Compugen: The Evolution of a New Platform for the Rational Design of Therapeutics

In March 2008 Compugen announced the development and validation of its Blockers of Disease Associated Conformation ("DAC Blockers") discovery platform for the identification of peptides that block proteins from adopting their disease associated conformations. A little over a year since this announcement, there have been further announcements concerning the platform's initial therapeutic candidates, CGEN-25007 for inflammatory bowel disease and CGEN-25017 for retinopathy, both of whose in vivo results are best understood from the attestations of the outside parties who performed the testing.

Re CGEN 25007:

"Professor Markus F. Neurath, from the University of Erlangen, Germany, who supervised the study and is a recognized world expert in this field stated, 'The results achieved with CGEN- 25007 are very impressive. In the past, we have evaluated numerous molecules in this model but never saw such dramatic effects. If these results continue to be confirmed in further studies, this molecule should represent a very exciting drug candidate for this substantial, and largely unmet medical need.'"

Re CGEN-25017:

"Professor John S. Penn, from the Department of Ophthalmology and Visual Sciences at the Vanderbilt University School of Medicine, who supervised the study and is a recognized world expert in this field stated, 'The efficacy achieved with CGEN- 25017 is a fairly rare finding in this model. Based upon our past experience conducting efficacy trials of this type, CGEN-25017 falls within the top 10% of all test compounds that have passed through our hands. Thus, in my opinion, CGEN-25017 warrants further development and study as a potential therapy for angiogenesis-related diseases.'"

There is nothing "hit or miss" about these discoveries. As noted by Compugen:

"To date, peptide blockers predicted by this platform have been validated experimentally in functional assays for 11 out of 12 protein targets selected for screening."

At a time when Big Pharma's pipelines are going dry, how did this new discovery platform evolve? Compugen will never disclose all of the platform's underlying proprietary wizardry. In addition, it seems inane for an "outsider" to summarize the platform's scientific underpinnings, premised upon 10 years of R&D, within the space of a blog entry, yet here is my attempt:

Proteins consist of long strings of amino acids, generally between 50 and 2,000 amino acids in length and consisting of 20 types of amino acids. The location of these amino acids determines their many possible shapes (for example, Alpha Helix, Beta Helix, turns and loops), i.e. how these proteins fold. A protein's shape, in turn, determines its function.

Although proteins normally fold into a single stable conformation, slight changes can subsequently occur within certain proteins, causing them to become active or inactive, i.e. giving rise to "disease associated conformations". The literature indicates there are dozens of such disease associated conformations potentially causing pathologies, but how do you even begin to influence these minuscule transformations, which can cause, for example, solid cancers and inflammatory diseases?

Some 10 years ago it was already known that peptides (protein fragments) could be used to seal off cells from viruses, e.g., HIV, seeking to penetrate their membranes. It was believed that peptides could similarly be used to bind to proteins at relevant sites, thereby preventing them from adopting their disease associated conformations, but it would be necessary to know the specific segment of the given protein. Compugen seized upon this idea and began to construct its platform:

"The [DAC Blockers] platform is based on the integration of methods and ideas varying from information theory, through machine learning and statistics, to mathematical analysis for detecting intra-molecular interactions within the protein of interest."

Details concerning a resultant product candidate? Let's look at CGEN-25007, which interacts with the glycoprotein, gp96. As observed in Compugen's website:

"extracellular gp96 plays an important role in activation of innate immunity, through direct action on various types of immune cells, including dendritic cells, monocytes, macrophages and neutrophils, promoting the induction of proinflammatory cytokines."

Cytokines are secreted by immune cells that encounter pathogens, thus recruiting additional immune cells to augment the body's response, which can cause acute inflamation, and the DAC Blockers platform was initially validated by Compugen by demonstrating that CGEN-25007 significantly reduces the serum levels of inflammatory cytokines in mice treated with lipopolysacharide, which acts as a toxin and causes strong immune responses. Given that gp96 has been implicated in inflammatory bowel disease ("IBD"), the next step taken by Compugen was to test CGEN-25007 on an IBD animal model. The results of the testing conducted by Dr. Neurath (see above) were announced in June:

"In a recently completed study of TNBS-induced colitis, which is a well accepted animal model of inflammatory bowel disease, administration of CGEN-25007 protected mice from the effects of lethal colitis. Study data showed an increase in survival rate and reversal of weight loss, while mice treated with a negative control showed an irreversible and fatal wasting syndrome. This protective effect of CGEN-25007 was confirmed by improved endoscopic colitis scores, which were similar to those obtained with corticosteroids as a positive control."

With respect to IBD, there are 500,000 persons in the U.S. suffering form Crohn's Disease and another 5 million persons suffering from Irritable Bowel Syndrome. We will see whether Compugen now also tests CGEN-25007 on an in vivo model of rheumatoid arthritis, which affects some 1% of the world's population and for which there is no known cure.