CD137 AS A TARGET FOR THE IMMUNOTHERAPY OF CANCER

CD137 作为癌症免疫治疗的靶点

• 批准号: 7294885
• 负责人: Daniel G. Schindler
• 金额: $ 68.48万
• 依托单位: GTC BIOTHERAPEUTICS, INC.
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-04-15 至 2009-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7294885
• 关键词: Affinity; Animals; Antibodies; Antineoplastic Agents; Antithrombins; Antitumor Response; Autoimmune Process; Autoimmunity; B-Lymphocytes; Binding; Biological Response Modifier Therapy; Biopsy; Blood Cells; Blood specimen; Breast; CD4 Positive T Lymphocytes; Caliber; Cancer Patient; Cattle; Cell Surface Receptors; Cells; Characteristics; Chimeric Proteins; Clinical; Clinical Trials; Complementary DNA; Dendritic Cells; Disease regression; Doctor of Medicine; Doctor of Philosophy; Drug Formulations; Engineering; Experimental Models; Future; Generations; Genus Capra; Goals; Goat; Grant; Helper-Inducer T-Lymphocyte; Human; Human papillomavirus 16; Immune system; Implant; In Situ Hybridization; In Vitro; Knock-out; Lead; Leukocytes; Ligands; Lymphoma; Malignant Neoplasms; Malignant neoplasm of ovary; Maryland; Measures; Membrane Glycoproteins; Methods; Milk; Modeling; Molecular; Molecular Weight; Monoclonal Antibodies; Mus; Natural Killer Cells; Numbers; Parents; Patients; Pharmacologic Substance; Phase; Plasmacytoma; Pre-Clinical Model; Preparation; Process; Proteins; Protocols documentation; Qualifying; RNA; Range; Rattus; Reaction; Recombinants; Research; Role; SCID Mice; Safety; Signal Transduction; Site; Skin; Small Business Funding Mechanisms; Small Business Innovation Research Grant; Solid Neoplasm; Southern Blotting; Specificity; Standards of Weights and Measures; T-Lymphocyte; Testing; Therapeutic; Therapeutic Agents; Therapeutic Uses; Transgenes; Transgenic Organisms; Translations; Treatment Protocols; Tumor Immunity; Universities; Xenograft Model; antigen binding; base; cancer immunotherapy; cancer therapy; cell growth; chimeric antibody; design; eosinophil; in vivo; medical schools; melanoma; mouse model; neutrophil; novel; pre-clinical; programs; protein purification; reconstitution; research clinical testing; response; scale up; success; sugar; therapeutic protein; tumor; tumor growth; tumor xenograft

DESCRIPTION (provided by applicant): The objective of this Phase II SBIR project is to build on the success of a Phase 1 SBIR FLAIR grant to produce and characterize a chimeric form of antibody against human CD137 that is suitable for human clinical testing. CD137 (also called 4-1BB) is a membrane glycoprotein that is inducibly expressed on human leukocytes. Stimulation of CD137 by its natural ligand or by agonistic antibodies potentiates an antitumor response that causes regression of established mouse tumors in various models. Anti-CD137 offers great promise as a potential therapeutic agent against certain solid tumors. In Phase I, we generated transgenic goats expressing anti-human CD137 at commercially feasible levels and provided preliminary evidence of bioactivity in a human tumor xenograft model in SCID mice. This antibody is a chimeric protein that contains: 1) the antigen binding regions from a well-characterized agonistic mouse anti-human CD137 mAb (Clone GW); and 2) human CH and CL sequences that are designed to minimize reactions against murine proteins in therapeutic regimens that require repeated administrations. The next steps in the clinical translation of anti-CD137 for human cancer therapy are to: 1) qualify the transgenic goats as founder animals; 2) optimize and scale up a commercially feasible process to purify chimeric anti-human CD137 from goat milk; 3) biochemically characterize the purified anti-human CD137; and 4) test the efficacy of purified anti-human CD137 against human tumors in mice. The long-term goal of this research program is to produce a novel anti-cancer drug, chimeric anti-human CD137 monoclonal antibody, in the milk of transgenic goats and to test purified preparations in appropriate experimental models in preparation for future clinical trials in melanoma cancer patients. Successful completion of this project will lead to final preclinical safety analysis and then to human clinical trials to test the efficacy of anti-human CD137 against solid tumors.

描述（由申请人提供）：第二阶段 SBIR 项目的目标是在第一阶段 SBIR FLAIR 拨款成功的基础上，生产和表征适合人类临床测试的针对人类 CD137 的嵌合形式抗体。 CD137（也称为 4-1BB）是一种在人类白细胞上诱导表达的膜糖蛋白。 CD137 通过其天然配体或激动性抗体的刺激可增强抗肿瘤反应，从而导致各种模型中已建立的小鼠肿瘤消退。抗 CD137 作为针对某些实体瘤的潜在治疗剂具有巨大的前景。在第一阶段，我们培育了以商业可行水平表达抗人 CD137 的转基因山羊，并在 SCID 小鼠的人类肿瘤异种移植模型中提供了生物活性的初步证据。该抗体是一种嵌合蛋白，包含：1) 来自充分表征的激动性小鼠抗人 CD137 mAb（克隆 GW）的抗原结合区； 2) 人类 CH 和 CL 序列，旨在最大限度地减少需要重复给药的治疗方案中针对鼠蛋白的反应。抗CD137用于人类癌症治疗的临床转化的下一步是：1）将转基因山羊鉴定为创始动物； 2) 优化并扩大商业上可行的工艺，从羊奶中纯化嵌合抗人CD137； 3)对纯化的抗人CD137进行生化表征； 4）测试纯化的抗人CD137在小鼠体内对抗人类肿瘤的功效。该研究计划的长期目标是在转基因山羊奶中生产一种新型抗癌药物——嵌合抗人CD137单克隆抗体，并在适当的实验模型中测试纯化制剂，为未来黑色素瘤的临床试验做准备。癌症患者。该项目的成功完成将导致最终的临床前安全性分析，然后进行人体临床试验，以测试抗人CD137对抗实体瘤的功效。

项目成果

Fc-dependent expression of CD137 on human NK cells: insights into "agonistic" effects of anti-CD137 monoclonal antibodies.

CD137 在人类 NK 细胞上的 Fc 依赖性表达：深入了解抗 CD137 单克隆抗体的“激动”作用。

• 发表时间: 2008-08-01
• 影响因子: 20.3
• 作者: Lin, Wei;Voskens, Caroline J;Zhang, Xiaoyu;Schindler, Daniel G;Wood, Aaron;Burch, Erin;Wei, Yadong;Chen, Lieping;Tian, Guoliang;Tamada, Koji;Wang, Lai;Schulze, Dan H;Mann, Dean;Strome, Scott E
• 通讯作者: Strome, Scott E