Humanized, Reshaped, Humouse antibodies?

Mike Clark mrc7 at cam.ac.uk
Wed May 5 03:57:34 EST 1999

I am about to write a review on the topic of antibody humanization and
would be interested in any views, comments, on my thoughts below.
Particularly if backed up with experimental evidence! 

As someone who has been heavily involved in the humanisation of monoclonal
antibodies for therapy I have become increasingly frustrated at the number
of claims and counter claims (mainly from commercial organisations) that
one method of producing human or humanized antibodies produces antibodies
which are "less immunogenic because they are more human" compared to
another. Methods include humanisation of rodent antibodies by CDR grafting,
framework grafting, veneering, resurfacing, etc  versus the production of
antibodies using human V-regions in phage libraries or alternatively mice
transgenic for human V-regions. 

Unfortunately there is in my opinion little or no scientific
evidence to support these claims! I guess that it is difficult to justify
commercial costs as well as perhaps gain ethical approval to prepare
several similar antibodies by the alternative methods and to then treat
enough patients to compare antiglobulin responses and thus test the claims
in a proper scientific manner.

It seems that most of these claims are based on the "opinion" that the more
human an antibody sequence is the less immunogenic it will be in humans.

However contrary to this experimental evidence demonstrates that it is
possible to raise anti-idiotypic antibodies in animal models and it is also
possible to tolerise animals to "foreign" immunoglobulins. Of course the
whole concept of humanisation of antibodies for therapy is based upon the
hypothesis that the immune system discriminates on a self versus non-self
basis. Of course if like me you also wish to try and take account of the
alternative view of danger versus non-danger then you come to different

So are antibodies which are destructive in vivo ie ones which bind to Fc
receptors, activate complement and cause cell killing, likely to be more
immunogenic than antibodies which do not independent of how "human" they

Any comments, suggestions, references I should consider?


Mike Clark,                        <URL:http://www.path.cam.ac.uk/~mrc7/>
 o/ \\    //            ||  ,_ o   M.R. Clark, PhD. Division of Immunology
<\__,\\  //   __o       || /  /\,  Cambridge University, Dept. Pathology
 ">    ||   _`\<,_    //  \\ \> |  Tennis Court Rd., Cambridge CB2 1QP
  `    ||  (_)/ (_)  //    \\ \_   Tel.+44 1223 333705  Fax.+44 1223 333875

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