Long lasting ghrelin derivatives for the treatment of cancer cachexia

描述（由申请人提供）：恶病质是一种复杂的综合征，其特征为不自主的体重减轻和骨骼肌消耗，导致疲劳、虚弱和食欲不振，热量消耗增加无法逆转。超过一半的癌症患者发展为恶病质，并且它负责超过40%的所有癌症死亡。与恶病质相关的许多并发症包括对药物治疗的反应受损、感染机会增加、预后不良和生活质量下降。目前，还没有FDA批准的恶病质治疗方法，但激素生长激素释放肽最近作为一种具有巨大潜力的分子出现。在动物和人类中的几项研究表明，生长激素释放肽增加食物摄入，导致体重增加。Ghrelin还刺激生长激素的释放，导致肌肉质量增加，据报道Ghrelin具有抗炎活性。然而，由于以下几个原因，生长素释放肽作为治疗的用途受到限制：1）生长素释放肽必须每天给药2-3次以观察功效，这是由于其具有抗肿瘤活性。 固有的短半衰期为11分钟; 2）生长素释放肽脱酰化为无活性形式在少于5分钟内发生;和3）生长素释放肽目前静脉内给药以观察治疗效果。本申请中提出的研究解决了这些问题中的每一个，导致开发了可以不太频繁地给药的长效生长素释放肽衍生物。Extend Biosciences有一种专有的载体分子，可以延长循环半衰期，但又足够小， 干扰与其缀合的肽的活性。我们之前已经证明，当我们的载体与生长素释放肽缀合时，我们可以将半衰期延长22倍，这是对天然生长素释放肽的显著改善。此外，我们已经表明，在体外，载体缀合的生长素释放肽具有相同的受体结合亲和力作为未缀合的生长素释放肽。我们还证明，当皮下给药时，载体分子大大提高了小蛋白的生物利用度。本I期申请中提出的研究将调查我们的长效ghrelin刺激垂体细胞释放生长激素并增加健康大鼠的食物摄入量和体重的能力。这将使我们能够显示缀合的生长素释放肽的体内功能。我们将通过测试结合生长素释放肽的组成型活性形式来解决酰化的重要性。然后，我们将在一个已建立的大鼠癌症诱导恶病质模型中测试这些研究中的主要候选药物。另一个探索性目的是测试我们的长效生长激素释放肽沿着皮下给药与传统的静脉给药。SBIR第二阶段的资金将集中在GLP生产和额外的体内和毒理学研究需要开始人体试验。一旦完全开发，我们的长效生长激素释放肽衍生物将提供一种患者友好的恶病质治疗，将显着改善癌症患者的预后和生活质量，以及其他慢性疾病，如充血性心力衰竭（CHF）和慢性阻塞性肺病（COPD）。该技术还可以改善其他肽治疗剂的半衰期和生物利用度。

DESCRIPTION (provided by applicant): Cachexia is a complex syndrome characterized by involuntary weight loss and skeletal muscle wasting that leads to fatigue, weakness and a loss of appetite that is not reversed by increased caloric consumption. More than half of all cancer patients develop cachexia and it is responsible for more than 40% of all cancer deaths. Numerous complications associated with cachexia include an impaired response to drug treatment, an increased chance of infection, a poor prognosis and a decreased quality of life. Currently, there are no FDA- approved treatments for cachexia, but the hormone ghrelin has recently emerged as a molecule with great potential. Several studies in both animals and humans have shown that ghrelin increases food intake resulting in increased body weight. Ghrelin also stimulates the release of growth hormone, resulting in increased muscle mass, and ghrelin is reported to have anti-inflammatory activity. However, the use of ghrelin as a treatment is limited for several reasons: 1) ghrelin must be dosed 2-3 times daily to see efficacy due to its inherently short half-life of 11 min; 2) deacylation of ghrelin to an inactive form occurs in less than 5 min; and 3) ghrelin is currently dosed intravenously to see a therapeutic effect. The studies proposed in this application address each of these issues, resulting in the development of a long-acting ghrelin derivative that could be dosed less frequently. Extend Biosciences has a proprietary carrier molecule that lengthens circulating half-life, but is small enough so as not to interfere with the activity of a peptide to which it is conjugated. We have previously shown that when our carrier is conjugated to ghrelin, we can extend the half-life 22-fold, which is a significant improvement over native ghrelin. Additionally, we have shown that in vitro, carrier-conjugated ghrelin has the same receptor binding affinity as unconjugated ghrelin. We have also demonstrated that the carrier molecule greatly improves the bioavailability of a small protein when administered subcutaneously. The studies proposed in this Phase I application will investigate the ability of our long-acting ghrelin to stimulate growth hormone release from pituitary cells and increase food intake and body weight in healthy rats. This will allow us to show the in vivo functionality of conjugated ghrelin. We will address the importance of acylation by testing a constitutively active form of conjugated ghrelin. We will then test the leading candidate from these studies in an established model of cancer-induced cachexia in rats. An additional exploratory aim is to test subcutaneous dosing of our long-acting ghrelin along with the traditional intravenous dosing. SBIR Phase II funding will focus on GLP production and additional in vivo and toxicology studies needed to begin human trials. Once fully developed, our long-acting ghrelin derivative would provide a patient-friendly cachexia therapy that would significantly improve the prognosis and quality of life in patients with cancer and also in patient with other chronic disorders such as congestive heart failure (CHF) and chronic obstructive pulmonary disease (COPD). This technology can improve half-life and bioavailability of other peptide therapeutics as well.