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Author: Australopithecus One star, 50 posts Old School Fool Add to my Favorite Fools Ignore this person (you won't see their posts anymore) Number: of 27  
Subject: Antibody Humanization Date: 5/14/2006 1:00 PM
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There was a discussion on the HG boards concerning biotech companies that humanize antibodies for a living. I thought that some of the technical aspects of this discussion might be appropriate for this board so I'm reproducing them here.

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I would personally recommend being very careful about investing in companies that have antibody humanization as a large component of their core business. I will try to give a little background here and for anybody who's interested and I could provide a more detailed explanation offline.

Most therapeutic antibodies are raised in animals such as mice and rabbits by injecting the antigen into the animal and harvesting the resulting antibodies generated by the animal's immune system, usually from its spleen. With a bit of trickery, the resulting initial pool of diverse antibodies (referred to as polyclonal) can be narrowed down to a single antibody (a monoclonal) that recognises and binds a specific feature of the antigen. So for example, a drug company that wants to make an anticancer antibody injects a human tumor antigen into say - a mouse, and generates a monoclonal antibody that will target a human tumor that bears the original injected antigen.

There's a problem here though ... in exactly the same way that the mouse immune system recognised the human tumor antigen as "foreign" and raised antibodies to neutralize it, a monoclonal antibody from a mouse will look foreign to a human immune system (because of the subtle differences between mouse and human antibody proteins). In the best case scenario, treatment of a human cancer patient with the mouse antibody will eventually become ineffective as the patient raises antibodies against the therapeutic agent itself. In the worst case scenario, the patient will be killed by anaphylactic shock upon subsequent re-injection of the antibody to which his own immune system is now beoming hypersensitive.

The process of humanization involves re-engineering the "mousey" regions of the antibody to their human equivalents for which there are several approaches in current use. The most radical of these is to graft the small regions of the original mouse antibody that recognise and bind the target antigen, into a human antibody. The goal is to produce an antibody that looks human to a human immune system and will therefore not be immunogenic in the treated patient.

While this idea sounds enticing, more and more clinical studies are starting to show evidence that humanization often fails to produce non-immunogenic antibodies, with significant numbers of tested patients showing a strong immune response to these therapeutic antibodies. In a nutshell, sometimes humanization works and sometimes it does not. Why this happens is not entirely understood and a discussion of the possible reasons for the failures of humanization is beyond the scope of this post, but I would qualify my own opinions in this area by saying that I am a scientist who is actively involved in this field myself.

Other alternatives to humanization are already being explored and validated and while it is entirely inappropriate to assign humanization to the graveyard of "failed technologies", I would say that the industry's previous optimism and confidence in this approach has been somewhat shaken of late by the wealth of clinical data that is emerging from trials of these therapeutic antibodies in human patients.

Therefore, when it comes to investing in antibody humanization, a good maxim might be "caveat emptor" unless you feel that the company you're interested in has some real technological edge over the various approaches that the rest of industry is already using for humanization.

Best

Gordon
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