DEVELOPMENT OF GM-CSF ANTOGONISTS

由于分子技术的发展，药物开发正在迅速发展 以及它们在分析配体-受体相互作用方面的应用。 抗体可以作为研究结构方面的分子探针。 受体结合和激活。这一点最近已扩展到 基于结构分析的生物活性多肽研究进展 抗体可变区。这些技术现在可以应用于 与临床相关的生物分子，最终目标是开发新的 治疗学。 粒细胞/巨噬细胞集落刺激因子(GM-CSF)在 在髓系分化中的作用，并与几种免疫有关 和炎症过程。GM-CSF与特定细胞受体结合 (GM-CSFR)属于最近发现的一个超基因家族。这些 受体是设计用于药物治疗的潜在靶点。 各种治疗应用。此类药理药物的设计 取决于对配体-受体相互作用的分子理解。这个 这笔赠款的总体目标是利用单抗和 重组抗体作为分析GM-CSF-GM-CSFR的分子工具 互动。这将遵循开发的一般方法 基于抗体结构的生物活性多肽。 具体来说，单抗(MAbbs)和重组抗体 将开发与GM-CSF结合并中和GM-CSF活性的RABS。 随后，将开发与GM-CSFR结合的抗GM-CSFR单抗和RAB GM-CSFR上与GM-CSF结合的位置相同。直接抗受体 将开发GM-CSF的抗体和抗独特型类似物。这个 这些单抗/单抗的分子结构将以比较的方式分析 与GM-CSFR和GM-CSF一起时尚。这将允许分析潜在的 GM-CSFR和中和抗体共同的结合策略， 以及GM-CSF和抗受体抗体。此信息将允许 与GM-CSF特异性结合的多肽的研究进展 通用-CSFR。这些多肽可以作为强大的分析工具 分子间相互作用对GM-CSF活性至关重要。这样的多肽 在体外具有生物活性将使药物设计成为可能 潜在的临床应用价值。

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.