MELANOMA IMMUNOTHERAPY WITH ANTI-ID MONOCLONAL AB

GD3神经节苷脂是一种有前途的免疫治疗靶点， 黑色素瘤由于：a）在几乎所有黑色素瘤上的大量表达，B） 在正常组织上的限制性分布，和c）观察到， 用小鼠单克隆抗体（MAb）治疗黑素瘤患者 针对GD3的治疗导致了主要的临床反应， 副作用. 尝试使患者对GD3免疫，并提供 使用黑色素瘤细胞、裂解物或纯化的GD3的主动免疫已经被 由于GD3的免疫原性低，因此不成功。 为了克服这一点，我们 已经开发了一种模拟GD3的小鼠抗独特型（抗id）单克隆抗体 神经节苷脂 用这种抗id单克隆抗体免疫的兔，命名为BEC 2， 产生特异性抗GD3的IgG。 广泛的长期目标 本申请旨在探索抗id单克隆抗体诱导 针对非蛋白质肿瘤抗原的免疫，并确定如何 优化这种疫苗。 这项建议的具体目的是 确定需要BEC 2的哪个部分来模拟GD3。 这是 重要是因为：a）模拟非蛋白质肿瘤抗原的抗id MAb， 蛋白质如何模拟糖脂的机制并不罕见， 理解，B）这将允许疫苗的进一步改进 包括嵌合分子的生物工程，以及c）这可能揭示 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， 被测序。 存在的可能性是，第二重链也是 制作。 最初的实验将集中在确定哪些重型和 轻链负责模拟GD3。 后续研究将更多 精细地绘制了重链和轻链中负责 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.