Superantigens (SAGs) comprise a class of toxins that elicit massive T cell proliferation through simultaneous interaction with major histocompatibility complex (MHC) and T cell receptor (TCR) molecules. SAGs have been implicated in the pathogenesis of a number of human diseases, including toxic shock syndrome, food poisoning and several autoimmune disorders, thought to be the result of the stimulation of large numbers of T cells and their subsequent release of inordinate levels of pyrogenic and inflammatory cytokines. Due to their extreme virulence and relative ease with which they could be produced and dispersed throughout a population, SAGs represent credible candidates for biological weapons of mass destruction. Indeed, SAGs have been identified as Category B Agents of Bioterrorism by the Centers for Disease Control and Prevention. The development of therapeutics against SAG-induced disease, against which no drug or vaccine exists, is therefore one important facet of an overall national defense against bioterrorism. We propose to develop a group of engineered TCR fragments with markedly improved affinity for SAGs that will specifically abrogate interactions between SAGs and their cell surface ligands in vivo, thereby inhibiting the pyrogenic cascade in its initial stages and curtailing SAG-induced disease. We will create these SAG-TCR interaction antagonists following a step-wise approach. Milestones along the development pathway for potential therapeutics of SAG-induced disease include (1) structure-function analysis of SAG-TCR interactions, (2) engineering of affinity matured TCR beta domain antagonists, (3) analysis of the in vivo efficacy of antagonists, (4) modification of antagonists to improve the in vivo efficacy, and (5) development of broad spectrum SAG-TCR antagonists. We will focus our initial efforts on guiding an antagonist that has been developed to inhibit interactions between SEC3 and the mouse TCR Vbeta8.2 domain through this development pathway, not only to produce an effective anti-SEC3 therapeutic but also as a general proof-of-principle exercise for the design of anti-SAG biologics. With knowledge gained from studies involving this engineered antagonist, we will shift our focus to targeted antagonism of the numerous hVbeta2.1-specific SAGs by analogous methods.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Exploratory/Developmental Grants (R21)
Project #
7R21AI055882-03
Application #
6924105
Study Section
Allergy and Immunology Study Section (ALY)
Program Officer
Rathbun, Gary
Project Start
2003-07-15
Project End
2006-06-30
Budget Start
2004-07-03
Budget End
2006-06-30
Support Year
3
Fiscal Year
2004
Total Cost
$300,000
Indirect Cost
Name
Boston Biomedical Research Institute
Department
Type
DUNS #
058893371
City
Watertown
State
MA
Country
United States
Zip Code
02472
Cho, Sangwoo; Swaminathan, Chittoor P; Bonsor, Daniel A et al. (2010) Assessing energetic contributions to binding from a disordered region in a protein-protein interaction . Biochemistry 49:9256-68
Yang, Xi; Buonpane, Rebecca A; Moza, Beenu et al. (2008) Neutralization of multiple staphylococcal superantigens by a single-chain protein consisting of affinity-matured, variable domain repeats. J Infect Dis 198:344-8
Kasper, Katherine J; Xi, Wang; Nur-Ur Rahman, A K M et al. (2008) Molecular requirements for MHC class II alpha-chain engagement and allelic discrimination by the bacterial superantigen streptococcal pyrogenic exotoxin C. J Immunol 181:3384-92
Sundberg, Eric J; Deng, Lu; Mariuzza, Roy A (2007) TCR recognition of peptide/MHC class II complexes and superantigens. Semin Immunol 19:262-71
Gunther, Sebastian; Varma, Ashok K; Moza, Beenu et al. (2007) A novel loop domain in superantigens extends their T cell receptor recognition site. J Mol Biol 371:210-21
Brouillard, Jean-Nicholas P; Gunther, Sebastian; Varma, Ashok K et al. (2007) Crystal structure of the streptococcal superantigen SpeI and functional role of a novel loop domain in T cell activation by group V superantigens. J Mol Biol 367:925-34
Moza, Beenu; Varma, Ashok K; Buonpane, Rebecca A et al. (2007) Structural basis of T-cell specificity and activation by the bacterial superantigen TSST-1. EMBO J 26:1187-97
Rahman, A K M Nur-ur; Herfst, Christine A; Moza, Beenu et al. (2006) Molecular basis of TCR selectivity, cross-reactivity, and allelic discrimination by a bacterial superantigen: integrative functional and energetic mapping of the SpeC-Vbeta2.1 molecular interface. J Immunol 177:8595-603
Moza, Beenu; Buonpane, Rebecca A; Zhu, Penny et al. (2006) Long-range cooperative binding effects in a T cell receptor variable domain. Proc Natl Acad Sci U S A 103:9867-72
Cho, Sangwoo; Swaminathan, Chittoor P; Yang, Jianying et al. (2005) Structural basis of affinity maturation and intramolecular cooperativity in a protein-protein interaction. Structure 13:1775-87

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