MONOCLONAL ANTIBODY THERAPY AGAINST GANGLIOSIDE ANTIGENS

在本项目中，我们将继续研究使用单克隆 抗神经节苷脂抗原的抗体（mAb）作为癌症的治疗。 我们 将集中在两个神经节苷脂：GD 3在黑色素瘤患者，GD 2在黑色素瘤患者。 小细胞肺癌（SCLC）患者。 神经节苷脂GD 2和GD 3 被选为目标有几个原因。 GD 3是一种 GD 2在几乎所有黑素瘤上表达，GD 2在SCLC上表达。 MAbR24 抗GD 3具有有效的免疫效应子功能，包括激活 补体和介导抗体依赖性细胞毒性。 mAb 神经节苷脂也可以直接抑制黑色素瘤的粘附， 增殖 我们和其他人之前的研究表明， 用小鼠mAb治疗的黑色素瘤患者的客观肿瘤消退 最后，已经发现抗GD 3的mAb激活 T细胞;低浓度的 白细胞介素2。 本项目将探索三种不同的方法， 靶向神经节苷脂肿瘤抗原的mAb：被动免疫，递送 细胞毒性剂量的辐射，并使用GD 3主动免疫， 抗独特型mAb。 该项目的具体目标是：1）确定是否被动 用针对GD 3的人源化形式的mAbR 24免疫可用于 在黑色素瘤患者中维持长期的抗体水平。2)测试 细胞因子是否可用于扩增和激活效应细胞 参与mAbR 24抗肿瘤作用的群体。 为了这一具体目标， 将进行mAbR 24与白细胞介素-2组合的临床试验 (to扩增并激活NK细胞和T细胞），并伴有肿瘤坏死 α因子（激活中性粒细胞）。3)确定131/I标记的 针对GD 2的人源化mAb 3F 8可以定位于SCLC肿瘤部位， 客观的抗肿瘤反应。4)创造最佳条件， 使用抗独特型抗体免疫黑素瘤患者以对抗GD 3神经节苷脂 mAbBEC 2，其模拟GD 3。 在一系列临床试验中测试的条件 试验将包括：添加免疫佐剂QS 21，改变 BEC 2分子以增强可变结构域的免疫原性， 载体分子与强T细胞表位的缀合，和 在用BEC 2引发后用GD 3神经节苷脂免疫患者 疫苗 一旦优化，疫苗将在患有以下疾病的患者中进行测试： 可测量的疾病，以确定客观的肿瘤消退是否可以 观察

In this project, we will continue to study the use of monoclonal antibodies (mAb) against ganglioside antigens as treatment for cancer. We will focus on two gangliosides: GD3 in patients with melanoma, and GD2 in patients with small cell lung cancer (SCLC). Gangliosides GD2 and GD3 have been selected as targets for several reasons. GD3 is abundantly expressed on virtually all melanomas and GD2 is expressed on SCLC. MAbR24 against GD3 has potent immune effector functions including activation of complement and mediation of antibody-dependent cellular cytotoxicity. MAb to gangliosides can also directly inhibit melanoma adhesion and proliferation. Previous studies, by us and by others, have demonstrated objective tumor regression in melanoma patients treated with mouse mAb against GD3 or GD2, Finally, mAb against GD3 have been found to activate T cells; this effect is markedly augmented by low concentrations of interleukin-2. This project will explore three different approaches using mAb to target ganglioside tumor antigens: passive immunization, delivery of cytotoxic doses of radiation, and active immunization against GD3 using an anti-idiotypic mAb. The specific aims of this project are: 1) Determine whether passive immunization with humanized versions of mAbR24 against GD3 can be used to maintain long-term levels of antibody in patients with melanoma. 2) Test whether cytokines can be used to expand and activate effector cell populations involved in mAbR24 anti-tumor effect. For this specific aim, clinical trials will be carried out combining mAbR24 with interleukin-2 (to expand and activate NK cells and T cells) and with tumor necrosis factor-alpha (to activate neutrophils). 3) Determine whether 131/I-labeled humanized mAb3F8 against GD2 can localize to SCLC tumor sites and result in objective anti-tumor responses. 4) Develop optimal conditions for immunizing melanoma patients against GD3 ganglioside using anti-idiotypic mAbBEC2 which mimics GD3. Conditions to be tested in a series of clinical trials will include: addition of the immune adjuvant QS21, alteration of the BEC2 molecule to enhance the immunogenicity of the variable domains, conjugation of carrier molecules with strong T cell epitopes, and immunization of patients with GD3 ganglioside after priming with the BEC2 vaccine. Once optimized, the vaccine will be tested in patients with measurable disease to determine whether objective tumor regressions can be observed.