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

基于低剂量 IL-2 的 PAH 免疫调节疗法

基本信息

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
项目类别：
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

项目摘要

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（由适用提供）：尽管有证据表明炎症机制在肺动脉高压（PAH）中启动并使病理生理复杂化，但尚未制定针对涉及炎症细胞的策略。此外，多年来，自身免疫性疾病与某些形式的PAH有关。因此，迫切需要新的治疗来减轻慢性感染，恢复免疫稳态和反向不良血管重塑，以实现肺部和右心室功能的持续改善。天然发生的胸腺衍生的CD4+CD25+FOXP3+调节性T细胞（NTREG）在控制过度的炎症反应并预防自身免疫性疾病方面起着至关重要的作用。白介素-2（IL-2）是通过直接结合其高亲和力受体的生成，生存和功能的关键细胞因子，该受体由三个亚基组成， IL2Rα（CD25），IL2Rβ（CD122）和ɣC（CD132）。最近的临床试验表明，低剂量IL2的治疗增加了NTREG细胞的种群，并且与经历同种异性造血干细胞移植的患者中糖皮质激素 - 慢性慢性慢性染色体移植物伴有宿主疾病有关。我们已经设计了Apt602，一种在哺乳动物细胞中产生的人血清白蛋白（HSA）和IL-2的融合蛋白。未糖基化的融合蛋白（85KD）可提高溶解度和体外效力5倍，并将血浆半衰期延长25倍（5H）。引入了单个突变，以消除与内皮细胞的相互作用，并降低血管泄漏综合征的风险。因此，低剂量APT602将使对IL2Rαβ受体高亲和力的NTREG细胞具有安全，选择性和方便的刺激，同时最大程度地减少具有中间亲和力IL2Rβɣ受体的效应免疫细胞的激活。在由SU5416/缺氧引起的严重和“不可逆”的PAH模型中，大鼠类似于人类PAH病理生理学，其特征是全身性炎症和氧化应激，每周两次APT602治疗3周，持续3周有效地恢复了免疫稳态，并恢复了Lung和Runung reversal everversal和RV的纤维化。相比之下，波森坦（FDA批准）的一线血管疾病疗法都不是安全或有效的Gleevec（在III期试验中有效但有毒）。在此I阶段I SBIR赠款应用中，我们将确定使用APT602的瞬时处理是否会长期改善肺和RV功能。具体目标。确定在PAH诱导后21天启动的每周两次APT602的处理是否会安全地逆转肺和RV重塑，并在SU5416/SU5416/低氧诱导的严重PAH的大鼠模型中进行后续处理12周。