Research
During the past two decades a large number of outbreaks of infectious diseases have occurred in the United States and around the world. Many of the pathogenic agents involved in these outbreaks were previously unknown to man, while many others reemerged in more invasive forms. The problem of emerging infectious diseases is further gravitated by the growing threat of bioterrorism and the alarming increase in the rate of drug resistant infections. Except for HIV and influenza, most of the emerging infectious diseases represent small to mid size markets. Tackling this problem requires partnership between private industry and Government agencies. Based on this philosophy, and a strong portfolio of novel technologies, Integrated BioTherapeutics Inc (IBT) has forged strong partnerships with the government and industry partners to develop specific vaccines and therapeutics primarily for two important groups of emerging infectious diseases: i) infections and septic shock caused by staphylococcal and streptococcal infections, and ii) viral hemorrhagic fevers.
A Novel Paradigm for fighting staphylococcal and streptococcal infections and their complications
Staphylococcal enterotoxins (SEs) and the toxic shock syndrome toxin 1 (TSST-1) constitute a major group of virulence factors produced by the bacterial agent Staphylococcus aureus. These toxins are involved in a variety of human pathologies ranging from hospital and community-acquired infections, septicemia, toxic shock syndrome, to atopic dermatitis. Staphylococcal enterotoxin B (SEB) is also considered as a potential agent of bioterrorism. Currently no vaccines or immunotherapeutics are available against staphylococcal toxins or S. aureus infections. The most recent efforts targeting capsule components or mediators of bacterial adhesion were unsuccessful. IBT follows a novel paradigm in the fight against these pathogens by targeting the toxins released by the bacteria which can distract the immune system and cause massive damage and even lead to death.
Superantigens
Figure 1: Cascade of toxic events resulting from release of superantigens in the bloodstream.
These toxins along with their streptococcal counterparts, streptococcal pyrogenic exotoxins (SPE) constitutes the so called bacterial superantigens (SAg). SAgs bind to human major histocompatibility complex (MHC) class II on antigen presenting cells (APC), cross-links MHC to the T-cell receptor (TCR) leading to polyclonal activation of T-lymphocytes resulting in massive release of inflammatory cytokines, activation of different arms of the immune system culminating in capillary leak and multiorgan failure (Figure 1). Interactions of superantigens with host cells (Figure 2) differ from conventional antigens in that SAgs: 1) directly bind outside the peptide-binding groove of MHC class II; 2) and exert biological effects without internalization or "proteolytic processing" by APC; and 3) are not MHC-restricte. As a result, superantigens stimulate both APC and T cells resulting in activated T cells that massively proliferate and produce large quantities of pro-inflammatory cytokines. Superantigens are also known to increase the host susceptibility to endotoxin. Superantigens also cause T cell apoptosis and/or anergy thus allowing for the pathogen to evade the adaptive immune response.
Based on compelling scientific evidence it is evident that neutralizing antibodies represent the most promising therapeutic approach for treatment of SE intoxications (Figure 2). IBT's vaccines are designed to induce the most effective antibodies for neutralization of superantigens.
IBT's vaccines rely on a structure-based design, lead by the US Army Medical Research Institute of Infectious Diseases (USAMRIID), which resulted in the successful pre-clinical development of recombinant, attenuated vaccine candidates for multiple SEs and TSST-1. These recombinant proteins are mutated to lose binding to human MHC class II protein while maintaining their immunogenicity. IBT's first of these vaccine series, the recombinant SEB (rSEB) vaccine (STEBVax) is scheduled to enter Phase I clinical trial in Spring 2008 supported by the National Institute of Infectious Diseases (NIAID), Food and Waterborne Disease Program. Other vaccines, the recombinant SEA, SEC1, and TSST-1 are within 1-3 years from entering the clinic.
IBT is also developing a set of recombinant vaccines for streptococcal pyrogenic exotoxins (SPE). These vaccines are in mid pre-clinical stage of development.
A Major goal for IBT is to develop human polyclonal antibodies against these toxins for treatment of staph and strep complications. For this purpose IBT has an ongoing collaboration with Omrix Biopharmaceuticals, one of the world's leading plasma fractionation companies. IBT-Omrix collaborative work is supported by the Department of Defense.
A vector-free vaccine platform for filoviruses Ebola and Marburg
Figure 3:Electron microscopic image of Ebola VLP vaccine. Dots represent immunostaining with antibodies that recognize Ebola surface glycoprotein.
Viral hemorrhagic fever (VHF) viruses constitute a diverse array of viruses that can cause severe diseases leading to death up to 70% in the case of filovirus VHFs Ebola and Marburg. There are currently no vaccines or therapeutics available for most VHFs. IBT is collaborating with colleagues at USAMRIID to develop a vector-free vaccine with broad spectrum activity toward different strains of Ebola and Marburg viruses. This vaccine is based on virus-like particles (VLP) developed by IBT's Founder and his co-workers at USAMRIID. The VLPs are strikingly similar to the authentic virus and are covered with the filovirus glycoprotein on the surface (Figure 3). The vaccine has been successfully tested in multiple animal models including monkeys. IBT intends to complete the cGMP manufacture and GLP-safety studies for this vaccine and file an IND to initiate phase I clinical trials within 2-5 years.