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.

该副本是利用众多研究子项目之一 由NIH/NCRR资助的中心赠款提供的资源。子弹和 调查员（PI）可能已经从其他NIH来源获得了主要资金， 因此可以在其他清晰的条目中代表。列出的机构是 对于中心，这不一定是调查员的机构。 该项目的范围没有变化。它仍然专注于双特异性抗体的发展，这些抗体可以测试，以募集细胞对皮肤和肌肉损伤部位的募集。 双特异性抗体（BIAB）引起了研究界的极大关注。 它们的独特结构包含两个不同的抗原结合特异性，因此它们可用于任何应用，可以将其并列两个分子或细胞并置在几纳米范围内。 例如，可以将治疗剂放在一个手臂上，而另一只手臂则可以专门针对患病或受伤的组织。 这种治疗剂可以采用多种形式，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性细胞。 实际上，双特异性抗体已用于研究和临床努力，以靶向细胞毒性T和NK细胞以杀死肿瘤细胞。 考虑到鉴定组织，疾病和损伤特异性抗原的最新进展，以及对免疫学和干细胞生物学领域的更好理解，BIAB技术具有满足许多治疗需求的巨大希望。 该提案的目的是将我们从BIAB中学到的靶向杀伤细胞的应用中学到的知识，并证明它们在将各种细胞靶向各种受伤的组织中的广泛潜力。这些研究可能与组织修复中遇到的问题具有很大的治疗性相关。此外，建立可以帮助招募细胞到损伤部位的有用的BIAB可能会增加我们对细胞运输的理解以及某些细胞类型的作用，例如巨噬细胞和骨髓衍生的细胞。 我们假设特定的抗体将指导在分化为损伤部位的不同状态下特定细胞种群的运输，它们可以促进组织修复和重建。 为了检验该假设，我们提出1）将一个指向损伤相关抗原（即纤维蛋白肽A，VCAM-1等）的mAB与对“效应器”细胞种群特异的第二mAb（即F4/80）（即，由巨噬细胞表达的F4/80表达），由C-kterive sermant serment sermented sermanded sermak-serive sermar marowdeder，将一个MAB（即纤维蛋白肽A，VCAM-1等）相结合。双特异性抗体（BIAB），2）使用这些BIAB将这些选定的细胞群靶向相应的小鼠模型中实验诱导的伤口后受伤的皮肤和骨骼肌组织（即全厚度尾部缠绕和机械挤压损伤）； 3）评估双特异性抗体靶向细胞对组织修复和重构的影响。 这些研究将为BIABs作为平台技术的原理提供关键证明，以将细胞专门针对特定组织。 基于这些研究，设想了多种机械方法和组织修复中的临床应用，仅受鉴定靶向细胞和受伤的组织特异性抗原的限制。