DEVELOPMENT OF BISPECIFIC ANTIBODIES TO FACILITATE TISSUE REPAIR CELL RECRUITMEN

开发双特异性抗体以促进组织修复细胞招募

• 批准号: 8167641
• 负责人: Leslie P Cousens
• 金额: $ 22.04万
• 依托单位: ROGER WILLIAMS HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-05-01 至 2011-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8167641
• 关键词: Address; Antibodies; Antigens; Attention; Bispecific Antibodies; Blood Vessels; Bone Marrow; Cells; Clinical; Communities; Computer Retrieval of Information on Scientific Projects Database; Crush Injury; DNA; Development; Disease; Effector Cell; Enzymes; Fibrinopeptide A; Funding; Gene Transduction Agent; Goals; Grant; Immunology; Injury; Institution; Killer Cells; Learning; Mechanics; Muscle; Natural Killer Cells; Pharmaceutical Preparations; Population; Prodrugs; Proto-Oncogene Protein c-kit; Recruitment Activity; Research; Research Personnel; Resources; Role; Series; Site; Skeletal Muscle; Skin; Source; Specificity; Stem cells; Structure; Tail; Technology; Testing; Therapeutic; Therapeutic Agents; Thick; Tissues; Toxin; United States National Institutes of Health; Vascular Cell Adhesion Molecule-1; Wound Healing; antigen binding; arm; base; cell type; clinical application; cytotoxic; injured; killings; macrophage; mouse model; nanometer; neoplastic cell; reconstitution; stem cell biology; trafficking; tumor

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. There has been no change in the scope of this project. It remains focused on the development of bispecific antibodies that can be tested for cell recruitment to sites of injury in skin and muscle. Bispecific antibodies (BiAbs) have drawn considerable attention from the research community. Their unique structure contains two distinct antigen-binding specificities, so they can be used for any application where it is desirable to juxtapose two molecules or cells within a distance of a few nanometers. For instance, a therapeutic agent can be placed on one arm, while the other is available to specifically target a diseased or injured tissue. This therapeutic agent can take many forms, including that of a toxin, drug, prodrug, enzyme, DNA, anti-vascular agent, gene therapy vector, radionucleotide or even a functional cell. Indeed, bispecific antibodies have been used in both research and clinical efforts to target cytotoxic T and NK cells to kill tumor cells. Considering recent advances in the identification of tissue-, disease-, and injury-specific antigens together with a better understanding in the fields of immunology and stem cell biology, BiAb technology holds great promise for addressing a number of therapeutic needs. The goal of this proposal is to take what we have learned from the application of BiAbs in targeting killer cells to tumors and demonstrate their broader potential in targeting a variety of cells to different injured tissues. These studies could have great therapeutic relevance to problems encountered in tissue repair. Moreover, establishing useful BiAb that can help recruit cells to the site of injury could increase our understanding of cell trafficking and the role of certain cell types, for example macrophages and bone marrow derived cells. We hypothesize that specific antibodies will direct trafficking of specific cell populations in different states of differentiation to sites of injury, where they can facilitate tissue repair and reconstitution. To test this hypothesis, we propose 1) to combine (chemically heteroconjugate) one mAb directed at an injury-associated antigen (i.e. fibrinopeptide A, VCAM-1, etc.) with a second mAb specific for an "effector" cell population (i.e. F4/80 expressed by macrophages, c-kit expressed by bone marrow-derived stem cells, etc.) to produce a series of bispecific antibodies (BiAb), 2) to use these BiAbs to target these selected cell populations to injured skin and skeletal muscle tissues after experimentally-induced wounds in the respective mouse models (i.e. a full thickness tail-wound and a mechanical crush injury); and 3) to evaluate the effects of bispecific-antibody targeted cells on tissue repair and reconstitution. These studies will provide critical proof of the principle that the BiAbs can be used as a platform technology to specifically target cells to particular tissues. Based on these studies, a variety of mechanistic approaches and clinical applications in tissue repair are envisioned, limited only by the identification targeted cell- and injured tissue-specific antigens.

该子项目是利用该技术的众多研究子项目之一 资源由 NIH/NCRR 资助的中心拨款提供。子项目及 研究者 (PI) 可能已从 NIH 的另一个来源获得主要资金， 因此可以在其他 CRISP 条目中表示。列出的机构是 对于中心来说，它不一定是研究者的机构。 该项目的范围没有变化。它仍然专注于双特异性抗体的开发，可以测试细胞募集到皮肤和肌肉损伤部位的情况。 双特异性抗体（BiAb）引起了研究界的广泛关注。 它们独特的结构包含两种不同的抗原结合特异性，因此它们可用于任何需要在几纳米距离内并置两个分子或细胞的应用。 例如，可以将治疗剂放置在一只手臂上，而另一只手臂则可专门针对患病或受伤的组织。 这种治疗剂可以采取多种形式，包括毒素、药物、前药、酶、DNA、抗血管剂、基因治疗载体、放射性核苷酸甚至功能细胞的形式。 事实上，双特异性抗体已被用于研究和临床工作中，以靶向细胞毒性 T 细胞和 NK 细胞来杀死肿瘤细胞。 考虑到组织、疾病和损伤特异性抗原识别方面的最新进展，以及对免疫学和干细胞生物学领域的更好理解，BiAb 技术在满足许多治疗需求方面具有巨大的前景。 该提案的目标是利用我们从 BiAb 在靶向杀伤细胞肿瘤方面的应用中学到的知识，并展示其在将多种细胞靶向不同受损组织方面的更广泛潜力。这些研究可能对组织修复中遇到的问题具有很大的治疗意义。此外，建立可以帮助将细胞募集到损伤部位的有用 BiAb 可以增加我们对细胞运输和某些细胞类型（例如巨噬细胞和骨髓衍生细胞）作用的理解。 我们假设特异性抗体将引导处于不同分化状态的特定细胞群运输到损伤部位，在那里它们可以促进组织修复和重建。 为了检验这一假设，我们建议 1) 将一种针对损伤相关抗原（即纤维蛋白肽 A、VCAM-1 等）的 mAb 与另一种针对“效应”细胞群（即“效应”细胞群）特异的 mAb 组合（化学杂合）。巨噬细胞表达的F4/80、骨髓来源干细胞表达的c-kit等）产生一系列双特异性抗体（BiAb），2）利用这些BiAb 将这些选定的细胞群靶向在相应小鼠模型中实验诱导伤口（即全层尾部伤口和机械挤压伤）后受伤的皮肤和骨骼肌组织； 3) 评估双特异性抗体靶向细胞对组织修复和重建的影响。 这些研究将为 BiAb 可用作平台技术以将细胞特异性靶向特定组织的原理提供关键证据。 基于这些研究，设想了组织修复中的各种机制方法和临床应用，仅受识别靶细胞和损伤组织特异性抗原的限制。