Treatment of Transplant Reperfusion with CD47 antibody
DESCRIPTION (provided by applicant): Vasculox, Inc. is developing a humanized anti-CD47 mAb for reducing ischemia-reperfusion injury (IRI) in organ transplantation. In spite of improvements in surgical technique, organ preservation and immunosuppression, IRI remains a serious limitation and is responsible for delayed graft function, initial graft failure and contribtes to poor long-term graft survival, thus representing an area of significant unmet medical need. Increasing nitric oxide (NO) signaling can provide a substantial therapeutic benefit in reducing IRI. The founders of Vasculox discovered that thrombospondin-1 (TSP1) binding to its receptor, CD47, limits NO signaling in all vascular tissues. Blocking TSP-1 binding with an anti-CD47 monoclonal antibody (anti-CD47 mAb) relieves this inhibition of NO signaling and improves outcomes in several animal models of IRI. We have recently demonstrated efficacy of an anti-CD47 mAb to improve liver function in an ex vivo perfusion model and in a rat liver transplant model. Vasculox has characterized a panel of 9 mouse monoclonal mAbs (400 series mAbs) that are unique in reacting broadly across species with human, rodent, dog and pig providing a significant advantage for clinical development. Three of these mAbs reverse the TSP1-CD47 mediated inhibition of NO-stimulated cGMP formation in cultured cells and one of these will be taken forward for humanization. In this Phase II SBIR grant the specific aims are: Aim 1. Humanize the lead CD47 mAb candidate, produce research grade material for preclinical studies. Aim 2A. Establish optimal conditions for efficacy of CD47 mAb in a rat syngeneic liver transplant model including administration and dosing modality (pre-treat organ alone, treat recipient alone or treat both) and adjuvant treatments to enhance the NO signaling pathway (arginase inhibitors and/or L-arginine) Aim 2B. Demonstrate efficacy of the humanized mAb in a large animal (porcine) model of transplant using the optimized treatment modality as determined in Aim2A. Aim 3. Carry out non-GLP (preliminary) pharmacokinetic and safety studies in the rat and non-human primate using the CD47 humanized mAb to prepare for GLP IND-enabling studies. This phase II proposal addresses several critical path milestones for Vasculox that will allow us to address transplant IRI as well as additional indications for anti-CD47 therapy including IRI arising from surgical procedures, trauma, sickle cell crisis and pulmonary hypertension. PUBLIC HEALTH RELEVANCE: Ischemia reperfusion injury (IRI) is a complicating factor in many cardiovascular diseases and surgical procedures including organ transplantation. Increasing nitric oxide (NO) signaling can provide a substantial therapeutic benefit in reducing IRI. The founders of Vasculox discovered that a receptor called CD47 limits NO signaling. Blocking CD47 with a monoclonal antibody (CD47mAb) relieves this inhibition of NO signaling and has the potential to enhance organ transplantation and save lives. Vasculox is developing a humanized CD47mAb for reducing IRI in organ transplantation that reacts with many different species. In this proposal we will humanize the lead CD47mAb candidate and determine its optimal dosing modality in rat liver transplantation. We will then confirm its efficacy in pigs, a more human-like species. Finally, we will conduct studies of how long the mAb is available in the circulation and test the CD47mAb for safety in two animal species as required by the FDA. These studies represent critical path milestones for Vasculox and must be accomplished before we can begin clinical trials to improve organ transplantation, allow for more transplantable organs and thereby save more lives.
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