Quantitative and Spatial Optimization for Designing Cancer Therapeutics

描述（由申请人提供）：黑色素瘤，虽然罕见，是最致命的皮肤癌。与大多数癌症一样，治疗黑色素瘤的一个困难是， 以不损害非癌组织的方式治疗它们。黑色素瘤（以及神经母细胞瘤）的特征是在其细胞表面表达二唾液酸神经节苷脂标记物GD2，其可以被14.18小鼠单克隆抗体靶向。我打算使用帕梅拉银教授实验室开创的嵌合激活剂方法，将一种治疗剂，即天然存在的蛋白质干扰素α 2a（IFN），靶向表达GD2的细胞。该方法通过将可以结合靶细胞（GD2）上表达的抗原的靶向元件（这里是14.18抗体）与细胞毒性活性元件（这里是IFN）连接在一起来起作用，所述细胞毒性活性元件已经被突变以降低其结合能力。由于这种减弱的结合，细胞毒素只有在比野生型高得多的浓度下才能发挥作用。当靶向元件结合GD2时，连接的细胞毒素保持在细胞表面附近，导致非常高的有效局部浓度，使其结合。因此，嵌合激活剂方法允许细胞毒性作用集中在肿瘤位置，因为治疗剂将在抗体不结合的任何地方处于低得多的浓度。我将通过三个途径来实现这种特异性增强。首先，如上所述的原始嵌合激活剂方法。第二，建模和模拟的方法，旨在提供洞察力，以增加特异性的确切机制。第三，另一种减少脱靶效应的方法，不是突变干扰素来削弱它，而是让它与减弱的受体结合。本研究的目标是开发一种有效的治疗黑色素瘤和神经母细胞瘤的方法，并为采用相同方法的进一步治疗铺平道路。

DESCRIPTION (provided by applicant): Melanoma, while rare, is the most lethal of skin cancers. A difficulty in treating melanoma, as with most cancers, is that it is difficult to target therapeutics to them in a way that does not damage non-cancerous tissue. Melanomas (as well as neuroblastomas) characteristically express the disialioganglioside marker GD2 on their cell surfaces, which can be targeted by the 14.18 mouse monoclonal antibody. I intend to target a therapeutic agent, the naturally occurring protein interferon alpha 2a (IFN), to GD2-expressing cells using the chimeric activator approach pioneered by the lab of Professor Pamela Silver. The approach works by linking together a targeting element (here the 14.18 antibody) which can bind an antigen expressed on the target cell (GD2) together with a cytotoxic active element (here IFN), which has been mutated to reduce its ability to bind. Thanks to this weakened binding, the cytotoxin will have its effect only at much higher concentrations than the wild type. When the targeting element binds GD2, the linked cytotoxin is kept near the cell surface, resulting in a very high effective local concentration, allowing it to bind. Thus, the chimeric activator approach allows the cytotoxic effect to be concentrated at tumor locations, since the therapeutic will be at much lower concentration anywhere the antibody does not bind. I will approach this specificity enhancement through three avenues. First, the original chimeric activator approach, as described above. Second, a modeling and simulation approach which aims to offer insight as to the precise mechanism of increased specificity. Third, an alternate approach to reducing off-target effects where instead of mutating the IFN to weaken it I leave it bound to a weakened form of its receptor. The goal of this research is to develop an effective therapeutic for melanoma and neuroblastoma as well as to pave the the way for further therapeutics following the same approach.