Project 4

项目4

• 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
• 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

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.

抗体疗法的主要局限性是其向谣言与正常组织的次优递送。一个新兴 技术是多步靶（MST），可以大大改善治疗指数。肿瘤细胞首先 由抗体偶联物靶向，随后将由细胞毒性配体结合。 MST尤其是 与小儿癌症相关，急性毒性和迟到的影响极大地关注。我们建议研究SCFV- 神经母细胞瘤（NB）中的链霉亲和素MST，这是标准治疗疗法的儿童转移性实体瘤 存在。我们在表达由单链FV片段和 链霉亲丁使该提案成为可能。 NB对于MST具有独特的优势，因为目标很丰富 抗原GD2，该GD2在治疗后无抗原调节或损失均匀表达。初步的 研究表明，抗GD2-SCFV-链霉亲和素的选择性递送大大改善 NB异种移植物，SCFV-SA MST，使用小的生物素化配体（例如Dota-biotin）达到了典型的累积 次要和血液之间的时间活性差异> 50：1。相反，使用整个IgG作为靶向剂， 比率仅为4：1。此外，MST可以选择肽甚至牛血清Albnmin。迄今为止， MST的努力主要集中在放射免疫疗法上，而没有充分利用上级肿瘤：正常 组织比。 MST在血液和骨髓中的转移很常见的肿瘤模型中特别相关，如 ncuroblastoma。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，以重定向NK/NKT细胞增强肿瘤细胞毒性。 体内验证将使用异种移植肿瘤模型进行：（1）使用90Y- dota烧毁皮下和转移性肿瘤，以及（2）靶向MST的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临床试验之前，这些研究 将提供有关针对神经母细胞瘤的MST肿瘤疗法的关键临床前信息。 MST针对的 GD2也适用于骨肉瘤，脑肿瘤和小细胞肺癌。我们计划应用这些 对于包括GP58在内的其他抗原系统的成功，该系统在Ewing的肉瘤中广泛表达， 横纹肌肉瘤，骨肉瘤，神经母细胞瘤和大脑未成年人。这些是利用的独特机会 MST用于在这些小儿癌中递送靶向疗法。