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To: scaram(o)uche who wrote (250)	11/20/1998 3:31:00 PM
From: mike mulhearn	Read Replies (2) \| Respond to of 1073

Mobilizing the Immune System Gene immunotherapy stimulates a patient's own immune system to attack tumors. Many other gene therapy techniques work by causing cancer cells to self-destruct, requiring delivery of a drug into every cancer cell. By eliminating this requirement, gene immunotherapy shows tremendous promise for treating metastatic disease or inaccessible tumors. Genzyme Molecular Oncology applies three technological approaches to gene immunotherapy: cancer vaccines, stress genes, and the use of dendritic/cancer cell fusion technology. These approaches seek to stimulate the patient's immune response to attack and kill cancerous cells. Cancer vaccines combine a tumor antigen gene with a delivery vector. Tumor antigens are proteins produced by tumors but not by normal cells. Genzyme Molecular Oncology is focused on the discovery of tumor antigens that prompt a potent cellular immune response against the tumor. We use SAGE™ and other proprietary technologies to identify and optimize tumor antigens for the development of cancer vaccine products. These technologies may allow us to discover novel antigens more quickly and in much greater quantities than previously possible. Working with the National Cancer Institute, we have completed two phase I clinical studies in melanoma, the most serious type of skin cancer. These studies demonstrated that our adenoviral vectors containing melanoma tumor antigens MART 1 and gp100 genes were safe and well-tolerated. In addition, a small number of patients showed clinically significant tumor regression. We have designed additional phase I studies, in order to better understand how to consistently elicit this powerful immune response. We plan to use the knowledge gained from these trials, along with novel antigens identified in our research program, to target other cancer indications. A second and complementary gene immunotherapy approach is the use of stress genes to stimulate an immune response. Delivery of stress genes to tumor cells appears to make these cells more recognizable by the immune system. We have formed a joint venture with StressGen Biotechnologies Inc. to develop stress genes for the treatment of ovarian and other cancers. Genzyme Molecular Oncology has an option to license technology from the Dana Farber Cancer Institute that may be developed as a cell-based immunotherapy. This technology combines dendritic cells, a type of antigen-presenting cell, with tumor cells. The resulting "fusion" cell is administered to the patient with the purpose of eliciting a strong immune response against tumor cells that contain the same tumor antigens that are present on the fusion cell.

To: scaram(o)uche who wrote (250)	11/20/1998 3:33:00 PM
From: mike mulhearn	Read Replies (1) \| Respond to of 1073

Pinpointing Cancer Cells Our second area of focus within gene therapy is tumor targeting, which involves delivering genes directly into cancer cells. This may include delivering tumor suppressor genes to control growth, suicide genes to kill tumor cells, or genes that prevent the blood vessel formation necessary for tumors to grow. For these types of therapies, the critical challenge lies in reaching tumor cells or tumor vasculature, wherever they may be in the body. In preclinical models, Genzyme Molecular Oncology's lipid delivery vectors have demonstrated the ability to travel through the bloodstream and seek out cancerous cells. Our expertise in gene delivery represents a valuable resource for collaborators. We signed the first such collaboration with Schering-Plough Corporation in late 1997. Schering-Plough has an option to use our lipid vectors with six proprietary genes, beginning with the p53 tumor suppressor gene. This gene, which encodes a protein responsible for controlling cell growth, has been shown to be defective in over 50 percent of all cancers. A gene therapy able to restore p53 function could be a revolutionary advance for many cancer patients. In the future, we plan to continue to optimize gene delivery technology for use with our proprietary cancer genes, while also seeking additional partners in need of the most effective methods for gene delivery.

To: scaram(o)uche who wrote (250)	11/20/1998 3:42:00 PM
From: mike mulhearn	Read Replies (1) \| