Growth Factor Imaging

生长因子成像

• 批准号: 8349090
• 负责人: peter L choyke
• 金额: $ 199.07万
• 依托单位: DIVISION OF BASIC SCIENCES - NCI
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8349090
• 关键词: Animals; Antibodies; Antigens; Binding; Blocking Antibodies; CCR; Cancer Patient; Cell Proliferation; Cell membrane; Cetuximab; Childhood Medulloblastomas; Client; Clinical; Clinical Research; Clinical Trials; Collaborations; Colon Carcinoma; Color; Devices; Diagnosis; Drug Kinetics; ERBB2 gene; Endoscopy; Epidermal Growth Factor Receptor; Epithelial; Family; Fluorescence; Growth; Growth Factor; Growth Factor Receptors; Human; IL2 gene; Image; Immunohistochemistry; Indium; Individual; Isotopes; Label; Laboratories; Light; Lung; Lymphoma; Magnetic Resonance Imaging; Malignant Neoplasms; Malignant neoplasm of lung; Measures; Modality; Modeling; Molecular Biology; Monitor; Monoclonal Antibodies; Mus; Nanotechnology; Neoplasm Metastasis; Neurofibromatoses; Operative Surgical Procedures; Patient Selection; Patients; Pharmaceutical Preparations; Pharmacodynamics; Pharmacotherapy; Phase; Phenotype; Phosphotransferases; Photosensitizing Agents; Positron-Emission Tomography; Process; Prodrugs; Proliferation Marker; Protocols documentation; Radioimmunoconjugate; Radioimmunotherapy; Radiolabeled; Radionuclide Imaging; Receptor Protein-Tyrosine Kinases; Research; Resources; Roche brand of trastuzumab; Role; Sampling; Silicon Dioxide; Testing; Therapeutic; Thymidine; Time; Tissue Sample; Transplantation; Trastuzumab; Tumor Antibodies; United States National Institutes of Health; Work; Writing; cancer cell; cancer imaging; cancer therapy; design; drug discovery; drug testing; fluorescence imaging; fluorodeoxyglucose positron emission tomography; fluorophore; graduate student; improved; in vivo; inhibitor/antagonist; iron oxide; leukemia; malignant breast neoplasm; member; mesothelin; molecular imaging; mouse model; nanoparticle; novel; optical imaging; overexpression; pre-clinical; pre-clinical research; preclinical study; programs; radiotracer; receptor; receptor expression; single photon emission computed tomography; small molecule; tumor; tumor progression; uptake; vector

Imaging of Growth Factor Receptors Background The recognition of the role of growth factor receptors in the growth and progression of tumors has had widespread implications for cancer treatment. Not only have blocking antibodies been developed , but downstream small molecule inhibitors have also been developed. Both drug types have already had impact on the management of several major cancers. Regardless of the receptor imaged, imaging represents a potentially important avenue of research. Potential uses of imaging agents targeting receptors include more accurate sampling of tissue, patient selection for drug trials, monitoring of therapies directed at the receptor or its downstream clients which impact receptor expression, developing immuno-conjugates for delivering specific drug therapy and radioimmunotherapy/photoimmunotherapy in which therapeutic isotopes or photosensitizers are attached to the antibody. We are conducting a variety of pre-clinical and clinical studies to investigate the potential roles of this class of imaging agents. Pre-Clinical Research Individual antibodies have limitations because a tumor may express polyclonal distribution of receptors. For instance, part of the tumor may express HER2 but another part may express MET, HER1 or Mesothelin. We have explored the idea of a labeled cocktail of antibodies for tumor diagnosis and characterization. The potential use of optically labeled monoclonal antibodies for diagnosis is being explored by mixing combinations of antibodies and injecting the cocktail. Cocktails of optically labeled antibodies (Trastuzumab-anti HER2, Cetuximab, anti-HER2, and Declizimab anti-IL2) are injected into mice growing tumors expressing different antigens. The optically labeled antibodies, each labeled with a fluorophore of a unique wavelenth, attach to their respective cancer cells opening the possibility of performing in vivo immunohistochemistry. This may find particular application in improving the sampling of tumors during surgery or during endoscopy. However, another potential use is to use various pro-drug strategies to deliver each part of the pro-drug via different monoclonal antibody vectors. Proof of this concept is provided by optical imaging that can demonstrate the co-localization and internalization of two or more monoclonal antibodies in vivo. An advantage of optical imaging over radionuclide imaging is that optical imaging is inherently polychromatic allowing each agent to be tagged individually. This allows real time pharmacodynamic analysis of drug effects of tumors (visible superficially at least) and is of potential importance to drug discovery and drug testing(2). Recently, we have discovered that when the antibody is attached to a unique photofluor, near infrared light at one intensity could be used for diagnosis but by increasing the intensity the tumor can actually be treated. This process is known as photoimmunotherapy and holds great promise for the treatment of some forms of cancer that can be approached with near infrared light. In collaboration with Dr. Brechbiels lab we are testing PET and SPECT labeled monoclonal antibodies and have performed this with both trastuzumab and cetuximab and panitumimab(3). It is still unclear whether SPECT or PET imaging is preferred and a comparison trial using the Small Animal Imaging Programs PET-SPECT-CT device will be conducted. Recently, this work has been enabled in Bethesda using microSPECT and microPET cameras in the Molecular Imaging Program. We have also explored theuse of radiolabeled affibodies which are considerably smaller than antibodies. HER2 binding affibodies have proven to be more sensitive than FDG PET for detecting metastases in mouse models of lung metastases. Extensive work has been done on MET receptor where we have labeled both the external and internal domains of this receptor. We are developing an F18 labeled version of this agent for human use. Over the past two years we have also sponsored an NIH-Oxford Graduate student, Ambika Bumb, who has designed an implemented a nanoparticle with antibody targeting. The nanoparticle consists of a core of iron oxide (for MRI) with a shell of silica embedded with C5.5 (for optical imaging) (presented originally by A. Bumb NanoTech 07 San Diego,CA, 2007). To this platform agent, trastuzumab, chelated with Indium (for SPECT imaging) is attached. We intend to test this nanoparticle in several in vivo murine models of HER2+ tumors. Anti-Mesothelin antibody (Raffit Hassan, Ira Pastan, Laboratory of Molecular Biology) has also been developed. This receptor is associated with an aggressive phenotype. We have performed preclinical studies in mice with this labeled antibody and will shortly initiate a clinical trial. Clinical Studies We are conducting several studies involving growth factor receptors. The original clinical study used 111Indium trastuzumab in breast cancer patients. This protocols tests the uptake of trastuzumab (Herceptin) in patients with breast cancer who either overexpress or do not overexpress HER2/neu. Preliminary JDC approval was also received for 111Indium-panitumimab to be used in patients with colon and lung cancer. The preliminary pre-clinical work has been submitted to the Cancer Imaging Program for incorporation into an xIND submission and SOPs are being written for a GMP product. Indium labeled mesothelin (MORAb009) will begin clinical trials shortly. Cell proliferation is a direct result of activation of the growth factor receptors. We have investigated the ability to measure proliferation with a novel PET agent for human use, 18 F-L-thymidine, a proliferation marker for cancer. We have been using this agent in a variety of tumors and have demonstrated its utility. This work is ongoing in a trial of lymphoma and pediatric medulloblastoma, neurofibromatosis and leukemia post transplant. 1. Koyama, Y., Hama, Y., Urano, Y., Nguyen, D. M., Choyke, P. L., and Kobayashi, H. Spectral fluorescence molecular imaging of lung metastases targeting HER2/neu. Clin Cancer Res, 13: 2936-2945, 2007. 2. Hama, Y., Koyama, Y., Choyke, P. L., and Kobayashi, H. Two-color in vivo dynamic contrast-enhanced pharmacokinetic imaging. J Biomed Opt, 12: 034016, 2007. 3. Xu, H., Baidoo, K., Gunn, A. J., Boswell, C. A., Milenic, D. E., Choyke, P. L., and Brechbiel, M. W. Design, Synthesis, and Characterization of a Dual Modality Positron Emission Tomography and Fluorescence Imaging Agent for Monoclonal Antibody Tumor-Targeted Imaging. J Med Chem, 2007.

