The principal overall objective of this project is the development of novel, safer and more effective therapy for Multiple Sclerosis (MS), specifically a monoclonal antibody (mAb) that disrupts the interaction between leukocytes (Mac-1) and platelets (GPIb?), which have been implicated in the pathophysiology of MS. MS is a chronic inflammatory disease of the CNS, affecting approximately 2.3 million people worldwide, in which lymphocytes cross the blood brain barrier and attack the myelin sheath of neurons in the brain and spinal cord. Currently approved medications for MS do not have disease-modifying capabilities, and have significant safety and tolerability issues. Accordingly, the biggest unmet medical need in the MS field is to find a therapy that would provide either neuroprotection and/or preserve myelin, and slow or halt disease progression. In the application Sujana Biotech plans to translate previous pioneering work by its scientific founders, Drs. Dan Simon and Ed Plow, defining the precise points of interaction between a leukocyte-expressed integrin and a platelet-expressed glycoprotein counter-receptor. This research not only identified the specific amino acids that mediating binding but also demonstrated that it is possible to selectively inhibit leukocyte-platelet interaction without interfering with other critical interactions, including those that mediate normal hemostasis. Preliminary studies by the applicants, using polyclonal antibodies directed against Mac-1 on leukocytes, provided preclinical evidence of efficacy in the EAE-model of MS. In addition, platelets have been found in human chronic active MS lesions and increased platelet activation was demonstrated in the peripheral blood of MS patients. The proposed studies are a logical extension of our previous studies testing an anti-Mac-1 humanized mAb as a viable, novel treatment for MS. We will examine the effects of the mAb in the EAE model of MS. The specific aims of this proposal are: 1) Evaluate selectivity of anti-Mac-1 mAb in binding to Gp1b? blocking platelet-leucocyte interaction; and 2) Evaluate in vivo efficacy of anti-Mac-1 mAb in the EAE model. The long-term goal of this project is to develop a novel, potent anti-Mac-1 humanized mAb as a more effective and safer medicine than current treatments for MS, which will slow- down or potentially halt disease progression.
Public Health Relevance Statement: Narrative Multiple Sclerosis (MS) is a common, chronic inflammatory demyelinating disease of the central nervous system. Current drugs relieve the symptoms but do not cure the disease. The goal of this project is to identify and test a new, potent, injectable humanized monoclonal antibody that prevents the interaction between blood platelets and white blood cells, and by this mechanism will provide neuroprotection and greater medical benefit and less side-effects than current medicines for millions of patients at with MS.
Project Terms: Adverse effects; Affect; Affinity; Amino Acids; Anti-inflammatory; base; Binding; Biotechnology; Blood - brain barrier anatomy; Blood Platelets; Brain; C3bi; Cells; central nervous system demyelinating disorder; Central Nervous System Diseases; Chronic; Clinical; Collaborations; commercialization; Complex; Development; Dexamethasone; Disease; Disease Progression; effective therapy; Experimental Autoimmune Encephalomyelitis; Fibrinogen; Filament; Functional disorder; Funding; Glycoproteins; Goals; Hemostatic function; Human; humanized monoclonal antibodies; Immunoglobulin G; in vivo; Inflammatory; Inflammatory Response; Injectable; Innovative Therapy; Integrins; Intercellular adhesion molecule 1; interest; ITGAM gene; ITGB2 gene; Lesion; Letters; leukocyte mediator; Leukocytes; Ligands; Lymphocyte; Macrophage-1 Antigen; Mediating; Medical; medical specialties; Medicine; Modeling; Molecular; Monoclonal Antibodies; Multiple Sclerosis; Multiple Sclerosis Lesions; multiple sclerosis patient; multiple sclerosis treatment; Mus; Myelin; Myelin Proteolipid Protein; Myelin Sheath; myelination; Nature; Neurons; neuroprotection; Neurosciences; novel; novel therapeutic intervention; Pathogenesis; Patients; Peptides; peripheral blood; Pharmaceutical Preparations; Physiological; Platelet Activation; Platelet Glycoproteins; polyclonal antibody; pre-clinical; prevent; Publishing; receptor; reduce symptoms; relating to nervous system; Research; Safety; secondary endpoint; Secure; Specificity; Spinal Cord; Stains; Testing; Therapeutic; Thrombus; TNFSF5 gene; tool; Translating; United States National Institutes of Health; Validation; Work
