Synergistic Efficacy of an Interleukin 2 Analog and Antitumor Antigen Antibody

白细胞介素 2 类似物和抗肿瘤抗原抗体的协同功效

基本信息

批准号：
9905448
负责人：
RIDONG CHEN
金额：
$ 30万
依托单位：
APT THERAPEUTICS, INC.
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-09-18 至 2021-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9905448
关键词：
Affinity Aldesleukin Alleles Antibodies Antibody Therapy Antigens Binding Binding Sites Biodistribution Blood Vessels CD8-Positive T-Lymphocytes CD8B1 gene CT26 Cancer Patient Cells Cetuximab Chimeric Proteins Clinical Colon Adenocarcinoma Cyclic GMP Data Disease remission Dose Drug Combinations Endothelial Cells Eragrostis Escherichia coli Evaluation FOXP3 gene Goals Half-Life Hepatic Hour Human IL2RA gene Immune Immune response Immunosuppression Immunosuppressive Agents Immunotherapy In complete remission Infusion procedures Interleukin-2 Interleukins Intravenous Investigational Drugs Longterm Follow-up Lymphoma MC38 Malignant Neoplasms Mammalian Cell Modeling Mus Mutation Natural Killer Cells Patients Pharmaceutical Preparations Phase Plasma Principal Investigator Proteins Protocols documentation Pulmonary Edema Recombinant Proteins Regimen Regulatory T-Lymphocyte Renal Cell Carcinoma Renal carcinoma Safety Serum Albumin Syndrome TYRP1 gene Therapeutic Effect Therapeutic Index Thymus Gland Toxic effect Toxicology Trastuzumab Treatment Efficacy Tumor Antibodies Tumor Antigens Tyrosine Withholding Treatment Work analog antibody-dependent cell cytotoxicity anticancer activity cancer immunotherapy cost cytotoxic design immunogenic improved innovation macrophage melanocyte melanoma mouse model neoplastic cell neutrophil pre-clinical preservation prevent programs receptor response rituximab side effect success tumor

项目摘要

Principal Investigator/Program Director (Last, First, Middle: Chen, Ridong Abstract Interleukin-2 (IL-2) immunotherapy can result in remarkable long-term responses in some cancer patients by stimulating the immune response to kill tumor cells. However, current rIL-2 therapy is limited to highly selected patients due to its requirements for high and frequent dosing, which can result in severe side effects. Moreover, rIL-2 also activates CD4+ regulatory T cells, which suppress the immune response. To ameliorate the liabilities of the current rIL-2 drug, we have designed a long-acting IL-2 analog that selectively preserves immune response activation (CD8+ T, NK cells), without activating regulatory T cells and endothelial cells; thereby, minimizing immune suppression and vascular leak syndrome. We propose to optimize combination of rIL2 analog treatment plus antitumor antibody to safely and effectively kill tumor cells via a concerted innate and adaptive response involving neutrophils, NK cells, macrophages, and CD8+ T cells. In this study, the Specific Aim is to use the syngeneic mouse model of B16-F10 to determine whether the combination of the proprietary IL-2 analog with an antitumor antigen antibody effectively eradicates established tumors without inducing adverse side effects. Our long-term goal is to develop the proprietary IL-2 analog as a safe immunotherapy to cure cancer or extend survival of patients.

首席研究员/项目主任（姓、名、中：陈日东抽象的白细胞介素 2 (IL-2) 免疫疗法可通过以下方式对某些癌症患者产生显着的长期反应：刺激免疫反应杀死肿瘤细胞。然而，目前的 rIL-2 疗法仅限于高度选择性的由于其需要高剂量和频繁的剂量，这可能会导致严重的副作用。而且， rIL-2 还会激活 CD4+ 调节性 T 细胞，从而抑制免疫反应。改善负债针对目前的rIL-2药物，我们设计了一种长效IL-2类似物，可以选择性地保留免疫反应激活（CD8+ T、NK 细胞），而不激活调节性 T 细胞和内皮细胞；从而，最大限度地减少免疫抑制和血管渗漏综合征。我们建议优化 rIL2 类似物治疗的组合加上抗肿瘤抗体，通过协调一致的先天和适应性反应安全有效地杀死肿瘤细胞涉及中性粒细胞、NK 细胞、巨噬细胞和 CD8+ T 细胞。本研究的具体目标是利用 B16-F10 的同基因小鼠模型来确定是否专有的 IL-2 类似物与抗肿瘤抗原抗体的组合可有效根除已建立的肿瘤，而不引起不良副作用。我们的长期目标是开发专有的 IL-2 类似物作为安全的免疫疗法可以治愈癌症或延长患者的生存期。