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. ? ?
