The principal objective of this application is the development of safer and more effective anti-thrombotic that does not increase bleeding risk. Cardiovascular disease, primarily myocardial infarction (MI), is the leading cause of Death in the United States. Each year, almost 800,000 people suffer a stroke and 1.5 million an MI. Total US healthcare expenditures in 2015 for coronary heart disease and stroke are estimated to be a staggering $182 billion and $95 billion, respectively, with an associated cost of drug therapies estimated to exceed $20 billion worldwide. Current drugs are subject to significant bleeding risk associated with increased mortality. While new antiplatelet and Anticoagulant Agents have been introduced, they are associated with a 25- 30% increase in the rate of bleeding. There is clearly an acute need for a safer (lower bleeding risk), effective anti-thrombotic. BioAtla plans to translate recent work defining the precise points of interaction between a leukocyte-expressed integrin and a platelet-expressed glycoprotein counter-receptor. This work has not only identified specific amino acids mediating Binding but also demonstrated that it is possible to selectively inhibit leukocyte-platelet interaction without interfering with other critical interactons, including those that mediate normal hemostasis. Associated work is revealing the importance of leukocyte-platelet interaction in the early stages of pathological thrombus formation. In sum, this work points to a new class of anti-thrombotic drugs with a significantly higher safety profile. Preliminary studies by the applicants using affinity-purified polyclonal antibodies demonstrate the feasibility of Selective Inhibition and provide preclinical evidence for efficacy showing reduced tissue injury in mouse models of restenosis, vasculitis, and other Inflammatory diseases. The long term goal of this project is to develop a potent monoclonal antibody for treatment of MI, stroke, and venous thromboembolic disease that does not increase bleeding risk. This Phase I project is designed to provide critical information to support launch of a preclinical drug discovery program. The specific aims of this proposal are: 1: to identify humanized IgG monoclonal antibodies specific for human and mouse M2 sequence; and, 2: to demonstrate Inhibition of thrombus formation with preservation of hemostasis.
Public Health Relevance Statement: Public Health Relevance: Thrombotic cardiovascular diseases, including myocardial infraction and stroke, are the leading cause of Death in developed countries. While current drugs such as aspirin and clopidogrel are effective in reducing thrombosis, they are also associated with significant bleeding complications and a higher risk of eventual Death. Attempts to develop effective and safe drugs to reduce thrombosis have met with little success. The goal of this project is to identify a potent, injectable humanized monoclonal antibody that prevents the interaction between Blood Platelets and White Blood Cells, and in the process inhibiting Inflammatory thrombus formation without interfering with normal hemostasis, providing a much safer anti-thrombotic drug for millions of patients at risk.
Project Terms: Acute; acute coronary syndrome; Adhesions; Affinity; Amino Acids; Anticoagulants; Antiplatelet Drugs; Aspirin; Binding; Biological Preservation; Biology; Bleeding time procedure; Blood Platelets; C3bi; Cardiovascular Diseases; Carotid Arteries; Cause of Death; Cessation of life; Clinical; clopidogrel; commercialization; Complex; Coronary heart disease; cost; design; Developed Countries; Development; Disease; drug discovery; Evaluation; Event; Expenditure; Experimental autoimmune encephalomyelitis; FDA approved; Fibrinogen; Glycoprotein Ib; Glycoproteins; Goals; Healthcare; Hemorrhage; Hemostatic function; high risk; Human; humanized monoclonal antibodies; Immunoglobulin G; improved; Inflammation; Inflammatory; Injectable; Injury; innovation; insight; Integrins; Intercellular adhesion molecule 1; interest; ITGAM gene; ITGB2 gene; Lead; Letters; Leukocyte mediator; Leukocytes; Ligands; Link; Macrophage-1 Antigen; Marketing; Mediating; meetings; Modeling; Molecular; Monoclonal Antibodies; mortality; mouse model; Mus; Myocardial; Myocardial Infarction; novel; Pathological Staging; Patients; Pharmaceutical Preparations; Pharmacologic Substance; Pharmacotherapy; Phase; Platelet Glycoproteins; polyclonal antibody; pre-clinical; Pre-Clinical Model; prevent; Process; programs; public health relevance; Qualifying; receptor; restenosis; Risk; Rodent; Safety; Secure; Site; Small Business Innovation Research Grant; Staging; stroke; success; Sum; System; Tail; Therapeutic; Thrombosis; Thrombus; Time; Tissues; Translating; United States; Vasculitis; Venous; von Willebrand Factor; Work
