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

创新的抗生素免疫疗法可治疗老年患者严重细菌感染引起的脓毒症和急性呼吸窘迫综合征（ARDS）中致命的过度炎症

• 批准号: 10300896
• 负责人: Eugene Roussel
• 金额: $ 37.6万
• 依托单位: BIOPROVAR CORPORATION
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-30 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10300896
• 关键词: Adult Respiratory Distress Syndrome; American; Animal Model; Animals; Antibiotics; Antibodies; Antigens; Bacterial Infections; Binding; Biological; Biological Assay; Blood; Blood Platelets; COVID-19 mortality; Cause of Death; Cavia; Cells; Cessation of life; Characteristics; Chemicals; Complex; Computer software; Cyclic GMP; Data; Diagnosis; Disease; Dose; Drug Kinetics; Elderly; Enterobacteriaceae; Enzyme-Linked Immunosorbent Assay; FDA approved; Fluorescence; Fluorescent Dyes; Formulation; Funding; Genetic Engineering; Goals; Half-Life; Human; Immune response; Immunotherapy; Infection; Inflammation; Inflammation Mediators; Inflammatory; Intensive Care; Joints; Knowledge; Label; Lead; Ligand Binding; Ligands; Lung; Medical emergency; Microbiology; Modeling; Molecular; Molecular Analysis; Monoclonal Antibodies; Mus; Myeloid Cells; Non-Rodent Model; Organ; Organism; Pathway interactions; Patients; Peptides; Pharmacodynamics; Phase; Pichia; Preparation; Probability; Process; Production; Proteins; Pseudomonas aeruginosa; RNA Splicing; Receptor Activation; Recombinants; Regimen; Request for Proposals; Rights; Rodent; Role; Salmonella; Scientist; Sepsis; Small Business Innovation Research Grant; Staphylococcus aureus; Structure; Superantigens; Surface; System; TLR4 gene; Tail; Technology; Testing; Therapeutic; Time; Toxicology; Toxin; Treatment Efficacy; Variant; Work; aged; base; cGMP production; cecal ligation puncture; cytokine; cytokine release syndrome; effective therapy; efficacy study; experimental study; improved; in vivo; inhibitor/antagonist; innovation; intravenous injection; juvenile animal; macrophage; manufacturing process; neutrophil; novel therapeutics; older patient; pathogenic bacteria; pharmacokinetics and pharmacodynamics; pre-clinical; preclinical trial; prevent; receptor; response; stability testing; systemic inflammatory response

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.

美国每年有1,665,000例败血症（H-CUP＃122），近500,000例相关死亡，目前尚无FDA批准的治疗。 ARDS（急性呼吸窘迫综合征）和败血症是需要重症监护的医疗紧急情况，在30-70％的病例中是致命的。 ARDS和败血症是老年患者死亡的主要原因。它们会因产生致命毒素的细菌而产生严重的感染。肠杆菌科，铜绿假单胞菌，沙门氏菌属和金黄色葡萄球菌主要是由于原因。这些毒素将免疫响应驱动到致命的超过。它们与血小板（PT）结合，激活它们以表达trem1的配体（触发受体在髓样细胞1中表达1），巨噬细胞（Mφ）和中性粒细胞的潜在激活受体。多个活化的PT配体与Mφ，Overtrigger Trem1结合，过度激活Mφ释放大量炎症介质产生过量的全身性炎症反应（SIR）。表达TREM1的活性Mφ是败血症和ards的特征。超过450篇科学文章记录了TREM1在炎症中的作用。 Bioprovar的科学家发现了TREM1-SV，这是在血液和调节中发现的TREM1激活途径（TAP）的天然剪接变体竞争受体。作为一种对抗生素的免疫疗法（AT），Trem1-SV具有强大的有效性，可提高Cecum-Rigation穿刺（CLP）的SIR小鼠的存活率，从而将存活率从0％（单独）提高到67％。根据比较，抑制LPS激活途径的肽阻断Toll样受体4对生存没有显着影响。基于这些数据和当前的知识，生物主机正在开发生物环境，以用抗生素为败血症和ARDS患者使用人类重组（Hu R）Trem1-SV补充，以减轻SIR并防止死亡。理由是，通过竞争过量的TREM1配体，Trem1-SV通过减少触发激活，挫败Mφ过度激活的Trem1-Rigand复合物的数量来调节TAP，从而维持有效的免疫反应。我们的目的是收集GLP生产和毒理学研究工作所需的临床前数据。我们旨在通过传输到CGMP的系统并对其结构身份进行分析表征来优化HU RETrem1-SV的非GLP产生。在使用不同剂量和方案的CLP诱导的动物模型中，Biotremvar的广泛疗法有效性将被证明是一种免疫疗法。使用小鼠和豚鼠（非生产）动物模型，我们将生成药效学，药代动力学，PK/PD关系数据，并计算生物环境的半衰期。 Bioprovar拥有TREM1-SV的权利。我们的长期目标是在溶液中验证生物环境CGMP静脉注射以治疗败血症和ARDS患者。在抑制中心机制方面具有广泛有效的治疗能力至关重要。在败血症或Ards中使用生物环境来抑制SIR是创新的，科学的，并将挽救许多生命。