Quantitative and Spatial Optimization for Designing Cancer Therapeutics

描述(申请人提供)：黑色素瘤虽然罕见，但却是最致命的皮肤癌。与大多数癌症一样，治疗黑色素瘤的一个困难是很难靶向治疗。 以不损害非癌症组织的方式对他们进行治疗。黑色素瘤(以及神经母细胞瘤)在其细胞表面特征性地表达二唾液神经节苷脂标记GD2，该标记可被14.18小鼠单抗靶向。我打算利用帕梅拉·西尔弗教授的实验室开创的嵌合激活剂方法，将一种治疗剂--自然产生的蛋白质干扰素α2a(干扰素)--靶向表达GD2的细胞。这种方法的工作原理是将靶向元件(这里是14.18抗体)和细胞毒性活性元件(这里是干扰素)联系在一起，后者可以结合靶细胞(GD2)上表达的抗原，细胞毒性活性元件已经突变，降低了它的结合能力。由于这种结合减弱，细胞毒素只有在比野生型高得多的浓度时才会起作用。当靶向元件与GD2结合时，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，使其能够结合。因此，嵌合激活剂方法允许细胞毒作用集中在肿瘤部位，因为治疗药物的浓度将在没有抗体结合的地方低得多。我将通过三个途径来探讨这种特异性的增强。首先，如上所述，原始的嵌合激活剂方法。第二，一种建模和模拟方法，旨在提供关于增加特异性的准确机制的洞察力。第三，另一种减少脱靶效应的方法，不是通过突变干扰素来削弱它，而是让它与其受体的一种减弱形式结合。这项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，并为采用同样的方法进行进一步的治疗铺平道路。

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.