There is an urgent need for improved therapies for acute and chronic myocardial ischemia. Bone marrow-derived stem cells (SC) injected into acutely injured as well as chronically ischemic myocardium improve left ventricular function. However, a major limitation of direct infusion or injection of SC is the targeting and retention of these cells at the site of myocardial injury. To address these problems, we have developed an improved, proprietary approach using bispecific antibody (BiMab)-targeted SC. This approach is less invasive, more specific and more efficacious. In phase I we used a xenogeneic rodent model of myocardial infarction (MI) to demonstrate that CD34+ SC derived from human peripheral blood can be antibody-targeted to injured myocardium when injected intravenously. In these studies an anti-CD45 antibody recognizing the CD34+ enriched SCs was chemically conjugated to an antibody recognizing myosin light chain (MLC) exposed in injured cardiac tissue. Starting two weeks post-MI and extending for at least 3 months, individuals receiving BiMab-armed SC had significantly improved myocardial function vs. those receiving unarmed SC. These exciting results provide proof-of-concept for antibody-targeted SC to enhance myocardial repair. In Phase II, to further develop and improve this technology with the ultimate aim of filing an IND, we will identify and characterize human antibodies recognizing CD45 and MLC. The recombinant human monoclonal antibodies (Mabs) will be linked to create a BiMab, """"""""CorTarga,"""""""" which will be evaluated using a preclinical rat model of myocardial infarction. Efficacy will be improved by optimizing cell types and numbers, timing of and strategies for administration of CorTarga. Finally, pre-clinical pharmacology and toxicology studies will be initiated. Successful outcome of this work will demonstrate a general method to improve the use of stem cell therapies for severe cardiac disease as well as many other indications in cell-based regenerative medicine.
Myocardial repair by targeted stem cells Major problems of cell targeting and retention limit the efficacy of stem cell therapy for myocardial injury. Bispecific antibodies recognizing an injury specific target and an antigen on the stem cells provides a novel means to greatly improve the efficiency of cell-based regenerative therapies.
