GHRELIN VACCINES FOR CONTROLLING OBESITY

用于控制肥胖的生长素释放肽疫苗

• 批准号: 7189108
• 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 2009-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7189108
• 关键词: Adult; Affect; Affinity; Animals; Antibodies; Antibody Specificity; Antigens; Autoantigens; Autoimmune Diseases; Binding; Blood; Blood Circulation; Body Weight decreased; Brain; Catalytic Antibodies; Cessation of life; Child; Cleaved cell; Eating; Effectiveness; Epidemic; Epitopes; Esters; Fasting; Flow Cytometry; Food; Gastric Bypass; Gastric Emptying; Half-Life; Health; Hormones; Human; Hunger; Hybridomas; Immunization; Immunotherapeutic agent; Immunotherapy; Individual; Intercept; Keyhole Limpet Hemocyanin; Length; Libraries; Link; Measures; Modeling; Modification; Monkeys; Monoclonal Antibodies; Mus; Nickel; Obesity; Operative Surgical Procedures; Patients; Peptides; Phase II Clinical Trials; Physiological; Plasma; Proteins; RNA Interference; Research; Risk; Safety; Saline; Serum; Site; Sorting - Cell Movement; Stream; Testing; Therapeutic; Therapeutic Uses; Thermodynamics; United States; Vaccinated; Vaccines; Weight Gain; Yeasts; analog; bariatric surgery; base; commercial application; concept; design; diet and exercise; ghrelin; magnetic beads; microcalorimetry; nonhuman primate; novel; prevent; research study; response; technological innovation; therapeutic vaccine

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都有不利影响。虽然节食和锻炼对整个问题几乎没有影响，但胃旁路手术已经实现了显着的长期减肥。并发症和死亡的风险限制了这种手术只能用于病态肥胖。然而，研究表明，伴随的血浆生长素释放肽水平的显着抑制是这种外科手术有效性的可能生理基础。Ghrelin是一种由空腹产生的辛酰化肽，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管理的抗体，可以拦截生长激素释放肽在血液中。这些抗体会与生长激素释放肽紧密结合，或催化生长激素释放肽，使其不能进入大脑并引起饥饿。因此，通过降低生长激素释放肽水平，免疫疗法应该模仿胃旁路术的结果，平息饥饿和控制肥胖。治疗肥胖症的疫苗将具有很高的商业价值。小鼠和猴子在用本研究中产生的不同生长素释放肽疫苗免疫后产生了抗生长素释放肽抗体。猴子是健康的，没有显示出自身免疫性疾病，即使ghrelin是一种自身抗原。小鼠单克隆抗体产生对天然生长素释放肽和生长素释放肽过渡态类似物。后者被设计为通过切割其辛酰酯来引发催化抗体，该催化抗体将促生长素释放肽。当小鼠禁食一夜以刺激其分泌ghrelin时，如果给它们腹腔注射抗ghrelin单克隆抗体而不是生理盐水，它们早上吃的食物会更少。Ghrelin特异性的人单链抗体已经从酵母重组口服展示文库获得。这些新型免疫抑制剂的安全性将在猴子中进行测试。然后可以评估这些人单链抗体在抑制饥饿和减少患者肥胖方面的作用。