Soluble high-affinity T cell receptors prevent MRSA lethality
DESCRIPTION (provided by applicant): Methicillin resistant Staphylococcus aureus (MRSA) and methicillin sensitive S. aureus (MSSA) are highly significant human health threats that are responsible for a range of diseases. Recently, the CDC and colleagues reported that MRSA are the most significant causes of serious infections and infectious disease deaths in the United States. A major factor involved in the lethality of MRSA and MSSA are secreted toxins, known as superantigens. The lethality associated withthese superantigens has been appreciated for decades, as the U.S. military stockpiled large amounts of staphylococcal enterotoxin B (SEB) under its old bioweapons program that was terminated in 1969. The mechanism of action of the toxins is well known - they act extracellularly by binding to the T cell receptor on T cells and stimulating massive release of inflammatory cytokines. The objective of the proposed work is to test the feasibility of using a novel potential drug, a soluble T cell receptor protein(G5-8) that has been engineered for very high-affinity binding to SEB, to prevent lethality. Two rabbit models of SEB-induced lethality will be examined, pulmonary exposure to the toxin alone (as would occur in a bioterrorism incident) or pulmonary infection with a strain of MRSA that produces SEB. The hypotheses of the Phase I work are that yields of the engineered V2 protein G5-8 can be improved, and that the doses and timing of administration that will reduce the severity of pulmonary diseases associatedwith SEB exposure can be determined. The Specific Aims are: 1) To determine the best conditions for optimizing the yield and long-term storage of the V2-TCR G5-8 protein; 2) To determine the efficacy of using G5-8 to protect rabbits from death due to intrapulmonary challenge with SEB; and 3) To determine the efficacy of using G5-8 to protect rabbits from death due to intrapulmonary challenge with an SEB+ CA-MRSA USA400 strain. In Phase II work, ImmuVen would test whether long-term stored G5-8 prevents lethality in rabbits exposed to additional SEB+ MRSA strains, and whether the G5-8 can be used in nebulized form. ImmuVen will also begin development of a cGMP process for additional pre-clinical and clinical studies. G5-8 and similar proteins in development for other S. aureus exotoxins (SEC, TSST-1) represent clinical and commercial opportunities to treat a host of diseases caused or worsened by MRSA and MSSA. PUBLIC HEALTH RELEVANCE: Antibiotic-resistant Staphylococcus aureus isolates frequently initiate serious human diseases through the bacterium's colonization of respiratory mucosa and skin, followed by secretion of potent toxins referred to as superantigens. Illnesses include serious post- viral pneumonias, allergic skin diseases, and delayed woundhealing that affect thousands of individuals each year in the United States. The secreted toxins are directly involved in the disease effects, including death. This application studies a novel protein- based drug that acts to block the disease-causing effects of bronchially-administered superantigens (as would be the case in a bioterrorism agent) and of infections with antibiotic-resistant S. aureus.
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