Targeted Alpha-Particle Radiotheraphy of Brain Tumors with 211At-81C6 Antibody

目前治疗原发性恶性胶质瘤(GBM)的方法大多不成功，大多数 基底膜复发于原发部位或邻近部位，表明未能根除局部肿瘤生长； 此外，这些治疗缺乏肿瘤特异性，经常导致正常的脑毒性，导致下降。 在生活质量方面。我们的假设是，这些限制可以通过结合GBM反应来克服 含有放射性核素的单抗(MAb)，具有高度的细胞毒性和焦点辐射。我们的临床目标是 ~(211)At标记抗Tenascin单抗81C6对初诊肾小球基底膜的治疗潜力 病人。Astatine-211释放出具有更大细胞毒性效果且不太容易感染的颗粒 比常规辐射更耐辐射，并具有在组织范围内仅有几个细胞直径的特点 这为脑肿瘤的治疗提供了重要的优势。在我们对嵌合体81C6进行的初步研究中 (Ch81C6)经N-琥珀酰亚胺-3-[211At]-[211At]-二苯甲酸酯(SAB)标记在复发性脑肿瘤患者中的应用 在毒性最小的情况下获得了令人鼓舞的反应，2名GBM患者存活了近3年。 然而，由于~(211)At辐射分解引起的问题，最大耐受量没有确定。 在更高的活动水平上贴标签。在过去的几年里，基本的放射化学研究现在已经取得了 解决这个问题的办法。同时，我们的临床前目标是为最终的临床奠定基础。 ~(211)At标记的CH81C6联合低能发射体标记的单抗扩大区域的评价 超越SCRC界面的治疗效果。我们的具体目标是：1)完成放射化学 研究在可靠剂量升级所需的活性水平上优化使用211 At标记ch81C6；2) ~(211)At标记的ch81C6用于新诊断的GBM的SCRC的I/II期临床试验 患者，第一阶段研究以递增剂量211 At(MCI)进行，第二阶段剂量按目标剂量进行 SCRC边缘的辐射剂量(Gy值)；3)评估抗张力蛋白的疗效和正常组织毒性 利用粒子发射体~(211)At和粒子发射体~(177)Lu的81C6联合治疗方法 或131I。

Current approaches for the treatment of primary malignant glioma (GBM) are largely unsuccessful, with most GBM recurring at or adjacent to their site of origin, indicating a failure to eradicate local tumor growth; moreover, these treatments lack tumor specificity, frequently inducing normal brain toxicity, resulting in decline in quality of life. Our hypothesis is that these limitations can be overcome by combining a GBM reactive monoclonal antibody (MAb) with a radionuclide emitting highly cytotoxic and focal radiation. Our clinical goal is to evaluate the therapeutic potential of 211At-labeled anti-tenascin MAb 81C6 in newly diagnosed GBM patients. Astatine-211 emits ¿-particles that have a greater cytotoxic effectiveness and are less susceptible to resistance than conventional radiation, and have a range in tissue of only a few cell diameters, characteristics that can offer important advantages for brain tumor treatment. In our pilot study performed with chimeric 81C6 (ch81C6) labeled via N-succinimidyl 3-[211At]astatobenzoate (SAB) in recurrent brain tumor patients, encouraging responses were obtained with minimal toxicity, with 2 GBM patients surviving for nearly 3 years. However, the maximum tolerated dose was not determined because of radiolysis-induced problems with 211At labeling at higher activity levels. Basic radiochemistry investigations over the past few years have now yielded a solution to this problem. In parallel, our preclinical goal is to lay the groundwork for eventual clinical evaluation of 211At-labeled ch81C6 combined with MAb labeled with a low-energy ¿-emitter to extend the zone of therapeutic effectiveness beyond the SCRC interface. Our Specific Aims are: 1) To complete radiochemistry studies optimizing labeling of ch81C6 with 211At at the activity levels needed for reliable dose escalation; 2) to conduct a Phase I/II clinical trial of 211At-labeled ch81C6 administered into the SCRC of newly diagnosed GBM patients, with the Phase 1 study done at escalating doses of 211At (mCi) and the Phase II dose at a targeted radiation dose (Gy) to the SCRC margins; 3) to evaluate efficacy and normal tissue toxicity of an anti-tenascin 81C6 combination therapy approach utilizing the ¿-particle emitter 211At and either the ¿-particle emitter 177Lu or 131I.