Intravenous application of bispecific antibody for cardiac regenerative therapy after heart ischemia/reperfusion injury

Statement of Purpose: Stem cell therapy, which makes use of cellular paracrine secretions, is a promising strategy for therapeutic heart regeneration. In the last decade, scientists have been using biomaterial and bioengineering approaches to deliver different stem cells and stem-cell products to the heart, for myocardial infarction (MI) treatment. However, the transplantation of biomaterials or allogeneic stem cells for MI treatment still has to overcome a number of hurdles, such as the quality control of cell products, clinical practicality, toxicity of biomaterial degradation, low cell retention/engraftment, and immune reactions. To overcome these limitations, our study introduces an immunotherapy approach to cardiac regenerative therapy. Bispecific antibodies have been widely recognized as therapeutic molecules in cancer immunotherapy. They are capable of binding two different targets simultaneously by combining variable domains of desired monoclonal antibodies into an integrated structure. Thus, instead of recruitment of immune cells for tumor resolution, we designed bispecific antibodies (BsAb) via the chemical cycloaddition of F(ab')2 fragments from monoclonal antibodies which specifically bind to injured myocardium or bone marrow derived stem cells. The intravenous administration of BsAb not only efficiently recruited endogenous bone marrow stem cells, but also helped the cells target the ischemia/reperfusion injured myocardium (Fig. 1). The binding efficiency of BsAb has been confirmed through in vitro models. The safety and therapeutic efficacy of BsAb has been confirmed through coculture with injured cardiomyocytes in vitro and a mouse model of ischemia/reperfusion in vivo. Our preliminary results demonstrate that the intravenous administration of BsAb supports cardiac recovery by reducing scarring, promoting angiomyogenesis, and boosting cardiac function. Compared to current cardiac treatment strategies, BsAb offers clinically-feasible, easy-to-store, and cell-free advantages.