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Tuesday, August 14, 2012

Monoclonal Antibodies for Dummies Like Myself, Part II

Enough today about the woeful world of politics. Let's talk instead about science and saving lives.

A month and a half ago, Compugen, which created a monoclonal antibody target discovery platform, issued a press release announcing "results demonstrating the therapeutic potential of CGEN-15022, a Compugen-discovered B7/CD28-like membrane protein, as an immune checkpoint target for treatment of multiple cancers." What is an "immune checkpoint target"? As explained in the press release (http://cgen.com/press-releases/188-compugen-announces-validation-results-for-a-second-potential-immune-checkpoint-target-for-cancer-immunotherapy):

"Immune checkpoints are inhibitory receptors and their ligands, which are crucial for the maintenance of self-tolerance (that is, the prevention of autoimmunity) and for the protection of tissues from damage when the immune system is responding to pathogenic infection."

But what does this mean to a simpleton like myself?

In fact, unbeknownst to ourselves as we go about our daily activities, our bodies are sophisticated battlegrounds in which our immune systems are engaged in perpetual search and destroy missions premised upon "identification friend or foe." That which belongs to our bodies is intended to be left in peace, whereas intruders are tagged for destruction.

All is fine and well, except when our immune systems "overreact" and attack the body itself, giving rise to autoimmune diseases such as multiple sclerosis and rheumatoid arthritis. Alternatively, our immune systems can fail in their mission and permit pathogens to get past their defenses, giving rise to infections.

And then there is a third, ugly, possibility: cancer cells, which should be identified as foreign, are able to camouflage themselves and avoid detection by our immune systems.

Note the relationship between autoimmune diseases and cancer: If our immune systems overreact, our bodies can be savaged by autoimmune diseases; if our immune systems fail in their mission to detect intruders owing to surreptitious attempts to disguise pathogens, various kinds of cancer can proliferate.

And if immune checkpoints, which can be likened to switchboards responsible for routing our immune responses, malfunction, a host of disorders can result.

Which now takes us back to Compugen.

Compugen knew that the B7 family of proteins had been linked to the workings of these immune checkpoints and that exciting new therapeutics for both autoimmune diseases and cancers had been derived from these proteins. Moreover, Compugen was convinced that more of these proteins could be discovered, potentially giving rise to additional therapeutics.

Working its computerized predictive magic, Compugen reported the discovery of nine distinct, heretofore unknown, B7/CD28-like membrane proteins. Detaching the extracellular portions of these proteins and fusing them to antibody Fc "tails," Compugen was able to create new proteins, and five out of six of the initially tested Fc-fusion proteins were shown to be efficacious in autoimmune disease models.

Given this remarkable rate of success for these fusion proteins, Compugen had reason to believe that the distinct, naturally occurring parent proteins, whose existence was predicted by the company, also played an important role in the modulation of our immune systems and could serve as targets for monoclonal antibody therapy for various kinds of cancer. It was thought that these "negative costimulatory proteins" could be involved in "highjacking" the autoimmune process and protecting tumors from discovery and destruction.

Lo and behold, the first of these B7/CD28-like membrane proteins to be disclosed by Compugen, CGEN-15001T, was discovered to be over expressed in prostate cancer, melanoma, Hodgkin's lymphoma and Non-Hodgkin's lymphoma, such as T and B cell lymphomas. The second such protein to be disclosed by Compugen, CGEN-15022, was found to be over expressed in a complementary set of epithelial cancers with significant unmet clinical needs, such as liver, colorectal, lung and ovarian cancers.

And these are only the first two B7/CD28-like membrane proteins for which Compugen has provided results.

How might monoclonal antibodies developed against these membrane protein targets provide therapeutic answers to various cancers? The monoclonal antibodies that bind to these targets can of course mark the cancerous cells for destruction.

More provocative, however, is the possibility that by binding to these targets, the monoclonal antibodies remove the tumor's "cloak of immunity," thereby allowing the body's immune system to search out and destroy the specific cancer cells by itself. This could result in durable clinical responses and improve the success of antibody-based cancer therapies.

