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

目前用于治疗原发性恶性胶质瘤（GBM）的方法在很大程度上是不成功的，其中大多数方法都是针对恶性胶质瘤的。 GBM在其起源部位或邻近其起源部位复发，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，经常诱导正常的脑毒性，导致肿瘤发生率下降。 在生活质量上。我们的假设是，这些局限性可以通过结合GBM反应来克服。 单克隆抗体（MAb）与放射性核素发射高细胞毒性和局灶性辐射。我们的临床目标是 评价211 At标记的抗腱生蛋白单克隆抗体81 C6在新诊断GBM中的治疗潜力 患者Astatine-211释放的颗粒具有更大的细胞毒性作用， 电阻比常规辐射，并有一个范围内的组织只有几个细胞直径，特点 可以为脑肿瘤治疗提供重要优势。在我们用嵌合体81 C6进行的初步研究中， 在复发性脑肿瘤患者中通过N-琥珀酰亚胺基3-[211 At]阿司他滨苯甲酸酯（SAB）标记的（ch 81 C6）， 以最小的毒性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放射性溶解诱导的问题，最大耐受剂量未确定 在更高的活性水平上标记。在过去的几年里，基础放射化学研究已经产生了 解决这个问题的方法。同时，我们的临床前目标是为最终的临床试验奠定基础。 211 At标记的ch 81 C6与用低能量发射体标记的MAb组合以扩展区域的评价 在SCRC接口之外的治疗效果。我们的具体目标是：1）完成放射化学 在可靠剂量递增所需的活性水平下，优化用211 At标记ch 81 C6的研究; 2） 进行211 At标记的ch 81 C6施用于新诊断GBM的SCRC的I/II期临床试验 1期研究以递增剂量的211 At（mCi）进行，II期研究以目标剂量进行。 对SCRC边缘的辐射剂量（戈伊）; 3）评价抗腱生蛋白的功效和正常组织毒性 81 C6组合治疗方法，其利用<$粒子发射器211 At和<$粒子发射器177 Lu 或131 I。

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.