Modular immunoconjugates

模块化免疫偶联物

• 批准号: 7936183
• 负责人: Vaughn Vasil Smider
• 金额: $ 50万
• 依托单位: SCRIPPS RESEARCH INSTITUTE, THE
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-30 至 2012-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7936183
• 关键词: Amino Acids; Animal Model; Animals; Base Pairing; Binding; Biocompatible Materials; Bispecific Antibodies; Cells; Complement; Coupled; Coupling; DNA; Data; Diagnostic; Disease; Engineering; Future; Genetic; Goals; Image; Immunoconjugates; Immunoglobulin Constant Region; Immunoglobulin Fragments; In Vitro; Label; Link; Medicine; Muromonab-CD3; Nucleic Acids; Oligonucleotides; Positioning Attribute; Process; Proteins; Site; Specificity; Technetium; Techniques; Technology; Testing; Therapeutic; Therapeutic Agents; Toxin; base; combinatorial; design; efficacy testing; in vivo; killings; neoplastic cell; novel; public health relevance; single molecule; single photon emission computed tomography; success; therapeutic protein; tumor

DESCRIPTION (provided by applicant): (13) Smart Biomaterials - Theranostics 13-EB-101*Theranostics: Combined delivery of diagnostic and therapeutic agents. Multimeric polyspecific protein therapeutics are difficult to design and produce. The ability to link binding, effector, and imaging components together in a single molecule would be a significant advantage. We propose to develop unnatural amino acid- oligonucleotide technology (UAA-oligo) in order to precisely control formation of modular therapeutics and diagnostics. An unnatural amino acid engineered in a single position will allow site-specific coupling of an oligonucleotide. The oligonucleotide can then be hybridized to its complement which is conjugated to a second modular protein. The base-pairing rules of DNA will allow higher order heterodimers, trimers, tetramers, and other multimers to be produced. This strategy will allow diagnostic and therapeutic modules to be coupled in a single molecule to produce a "Theranostic". PUBLIC HEALTH RELEVANCE: The ability to create modular protein therapeutics, such that novel binding, effector, and diagnostic proteins can be combined in a single "theranostic" has considerable importance in medicine. Specifically, this proposal aims to create the platform for discovery of such molecules as well as for their facile construction. We will use oligonucleotides and unnatural amino acids to site specifically link two or more proteins together through the complementary base pairing of nucleic acids. Molecules that we create could simultaneously detect, bind, and kill tumor cells through imaging, binding, and toxin modules. This "lego" block assembly process will allow a vast array of combinatorial protein theranostic modules to be created and evaluated against a myriad of diseases.

描述（由申请人提供）：（13）Smart Biomaterials - Theranostics 13-EB-101*Theranostics：诊断剂和治疗剂的联合递送。 多聚体多特异性蛋白质治疗剂难以设计和生产。在单个分子中将结合、效应物和成像组分连接在一起的能力将是显著的优势。我们建议开发非天然氨基酸-寡核苷酸技术（UAA-oligo），以精确控制模块化治疗和诊断的形成。在单个位置工程化的非天然氨基酸将允许寡核苷酸的位点特异性偶联。然后寡核苷酸可以与其互补物杂交，所述互补物与第二模块蛋白缀合。DNA的碱基配对规则将允许产生更高阶的异源二聚体、三聚体、四聚体和其他多聚体。这种策略将允许诊断和治疗模块在单个分子中偶联以产生“治疗诊断”。 公共卫生关系：创造模块化蛋白质治疗剂的能力，使得新的结合、效应和诊断蛋白质可以组合在单个“治疗诊断剂”中，在医学中具有相当重要的意义。具体而言，该提案旨在为发现此类分子及其简易构建创建平台。我们将使用寡核苷酸和非天然氨基酸通过核酸的互补碱基配对将两个或多个蛋白质位点特异性地连接在一起。我们创造的分子可以通过成像，结合和毒素模块同时检测，结合和杀死肿瘤细胞。这种“乐高”积木组装过程将允许创建大量组合蛋白质治疗诊断模块，并针对无数疾病进行评估。