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IXSYS SCIENTISTS REPORT ABILITY TO ENHANCE THERAPEUTIC VALUE OF MONOCLONAL ANTIBODIES BEYOND THAT ACHIEVED BY THE HUMAN IMMUNE SYSTEM

 SAN DIEGO, Dec. 15 /PRNewswire/ -- Scientists today reported that they can create monoclonal antibodies that are more therapeutically effective than the antibodies produced by the human immune system. In two papers published in the Dec. 15 issue of the Journal of Immunology(a), scientists from Ixsys Inc. and Bristol-Myers Squibb describe revolutionary technologies that have been used to create new antibodies with 15 times greater affinities to certain tumor cells, according to William D. Huse, M.D., Ph.D., chief scientific officer and founder of Ixsys.
 "Researchers have tried to mimic the process the body uses to select antibodies," Huse said. "However, no one has ever determined what the limits of this natural process are or found ways of overcoming and surpassing those limits. At Ixsys we did just that. We have refined the use of bacterial systems and, using what we call codon-based mutagenesis, we improved upon the natural selection process and created, in vitro, optimized, high-affinity antibodies that even the human immune system cannot duplicate. We believe that by using these revolutionary technologies and another process developed at Ixsys, we have overcome the obstacles that have hindered scientists from successfully developing therapeutic monoclonal antibodies."
 As reported in the journal, Ixsys scientists used a unique system to express an antibody specific to several human cancer tumors in bacteria. Once a candidate was identified, scientists used Ixsys' codon-based mutagenesis, a genetic engineering tool, to further enhance the antibody's affinity and specificity. More recently, Ixsys scientists used the same novel technologies to enhance the affinity of two different anti-carcinoma antibodies toward tumor antigens.
 In nature, antibodies are produced by the immune system in response to exposure to an antigen (foreign particle) and are part of the body's arsenal of weapons against foreign substances. Antibodies are made up of sequences of amino acids, with each amino acid coded for by sets of three nucleotides known as codons. Each time the body is exposed to an antigen, antibodies are created and subsequently refined by the human immune system to increase their effectiveness in combating the antigen. During this process of affinity maturation, these changes are made one nucleotide at a time. Since three nucleotides are required to code each amino acid in a protein, it may require three nucleotide changes to achieve a desired amino acid change.
 In contrast, Ixsys' codon-based mutagenesis rapidly and efficiently alters the codons in the DNA within the region of the antibody genes that determine its antigen binding characteristics. Unlike the human immune system, during codon-based mutagenesis entire codons are replaced, rather than individual nucleotides. This process results in the identification of antibodies which would not be identified by single nucleotide changes. This means that many of the antibodies that are created by codon mutagenesis are superior to those created by the human immune system.
 "The human immune system is limited by the fact that changes to antibodies are made one nucleotide at a time," according to Scott Glaser, Ph.D., a principle author of both papers. "Codon-based mutagenesis makes codon changes, three-nucleotides-at-a-time, that are necessary to provide the optimal diversity of new antibody candidates. These new antibodies are most likely to have higher affinity and higher specificity. Through selection procedures we can then isolate the antibody that is the most effective."
 Ixsys scientists have also developed methods to immunize cultures of human spleen cells to generate human monoclonal antibodies. The spleen is a central organ where antibodies are generated and selected by the human immune system. Antibodies isolated from these spleen cultures are candidates for optimization by codon-based mutagenesis. Scientists attempting to develop therapeutic monoclonal antibodies have traditionally produced mice (murine) or mouse:human hybrids (chimeric) antibodies. However, antibodies created in this way generate a human anti-mouse antibody (HAMA) response, similar to an allergic response, which neutralizes the effect of the antibody. Human antibodies are much more desirable because the human immune system does not react to them as being foreign and therefore does not mount a defense against them.
 "We've overcome the three of the major obstacles that have hindered the successful development of therapeutic monoclonal antibodies: we've developed truly human monoclonal antibodies together with a series of technologies that substantially increase the affinity and specificity of these antibodies so that they can be effective as therapeutics," Huse said.
 "We are extremely pleased with the progress and results we have made in developing these particular antibodies and expect to begin preclinical trials in the near future," Huse added.
 Ixsys intends to use these technologies to develop monoclonal antibody products in the cancer and infectious disease area. The company has already singed a research agreement with Bristol-Myers Squibb for the development of monoclonal antibodies directed toward certain tumor-associated antigens.
 "Our initial success in the antibody area is being duplicated in our peptide projects," according to Huse. "Ixsys' peptide focus will be in the area of growth factor receptors that are related to a variety of diseases."
 Ixsys Inc. is a leader in the discovery, development and production of high-affinity and specific peptides and human monoclonal antibodies for use as pharmaceutical products. The company's proprietary protein engineering technologies enable it to rapidly generate and optimize peptides and human monoclonal antibodies. Its principal investors include Medicus Venture Partners, Delphi Bio Ventures and Domain Associates.
 (a) Papers available upon request:
 "Application of Filamentous Phage pVIII Fusion Protein System Suitable for Efficient Production, Screening and Mutagenesis of F(ab) Antibody Fragments," Huse, William D.; Stinchcombe, Timothy J.; Glaser, Scott M.; Starr, Lisa; Maclean, Michael; Hellstrom, Karl E.; Hellstrom, Ingegerd; Yelton, Dale E.
 "Antibody Engineering by Codon-Based Mutagenesis in Filamentous Phage Vector System," Glaser, Scott M.; Yelton, Dale E.; Huse, William D.
 -0- 12/15/92
 /CONTACT: Michael J. Hanifin, VP-business development of Ixsys, 619-455-2350; or Linda Seaton of Keatinge/Seaton Communications, 619-625-2100, for Ixsys/


CO: Ixsys Inc.; Bristol-Myers Squibb ST: California IN: MTC SU:

JB-JL -- SD003 -- 7066 12/15/92 09:16 EST
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