Project 4

项目4

基本信息

批准号：
7556973
负责人：
NAI-KONG V CHEUNG
金额：
$ 33.23万
依托单位：
SLOAN-KETTERING INST CAN RESEARCH
依托单位国家：
美国
项目类别：
财政年份：
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/7556973
关键词：
90Y Acids Acute Adult Aftercare Antibodies Antibody Therapy Antigen Targeting Antigens Applications Grants Area Under Curve Binding Biotin Blood Bos taurus Bovine Serum Albumin Brain Brain Neoplasms CSF2 gene Cattle Cell surface Cell-Mediated Cytolysis Cells Child Childhood Chimeric Proteins Clinic Clinical Research Clinical Trials Complication DOTA-biotin Data Disease Drug Kinetics Emerging Technologies Ewings sarcoma Gene Proteins Genetic Genetic Transcription Granulocyte-Macrophage Colony-Stimulating Factor Human IL2 gene Immune Immunoglobulin G Immunoglobulin Variable Region Immunotherapy In Vitro Interleukin-2 Late Effects Leukocytes Ligands Light Lymphocyte Malignant Childhood Neoplasm Marrow Measures Mediating Metals Minor Modality Modeling Monoclonal Antibodies Monoclonal Antibody HuM291 Muromonab-CD3 Neoplasm Metastasis Neuroblastoma Normal tissue morphology Patients Peptides Phase Radiation Radioactive Radioactivity Radioimmunotherapy Reagent Recombinant Antibody Recombinants Research Rhabdomyosarcoma Serum Site Solid Neoplasm Specificity Staging Standards of Weights and Measures Streptavidin System T-Lymphocyte Technology Testing Therapeutic Therapeutic Index Time Toxic effect Translating Translations Validation Xenograft procedure antibody conjugate antibody-dependent cell cytotoxicity base chemical conjugate cytokine cytotoxic cytotoxicity improved in vitro Model in vivo lung small cell carcinoma monoclonal antibody 3F8 mouse model neoplastic cell neutrophil osteosarcoma pre-clinical programs research study subcutaneous success targeted delivery tumor tumor xenograft

项目摘要

A major limitation of antibody therapy is its suboptimal delivery to rumor versus normal tissues. An emerging technology is multistep targeting (MST), which can greatly improve the therapeutic index. Tumor cells are first targeted by an antibody-conjugate, which will subsequently be bound by' a cytotoxic ligand. MST is particularly relevant in pediatric cancers where acute toxicity and late effects arc of great concern. We propose to study scFv- streptavidin MST in neuroblastoma (NB), a metastatic solid tumor in children where standard curative therapy does not exist. Our success in expressing the recombinant antibody-conjugate consisting of single chain Fv fragment and streptavidin has made this proposal possible. NB has unique advantages for MST because of the abundance of target antigen GD2, which is homogeneously expressed without antigen modulation or loss after treatment. Preliminary studies have demonstrated substantial improvement in selective delivery of anti-GD2-scFv-streptavidin (scFv-SA) to NB xenografts, scFv-SA MST, using small biotinylated ligands such as DOTA-biotin, achieved a typical cumulative time-activity differential between minor and blood of >50:1. In contrast, using whole IgG as the targeting agent, the ratio was only 4:1. Moreover, peptides and even bovine serum albnmin can be selective1 y targeted by MST. To date, MST efforts have primarily been focused on radioimmunotherapy, without fully exploiting the superior tumor : normal tissue ratio. MST is particularly relevant in tumor models where metastasis in blood and marrow is common, as in ncuroblastoma. We propose to use in vitro models to optimize cytokine targeting by MST to enhance ADCC, as well as to use biotin-anti-lymphocyte antibody as bispecific reagents to redirect NK/NKT cells to enhance tumor cytotoxicity. In vivo validation will be carried out using xenograft tumor models: (1) to study MST radioimmunotherapy using 90Y- DOTA to ablate subcutaneous and metastatic tumors, and (2) MST-targeted IL2 or anti-CD3/anti-CD56 antibodies to enhance and redirect cytotoxic lymphocytes. Before the implementation of any phase I/I1 clinical trial, these studies will provide critical preclinical information on MST tumor therapy directed against neuroblastoma. MST targeted at GD2 will also be applicable to osteosarcoma, brain tumors and small cell lung cancer. We plan to apply these successes to other antigen systems including gp58 which is widely expressed among Ewing's sarcomas, rhabdomyosarcomas, osteosarcomas, neuroblastomas, and brain minors. These are unique opporttmities to exploit MST for delivery of targeted therapies in these pediatric cancers.

抗体疗法的一个主要限制是与正常组织相比，其对肿瘤的递送效果欠佳。一个新兴的技术是多步靶向（MST），可以大大提高治疗指数。首先是肿瘤细胞被抗体缀合物靶向，该抗体缀合物随后将被细胞毒性配体结合。 MST 特别是与儿童癌症相关，其中急性毒性和迟发效应受到高度关注。我们建议研究 scFv- 链霉亲和素 MST 用于神经母细胞瘤 (NB)，这是一种儿童转移性实体瘤，标准治疗方法无法奏效存在。我们成功表达了由单链 Fv 片段和链霉亲和素使这一提议成为可能。由于目标丰富，NB对于MST具有独特的优势抗原 GD2，治疗后均匀表达，没有抗原调节或丢失。初步的研究表明，抗 GD2-scFv-链霉亲和素 (scFv-SA) 的选择性递送显着改善 NB 异种移植物 scFv-SA MST 使用小型生物素化配体（例如 DOTA-生物素）实现了典型的累积未成年人与血液之间的时间-活动差异>50:1。相比之下，使用整个 IgG 作为靶向剂，比例仅为4：1。此外，MST 可以选择性地靶向肽甚至牛血清白蛋白。迄今为止， MST 的努力主要集中在放射免疫治疗上，没有充分利用上位肿瘤：正常组织比。 MST 在血液和骨髓转移常见的肿瘤模型中特别相关，例如神经母细胞瘤。我们建议使用体外模型来优化 MST 的细胞因子靶向，以增强 ADCC，以及使用生物素-抗淋巴细胞抗体作为双特异性试剂来重定向NK/NKT细胞以增强肿瘤细胞毒性。将使用异种移植肿瘤模型进行体内验证：（1）使用90Y-研究MST放射免疫疗法 DOTA 消融皮下和转移性肿瘤，以及 (2) MST 靶向 IL2 或抗 CD3/抗 CD56 抗体增强和重定向细胞毒性淋巴细胞。在实施任何 I/I1 期临床试验之前，这些研究将提供针对神经母细胞瘤的 MST 肿瘤治疗的重要临床前信息。 MST 目标为 GD2还将适用于骨肉瘤、脑肿瘤和小细胞肺癌。我们计划应用这些其他抗原系统的成功，包括在尤文氏肉瘤中广泛表达的 gp58，横纹肌肉瘤、骨肉瘤、神经母细胞瘤和脑未成年人。这些都是值得利用的独特机会 MST 用于针对这些儿科癌症提供靶向治疗。