MELANOMA IMMUNOTHERAPY WITH ANTI-ID MONOCLONAL AB

GD3神经节苷脂是一种有希望的免疫治疗靶点 黑色素瘤：a)几乎所有黑色素瘤都有大量表达，b) 在正常组织上的有限分布，以及c)观察到 小鼠单抗治疗黑色素瘤的研究 抗GD3导致了主要的临床反应，但没有明显的 副作用。试图为患者接种GD3疫苗，并提供 主动免疫，使用黑色素瘤细胞，裂解物或纯化的GD3已被 由于GD3免疫原性低，未获成功。为了克服这一点，我们 我已经开发出一种模仿GD3的小鼠抗独特型(抗id)单抗 神经节苷脂。用这种名为BEC2的抗id单抗免疫兔子， 研制针对GD3的特异性免疫球蛋白。的广泛和长期目标 本研究旨在探讨抗id单抗诱导机体免疫应答的能力。 对非蛋白肿瘤抗原的免疫并确定如何 优化这种形式的疫苗。这项建议的具体目的是 确定需要使用BEC2的哪个部分来模拟GD3。这是 重要的原因是：a)模拟非蛋白肿瘤抗原的抗id单抗 蛋白质如何模仿糖脂的机制并不罕见 了解，b)这将允许进一步改进疫苗 包括对嵌合分子进行生物工程，以及c)这可能有助于 如何使其他非蛋白质肿瘤抗原具有免疫原性。BEC2 杂交瘤产生两条轻链和一条重链，它们已经 已经被测序了。存在第二个重链也存在的可能性 制作。最初的实验将集中在确定哪种重量和 轻链负责模拟GD3。后续研究将有更多 精细绘制重链和轻链中负责 模仿GD3。

GD3 ganglioside is a promising target for immunotherapy in patients with melanoma due to: a) abundant expression on virtually all melanoma, b) restricted distribution on normal tissue, and c) the observation that treatment of melanoma patients with mouse monoclonal antibodies (MAb) against GD3 has resulted in major clinical responses without significant side effects. Attempts to immunize patients against GD3, and provide active immunity, using melanoma cells, lysates or purified GD3 have been unsuccessful due to the low immunogenicity of GD3. To overcome this, we have developed a mouse anti-idiotypic (anti-id) MAb that mimics GD3 ganglioside. Rabbits immunized with this anti-id MAb, designated BEC2, develop IgG specifically against GD3. The broad, long-term objectives of this application are to explore the ability of anti-id MAb to induce immunity against non-protein tumor antigens and to determine how to optimize this form of vaccine. The specific aim of this proposal is to determine which portion of BEC2 is required to mimic GD3. This is important because: a) anti-id MAb mimicking non-protein tumor antigens are rare and the mechanism of how a protein mimics a glycolipid is not understood, b) this will permit further improvements of the vaccine including bioengineering a chimeric molecule, and c) this may shed light on how other non-protein tumor antigens can be made immunogenic. The BEC2 hybridoma produces two light chains and a heavy chain which have already been sequenced. The possibility exists that a second heavy chain is also produced. Initial experiments will focus on determining which heavy and light chain is responsible for mimicking GD3. Subsequent studies will more finely map the regions within the heavy and light chains responsible for mimicking GD3.