Selective inhibition of platelet GPIb-alpha binding to leukocyte Mac-1 as a novel anti-thrombotic therapeutic

DESCRIPTION provided by applicant 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 people suffer a stroke and million an MI Total US healthcare expenditures in for coronary heart disease and stroke are estimated to be a staggering $ billion and $ billion respectively with an associated cost of drug therapies estimated to exceed $ 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 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 To identify humanized IgG monoclonal antibodies specific for human and mouse M sequence and To demonstrate inhibition of thrombus formation with preservation of hemostasis 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