An Innovative Immune Therapy with Antibiotics to Treat Deadly Excess Inflammation in Sepsis and ARDS Induced from Severe Bacterial Infection in Geriatric Patients

在美国，每年有166.5万例败血症病例（H-CUP#122），其中近50万人死亡，目前没有FDA批准的治疗方法。急性呼吸窘迫综合征（ARDS）和败血症是需要重症监护的医疗紧急情况，30-70%的病例是致命的。急性呼吸窘迫综合征和败血症是老年患者死亡的主要原因。他们会受到产生致命毒素的细菌的严重感染。肠杆菌科、铜绿假单胞菌、沙门氏菌和金黄色葡萄球菌是主要病因。这些毒素使免疫反应达到致命的过量。它们与血小板（PT）结合，激活血小板表达TREM1（髓样细胞上表达的触发受体1）的配体，TREM1是巨噬细胞（MΦ）和中性粒细胞的有效激活受体。多个激活的PT配体结合MΦ，过度触发TREM1，过度激活MΦ释放大量炎症介质，产生过量的全身炎症反应（SIR）。活性MΦ表达TREM1是脓毒症和ARDS的特征。超过450篇科学文章记录了TREM1在炎症中的作用。BioPROVAR的科学家们发现了TREM1-sv，这是一种在血液中发现的TREM1的天然剪接变体竞争受体，可调节TREM1激活途径（TAP）。作为一种抗生素（AT）免疫疗法，TREM1-sv对盲肠结扎穿刺（CLP） SIR小鼠的生存率有很强的提高作用，将生存率从0% （AT单独）提高到67%。相比之下，用阻断toll样受体4的肽抑制lps激活途径对存活没有显著影响。基于这些数据和现有的知识，BioPROVAR正在开发BioTremvarTM，为败血症和ARDS患者补充人重组（hu r） TREM1-sv和抗生素，以减轻SIR和预防死亡。其原理是，通过竞争过量的TREM1配体，TREM1-sv通过减少触发激活的TREM1配体复合物的数量来调节TAP，从而阻止MΦ过度激活，从而维持有效的免疫反应。我们的目标是收集GLP生产和毒理学研究的ind工作所需的临床前数据。我们的目标是利用可转移到cGMP的系统优化非glp生产hu rTREM1-sv，并对其结构特性进行分析表征。BioTremvar的广泛治疗效果将在clp诱导的SIR动物模型中使用不同剂量和方案，作为抗生素的免疫治疗。使用小鼠和豚鼠（非啮齿动物）动物模型，我们将生成药效学、药代动力学、PK/PD关系数据，并计算BioTremvarTM的半衰期。BioPROVAR拥有TREM1-sv的权利。我们的长期目标是验证BioTremvarTM cGMP静脉注射溶液治疗败血症和ARDS患者。重要的是要有一个治疗广泛有效的抑制中枢机制维持这些疾病。使用BioTremvarTM来抑制败血症或ARDS中的SIR是创新的、有科学依据的，将挽救许多生命。

There are 1,665,000 cases of sepsis annually in the U.S. (H-CUP#122) with near 500,000 associated deaths, and currently, no FDA approved treatment. ARDS (acute respiratory distress syndrome) and sepsis are medical emergencies requiring intensive care and are fatal in 30-70% of cases. ARDS and sepsis are main causes of death in geriatric patients. They develop severe infection from bacteria producing deadly toxins. Enterobacteriaceae, Pseudomonas aeruginosa, Salmonella spp, and Staphylococcus aureus are largely at cause. These toxins drive the immune response to a deadly excess. They bind to platelets (PT), activating them to express a ligand for TREM1 (Triggering Receptor Expressed on Myeloid Cells 1), a potent activation receptor of macrophages (MΦ) and neutrophils. Multiple activated PT ligands bind to MΦ, overtrigger TREM1, hyperactivating MΦ to release large amounts of inflammatory mediators producing an excess of systemic inflammatory response (SIR). Active MΦ expressing TREM1 are characteristic of sepsis and ARDS. Over 450 scientific articles document the role of TREM1 in inflammation. BioPROVAR's scientists have discovered TREM1-sv, a natural splice variant competitive receptor of TREM1 found in the blood and regulating the TREM1-activation pathway (TAP). As an immune therapy with antibiotics (AT), TREM1-sv showed a strong efficacy to increase survival probability in mice with SIR from cecum-ligation puncture (CLP), improving survival from 0% (AT alone) to 67%. Per comparison, inhibiting the LPS-activation pathway with a peptide blocking the Toll-Like Receptor 4 had no significant effect on survival. Based on these data and current knowledge, BioPROVAR is developing BioTremvarTM to administer supplement of human recombinant (hu r) TREM1-sv with antibiotics to sepsis and ARDS patients to alleviate SIR and prevent death. The rationale is that by competing for the excess of TREM1 ligands, TREM1-sv regulates TAP by reducing the number of TREM1-ligand complexes that trigger activation, thwarting MΦ hyperactivation, hence maintaining an effective immune response. Our objective here is to gather the preclinical data needed for the IND-enabling work of GLP production and toxicology studies. We aim to optimize non-GLP production of hu rTREM1-sv with a system transferable to cGMP and perform analytical characterization of its structural identity. BioTremvar's broad therapeutic efficacy will be demonstrated as an immune therapy with antibiotics in animal models of CLP-induced SIR using different doses and regimens. Using a mouse and a Guinea pig (nonrodent) animal model, we will generate pharmacodynamic, pharmacokinetic, PK/PD relationship data, and calculate the half-life of BioTremvarTM. BioPROVAR owns the rights to TREM1-sv. Our long-term goal is to validate BioTremvarTM cGMP in solution for intravenous injection to treat sepsis and ARDS patients. It is vital to have a therapeutic broadly effective at suppressing the central mechanism sustaining these diseases. The use of BioTremvarTM to inhibit SIR in sepsis or ARDS is innovative, scientifically grounded, and will save many lives.