Scientists from Ixsys Inc. and Bristol-Myers Squibb havecreated a new method to tailor-make monoclonal antibodieswith affinities that are about 15 times higher than the onesproduced by the human body's immune system. Theresearchers described their method--called codon-basedmutagenesis--in two articles appearing today in the Journal ofImmunology.
The codon-based mutagenesis procedure allows scientists toalter the antigen-binding H or complementarity determining Hregions (CDRs) of an antibody molecule three nucleotides at atime. The new procedure allows for a pace that is much quickerthan the body's own affinity maturation process which goesbase-by-base to fine-tune an antigen-specific antibody,increasing its binding affinity to that particular antigen.
The cloning vehicle used in these papers is the filamentousbacteriophage M13, which is able to express the antibodyamino acid sequences as F(ab) fragments, either on the surfaceof the phage or in the periplasmic space of the Escherichia colibacterium in which the phage grows. Using codon basedmutagenesis, the researchers generated a library of mutationsin the CDRs of the chimeric antibody L6, an antibody against atumor-associated cell surface antigen expressed by manyhuman carcinomas. [It is currently in human clinical trials forhepatocarcinoma and ovarian carcinoma, Huse told BioWorld.]
Because the method screens for high-affinity binding to atarget antigen, it allows one to select for predefinedphenotypes. And it follows that it would then be possible todetermine the nucleotide sequences that code for thatphenotype, the authors conclude.
The method doesn't depend on having the antigen alreadycharacterized, Huse told BioWorld, although "we can screenmutants faster when the antigen is characterized--about onemillion per day--than we can when it isn't--about 100 a day."
Ixsys is a private company, based in San Diego, Calif., whosemajor investors include Medicus Partners, Delphi Bio Venturesand Domain Associates.
-- Jennifer Van Brunt Senior Editor
(c) 1997 American Health Consultants. All rights reserved.