DEVELOPMENT OF GM-CSF ANTOGONISTS

GM-CSF拮抗剂的开发

• 批准号: 3305826
• 负责人: WILLIAM V WILLIAMS
• 金额: $ 15.27万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 1991
• 资助国家: 美国
• 起止时间: 1991-09-01 至 1994-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3305826
• 关键词: antireceptor antibody; chemical binding; colony stimulating factor; growth factor receptors; hybridomas; inhibitor /antagonist; laboratory mouse; monoclonal antibody; peptide analog; polymerase chain reaction; synthetic peptide

Pharmaceutic development is rapidly evolving due to molecular techniques and their application to analysis of ligand-receptor interactions. Antibodies can serve as molecular probes to study structural aspects receptor binding and activation. This has recently been extended to the development of biologically active peptides based on structural analysis of antibody variable regions. These techniques may now be applied to clinically relevant biomolecules with the ultimate goal of developing novel therapeutics. Granulocyte/macrophage colony stimulating factor (GM-CSF) plays a critical role in myeloid differentiation, and has been implicated in several immune and inflammatory processes. GM-CSF binds to specific cellular receptors (GM-CSFR) which belong to a recently described supergene family. These receptors are potential targets for pharmacologic agents designed for a variety of therapeutic applications. Design of such pharmacologic agents depends on a molecular understanding of ligand-receptor interactions. The overall aim of this grant is to utilize monoclonal antibodies and recombinant antibodies as molecular tools to analyze the GM-CSF - GM-CSFR interaction. This will follow the general approach of developing biologically active peptides based on antibody structures. Specifically, monoclonal antibodies (mAbs) and recombinant antibodies (rAbs) that bind GM-CSF and neutralize GM-CSF activity will be developed. Subsequently, anti-GM-CSFR mAbs and rAbs will be developed that bind to the same site on the GM-CSFR that GM-CSF binds. Direct anti-receptor antibodies and anti-idiotypic analogs of GM-CSF will be developed. The molecular structure of these mAbs/rAbs will be analyzed in a comparative fashion with the GM-CSFR and GM-CSF. This will allow analysis of potential binding strategies shared by the GM-CSFR and the neutralizing antibodies, and by GM-CSF and the antireceptor antibodies. This information will allow the development of peptides that specifically bind to GM-CSF and the GM-CSFR. These peptides can serve as powerful tools to analyze intermolecular interactions critical in GM-CSF activity. Such peptides with biological activity in vitro will allow design of pharmaceutics with potential clinical utility.

由于分子技术，药物开发正在迅速发展 及其在配体-受体相互作用分析中的应用。 抗体可以作为分子探针来研究结构方面 受体结合和激活。 这最近已扩展到 基于结构分析的生物活性肽的开发 抗体可变区。 这些技术现在可以应用于 临床相关的生物分子，最终目标是开发新的 疗法。 粒细胞/巨噬细胞集落刺激因子 (GM-CSF) 在 在骨髓分化中发挥作用，并与多种免疫相关 和炎症过程。 GM-CSF 与特定细胞受体结合 （GM-CSFR）属于最近描述的超基因家族。 这些 受体是药物制剂的潜在靶标 各种治疗应用。 此类药物的设计 取决于对配体-受体相互作用的分子理解。 这 这笔赠款的总体目标是利用单克隆抗体和 重组抗体作为分析 GM-CSF 的分子工具 - GM-CSFR 相互作用。 这将遵循开发的一般方法 基于抗体结构的生物活性肽。 具体来说，单克隆抗体 (mAb) 和重组抗体 将开发结合 GM-CSF 并中和 GM-CSF 活性的重组抗体 (rAb)。 随后，将开发与 GM-CSFR 结合的抗 GM-CSFR mAb 和 rAb。 GM-CSFR 上与 GM-CSF 结合的相同位点。 直接抗受体 将开发GM-CSF的抗体和抗独特型类似物。这 这些 mAb/rAb 的分子结构将进行比较分析 GM-CSFR 和 GM-CSF 的时尚。 这将允许分析潜力 GM-CSFR 和中和抗体共享的结合策略， 以及 GM-CSF 和抗受体抗体。 这些信息将允许 开发特异性结合 GM-CSF 的肽以及 GM-CSFR。 这些肽可以作为分析的强大工具 分子间相互作用对于 GM-CSF 活性至关重要。 此类肽 具有体外生物活性将允许设计具有 潜在的临床实用性。