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）：该II期SBIR项目的目的是建立在1阶段SBIR FLAIR赠款的成功基础上，以生产和表征针对人类CD137的嵌合形式的抗体形式，该抗体适用于人类临床测试。 CD137（也称为4-1BB）是一种在人白细胞上诱导表达的膜糖蛋白。通过天然配体或通过激动抗体刺激CD137会增强抗肿瘤反应，从而导致各种模型中已建立的小鼠肿瘤的消退。抗CD137作为针对某些实体瘤的潜在治疗剂提供了巨大的希望。在第一阶段，我们以市值可行的水平产生了表达抗人CD137的转基因山羊，并在SCID小鼠中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，其中包含：1）来自特征良好的激动小鼠抗人CD137 mAb（克隆GW）的抗原结合区域； 2）旨在最大程度地减少需要重复施用的治疗方案中对鼠蛋白的反应的人类CH和CL序列。用于人类癌症治疗的抗CD137临床翻译的下一步是：1）符合转基因山羊作为创始人的限定； 2）优化和扩展商业上可行的过程，从山羊奶中净化嵌合抗人类CD137； 3）生化表征纯化的抗人CD137； 4）测试纯化的抗人CD137对小鼠人类肿瘤的疗效。该研究计划的长期目标是在转基因山羊的牛奶中生产一种新型的抗癌药物嵌合抗人CD137单克隆抗体，并在适当的实验模型中测试纯化的制剂，以制备为黑色素瘤癌症患者的未来临床试验的准备。该项目的成功完成将导致最终的临床前安全分析，然后进行人类临床试验，以测试抗人CD137对实体瘤的功效。