GENERATION AND CLINICAL USE OF HUMAN ANTIID ANTIBODIES

肿瘤相关抗原（TAA）通常没有或只有非常弱的作用

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.