Cortisol is a steroid hormone that regulates a wide range of processes throughout the body, including metabolism and the immune response. It also has a very important role in helping the body respond to stress. High levels of adrenocorticotropic hormone (ACTH) in the adrenal glands stimulate the secretion of cortisol, causing blood levels of cortisol to rise. Too much cortisol for a long period of time leads to a condition called Cushing?s syndrome, characterized by rapid weight gain mainly in the face, chest and abdomen contrasted with slender arms and leg, a flushed and round face, high blood pressure, osteoporosis, skin changes, muscle weakness, mood swings that show as anxiety, depression or irritability and increased thirst and frequency of urination. When Cushing?s syndrome is caused by a tumor of the pituitary gland that secretes too much ACTH, the condition is known as Cushing?s disease. For reasons that are unclear, Cushing?s disease affects women more often than men by almost 3 to 1. Women with Cushing?s disease may experience irregular menstruation and have excessive hair growth on their face, abdomen, and legs. Left untreated, Cushing?s disease can be deadly, and the preferred course of action is to surgically remove the tumor without damaging the rest of the pituitary gland. When surgery is not possible or fails to completely remove the tumor, medication is often needed to block the effects of the excess cortisol. While steroid synthesis inhibitors, glucocorticoid receptor blockers, cabergoline, and somatostatin analogs have certainly made a great difference in the care of patients with Cushing?s disease, a substantial number of these patients are never adequately treated. There is a clear unmet medical need for novel treatments with better control of the disease and fewer side effects. We propose an antibody therapeutic as a novel approach to controlling excess cortisol that we believe can act across the entire patient population and that can work in concert with other medications. Our goal for this SBIR NIH grant is to initiate the necessary development work to make this new medicine possible.