A Therapeutic Agent for Radiation-induced Lung Fibrosis

肺纤维化是以炎性细胞浸润、成纤维细胞增生、肺实质细胞外基质蛋白（ECM）过度沉积为特征的一组病死率高的不治之症。全球有500万人受到肺纤维化的影响。仅在美国，就有20万人患有这种疾病。其中，每年有4万多人死亡，相当于死于乳腺癌的人数，是死于囊性纤维化的人数的40倍。肺纤维化对生活质量的影响是严重的。原因不明的肺纤维化被称为特发性肺纤维化（IPF）。肺纤维化也是多种原因的结果，包括肺肿瘤的放疗和化疗。放射诱导的肺纤维化是癌症患者放射治疗的一个主要问题。治疗性纤维化常常限制化疗和放疗联合治疗多种癌症的疗效。目前，肺纤维化没有有效的非手术治疗方法。因此，迫切需要开发预防和改善肺纤维化的治疗药物。越来越多的证据表明，转化生长因子-(TGF-())在其发病机制中起着重要作用。动物研究表明，通过TGF-结合蛋白治疗拮抗TGF-可以改善肺纤维化。因此，合成TGF-拮抗剂可能是治疗肺纤维化的重要药物。我们最近开发了一类合成的TGF-肽拮抗剂（称为TGF-肽拮抗剂），它可以阻断TGF-与TGF-受体的结合，并在培养细胞中拮抗TGF-活性。在标准动物皮肤损伤模型中局部应用含有TGF-肽拮抗剂的凝胶可促进伤口愈合，减轻纤维化。然而，使用TGF-肽拮抗剂治疗肺纤维化受到其在中性pH水溶液中溶解度差的限制。在最近的研究中，我们开发了一种新型聚乙二醇化的TGF-肽拮抗剂（称为PEG-TGF-肽拮抗剂），它在中性pH水溶液中具有优异的溶解度，通过培养细胞测量其有效的拮抗剂活性，并通过环磷酰胺诱导的大鼠膀胱损伤测定其上皮再生活性。经鼻给药该PEG-TGF-（肽拮抗剂）可有效预防博莱霉素诱导的小鼠肺纤维化，并减轻已建立的肺纤维化。这些结果提示，PEG-TGF-（肽拮抗剂）可能是预防和治疗人类肺纤维化的一种有价值的治疗剂。我们假设我们的PEG-TGF-（肽拮抗剂）在改善辐射诱导的肺纤维化方面是有效的。这项提议的主要目标是验证这一假设。拟建的I期研究结果应为这种新型PEG-TGF-（肽拮抗剂）的II期和临床试验提供基础。我们预测，我们的PEG-TGF-（肽拮抗剂）的临床可用性将使全球数百万患者受益。公共卫生相关性：本提案的目标是开发新型TGF-（肽拮抗剂）作为治疗目前缺乏有效治疗方法的放射性肺纤维化的候选药物。这种药物的可用性将使全世界数百万患者受益。

DESCRIPTION (provided by applicant): Lung fibrosis, a group of incurable lung diseases with high mortality rates, is characterized by inflammatory cell infiltration, fibroblast proliferation, and excessive deposition of extracellular matrix proteins (ECM) in lung parenchyma. Globally, five million people are affected by lung fibrosis. In the U.S. alone, 200,000 suffer from this disease. Of these more than 40,000 die annually, equivalent to the number who die from breast cancer, and forty times more than those who die from cystic fibrosis. The effect of lung fibrosis on quality of life is severe. Lung fibrosis of unknown causes is known as idiopathic pulmonary fibrosis (IPF). Lung fibrosis also develops as a consequence of multiple causes, including radiotherapy and chemotherapy for lung neoplasms. Radiation-induced lung fibrosis is a major concern for radiotherapy for cancer patients. Therapy-induced fibrosis often limits the efficacy of the combination of chemotherapy and radiotherapy in numerous cancers. Currently, there are no effective non-surgical treatments for lung fibrosis. Hence there is an urgent need to develop therapeutic agents that prevent and ameliorate lung fibrosis. Accumulating evidence indicates that transforming growth factor-( (TGF-() plays an important role in its pathogenesis. Animal studies have shown that antagonizing TGF-( by treatment with TGF-( binding proteins appears to ameliorate lung fibrosis. Therefore synthetic TGF-( antagonists may serve as important therapeutic agents for lung fibrosis. We recently developed a class of synthetic TGF-( peptide antagonists (termed TGF-( peptantagonists) that block TGF-( binding to TGF-( receptors and antagonize TGF-( activity in cultured cells. Topical application of gel containing a TGF-( peptantagonist in standard animal skin injury models promotes wound healing and attenuates fibrosis. However, the use of TGF-( peptantagonists to treat lung fibrosis is limited by its poor solubility in aqueous solution at neutral pH. In recent studies, we have developed a novel pegylated TGF-( peptantagonist (termed PEG-TGF-( peptantagonist) which has excellent solubility in aqueous solution at neutral pH, potent antagonist activity as measured using cultured cells, and epithelial regeneration activity as determined using cyclophosphamide-induced bladder injury in rats. Intranasal administration of this PEG-TGF-( peptantagonist effectively prevents bleomycin-induced lung fibrosis in mice and attenuates established lung fibrosis as well. These results suggest that PEG-TGF-( peptantagonist may be a valuable therapeutic agent for prevention and treatment of lung fibrosis in humans. We hypothesize that our PEG-TGF-( peptantagonist is effective in ameliorating radiation-induced lung fibrosis. The major goal of this proposal is to test this hypothesis. The results from the proposed phase I studies should provide the basis for Phase II and clinical trials of this novel PEG-TGF-( peptantagonist. We predict that the clinical availability of our PEG-TGF-( peptantagonist will benefit millions of patients worldwide. PUBLIC HEALTH RELEVANCE: The goal of this proposal is to develop novel TGF-( peptantagonist as a drug candidate for treating radiation-induced lung fibrosis which currently lacks effective treatments. The availability of such drug will benefit millions of patients worldwide.