Treatment of Surgical Sepsis with AM/AMBP-1

描述（由申请人提供）：SBIR II期提案旨在进一步开发一种新的治疗方法，以挽救脓毒症（特别是外科脓毒症）患者的生命，脓毒症每年仅在美国就影响75万人，并且在全球范围内造成高死亡率。虽然活化蛋白C [APC]， Drotrecogin α（活化），Xigris。是FDA批准的唯一针对败血症的特殊治疗药物，由于其对凝血的不良影响，不能用于败血症手术患者。因此，对外科败血症的有效新治疗方法的需求更大。一种新的抗败血症疗法的成功开发不仅将对医疗保健产生积极的影响，而且还将具有高度显着的商业效益。脓毒症治疗的全球市场潜力估计每年超过300亿美元。我们最近发现，血管对肾上腺髓质素（AM）的反应性，一种新报道的强效血管活性肽，在脓毒症大鼠中降低，并通过其新的结合蛋白（即AMBP-1）显着改善。大鼠AM联合人AMBP-1治疗可改善脓毒症大鼠盲肠结扎穿刺（CLP）模型的心血管功能，减轻组织损伤和炎症反应，降低死亡率，提示AM/AMBP-1可能是治疗人脓毒症的有效方法。阻碍AM/AMBP-1作为脓毒症治疗剂发展的一个障碍是大鼠蛋白在人类中的潜在免疫原性。在这方面，我们I期计划的主要目标是确定人AM/AMBP-1对败血症诱导的器官损伤、炎症和死亡率的影响。我们已经通过大鼠脓毒症CLP模型实现了这些里程碑。在第一期项目中，我们已经清楚地证明了人类AM/AMBP-1的有效性，从而确定了拟议的第二期项目的技术优点和可行性。然而，商用人AMBP-1的极高成本限制了人AM/AMBP-1作为抗脓毒症治疗药物的进一步发展。为了克服这一困难，我们以较低的成本成功地从正常人血清中分离和纯化了AMBP-1。因此，我们继续假设在脓毒症发病后晚期给药人AM/AMBP-1可以减轻组织损伤并提高生存率。在这个II期项目中，我们将首先扩大人AMBP-1的生产规模，然后进行额外的功效研究，以确定人AM/AMBP-1对脓毒症大鼠的最佳保护剂量。此外，还将评估人AM/AMBP-1在脓毒症中的药代动力学特征。为了将我们的技术推进到临床试验，我们将在猪脓毒症模型中研究人类AM/AMBP-1的疗效。这些拟议的研究应提供足够的临床前数据，使我们能够向FDA提交IND申请，启动临床试验，以获得人类AM/AMBP-1作为败血症患者安全有效治疗的商业利用，特别是那些创伤或大手术后发生败血症的患者。脓毒症是大多数重症监护病房死亡的主要原因之一。在美国，每年有超过21万人死于这种压倒性的感染。最近的一项流行病学研究估计，全国每年约有75万人患败血症，造成167亿美元的损失。考虑到治疗败血症患者所需的密集和长期护理，经济负担是沉重的。因此，迫切需要一种有效的新型治疗败血症患者的医学需求。

DESCRIPTION (provided by applicant): This SBIR Phase II proposal is a plan to further develop a new therapeutic approach that will save the lives of patients with sepsis (especially surgical sepsis), a condition that affects 750,000 people every year in the United States alone and also causes high mortality worldwide. Although activated protein C [APC, Drotrecogin alpha (activated), Xigris. marketed by Eli Lilly] is the only FDA- approved specific treatment for sepsis, it cannot be used in surgical patients with sepsis due to its adverse effects on coagulation. Thus, there is an even greater need for an effective novel treatment for surgical sepsis. Successful development of a new anti-sepsis therapy will not only have a positive impact on health care, but it will also have highly significant commercial benefits. The global market potential for sepsis treatment is estimated at over $30 billion annually. We have recently discovered that vascular responsiveness to adrenomedullin (AM), a newly-reported potent vasoactive peptide, decreases during sepsis in the rat and is markedly improved by its novel binding protein (i.e., AMBP-1). Treatment with rat AM combined with human AMBP-1 improved cardiovascular function, attenuated tissue injury and inflammatory responses, and reduced mortality in a rat cecal ligation and puncture (CLP, induced by surgery) model of sepsis, suggesting that AM/AMBP-1 may be an effective treatment for human sepsis. One obstacle hampering the development of AM/AMBP-1 as a therapeutic agent for sepsis is the potential immunogenicity of rat proteins in humans. In this regard, the primary objective of our Phase I proposal was to determine the effect of human AM/AMBP-1 on sepsis-induced organ injury, inflammation, and mortality. We have achieved these milestones using the rat CLP model of sepsis. In the Phase I project, we have clearly demonstrated the efficacy of human AM/AMBP-1 and thereby established the technical merit and feasibility of the proposed Phase II project. However, the extremely high cost of commercial human AMBP- 1 limits the further development of human AM/AMBP-1 as an anti-sepsis therapy. To overcome this difficulty, we have successfully isolated and purified AMBP-1 from normal human serum at a much lower cost. We therefore continue to hypothesize that the administration of human AM/AMBP-1 late after the onset of sepsis attenuates tissue injury and improves survival. In this Phase II proposal, we will first, scale up the production of human AMBP-1 and, then, perform additional efficacy studies in order to determine the optimal protective dosage of human AM/AMBP-1 in sepsis in the rat. Moreover, the pharmacokinetic characterization of human AM/AMBP-1 in sepsis will be assessed. To advance our technology to the clinical trials, the efficacy of human AM/AMBP-1 will be investigated in a swine model of sepsis. These proposed studies should provide sufficient preclinical data that will allow us to file an IND application to the FDA to initiate clinical trials in order to obtain the commercial utilization of human AM/AMBP-1 as a safe and effective therapy for patients with sepsis, especially those who develop sepsis after trauma or major surgery. PUBLIC HEALTH RELEVANCE Sepsis is one of the leading causes of death in most intensive care units. Over 210,000 people succumb to this overwhelming infection in the United States annually. A recent epidemiologic study estimated that about 750,000 people develop sepsis each year at a cost of $16.7 billion nationally. Given the intensive and prolonged care necessary to treat patients with sepsis, the economic burden is profound. Thus, there is an urgent unmet medical need for an effective novel therapy for septic patients.