Chronic rejection (CR) remains the primary cause of late graft loss following renal transplantation. Projections estimate that the 10-year survival rate for renal allografts is just 40 percent. While improved immunosuppresive therapy has decreased the occurrence of acute rejection, the percentage of allografts which eventually succumb to CR remains essentially unchanged. Recent advances in understanding the complex cellular mechanisms associated with CR, most notably the correlation between extracellular FGF-1 and increased peroxynitrite levels, is enabling more focused approaches to preventative therapies. In an animal model of CR increased FGF-1 levels were apparent in tubular epithelial cells just two weeks after transplantation, suggesting early involvement of FGF-1 during alloantigen-dependent mechanisms initiating CR. Accordingly, an effective inhibitor of extracellular FGF-1 has been suggested as a viable therapeutic for treating CR. The focus of this grant is to develop inhibitory antibodies to FGF-1. Target epitopes have been identified, and will be used to raise antibodies using an immune carrier which effectively presents non-linear epitopes. An animal model of CR, exhibiting elevated levels of FGF-1, will be used to evaluate candidate antibodies. In phase II, monoclonal antibodies will be generated, and humanized in preparation for human clinical trials which will be initiated during phase III.
The majority of transplant patients continue to exhibit complications of long term immunosuppression, including impairment of host defense mechanisms which increase the risk of opportunistic infections and malignancies. The simple conclusion is that current immunosuppressive drug therapy is not a satisfactory solution to the unremitting problem of CR. Currently, the only successful treatment is retransplantation. The correlation between extracellular FGF-1 and CR suggests that a specific antibody to FGF-1 would be valuable therapeutic treatment for CR, and other chronic diseases in which FGF-1 has been implicated, including arthritis, atheroschlerosis and tumorogenesis.
