Wednesday, October 14, 2009

Monoclonal Antibodies (mAbs) for Dummies Like Myself

Although the pharmaceutical industry as a whole is suffering from depleted pipelines, patent expiries and stiff competition from manufacturers of generics, the market for monoclonal antibodies has expanded dramatically in recent years. Monoclonal antibody drugs, which primarily target cancer and autoimmune disorders, had total sales of nearly $32bn in 2008 and today amount to more than 30% of the global biologic drug market.

Compugen yesterday announced that it is providing Bayer Schering Pharma, one of the world's largest pharma companies, with an option for a worldwide exclusive license to monoclonal antibody and other therapeutics targeting a specific oncology target and its splice variants. Given that monoclonal antibody therapeutics comprise such a fast growing segment of the pharmaceutical industry and given their relatively high levels of success after entering human clinical trials, this sounds impressive, but what are monoclonal antibody therapeutics? How are they capable of making cancer cells more visible to our immune systems, blocking undesired growth signals, and in some instances delivering radiation and drugs to cancer cells?

We all know that antibodies are proteins found in blood and used by our immune systems to identify and neutralize foreign objects, such as bacteria and viruses, i.e. "antigens". Although most of the structure of these "Y"-shaped antibodies is similar, one of its tips is variable, allowing antibodies to bind to millions of different, extremely specific antigens. Recognition of an antigen by an antibody tags it for destruction by other components of the immune system.

Given that antibodies bind to antigens, why don't our antibodies attack our cancer cells? This is because our antibodies do not perceive our cancer cells as foreign. Imagine, however, the advantages if we could create antibodies that would bind only with cancer cells while causing limited collateral damage to healthy cells. This is in fact the conundrum with which scientists have successfully wrestled over the past decades, resulting in the creation of monoclonal antibodies and the award of no small number of Nobel Prizes.

What is the recipe for monoclonal antibodies? In a nutshell, a laboratory mouse is injected with the human antigen target, and the mouse, which identifies the human antigen as foreign, begins to produce antibodies targeting this antigen. Spleen cells from the mouse, producing the desired antibodies, are then removed and fused with tumor cells ("myelomas") that replicate endlessly. The result of this cell fusion, no small fete in and of itself, is called a "hybridoma" and is the factory for production of identical "monoclonal", i.e. coming from only one kind of cell, antibodies.

End of story? No. When injected into humans to bind to the desired antigen, mouse antibodies are perceived by the human immune system as foreign, thus giving rise to "HAMA" (human anti-mouse antibodies), which can quickly eliminate the desired therapeutic antibodies from our bodies and cause immune responses that damage our kidneys. In response, using genetic engineering wizardry, "murine" (mice or rat) components of the monoclonal antibody, other than the tip that binds to the target antigen, have been replaced with human components, creating longer lasting, better tolerated therapeutics: "chimeric" (65% human) and "humanized" (95% human) antibodies. In addition, transgenic technology has been used to provide mice with human antibody genes, creating "fully human" antibodies.

Where does Compugen fit into this picture? Compugen's expertise is not in genetic engineering, but rather in target discovery; without mAb targets, there can be no mAb therapeutics. Moreover, as succinctly observed in Compugen's press release concerning the deal with Bayer:

"Like the known cancer target, this protein molecule and its variants are all trans-membrane proteins. However, each of the Compugen molecules has a unique sequence at the extracellular domain of the protein that enables the development of monoclonal antibodies specific to each of the respective splice variants.

Therefore each splice variant could represent a novel target for monoclonal antibody therapy. A common feature of Compugen's discovery platforms, such as the mAb Targets Discovery Platform used in this discovery, is the ability to predict and select multiple potential product candidates for each indication of interest.

The availability of multiple candidates, in this case a number of different splice variants, should increase the probability of success for the overall program."


[As noted in a prior blog entry, I am a Compugen shareholder, this blog entry is not a recommendation to buy or sell Compugen shares, and in mid-September 2009 I began work as a part-time external consultant to Compugen. The opinions expressed herein are mine and not necessarily those of Compugen.]

4 comments:

  1. "Option for a worldwide exclusive license"? "Fusing cells"? Oy!

    ReplyDelete
  2. Thanks for the more layman-like explanation. Sounds very promising but what about the money-cash payments etc from these collaborators? You say you are working as a part-time external consultant...What does that involve-raising money? awareness? Do you believe they will make any deals w/ cash payments or just future royalties....

    ReplyDelete
  3. Thank you for your comment. Two suggestions: 1. participate in or listen to the upcoming conference call pertaining to third quarter results, which I believe will take place on October 27; and 2. consider sending your questions to Compugen's CFO (dikla@compugen.co.il), who manages the company's IR.

    ReplyDelete
  4. Hello,

    This is the perfect blog for anyone who wants to know about this topic. Monoclonal antibodies are monospecific antibodies that are the same because they are made by identical immune cells that are all clones of a unique parent cell...

    ReplyDelete