链抗体已从酵母重组展示文库中获得。这些新型免疫治疗剂的安全性将在猴子身上进行测试。然后可以评估这些人类单链抗体在抑制患者饥饿和减少肥胖方面的作用。