Therapeutic Development of a Monoclonal Antibody to Treat Cardiomyopathies
Abstract
Topic Area: Cardiomyopathy. The proposal directly addresses the topic area of cardiomyopathy and is related to the following area of encouragement: (i) Development of novel therapeutic approaches for primary and secondary cardiomyopathies. Cardiomyopathies broadly refer to diseases of cardiac muscle. Heart attacks causing cardiac muscle death or dysfunction remain one of the most common cause of cardiomyopathy both in the civilian and military population and contribute to more than 40% of all cases of cardiomyopathy and heart failure. Following a heart attack, the heart muscle dies and is replaced by scar tissue. Unlike heart muscle, scar tissue does not contract and leads to a series of deleterious changes in the heart including enlargement of the cardiac chambers, increased wall stress on the remaining heart muscle, and ultimately development of heart failure. More than 700,000 patients are newly diagnosed with heart failure every year, and despite the use of current cardiovascular drugs, once a diagnosis of heart failure is made, the 5-year mortality rate is close to 50%. There is thus an immense need to develop novel therapeutic strategies for the prevention or treatment of cardiomyopathies and heart failure. As the human heart does not possess a robust ability to regenerate after heart attacks, strategies to attenuate or prevent the development of a cardiomyopathy has been focused on augmentation of pro-reparative mechanisms of wound healing in the heart. It is hoped that augmentation of pro-reparative mechanisms of wound healing would lead to decreased cardiac remodeling and better preservation of post-injury cardiac function. In this proposal, we describe a novel therapeutic approach to prevent the development of cardiomyopathy and heart failure after heart attacks and identify the gene ENPP1 (ectonucleotide pyrophosphatase-1) as a target to preserve heart function after heart attacks and prevent the development of a cardiomyopathy. Our laboratory was one of the first to demonstrate that ENPP1 played an important role in wound healing in the heart. In this proposal, we show the heart after heart attacks robustly expresses ENPP1. ENPP1 is an enzyme that breaks down extracellular ATP into AMP and PPi (pyrophosphate), and we show that increased ENPP1 activity after heart attacks initiates a series of pro-inflammatory changes that worsens wound healing, cell death, and inflammation in the heart. Moreover, we demonstrate that inhibition of ENPP1 leads to better preservation of post-injury heart function. In collaboration with a biotechnology company, we have created a monoclonal antibody (mAb) to target ENPP1 and demonstrate that injection of the monoclonal antibody in animal models of heart attacks leads to significant preservation of post-injury heart function. Monoclonal antibodies are highly specific therapeutic agents and in contrast to drugs that may exhibit toxicity, monoclonal antibodies are rarely toxic. Considering our observations, we hypothesize that a monoclonal antibody targeting ENPP1 will prevent the development of cardiomyopathy after heart attacks. In this application, we propose further therapeutic development of the monoclonal antibody against ENPP1 such that it can be manufactured under industry compliant standards for preclinical use and testing. We have assembled a team including industry consultants, consultants with specific expertise in mAb development, contract research organizations, U.S. Food and Drug Administration (FDA) regulatory experts including project management expertise at our institution. We anticipate that this proposal will lead to a new therapeutic agent in the form of anti ENPP1 monoclonal antibody that would hold promise for the treatment and prevention of cardiomyopathies especially after heart attacks.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Mar 10, 2021
- Source ID
- W81XWH2010238
Entities
People
- Arjun Deb
Organizations
- United States Army
- University of California, Los Angeles