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.

在美国，每年有1,665,000例败血症病例(H-CUP#122)，有近500,000人相关死亡，目前，FDA没有批准治疗。ARDS(急性呼吸窘迫综合征)和脓毒症是需要重症监护的紧急医疗事件，在30%-70%的病例中是致命的。ARDS和脓毒症是老年患者的主要死亡原因。它们会因产生致命毒素的细菌而受到严重感染。主要原因是肠杆菌科细菌、铜绿假单胞菌、沙门氏菌和金黄色葡萄球菌。这些毒素驱使免疫反应达到致命的过量。它们与血小板(PT)结合，激活它们表达TREM1(触发表达于髓系细胞1的受体)的配体，TREM1是巨噬细胞(MΦ)和中性粒细胞的有效激活受体。多个活化的PT配体与MΦ结合，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是脓毒症和急性呼吸窘迫综合征的特征。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，调节TREM1-激活途径(TAP)。作为抗生素(AT)的免疫治疗，TREM1-SV对盲肠结扎穿刺术(CLP)所致SIR小鼠的存活率有明显的提高作用，使小鼠的存活率从0%提高到67%。相比之下，用封闭Toll样受体4的多肽抑制内毒素激活途径对存活率没有显著影响。在这些数据和现有知识的基础上，BioPROVAR正在开发BioTremvarTM，给脓毒症和ARDS患者补充人类重组(HU R)TREM1-SV和抗生素，以减轻SIR和防止死亡。其基本原理是，通过竞争多余的TREM1配体，TREM1-SV通过减少触发激活的TREM1-配体复合体的数量来调节TAP，从而阻止MΦ的过度激活，从而维持有效的免疫反应。我们的目标是收集GLP生产和毒理学研究中使能IND的工作所需的临床前数据。我们的目标是通过一个可转移到cGMP的系统来优化Hu rTREM1-SV的非GLP生产，并对其结构同一性进行分析表征。BioTremvar的广泛疗效将作为一种抗生素免疫疗法在CLP诱导的SIR的动物模型中使用不同的剂量和方案进行证明。使用小鼠和豚鼠(非啮齿动物)动物模型，我们将产生药效学、药动学、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溶液中用于静脉注射治疗脓毒症和ARDS患者的有效性。至关重要的是，有一种广泛有效的治疗方法来抑制维持这些疾病的中央机制。在脓毒症或ARDS中使用BioTremvarTM抑制SIR是创新的、有科学依据的，将拯救许多人的生命。