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

• 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
• 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

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.

首席调查员/项目主任(最后、第一、中间：陈日东 摘要 白介素2(IL-2)免疫疗法可通过以下方式在某些癌症患者中产生显著的长期反应 刺激免疫反应杀死肿瘤细胞。然而，目前的rIL-2治疗仅限于高度选择。 患者由于其对剂量的要求高而频繁，这可能会导致严重的副作用。此外， RIL-2还能激活CD4+调节性T细胞，从而抑制免疫反应。减轻债务负担 在目前的rIL-2药物中，我们设计了一种长效的IL-2类似物，它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；从而最小化 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 添加抗肿瘤抗体，通过协调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。 在这项研究中，具体目的是利用B16-F10同基因小鼠模型来确定 专有的IL-2类似物与抗肿瘤抗原抗体的结合有效地根除了已建立的 对肿瘤无不良反应。我们的长期目标是开发专有的IL-2类似物作为 用于治愈癌症或延长患者生存时间的安全免疫疗法。