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(申请人提供)：肥胖症在美国已经达到流行的程度，对成年人和儿童的健康都有不利影响。虽然节食和锻炼对整体问题几乎没有影响，但胃旁路手术已经实现了戏剧性的长期减肥。并发症和死亡的风险限制了这种手术只适用于病态肥胖者。然而，研究表明，伴随而来的显着血浆Ghrelin水平的抑制可能是该手术有效的生理学基础。Ghrelin是一种辛酰化的多肽，由空腹产生，进入血液循环，然后进入大脑，引发饥饿反应。该项目使用主动和被动注射的抗体，可以拦截血液中的生长激素。这些抗体将与Ghrelin紧密结合或催化使激素失活，从而使其无法进入大脑并引发饥饿。因此，通过降低Ghrelin水平，免疫治疗应该模仿胃旁路治疗的结果，以消除饥饿和控制肥胖。治疗肥胖症的疫苗将具有很高的商业价值。小鼠和猴子在用为这项研究产生的不同的基于ghrelin的疫苗免疫后产生了抗ghrelin抗体。这些猴子是健康的，没有表现出自身免疫性疾病，尽管Ghrelin是一种自我抗原。制备了针对天然Ghrelin和一种Ghrelin过渡态类似物的鼠单抗。后者旨在诱导催化抗体，通过裂解Ghrelin的辛酸酯来使其失活。当小鼠被刺激通过隔夜禁食来分泌Ghrelin时，如果注射ip，它们早上吃的食物就会减少。用抗Ghrelin的单抗对抗生理盐水。从酵母重组展示文库中获得了Ghrelin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身上进行测试。然后，这些人类单链抗体可以被评估为抑制患者的饥饿和减少肥胖。