CD137 AS A TARGET FOR THE IMMUNOTHERAPY OF CANCER

CD137 作为癌症免疫治疗的靶点

• 批准号: 6779525
• 负责人: Daniel G. Schindler
• 金额: $ 30万
• 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 2006-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6779525
• 关键词: CD antigens; NOD mouse; SCID mouse; animal extract; antitumor antibody; biotechnology; clinical research; colostrums; flow cytometry; fluorescent in situ hybridization; genetically modified animals; glycoproteins; goats; human subject; hybrid antibody; hybridomas; immunologic substance development /preparation; membrane proteins; molecular cloning; neoplasm /cancer immunotherapy; polymerase chain reaction; site directed mutagenesis; transfection

DESCRIPTION (provided by applicant): The objective of this proposal is to establish the feasibility of producing anti-human CD137 antibody, an immune modulator that may be effective against solid tumors, in the milk of transgenic animals. CD137 (also called 4-1BB) is a membrane glycoprotein that can be induced in several types of lymphoid cells. An agonistic monoclonal antibody (mAb) against murine CD137 shrank mouse tumors in vivo and prevented their recurrence, suggesting that anti-CD137 may be effective against human tumors. The next technical hurdle to clinical translation is to develop a genetically engineered form of the anti-human CD137 that is suitable for clinical use, and to demonstrate that it is effective against human tumors in an appropriate mouse model. Genetic engineering can produce a chimeric anti-CD137 containing mostly human sequences, which should reduce the risk that patients will mount an immune response against the therapeutic antibody. GTC-Bio has developed a safe and cost-effective production source of mAbs, antibody fragments and modified immunoglobulin products by expressing recombinant proteins in the milk of transgenic dairy animals. We now propose to establish proof of principle for commercially production of chimeric anti-human CD137 by: 1) producing and characterizing transgenic mice expressing chimeric anti-human CD137 in their milk; and 2) demonstrating that this protein is bioactive in human tumor xenograft models in immuno-deficient mice. If this work is successful, it will lead to a Phase II proposal to produce chimeric anti-human CD137 in transgenic goats and to test purified preparations in preclinical studies and in clinical trials with ovarian cancer patients.

描述（由申请人提供）：本提案的目的是确定在转基因动物的乳汁中生产抗人 CD137 抗体的可行性，该抗体是一种可能有效对抗实体瘤的免疫调节剂。 CD137（也称为 4-1BB）是一种膜糖蛋白，可在多种类型的淋巴细胞中诱导产生。抗鼠 CD137 的激动性单克隆抗体 (mAb) 可缩小小鼠体内肿瘤并防止其复发，这表明抗 CD137 可能对人类肿瘤有效。临床转化的下一个技术障碍是开发一种适合临床使用的基因工程形式的抗人CD137，并在适当的小鼠模型中证明它对人类肿瘤有效。 基因工程可以产生主要含有人类序列的嵌合抗CD137，这应该会降低患者对治疗性抗体产生免疫反应的风险。 GTC-Bio 通过在转基因奶牛的乳汁中表达重组蛋白，开发了一种安全且具有成本效益的单克隆抗体、抗体片段和修饰免疫球蛋白产品的生产来源。我们现在建议通过以下方式建立嵌合抗人 CD137 商业化生产的原理证明：1) 生产并表征在乳汁中表达嵌合抗人 CD137 的转基因小鼠； 2) 证明该蛋白在免疫缺陷小鼠的人类肿瘤异种移植模型中具有生物活性。如果这项工作成功，将导致一项 II 期提案，即在转基因山羊中生产嵌合抗人 CD137，并在临床前研究和卵巢癌患者的临床试验中测试纯化制剂。