This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. 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.
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