CTLA4-IG-ANTICD40 FUSION PROTEIN FOR IMMUNOTHERAPY

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Blocking either of the two major T-cell costimulatory pathways, B7- CD28 or CD40-CD40L, alone is not sufficient to permit indefinite engraftment of highly immunogenic allografts. However, Larsen et al. Have recently shown that blocking the B7-CD28 and CD40-CD40L pathways simultaneously effectively aborts T-cell clonal expansion in vitro and in vivo, promotes long-term survival of fully allogeneic skin grafts, and inhibits the development of chronic vascular rejection of primarily vascularized cardiac allografts. These findings are of great importance for solid organtransplantation in humans, since despite the many advances in clinical immunosuppression, chronic vascular rejection remains the major source of transplant failure for which there remains no effective therapy. We therefore propose to generate a fusion protein based on the B7-binding capacity of CTLA4-lg and the CD40-blocking activity of the humanized anti-CD40 Mab 5D12. In phase I will create a fusion protein linking CTLA4-lg to the scFv form of 5D12. This fusion protein will be expressed and purified and in vitro immunomodulatory activity demonstrated. In phase II the protein will be studied in a rhesus monkey model of kidney transplantation. This fusion protein will provide a novel, proprietary therapy for allograft transplantation.