Exploiting activation-induced cell death as a means of inducing tolerance to kidney allografts

Fascure Therapeutics, Llc, Louisville KY

Investigators

Abstract

PROJECT SUMMARY Kidney transplantation is the preferred treatment for patients with end-stage renal disease. However, standard immunosuppression to control rejection is the major limitation. Although standard immunosuppression has gradually been improved for better efficacy and safety, it still carries a great risk for adverse effects ranging from malignancies and infections to cardiovascular complications. As such, there is an acute need for developing novel immunomodulatory approaches that obviate the need for chronic immunosuppression or mitigate immunosuppression for improved safety. The goal of this phase I SBIR application is to simultaneously target Fas and IL-2R as an innovative immunomodulatory approach to modulate pathogenic T effector (Teff) and protective T regulatory (Treg) cells for induction of tolerance to rat kidney allografts in the absence of any immunosuppression. FasCure Therapeutics is focused on the development of biologics with desired immunomodulatory activities for targeted indications. The Company has exclusive rights to a portfolio of proprietary novel immune inhibitory ligands as components of a therapeutic platform for prevention and treatment of autoimmune diseases and foreign graft rejection. The Company?s lead therapeutic platform involves the use of SA-FasL and IL-2D as novel forms of Fas and IL-2R agonists, respectively, to directly target pathogenic Teff cells for physical elimination (apoptosis) and protective Treg cells for expansion. Teff cells are the main culprits of allogeneic graft rejection. These cells upregulate Fas receptor on their surface following antigen activation, and become sensitive to Fas/FasL-mediated apoptosis. IL-2 is critical for the generation and expansion of CD4+CD25+FoxP3+ Treg cells. IL-2 is also involved in apoptosis of Teff cells by down-regulating anti-apoptotic genes. As such, the combination of SA-FasL and IL-2D has the potential to physically eliminate Teff and expand Treg cells. An increased Treg/Teff ratio has significant potential to sustain renal allograft survival in the absence of chronic immunosuppression. This notion is supported by strong preliminary data in allogeneic pancreatic islet and cardiac graft models in mice. The major goals of this phase I SBIR application is to: i) establish a lead SA-FasL+IL-2D treatment protocol that sustains permanent rat kidney allograft survival in the absence of any immunosuppression, and ii) investigate the mechanistic basis of sustained graft survival and the safety profile of the immunomodulatory protocol. If efficacy is shown in the proposed rat model, this protocol will be further developed as a novel product in a Phase II SBIR application for translation into nonhuman primates as a prelude to clinical trials.