A First-in-Class Human Antibody Therapeutic for Treatment of Cushing's Disease

皮质醇是一种类固醇激素，它调节全身的一系列过程，包括新陈代谢和免疫反应。它在帮助身体应对压力方面也起着非常重要的作用。肾上腺中促肾上腺皮质激素（ACTH）的高水平刺激皮质醇的分泌，导致血液中皮质醇的水平上升。长期过多的皮质醇会导致一种叫做库欣综合征的疾病，其特征是面部、胸部和腹部的体重迅速增加，而手臂和腿却很纤细，脸又红又圆，血压高，骨质疏松，皮肤变化，肌肉无力，情绪波动，表现为焦虑、抑郁或易怒，以及口渴和排尿频率增加。当库欣综合征是由垂体肿瘤引起的，分泌过多的ACTH，这种情况被称为库欣病。由于尚不清楚的原因，库欣氏病对女性的影响几乎是男性的3倍。患有库欣氏病的女性可能会经历月经不规律，面部、腹部和腿部的毛发生长过多。如果不及时治疗，库欣氏病可能是致命的，首选的治疗方案是手术切除肿瘤，同时不损害脑下垂体的其余部分。当手术不可能或不能完全切除肿瘤时，通常需要药物来阻止过量皮质醇的影响。而类固醇合成抑制剂，糖皮质激素受体阻滞剂，卡麦角林，

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.