HL-Development and Pharmacology of novel lipidic rAHF and biotherapeutics

HL-新型脂质性 rAHF 和生物治疗药物的开发和药理学

• 批准号: 9198565
• 负责人: SATHY VENKAT BALU-IYER
• 金额: $ 39.54万
• 依托单位: STATE UNIVERSITY OF NEW YORK AT BUFFALO
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-04-01 至 2019-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9198565
• 关键词: Animals; Antibodies; Antigens; Apoptotic; Autoimmune Diseases; B-Lymphocytes; Biological Response Modifier Therapy; Biophysics; Blood Coagulation Disorders; Blood coagulation; Cells; Characteristics; Charge; Clinical; Clinical Trials; Complication; Data; Dendritic Cells; Development; Disease; Disease model; Engineering; Experimental Designs; F8 gene; Factor IX; Factor VIII; Generations; Glucan 1,4-alpha-Glucosidase; Glycogen storage disease type II; Goals; Grant; Health; Hemophilia A; Hemophilia B; Hemorrhage; Hemostatic Agents; Human; Hypersensitivity; Immune; Immune Tolerance; Immune response; Immunization; Immunologics; Immunosuppressive Agents; Knowledge; Lead; Life; Lipids; Mediating; Memory B-Lymphocyte; Mission; Mus; Oral; Outcome; Outer Leaflet of the Lipid Bilayer; Pharmaceutical Preparations; Pharmacodynamics; Pharmacology; Phase; Phenotype; Phosphatidylinositols; Phosphatidylserines; Plasma; Pre-Clinical Model; Property; Proteins; Protocols documentation; Public Health; Regulatory T-Lymphocyte; Replacement Therapy; Research; Route; Safety; Savings; Signal Transduction; T-Lymphocyte; Testing; Tolerogen; Treatment Efficacy; Treatment Failure; United States National Institutes of Health; Vesicle; Work; base; biophysical properties; cost; density; design; enzyme replacement therapy; exosome; immunogenic; immunoregulation; improved; inhibitor/antagonist; innovation; insight; neutralizing antibody; novel; novel strategies; oxidation; particle; prevent; programs; protein S precursor; public health relevance; response; success; therapeutic protein; vaccination strategy; von Willebrand Disease

 DESCRIPTION (provided by applicant) The safety and efficacy of several life-saving protein therapeutics are compromised by unwanted immune responses. Currently there are no viable clinical options to reduce or reverse these responses. Our goal is to develop protein delivery strategies that improve therapeutic efficacy of protein drugs by reducing or reversing unwanted immune responses. During the previous project period, we observed that exposure of mice to protein therapeutics in the presence of phosphatidylserine (PS) resulted in an antigen specific immunological tolerance/hypo-responsiveness towards the protein, leading to our central hypothesis that PS is immune regulatory and has the capacity to convert immunogenic proteins into tolerogens. To fully realize the clinical potential of this observation, it is necessary to determine the structural characteristics of PS that contribute to its ability to convert an immunogen into a tolerogen (SA1), and to use this information to reduce (SA2) and reverse (SA3) unwanted immune responses to therapeutic proteins and improve their therapeutic efficacy. In SA1 we hypothesize that PS converts dendritic cells from an immunogenic to a tolerogenic phenotype, generating regulatory T-cells that in turn suppress antigen-specific T-cells and B-cells. We investigate the structural and biophysical determinants of PS that program dendritic cells to send tolerogenic over immunogenic signals. Since pre-exposure of mice to FVIII in the presence of PS significantly reduced their immune response during re-challenge with FVIII, in SA2, we investigate a similar pre-treatment approach with two other immunogenic therapeutic proteins to prevent or reduce unwanted immune responses to these proteins during therapy. Specifically we will test this approach with acid alpha glucosidase (GAA in Pompe disease, a lysosomal storage disorder) and Factor IX (in Hemophilia B, a bleeding disorder). We will determine the immune cells that are involved in the induction of tolerance, and establish the impact of such tolerance induction on the efficacy of these two replacement therapies. In SA3, we develop clinical strategies to reverse established responses to FVIII, FIX and GAA, and thereby improve the efficacy of treatments for these bleeding and lysosomal disorders. Since PS is exposed in outer layer of secreted vesicles such as apoptotic bodies and on exosomes released from cells, we propose and will test the hypothesis that lipid particles mimicking these natural vesicles will reverse the established immune responses to therapeutic proteins. Our goal in SA3 is the optimization of immunization protocol and testing of an artificial lipid particle tha mimics the secreted vesicles, to reverse the unwanted established immune responses. These studies are expected to lead to novel clinical strategies to reduce and reverse immune responses to therapeutic proteins and thereby improve the efficacy of several lifesaving protein-based therapies.

 描述（由申请人提供）几种挽救生命的蛋白质治疗剂的安全性和有效性受到不需要的免疫应答的损害。目前没有可行的临床选择来减少或逆转这些反应。我们的目标是开发蛋白质递送策略，通过减少或逆转不必要的免疫反应来提高蛋白质药物的治疗效果。在之前的项目期间，我们观察到小鼠在磷脂酰丝氨酸（PS）存在下暴露于蛋白质治疗剂导致对蛋白质的抗原特异性免疫耐受性/低反应性，导致我们的中心假设PS是免疫调节性的，并且具有将免疫原性蛋白质转化为耐受原的能力。为了充分实现这一观察结果的临床潜力，有必要确定有助于其将免疫原转化为耐受原（SA 1）的能力的PS的结构特征，并使用该信息减少（SA 2）和逆转（SA 3）对治疗性蛋白质的不需要的免疫应答并提高其治疗功效。在SA 1中，我们假设PS将树突状细胞从免疫原性表型转化为致耐受性表型，产生调节性T细胞，进而抑制抗原特异性T细胞和B细胞。我们研究了PS的结构和生物物理决定因素，这些决定因素使树突状细胞在免疫原性信号上发送致耐受性信号。由于在存在PS的情况下将小鼠预暴露于FVIII显著降低了其在用FVIII再激发期间的免疫应答，因此在SA 2中，我们研究了使用两种其他免疫原性治疗蛋白的类似预处理方法，以预防或减少治疗期间对这些蛋白的不必要的免疫应答。具体而言，我们将用酸性α葡糖苷酶（庞贝氏症，一种溶酶体贮积症中的GAA）和因子IX（血友病B，一种出血性疾病）测试这种方法。我们将确定参与诱导耐受的免疫细胞，并确定这种耐受诱导对这两种替代疗法疗效的影响。在SA 3中，我们开发了临床策略来逆转对FVIII、FIX和GAA的既定应答，从而提高这些出血和溶酶体疾病的治疗疗效。由于PS暴露在分泌囊泡的外层，如凋亡小体和从细胞释放的外泌体上，我们提出并将测试以下假设：模拟这些天然囊泡的脂质颗粒将逆转对治疗性蛋白质的既定免疫应答。我们在SA 3中的目标是优化免疫方案和测试模拟分泌囊泡的人工脂质颗粒，以逆转不需要的已建立的免疫应答。这些研究预计将导致新的临床策略，以减少和逆转对治疗性蛋白质的免疫反应，从而提高几种挽救生命的蛋白质疗法的疗效。