GENERATION AND CLINICAL USE OF HUMAN ANTIID ANTIBODIES

肿瘤相关抗原（TAA）通常是非特异性的或仅是非常弱的。 免疫原性，因此不促进肿瘤排斥。整体 该研究的目的是产生人抗独特型 （抗Id）单克隆抗体（MoAb）模拟黑色素瘤相关 GD 2抗原，最终目的是临床应用这些 作为抗肿瘤疫苗的试剂。 暴露于抗肿瘤单克隆抗体的患者通常会产生免疫应答， 外来蛋白质。这种人体免疫反应的一个组成部分是抗Id; 可显示与MoAb的抗原结合位点结合;并且可 潜在地模拟靶TAA（“内部图像”抗Id）。 该项目的重点将是： a.为了从接受抗GD 2单克隆抗体治疗的患者中收获淋巴细胞， 建立并使用它们来产生模拟GD 2的人抗Ids 抗原的 B.为了表征这些试剂产生的免疫应答， 关于B细胞和T细胞抗-抗-Id和抗-GD 2的动物模型 免疫反应。这些研究将确定那些真正 模拟GD 2抗原，可用作免疫模拟替代品。 C.一方面表征抗Id上模拟TAA的位点， 产生抗肿瘤免疫反应。为此，V区基因 将进行测序 D.在相关动物模型中确定剂量和免疫佐剂 组合，将引发最有效的免疫和抗肿瘤 反应 e.在高风险/低肿瘤负荷中进行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 这些研究将提供深入了解参与免疫机制， 人抗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.