Exciting science? You bet!

[As noted in prior blog entries, I am a Compugen shareholder, this blog entry is not a recommendation to buy or sell Compugen shares, and in September 2009 I began work as a part-time external consultant to Compugen. The opinions expressed herein are mine and are based on publicly available information. This blog entry has not been authorized, approved or reviewed prior to posting by Compugen.]

9 comments:

  1. Jeffrey, it appears that Compugen is doing remarkable things but Compugen can not do them alone and needs partners to survive. I am a long term supporter of the company and will continue to be one. But with all of our progress and discovery it does not appear (as of yet) that large partners are buying or that we are getting the recognition these discoveries seem to suggest. We feel good about the science but where is the recognition. Time is not on our side or the sides of those who need our findings. Thanks for your writings, on a personal note I purchased Genetics for Dummies to give me a better understanding of what is happening.

    Burt Seifman

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  2. Echoing Burt's comments. Share prices of Compugen are collapsing as Compugen's scientific breakthroughs unfold. Over the last 4 months (a period with notable Compugen discoveries) the stock price is down over 50%. Any ideas why the markets are having this reaction?
    Dave

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  3. Flatters to deceive 13-Aug-12 12:27 pm
    Just read the transcript from recent conference call on my return from summer vacation.In summary I have not learned anything new and the prepared presentations left me wondering "how long is a piece of string"??We are being told of increasing interest from pharmaceutical industry (deja vu) and the potential for agreements of significance (inferred)but there are several kinds of agreement viz. those to augment scientific knowledge and those to accelerate drug developement with clear financial reward.I am becoming increasingly pessimistic about the latter albeit in the next 18 months we will no doubt see more of the former. Cgen continue to flatter with their scietific progress but continually deceive shareholders and the financial community with their rhetoric!!
    I recently posted the above on a board out of sheer frustration.Your blog continues to add value for laymen such as myself but if the science is so leading edge and superb why are pharmaceutical companies not "biting our hand off"?

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    1. How do you explain the success that Evogene is having with same science on the plant side?

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  4. Jeff, any news about the possibility of curing cancer is always more than welcome, but you should respond to the question as to why phamaceutical companies are not interested in Compugen.

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  5. Questions concerning the stock market price and pharma company interest should be addressed to management. However, I would note that during the last conference call (see transcript: http://seekingalpha.com/article/787691-compugen-s-ceo-discusses-q2-2012-results-earnings-call-transcript?part=single), Martin stated: "And lastly, in our ongoing discussions with an increasing number of potential collaborators and license fees, we continue to see a growing interest in both our product candidates and our unique discovery capabilities." In addition, Anat stated: "As we continue our development activities for these Fc-fusion protein therapeutics, we’re in active discussions with a number of leading pharma companies regarding various forms of collaborations for product to development and commercialization. We’re very pleased by the interest now being shown in these candidates and optimistic about our ability to enter into partnership with the industry based on them [ph]. However, predicting an exact timetable for such partnership which we understand the front interest to our shareholder is never possible with any certainty, but please, do not interpret our inability to provide a timetable as an indication of lack of optimism on our part."

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    1. Jeff,I am reminded of a comment uttered by an ex boss of mine "if you are not confused you are not a thinking man".
      Recent commentaries have left me confused and as your word will have more power,being an external consultant, perhaps you could pass some of these replies to Martin and the executive team.
      Lest they be addressed they will be perceived as responses to fob off persistent difficult questions at agm's or indeed as words issued by the Captain of the Titanic!!

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  6. Perhaps pharma is waiting to see what the drastic decrease in the cost of DNA sequencing will bring. My very uneducated hope is that individual sequencing and compugen's predictive algos will be a great 1 two punch. Thx JG I may be able to explain monoclonal things to others now.

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  7. I like your blog. You are doing Good job. Keep it up.

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