Superantigen antagonist

Atox Bio has developed a powerful antagonist to the family of bacterial superantigen toxins produced by Staphylococcus aureus and Streptococcus pyogenes. This is a large and structurally divergent family of toxins. This diversity poses a complex medical problem calling for the development of a broad-spectrum superantigen antagonist. The uniqueness of this approach is in its focus on halting the "toxicity cascade" set off by superantigens even before the activation of T cells occurs. The superantigen antagonists have been found to modulate the Th1/Th2 immune balance.

Mechanism of action

Atox Bio scientists have gained a profound understanding of the mechanism of action of superantigens at the molecular level. Revealing the innate immune response’s novel strategy of subversion, they observed that structurally divergent superantigen toxins co-opt an additional host receptor, for use as their obligatory receptor. This insight led to the design of superantigen antagonist leads. The discovery of a novel superantigen receptor forms the basis of a platform technology for generation of novel mechanism-driven modulators of immune co-stimulation that alter the Th1/Th2 balance. This constitutes a wholly new approach to the treatment of autoimmune and inflammatory diseases.

Modulators of co-stimulation:

Th1 cells are considered to play a crucial role in mediating autoimmune diseases. The Th1 cell generates an inflammatory cytokine response when triggered. To become fully activated, Th1 cells must receive two distinct signals with coordinated timing. "Signal-1" is provided by the recognition of an antigen that is presented by MHC class II molecules on the surface of an Antigen Presenting Cell (APC) to the T cell receptor (TCR) located on the Th1 cell. This results in activation of signal transduction through the TCR. Signal-1 provides antigen specificity for T-cell activation. "Signal-2" (or "co-stimulatory signal") is mediated by binding of co-stimulatory receptors on T cells to molecules expressed on the surface of the APC. If Signal-1 is provided in the absence of Signal-2, the T cell does not become activated and instead becomes anergic (i.e. unable to respond to any signal) and may even undergo apoptosis. Atox Bio's drug-candidates designed to prevent the activation of Signal-2-mediated activation of Th1 cells are termed "modulators of co-stimulation".
Atox Bio's peptides act as immunomodulator by attenuating Signal-2 and thereby, attenuating an exaggerated Th1 cytokine response. These cytokines include TNF-alpha, IFN-gamma and IL-2.

Product candidates

Short peptides, administered IV for acute medical indications. For chronic medical indications, half-life prolongation technologies are used, with the peptides administered subcutaneously.

Proof of principle and scientific recognition

Proof of principle for Atox Bio’s modulators of co-stimulation has been demonstrated in mouse models of lethal toxic shock, septic shock and autoimmune diseases.
A novel pig incapacitation model that uses quantitative parameters for incapacitation symptoms, developed by Atox Bio, was accepted by the FDA as suitable for pre-clinical development.

The research was initially supported by the US Army and DARPA with US $6.5 million in grants.

The National Institute of Allergy and Infectious Diseases (NIAID) of the National Institutes of Health (NIH) is supporting Atox Bio's AB103 development in collaboration with the Hebrew University of Jerusalem with a grant of US $5.8 million. NIH has defined the research as unique in the world.

This recognition and funding validates the scientific merit and therapeutic value of Atox Bio’s technology.