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

使用 211At-81C6 抗体对脑肿瘤进行靶向α粒子放射治疗

基本信息

批准号：
8805239
负责人：
Michael Rod Zalutsky
金额：
$ 33.15万
依托单位：
DUKE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-09-24 至 2019-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8805239
关键词：
Adult Adverse effects Alpha Particles Antibodies Astatine Biological Brain Brain Neoplasms Bystander Effect Caliber Cells Characteristics Chemistry Child Clinical Clinical Trials Combined Modality Therapy Diffusion Disease Dose Drug Formulations Effectiveness External Beam Radiation Therapy Extracellular Matrix Failure Glioblastoma Glycoproteins Goals Half-Life Human Injection of therapeutic agent Investigation Kinetics Label Location Long-Term Survivors Malignant - descriptor Malignant Glioma Malignant neoplasm of brain Maximum Tolerated Dose Minor Monoclonal Antibodies Monoclonal Antibody 81C6 Neurocognitive Newly Diagnosed Normal tissue morphology Outcome Patients Phase Phase I Clinical Trials Pilot Projects Play Primary Brain Neoplasms Procedures Quality of life Radiation Radiation therapy Radioactivity Radiochemistry Radioisotopes Radiolabeled Reagent Recommendation Recurrence Resistance Role Series Site Solutions Surgically-Created Resection Cavity Tenascin Therapeutic Therapeutic Effect Time Tin Tissues Toxic effect Variant base bevacizumab conventional therapy cytotoxic cytotoxicity expectation improved novel strategies particle phase 1 study phase 2 study pre-clinical radiotracer research clinical testing response temozolomide therapeutic effectiveness tumor tumor growth tumor progression tumor specificity

项目摘要

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.

当前治疗原发性恶性神经胶质瘤（GBM）的方法在很大程度上没有成功，大多数 GBM在其起源部位或附近反复出现，表明无法放射性局部肿瘤生长；此外，这些治疗方法缺乏肿瘤特异性，经常引起正常的脑毒性，导致下降生活质量。我们的假设是可以通过组合GBM反应性来克服这些局限性单克隆抗体（MAB），其放射性抗体发射高度细胞毒性和局灶性辐射。我们的临床目标是评估新诊断的GBM中211AT标记的抗北辛MAB 81C6的治疗潜力患者。 Astatine -211发射�-具有更大的细胞毒性效果并且不易受到影响的粒子电阻比常规辐射，并且在仅几个细胞直径的组织中具有范围这可以为脑肿瘤治疗提供重要的优势。在我们用嵌合81C6进行的试点研究中（CH81C6）通过n-核酰亚胺基3- [211at] asatobenzoate（SAB）在复发性脑肿瘤患者中标记，用最少的毒性获得了令人鼓舞的反应，其中2名GBM患者存活了近3年。但是，由于辐射溶解引起的211AT问题，未确定最大耐受剂量在较高的活动水平上标记。过去几年的基本放射化学调查现已产生解决这个问题的解决方案。同时，我们的临床前目标是为最终的临床奠定基础评估211AT标记的CH81C6与标记为低能量�-邮件的MAB相结合以扩展区域 SCRC界面以外的治疗有效性。我们的具体目的是：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CH81C6标记的研究； 2）到进行211AT标记的CH81C6的I/II期临床试验，该试验被施用到新诊断的GBM的SCRC中患者，第1期研究以升级的剂量为211AT（MCI），而在目标的II期剂量进行辐射剂量（GY）到SCRC边缘； 3）评估抗甲状腺素的有效性和正常组织毒性 81C6组合疗法方法利用�-粒子发射极211 at和�-粒子发射极177lu 或131i。