GENERATION AND CLINICAL USE OF HUMAN ANTIID ANTIBODIES

人抗抗体的产生和临床应用

• 批准号: 2100172
• 负责人: MANSOOR N SALEH
• 金额: $ 16.92万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 1994
• 资助国家: 美国
• 起止时间: 1994-07-25 至 1997-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2100172
• 关键词: B lymphocyte; T lymphocyte; antiidiotype antibody; clinical trials; disease /disorder model; drug adverse effect; enzyme linked immunosorbent assay; human subject; human therapy evaluation; humoral immunity; immunomodulators; laboratory rabbit; melanoma; monoclonal antibody; neoplasm /cancer chemotherapy; neoplasm /cancer immunotherapy; neoplasm /cancer vaccine; tumor antigens; western blottings

Tumor associated antigens (TAA) are generally non- or only very weakly immunogenic and therefore do not promote tumor rejection. The overall objective of the proposed research is to generate human anti-idiotypic (anti-Id) monoclonal antibodies (MoAb)that mimic the melanoma associated GD2 antigen, with the ultimate purpose of clinically applying these reagents as anti-tumor vaccines. Patients exposed to anti-tumor MoAbs generally mount an immune response to the foreign protein. A component of this human immune response is anti-Id; can be shown to bind to the antigen combining site of the MoAb; and can potentially mimic the target TAA ("internal image" anti-Id). The focus of the project will be: a. To harvest lymphocytes from patients treated with anti-GD2 MoAbs at our institution and use these to generate human anti-Ids that mimic the GD2 antigen. b. To characterize the immune response generated by these reagents in animal models in regards to B-cell and T-cell anti-anti-Id and anti-GD2 immune responses. These studies will identify those anti-Ids that truly mimic the GD2 antigen and can be used as immunomimetic surrogates. c. To characterize sites on the anti-Id that mimic the TAA on one hand and generate the anti-tumor immune response. To this end, the V-region genes of the anti-Id will be sequenced. d. To identify, in relevant animal models, the dose and immune adjuvant combination that will elicit the most effective immune and anti-tumor response. e. To conduct a phase I clinical trial in high risk/low tumor burden melanoma patients to study the toxicity and immunologic response of the anti-Id vaccine. These studies will provide insight into the immune mechanisms involved in the application of human anti-Id vaccines and generate novel options for the biologic therapy of melanoma as well as other human malignancies.

肿瘤相关抗原 (TAA) 通常无或仅非常弱 具有免疫原性，因此不会促进肿瘤排斥。整体 拟议研究的目的是产生人类抗独特型 模拟黑色素瘤相关的（抗 Id）单克隆抗体（MoAb） GD2抗原，最终目的是临床应用这些 用作抗肿瘤疫苗的试剂。 接触抗肿瘤单克隆抗体的患者通常会产生免疫反应 外来蛋白质。这种人类免疫反应的一个组成部分是抗Id； 可以显示与MoAb的抗原结合位点结合；并且可以 可能模仿目标 TAA（“内部图像”反 Id）。 该项目的重点将是： 一个。在我们的中心从接受抗 GD2 MoAb 治疗的患者身上采集淋巴细胞 机构并使用它们来生成模仿 GD2 的人类抗 ID 抗原。 b.表征这些试剂产生的免疫反应 关于B细胞和T细胞抗抗Id和抗GD2的动物模型 免疫反应。这些研究将确定那些真正有效的抗 Ids 模拟 GD2 抗原，可用作免疫模拟替代物。 c.一方面表征抗 Id 上模仿 TAA 的位点，另一方面 产生抗肿瘤免疫反应。为此，V区基因 将对抗Id进行测序。 d.确定相关动物模型中的剂量和免疫佐剂 组合将引发最有效的免疫和抗肿瘤 回复。 e.开展高风险/低肿瘤负荷的I期临床试验 黑色素瘤患者研究其毒性和免疫反应 抗 ID 疫苗。 这些研究将深入了解涉及的免疫机制 人类抗 ID 疫苗的应用并产生新的选择 黑色素瘤以及其他人类恶性肿瘤的生物疗法。