Compugen Ltd (TEL AVIV, Israel),  focused on the discovery and licensing of product candidates to the drug and diagnostic industries, announced positive results from an in vivo study of CGEN-25007, a novel peptide antagonist of the gp96 protein. The gp96 protein triggers both the innate and adaptive arms of the immune system and is thought to play a key role in inflammatory responses, making it an important target for therapeutic intervention in the treatment of immune-related disorders. The data indicate that CGEN-25007 has immunosuppressive effects and therapeutic potential for the treatment of various inflammatory diseases and other immune related pathologies. CGEN-25007, which has been shown to bind to recombinant gp96 in a dose-dependent manner, was initially predicted using the Company’s previously announced DAC blockers platform. This platform was designed to predict peptides that block proteins of interest from achieving certain disease-associated conformations.

Using an animal model of endotoxemia, a condition in which there is a substantial increase in the levels of inflammatory cytokines and chemokines in serum, CGEN-25007 was shown to exhibit a profound and dose-dependent anti-inflammatory activity. In the study, the novel peptide was administered following the introduction of lipopolysaccharide (LPS), a bacterial substance that induces a strong response in the animal immune system leading to systemic inflammation. The administration of the agent resulted in a decrease of ~50% in the serum levels of inflammatory cytokines and chemokines, including TNFα, IL-6, IFN-g, MIP-1α, and MIP-2.

In addition, in ex-vivo experiments CGEN-25007 was found to strongly inhibit the secretion of inflammatory cytokines from human peripheral blood mononuclear cells (PBMCs) which had been challenged with LPS, staphylococcus epidermidis, or anti-CD3 antibody, compounds known to activate the human immune system through different receptors. PBMCs triggered with these compounds and treated with CGEN-25007 exhibited >80% inhibition of secretion of cytokines, including TNFα, IL-1β, IL-6, IL-8, IL-12, and MIP-1α. In addition, CGEN-25007 had only a 20% inhibitory effect on the secretion of GM-CSF and no effect on the secretion of IL-2, suggesting selectivity in the action of this peptide.

The results support the potential use of this peptide as a novel approach for the treatment of many immune related diseases, including autoimmune disorders, sepsis, cardiovascular diseases and acute transplant rejection.

Through its involvement in the innate branch of immunity, gp96 potentiates responsiveness for toll-like receptors (TLRs) on antigen presenting cells (APCs). TLR activation on APCs induces a pro-inflammatory response, including cytokine secretion and expression of costimulatory molecules, which in turn recruit and activate T-cells. In addition, gp96 enables specific immune responses by transferring immunogenic peptides to MHC class I molecules, thus facilitating antigen specific activation of cytotoxic T-cells.

Compugen’s current collaborations include Biosite; Medarex; Inc; Merck & Co, Inc; Ortho-Clinical Diagnostics (a Johnson & Johnson company); Roche Pharmaceuticals; Siemens Healthcare Diagnostics, Inc; and Teva Pharmaceutical Industries.