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。肾上腺中高水平的促肾上腺皮质激素(ACTH)刺激皮质醇的分泌，导致血液皮质醇水平上升。长期摄入过多的皮质醇会导致库欣综合征，其特征是体重迅速增加，主要集中在面部、胸部和腹部，而手臂和腿部细长，脸色发红和圆润，高血压，骨质疏松症，皮肤变化，肌肉无力，情绪波动，表现为焦虑，抑郁或易怒，口渴和尿频增加。当库欣综合征是由脑下垂体肿瘤分泌过多的ACTH引起的，这种情况被称为库欣病。由于不清楚的原因，库欣病影响女性的比例几乎是男性的3：1。患有库欣病的女性可能会经历月经不调，面部、腹部和腿部毛发过度生长。如果不进行治疗，库欣病可能是致命的，首选的治疗方案是在不损害脑下垂体其余部分的情况下，通过手术切除肿瘤。当手术不可能或未能完全切除肿瘤时，通常需要药物治疗来阻断过量皮质醇的影响。而类固醇合成抑制剂，糖皮质激素受体阻滞剂，卡麦角林， 生长抑素类似物在库欣病患者的治疗中肯定有很大的不同， 这些患者中有相当一部分从未得到充分治疗。显然，对小说有一种未得到满足的医学需求 更好地控制疾病和减少副作用的治疗。我们建议一种抗体疗法作为一种 控制过量皮质醇的新方法，我们相信这种方法可以作用于整个患者群体，并且 可以与其他药物协同工作。我们这笔SBIR NIH赠款的目标是启动必要的 开发工作使这种新药成为可能。

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.