Abstract 10880: Systemic Delivery of Bispecific Antibodies Promotes Stem Cell Homing and Improves Cardiac Function Post-Myocardial Infarction
Background: Experimental studies have demonstrated the ability of bone marrow-derived stem cells to enhance cardiac repair and regeneration post-myocardial infarction (MI). However, clinical trials utilizing similar approaches have shown only moderate improvements in cardiac function. This is likely due, in part, to the poor homing of stem cells to sites of cardiac damage.
Methods and Results: To increase stem cell homing to the injured heart, we generated a bispecific antibody (BiAb) which binds to both the stem cell marker c-kit and myosin light chain-1, a protein that is exposed at sites of myocyte damage. β-galactosidase+ (β-gal+) bone marrow cells from ROSA-26 mice were armed with the BiAb ex vivo and systemically injected into wild-type mice immediately post-cardiac ischemia-reperfusion injury. Immunohistochemical analysis 5 days later revealed a significant increase in the number of donor cells in the infarct area in mice receiving BiAb-armed bone marrow cells vs. unarmed control cells (24.73±3.50% vs. 10.89±0.83% β-gal+cells, respectively; p<0.05), suggesting that treatment with the BiAb increased c-kit+ cell homing to the infarct. To test whether delivery of the BiAb in vivo improves cardiac function after MI, mice underwent permanent coronary artery ligation followed by 3 days of G-CSF treatment to mobilize hematopoietic stem cells (or vehicle control). On the third day post-MI, BiAb was delivered i.v. Functional analysis by MRI 2 weeks later revealed enhanced ejection fraction in mice receiving the BiAb vs. control treatments (38.09±2.46% vs. 31.52±1.90% vs 32.34±2.40% in mice receiving BiAb, control Ab and vehicle, respectively; p<0.05 for BiAb vs. control Ab group). This was coupled with a reduction in left ventricular mass:body weight ratios, (4.69±0.18 vs. 5.32±0.22 vs. 5.12±0.30 in mice receiving BiAb, control Ab and vehicle, respectively; p<0.05 for BiAb vs. control Ab group), suggesting an attenuated hypertrophic response in the BiAb-treated mice. Importantly, these benefits were sustained in the BiAb-treated group for at least 3 months.
Conclusions: These data demonstrate that the use of bispecific antibodies to promote homing of stem cells to the injured heart may be a viable strategy for the treatment of ischemic heart disease.
- © 2010 by American Heart Association, Inc.