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（由申请人提供）：尽管有证据表明炎症机制引发肺动脉高压（PAH）并使病理生理学复杂化，但尚未开发出针对相关炎症细胞的策略。此外，多年来已知自身免疫性疾病与肺动脉高压（PAH）相关。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，以实现肺和右心室的持续改善。天然存在的胸腺来源的 CD4+CD25+Foxp3+ 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方面发挥着至关重要的作用。 nTreg 的功能是通过直接结合到由三个亚基组成的高亲和力受体， IL2Rα (CD25)、IL2Rβ (CD122) 和 ɣc (CD132) 最近的临床试验表明，低剂量 IL2 治疗可增加 nTreg 细胞数量，并与接受手术的患者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APT602，一种人血清白蛋白（HSA）的融合蛋白。哺乳动物细胞中产生的非糖基化融合蛋白（85kD）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 小时）。因此，低剂量 APT602 将能够安全、选择性、方便地刺激与 IL2Rαβɣ 具有高亲和力的 nTreg 细胞。在 SU5416/缺氧诱导的严重且“不可逆”的大鼠 PAH 模型中，该模型类似于人类 PAH 病理生理学，其特征是全身炎症和氧化应激，每周两次使用 APT602 治疗。 3周有效恢复免疫稳态并减轻纤维化，从而导致肺和右心室功能逆转。波生坦（FDA 批准的一线血管舒张疗法）和格列卫（在 III 期试验中有效，但有毒）都是安全或有效的。在本次 I 期 SBIR 拨款申请中，我们将确定 APT602 的短暂治疗是否能实现肺功能的长期改善。确定在 PAH 诱导后 21 天开始每周两次、持续 3 周的 APT602 治疗能否安全逆转 12 周的肺和 RV 重塑和功能。 SU5416/缺氧诱导的严重 PAH 大鼠模型治疗后的随访。