Acute myocardial infarction is the leading cause of death globally and while stem cell therapy has promise, there has been little progress. The heart is particularly difficult to treat due to slow cardiomyocyte turnover and the development of fibrosis as the extracellular matrix is remodeled. The lung has been identified as a reservoir of hematopoietic stem cells (HSCs) and major biogenesis site for platelets. Bispecific antibodies (BsAbs) are mainly used for treating cancers and autoimmune diseases, but we show that BsAbs can also treat cardiovascular disease.
Platelet-targeting bispecific antibodies (PT-BsAbs) were synthesized with click chemistry to conjoin the platelet binding motif, CD42b, with the HSC binding ligand, CD34. When administered by inhalation to a mouse MI model, the PT-BsAbs penetrate the respiratory tract barrier, transfer through the alveolar membrane, and enter the pulmonary blood circulation. During this, the PT-BsAbs bind HSCs to platelets, which naturally migrate to sites of cardiac injury. We showed inhalation therapy resulted in faster and higher accumulation of HSCs in the heart, mainly localizing to the border zone of the MI heart. Ultimately, based on echocardiograms, Western blot analysis, flow cytometry, qPCR, immunofluorescence assays, and histology, the PT-BsAb therapy improved cardiac repair and modulated inflammation in the MI microenvironment.
In this webinar, the development of BsAb therapy for the treatment of cardiovascular diseases and its potential was discussed.
Liu, M., Lutz, H., Zhu, D., Huang, K., Li, Z., Dinh, P.‐U. C., Gao, J., Zhang, Y., Cheng, K., Bispecific Antibody Inhalation Therapy for Redirecting Stem Cells from the Lungs to Repair Heart Injury. Adv. Sci. 2021, 8, 2002127.