生长因子受体的成像背景识别生长因子受体在肿瘤生长和进展中的作用对癌症治疗具有广泛的影响。不仅开发了阻塞抗体，而且还开发了下游小分子抑制剂。两种药物已经对几种主要癌症的管理产生了影响。无论成像如何，成像都代表了潜在的重要研究途径。 Potential uses of imaging agents targeting receptors include more accurate sampling of tissue, patient selection for drug trials, monitoring of therapies directed at the receptor or its downstream clients which impact receptor expression, developing immuno-conjugates for delivering specific drug therapy and radioimmunotherapy/photoimmunotherapy in which therapeutic isotopes or photosensitizers are attached to the antibody.我们正在进行各种临床前和临床研究，以研究此类成像剂的潜在作用。临床前研究个体抗体具有局限性，因为肿瘤可能表达受体的多克隆分布。例如，部分肿瘤可以表达HER2，但另一部分可以表达MET，HER1或中皮。我们已经探索了一个标记为肿瘤诊断和表征的抗体鸡尾酒的想法。通过混合抗体的组合并注入鸡尾酒，正在探索具有光学标记的单克隆抗体对诊断的潜在用途。将光学标记抗体的鸡尾酒（Trastuzumab-anti HER2，cetuximab，anti-her2和declizimab抗IL2）注射到生长表达不同抗原的肿瘤中。光学标记的抗体，每种抗体都用独特的Wavelenth的荧光团标记，它们附着在各自的癌细胞上，开放了进行体内免疫组织化学的可能性。这可能发现在手术期间或内窥镜检查过程中改善肿瘤的采样方面的特殊应用。但是，另一个潜在用途是使用各种促毒物策略通过不同的单克隆抗体向量传递pro-prug的每个部分。光学成像可以证明这种概念的证明，该光学成像可以证明体内两种或多种单克隆抗体的共定位和内在化。光学成像比放射性核素成像的优点是，光学成像本质上是多色，允许单独标记每个代理。这允许对肿瘤的药物作用进行实时药效分析（至少在表面上可见），并且对药物发现和药物测试具有潜在的重要性（2）。最近，我们发现，当抗体连接到独特的光氟时，可以将一种强度以一种强度的红外光用于诊断，但通过增加肿瘤的强度实际上可以治疗。该过程称为摄影疗法，对治疗某些形式的癌症具有巨大的希望，这些癌症可以用近红外光接近。与Brechbiels博士合作，我们正在测试PET和SPECT标记的单克隆抗体，并与Trastuzumab和Cetuximab和Panitumimab（3）一起进行了此操作。目前尚不清楚SPECT还是PET成像是首选的，并且将使用小型动物成像程序进行PET-SPECT-CT设备进行比较试验。最近，在分子成像程序中，使用Microspect和Micropet摄像机在Bethesda中启用了这项工作。我们还探索了比抗体小得多的放射性标记的affibodies的使用。事实证明，HER2结合杂质比FDG PET更敏感，用于检测肺转移小鼠模型中的转移。在MET受体上已经完成了广泛的工作，在那里我们标记了该受体的外部和内部结构域。我们正在开发该代理的F18标记版本，以供人类使用。 在过去的两年中，我们还赞助了NIH-Oxford的一名研究生Ambika Bumb，他设计了一种具有抗体靶向的纳米颗粒。纳米颗粒由氧化铁核心（对于MRI）组成，该核心带有嵌入C5.5的二氧化硅壳（用于光学成像）（最初由A. bumb Nanotech 07呈现，CA，CA，2007年）。对于这个平台试剂，静脉固定（用于SPECT成像）的曲妥珠单抗。我们打算在HER2+肿瘤的几种体内鼠模型中测试该纳米颗粒。抗中皮蛋白抗体（Raffit Hassan，Ira Pastan，Molecular Biology实验室）也已经开发出来。该受体与侵略性表型有关。我们已经在使用该标记的抗体的小鼠中进行了临床前研究，并将很快开始进行临床试验。 临床研究我们正在进行几项涉及生长因子受体的研究。最初的临床研究在乳腺癌患者中使用了111indium曲妥珠单抗。该方案测试了曲妥珠单抗（Herceptin）对过表达或过表达HER2/NEU的乳腺癌患者的摄取。还接受了111-甲图酰胺的初步JDC批准，用于结肠癌和肺癌患者。 初步的临床前工作已提交给癌症成像计划，以纳入Xind提交，并为GMP产品编写了SOP。标记为间皮素（Morab009）的鉴赏剂将很快开始临床试验。 细胞增殖是生长因子受体激活的直接结果。我们已经研究了使用新型宠物剂来测量人类使用的增殖的能力，18 f-l-l-胸苷，这是癌症的增殖标记。我们一直在各种肿瘤中使用该试剂，并证明了其效用。这项工作正在进行淋巴瘤和小儿髓母细胞瘤，神经纤维瘤病和移植后白血病的试验中。 1。Koyama，Y.，Hama，Y.，Urano，Y.，Nguyen，D.M.，Choyke，P.L。和Kobayashi，H。针对HER2/NEU的肺转移酶的光谱荧光分子成像。 Clin Cancer Res，13：2936-2945，2007。2。Hama，Y.，Koyama，Y.，Choyke，P。L.和Kobayashi，H。H.两种体内动态对比度增强药代动力学成像。 J Biomed Opt，12：034016，2007。3。Xu，H. J Med Chem，2007年。