GENERATION AND CLINICAL USE OF HUMAN ANTIID ANTIBODIES

肿瘤相关抗原(TAA)通常不是或仅非常弱 免疫原性，因此不促进肿瘤排斥反应。整体而言 这项拟议研究的目标是产生人类抗独特型 模拟相关黑色素瘤的(抗ID)单抗(MOAB) GD2抗原，最终目的是应用于临床 作为抗肿瘤疫苗的试剂。 暴露于抗肿瘤MoAbs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； 可以与摩押的抗原结合部位结合；并且可以 潜在地模仿目标TAA(“内部映像”反ID)。 该项目的重点将是： A.在我们的中心采集抗GD2 MoAbs治疗患者的淋巴细胞 并使用它们来生成模仿GD2的人类抗ID 抗原。 B.为了表征这些试剂产生的免疫反应， B细胞和T细胞抗-ID和抗-GD2的动物模型 免疫反应。这些研究将确定那些真正 模拟GD2抗原，可作为免疫仿生替代物。 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.在相关动物模型中确定剂量和免疫佐剂 将产生最有效的免疫和抗肿瘤的组合 回应。 E.在高风险/低肿瘤负担的情况下进行I期临床试验 对黑色素瘤患者进行毒性和免疫应答研究 抗身份证疫苗。 这些研究将提供对涉及到的免疫机制的洞察 人类抗ID疫苗的应用和产生新的选择 黑色素瘤和其他人类恶性肿瘤的生物治疗。

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.