Open Competition 3 - Biotechnology

Development of a Human Monoclonal Antibody Discovery Technology

Sponsor: Vaccinex, Inc.

• Project Performance Period: 5/1/2004 - 4/30/2006
• Total project (est.): $2,811,003.00
• Requested ATP funds: $1,993,619.00

Fully human monoclonal antibodies - antibodies of uniform specificity derived from clones of human antibody genes - are emerging as a major focus of research because of their potential to combat a wide range of diseases, notably cancer, inflammation and infectious diseases. Antibodies can bind to and cause elimination of disease causing cells and molecules with wonderful precision. The trick, however, is to sort through the vast number of different possible antibodies (it is estimated that every person can make more than 25,000,000 and perhaps more than 100,000,000 different antibodies) to find genes for the few antibody molecules that bind to a specific disease-causing cell or molecule strongly enough (have sufficiently high affinity) to be effective in eliminating the cause of disease. Once these antibody genes are isolated, methods exist for making sufficient quantities of the specific antibodies for therapeutic use. For most therapeutic applications, it is essential that these antibodies be of human origin to avoid being rejected by the human body. Today there are three major research platforms for human antibody discovery - making "humanized" versions of mouse antibodies produced using mouse hybridomas (the technique for which Köhler and Milstein won the Nobel Prize), creating those same antibodies using transgenic mice that have been engineered to produce human-like cells, or selecting antibodies expressed in bacterial viruses called phage. Each of these methods has limitations in that they are effective for some types of target molecules but not others. Both the techniques for humanization of mouse antibodies and selection of antibodies from transgenic mice are limited by the fact that many important proteins of humans and mice have similar functions and structures, including proteins that play an important role in diseases like cancer. As a result, mice are immunologically tolerant to many of these features (the mouse immune system learns not to react against its own proteins or any similar protein) and it is very difficult to induce production of good quality antibodies against these types of molecules. Antibodies expressed in phage do not have this same limitation, but because they are produced in bacteria the complex antibody proteins often have a weak affinity for their targets. To overcome these problems, Vaccinex proposes a novel, library-based platform that expresses antibodies in mammalian cells rather than in bacteria. The company will use a very large combinatorial library of human immunoglobulin genes in a vaccinia virus vector (a form of the same non-virulent virus originally used to immunize people against smallpox) and recombine the genes in mammalian cells grown in tissue culture. Vaccinex believes this technique will make it possible to produce a large and diverse repertoire of correctly assembled human antibodies that can be screened against known antigens for specific therapeutic applications. Because they are produced in mammalian cells, the antibodies will not require extensive molecular engineering to generate high affinity molecules suitable for use in humans. The major risks faced by Vaccinex are related to the novelty of the virus vector approach - achieving a sufficiently broad array of antibodies to permit selection of those that have therapeutically useful affinities for target cells and pathogenic molecules. As a test of the platform, the company will select specific antibodies against two very different target antigens, antibodies specific for C35, which is associated with human breast cancer, and antibodies specific for human papillomavirus (HPV) type 16, a common sexually transmitted disease that has been associated with cervical cancer. If successful, the Vaccinex project will result in a new and powerful discovery platform for developing monoclonal antibody therapies for a broad range of diseases. A new breast cancer treatment with 20 percent efficacy, for example, would save 12,000 to 16,000 lives annually. Moreover, because of its breadth and efficiency, the Vaccinex technology should be ideal for identifying antibody-based countermeasures for potential bioterrorism agents. A small company, Vaccinex needs ATP support because the proposed technology is in its infancy and requires further development and validation to attract outside investors and partners.

For project information:

R. Stan Holland, (585) 271-2700
sholland@vaccinex.com

ATP Project Manager

Thomas Wiggins, (301) 975-5416
thomas.wiggins@nist.gov