Targeted Alpha-Particle Emitter Therapy of Metastases

转移瘤的靶向阿尔法粒子发射治疗

• 批准号: 7535184
• 负责人: George Sgouros
• 金额: $ 27.87万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-12-09 至 2009-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7535184
• 关键词: Alpha Particle Emitter; Alpha Particles; Antibodies; Antigens; Autoradiography; Biodistribution; Bone neoplasms; Breast Carcinoma; Caliber; Cells; Clinical Data; Controlled Study; Cutaneous; Data; Data Analyses; Disease; Disseminated Malignant Neoplasm; Distant; Doctor of Philosophy; Dose; Dose-Limiting; Drug Kinetics; ERBB2 gene; Exhibits; Fatty acid glycerol esters; Half-Life; Heart; Heart Ventricle; Histopathology; Human; Image; Immunoglobulin Fragments; Immunoglobulin G; Immunohistochemistry; Indium-111; Individual; Injection of therapeutic agent; Kidney; Kinetics; Label; Left; Left ventricular structure; Liver; Lung; Magnetic Resonance Imaging; Mammary Neoplasms; Mammary gland; Maximum Tolerated Dose; Metastatic Neoplasm to the Bone; Metastatic Neoplasm to the Lung; Modeling; Morbidity - disease rate; Mucin-1 Staining Method; Mus; Neoplasm Metastasis; Normal Cell; Organ; Osteolytic; Pattern; Penetration; Radio; Radioisotopes; Radiolabeled; Rattus; Relative (related person); Research Personnel; Resistance; Roche brand of trastuzumab; Site; Spatial Distribution; Spleen; Staining method; Stains; Testing; Therapy Clinical Trials; Time; Tissue Extracts; Tissues; Toxic effect; Transgenic Mice; Transgenic Organisms; Tumor Antigens; Tumor Burden; Tumor Cell Line; Tumor Tissue; Work; analog; base; bone; cancer therapy; cross reactivity; dosimetry; erbB-2 Receptor; in vivo; irradiation; malignant breast neoplasm; neoplastic cell; pre-clinical; radiotracer; response; tumor

The overall objective of this proposal is to examine the feasibility of targeting disseminated metastatic cancer using intact antibody and antibody fragments radiolabeled with the alpha-particle emitter Bi-213 (T1/2= 45.6 min). We propose to test the following hypotheses: 1. Due to the permeable vasculature of early tumor metastases, the 45.6 minute half-life of Bi-213 is sufficiently long to target both vascularized and pre- vascularized early cancer metastases. 2. The 45.6 minute half-life of Bi-213 relaxes the constraint that the antibody exhibit no cross-reactivity with normal organs because penetration of the antibody into intact normal organs will occur after the radionuclide has decayed and also because the short 4-5 cell diameter range of alpha-particles will irradiate targeted tumor cells with minimal adjacent normal cell irradiation. The hypotheses will be tested using Neu-N transgenic mice bearing lung, liver and osteolytic bone metastases. SPECIFIC AIMS 1. Determine the relative expression of the rat/neu (analog to HER2/neu) receptor in tumors and in selected normal organs of the transgenic Neu-N murine model of breast carcinoma. 2. Determine the kinetics, in vivo, and spatial distribution, ex vivo, in tumors and normal organs of anti-neu IgG, F(ab')2, and Fab. 3. Evaluate the MTD and determine the dose-limiting organ in Neu-N mice treated with 213Bi-labeled anti-neu constructs. 4. Evaluate the efficacy of 213Bi-labeled anti-neu constructs against sub-cutaneous tumor and against lung, liver and bone metastases. 5. Perform microdosimetry to derive dose-response relationships to understand observed responses and toxicity in terms of absorbed dose. Current cancer treatment is rarely effective once the tumor has metastasized to distant sites. The eradication of such metastases requires a systemic, targeted therapy that is minimally susceptible to chemo- or radio-resistance, that is potent enough to sterilize individual tumor cells and cell clusters and that exhibits an acceptable toxicity. The work described in this application is intended to develop and evaluate such an approach.

该提案的总体目的是检查靶向传播转移性癌的可行性 使用完整的抗体和抗体片段与α粒子发射极BIBITER BI-213（T1/2 = 45.6）放射性标记 最小）。我们建议检验以下假设：1。由于早期肿瘤的可渗透脉管系统 转移酶，BI-213的45.6分钟半衰期足够长，可以靶向血管化和预靶 血管化早期癌症转移。 2。bi-213的45.6分钟半衰期放松了限制 抗体与正常器官没有交叉反应性，因为抗体渗透到完整的正常状态 在放射性核素腐烂后会发生器官，也是因为短的4-5个细胞直径范围 α粒子将以最小的相邻正常细胞照射照射靶向肿瘤细胞。这 假设将使用带有肺，肝脏和骨骨转移的NEU-N转基因小鼠进行测试。 具体目的1。确定肿瘤中大鼠/NEU（类似于HER2/NEU）受体的相对表达 以及在乳腺癌的转基因NEU-N鼠模型的选定正常器官中。 2。确定 动力学，体内和空间分布，在体内，在抗neu IgG的肿瘤和正常器官中，F（ab'）2和 工厂。 3。评估MTD并确定用213BI标记的Neu-N小鼠中的剂量限制器官 反神经结构。 4。评估213BI标记的反NEU构建体的功效 肿瘤和肺，肝脏和骨转移。 5。执行微测定法以得出剂量反应 了解观察到的反应和毒性在吸收剂量方面。当前的癌症 一旦肿瘤转移到远处的部位，治疗很少有效。消除这种 转移需要一种系统性的，有针对性的治疗，该治疗易受化学或放射性的影响， 这足以使单个肿瘤细胞和细胞簇消毒，并且表现出可接受的 毒性。本应用程序中描述的工作旨在开发和评估这种方法。

项目成果

213Bi (alpha-emitter)-antibody targeting of breast cancer metastases in the neu-N transgenic mouse model.

213Bi（α-发射体）抗体靶向 neu-N 转基因小鼠模型中的乳腺癌转移。

• DOI: 10.1158/0008-5472.can-07-6308
• 发表时间: 2008
• 期刊: Cancer research
• 影响因子: 11.2
• 作者: Song,Hong;Shahverdi,Karineh;Huso,DavidL;Esaias,Caroline;Fox,James;Liedy,Alyson;Liedy,Allison;Zhang,Zhe;Reilly,RTodd;Apostolidis,Christos;Morgenstern,Alfred;Sgouros,George
• 通讯作者: Sgouros,George

An immunotolerant HER-2/neu transgenic mouse model of metastatic breast cancer.

• DOI: 10.1158/1078-0432.ccr-07-4672
• 发表时间: 2008-10-01
• 期刊: Clinical cancer research : an official journal of the American Association for Cancer Research
• 作者: Song H;Shahverdi K;Huso DL;Wang Y;Fox JJ;Hobbs RF;Gimi B;Gabrielson KL;Pomper MG;Tsui BM;Bhujwalla Z;Reilly RT;Sgouros G
• 通讯作者: Sgouros G