MONOCLONAL ANTIBODY THERAPY AGAINST GANGLIOSIDE ANTIGENS

在这个项目中，我们将继续研究克隆的使用 针对神经节苷脂抗原的抗体(MAb)用于治疗癌症。我们 将专注于两种神经节苷脂：黑色素瘤患者的GD3和黑色素瘤患者的GD2 小细胞肺癌(SCLC)患者。神经节苷脂GD2和GD3 被选为目标有几个原因。GD3有丰富的 几乎所有的黑色素瘤都表达GD2，小细胞肺癌表达GD2。MAbR24 抗GD3具有强大的免疫效应功能，包括激活 补体与抗体依赖性细胞毒的中介作用。单抗 神经节苷脂还可以直接抑制黑色素瘤的粘连和 扩散。我们和其他人之前的研究表明， 目的观察小鼠单抗治疗黑色素瘤患者的肿瘤消退情况 针对GD3或GD2，最终发现抗GD3的mAb被激活 T细胞；这种效应在低浓度的 白介素2。这个项目将探索三种不同的方法，使用 靶向神经节苷脂肿瘤抗原的单抗：被动免疫、递送 辐射的细胞毒性剂量，以及使用GD3的主动免疫 一种抗独特型单抗。 本项目的具体目标是：1)确定是否被动 用人源化版本的mAbR24免疫GD3可用于 长期维持黑色素瘤患者的抗体水平。2)测试 细胞因子能否用于扩增和激活效应细胞 参与mAbR24抗肿瘤作用的人群。为了这个特定的目的， 将联合mAbR24和白细胞介素2进行临床试验 (扩增和激活NK细胞和T细胞)和肿瘤坏死 因子-α(激活中性粒细胞)。3)确定131/I标记的 人源化抗GD2单抗3F8可定位于小细胞肺癌肿瘤部位和结果 在客观抗肿瘤反应中。4)开发最佳条件 抗独特型抗体免疫黑色素瘤患者抗GD3神经节苷脂 MAbBEC2，模拟GD3。需要在一系列临床试验中测试的情况 试验将包括：添加免疫佐剂QS21，改变 BEC2分子增强可变区的免疫原性， 载体分子与强T细胞表位的结合，以及 BEC2免疫后GD3神经节苷脂免疫效果观察 疫苗。一旦优化，疫苗将在患有 可测量的疾病以确定目标肿瘤是否可以消退 观察到的。

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.