Low-dose IL-2-based Immunomodulatory Therapy for PAH

基于低剂量 IL-2 的 PAH 免疫调节疗法

• 批准号: 8829630
• 负责人: RIDONG CHEN
• 金额: $ 29.74万
• 依托单位: APT THERAPEUTICS, INC.
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-01 至 2016-10-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8829630
• 关键词: Address; Adverse effects; Affinity; Aftercare; Aldesleukin; Allogenic; Animal Model; Applications Grants; Attenuated; Autoimmune Diseases; Binding; Blood Vessels; Blood capillaries; Breathing; CD8B1 gene; Cells; Cessation of life; Chimeric Proteins; Chronic; Clinical Trials; Connective Tissue Diseases; Disease; Dose; Endothelial Cells; Endothelin-1; Epoprostenol; Escherichia coli; Exhibits; FDA approved; Failure; Fibrosis; Functional disorder; Generations; Gleevec; Glucocorticoids; Half-Life; Hematopoietic Stem Cell Transplantation; Homeostasis; Human; Hypoxia; IL2 gene; IL2RA gene; IL2RB gene; IL2RG gene; Iloprost; Immune; In Vitro; Infection; Inflammation; Inflammatory; Inflammatory Response; Interleukin-2; Intravenous; Kidney; Killer Cells; Lead; Lesion; Longevity; Lung; Lupus; Mammalian Cell; Memory; Modeling; Mutation; Nitric Oxide; Oxidative Stress; Pathway interactions; Patients; Peripheral; Pharmaceutical Preparations; Phase; Phenotype; Plasma; Play; Population; Principal Investigator; Prostaglandins I; Proteins; Pulmonary Vascular Resistance; Pulmonary artery structure; Rattus; Recombinants; Refractory; Regulatory T-Lymphocyte; Renal carcinoma; Respiratory physiology; Right Ventricular Function; Risk; Role; SU 5416; Serum Albumin; Small Business Innovation Research Grant; Solubility; Staging; Syndrome; Systemic Scleroderma; T-Lymphocyte; Therapeutic; Thymus Gland; Treprostinil; Vascular remodeling; Vasodilator Agents; Ventricular; Ventricular Ejection Fractions; Ventricular Remodeling; Workload; ambrisentan; base; bosentan; capillary; chronic graft versus host disease; clinically relevant; coronary fibrosis; cytokine; density; design; follow-up; heart function; immunogenicity; improved; melanoma; memory CD4 T lymphocyte; molecular size; novel; phase III trial; pressure; prevent; programs; public health relevance; pulmonary arterial hypertension; receptor; sildenafil; single molecule; tadalafil; vasoconstriction

 DESCRIPTION (provided by applicant): Despite evidence that inflammatory mechanisms initiate and complicate pathophysiology in pulmonary arterial hypertension (PAH), no strategies have been developed to target the inflammatory cells involved. Moreover, it has been known for years that autoimmune diseases are associated with certain forms of PAH. Hence, novel therapy is urgently needed to attenuate chronic inflammation, restore immune homeostasis and reverse adverse vascular remodeling in order to achieve a persistent improvement of pulmonary and right ventricular functions. Naturally occurring thymus-derived CD4+CD25+Foxp3+ regulatory T cells (nTreg) play vital roles in controlling excessive inflammatory responses and prevent autoimmune disease. Interleukin-2 (IL-2) is the key cytokine for the generation, survival, and function of nTreg by direct binding to its high affinity receptor consisting of three subunits, IL2Rα (CD25), IL2Rβ (CD122) and ɣc (CD132). Recent clinical trial shows that treatment with low-dose IL2 increased nTreg cells population and was associated with reversal of glucocorticoid-refractory chronic graft-versus host disease in patients who had undergone allogeneic hematopoietic stem cell transplantation. We have designed APT602, a fusion protein of human serum albumin (HSA) and IL-2 produced in mammalian cells. The unglycosylated fusion protein (85kD) improves solubility and the in vitro potency by 5 fold and extends plasma half-life by 25 fold (5h). A single mutation was introduced to eliminate the interaction with endothelial cell and lower the risk of vascular leak syndrome. Hence, low-dose APT602 will enable safe, selective, and convenient stimulation of nTreg cells with high-affinity to IL2Rαβɣ receptors while minimizing activation of effector immune cells with intermediate affinity IL2Rβɣ receptors. In the severe and "irreversible" PAH model induced by SU5416/hypoxia in rats, which resembles human PAH pathophysiology, characterized by systemic inflammation and oxidative stress, treatment with APT602 twice a week for 3 weeks effectively restored immune homeostasis and attenuated fibrosis which lead to reversal of lung and RV function. In contrast, neither bosentan (FDA-approved first line vasodilative therapy) nor Gleevec (effective but toxic in Phase III trial) were safe or effective. In this Phase I SBIR grant application, we will determie whether transient treatment with APT602 will achieve long-term improvement of pulmonary and RV function. Specific Aim. Determine whether treatment of APT602 twice a week for 3 weeks, initiated 21 days after PAH induction, will safely reverse pulmonary and RV remodeling and function 12 weeks of follow up post the treatment in the rat model of SU5416/hypoxia-induced severe PAH.

 描述（由申请人提供）：尽管有证据表明炎症机制启动了肺动脉高压（PAH）的病理生理学并使其复杂化，但尚未开发出靶向相关炎症细胞的策略。此外，多年来人们已经知道，自身免疫性疾病与某些形式的PAH有关。因此，迫切需要新的治疗方法来减轻慢性炎症，恢复免疫稳态和逆转不良血管重塑，以实现肺和右心室功能的持续改善。 胸腺来源的CD 4 + CD 25 + Foxp 3+调节性T细胞（nTreg）在控制过度炎症反应和预防自身免疫性疾病中发挥重要作用。白细胞介素-2（IL-2）是nTreg通过直接结合其由三个亚基组成的高亲和力受体而产生、存活和发挥功能的关键细胞因子， IL2Rα（CD25）、IL2Rβ（CD122）和IL2C（CD132）。最近的临床试验表明，低剂量IL 2治疗增加了nTreg细胞群，并与接受异基因造血干细胞移植的患者中糖皮质激素难治性慢性移植物抗宿主病的逆转相关。我们设计了人血清白蛋白（HSA）和IL-2在哺乳动物细胞中产生的融合蛋白APT 602。未糖基化的融合蛋白（85 kD）将溶解度和体外效力提高了5倍，并将血浆半衰期延长了25倍（5 h）。引入单一突变以消除与内皮细胞的相互作用并降低血管渗漏综合征的风险。因此，低剂量APT 602将能够安全、选择性和方便地刺激对IL 2 R αβ受体具有高亲和力的nTreg细胞，同时最大限度地减少对中等亲和力IL 2 R β β受体的效应免疫细胞的激活。 在大鼠中由SU 5416/缺氧诱导的重度和“不可逆”PAH模型中，其类似于人类PAH病理生理学，特征在于全身炎症和氧化应激，每周两次用APT 602治疗3周有效地恢复了免疫稳态并减弱了纤维化，这导致肺和RV功能逆转。相比之下，波生坦（FDA批准的一线血管舒张治疗）和格列卫（III期试验中有效但有毒）均不安全或有效。在这一I期SBIR资助申请中，我们将确定使用APT 602的短暂治疗是否会实现肺和RV功能的长期改善。 具体目标。在SU 5416/缺氧诱导的重度PAH大鼠模型中，确定在PAH诱导后21天开始的每周两次持续3周的APT 602治疗是否会安全地逆转肺和RV重塑以及治疗后12周的随访功能。