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）：肥胖在美国已经达到流行病的程度，并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几乎没有影响，但胃旁路手术已经取得了显著的长期减肥效果。并发症和死亡的风险限制了该手术仅适用于病态肥胖患者。然而，研究表明，伴随的血浆胃饥饿素水平的显著抑制可能是这种手术效果的生理基础。胃饥饿素是一种辛烷酰化的肽，由空腹产生，进入血液循环，然后进入大脑引发饥饿反应。这个项目使用主动和被动给药的抗体来拦截血液中的胃饥饿素。这些抗体会与胃饥饿素紧密结合，或者催化性地使这种激素失活，使其无法进入大脑并引起饥饿感。因此，通过降低胃饥饿素水平，免疫疗法可以模拟胃旁路治疗的效果，从而抑制饥饿和控制肥胖。治疗肥胖的疫苗将具有很高的商业价值。小鼠和猴子在接种了为本研究研制的不同的胃饥饿素疫苗后产生了抗胃饥饿素抗体。尽管胃饥饿素是一种自身抗原，但这些猴子是健康的，没有表现出自身免疫性疾病。制备了针对天然胃饥饿素和胃饥饿素过渡态类似物的小鼠单克隆抗体。后者被设计成引发催化抗体，通过切割胃饥饿素的辛烷酯来灭活它。当小鼠通过禁食一夜刺激分泌胃饥饿素时，与生理盐水相比，通过i.p.注射单克隆抗胃饥饿素抗体，它们在早上吃得更少。从酵母重组展示库中获得了ghrelin特异性的人单链抗体。这些新型免疫治疗剂的安全性将在猴子身上进行试验。然后可以评估这些人类单链抗体在抑制饥饿和减少患者肥胖方面的作用。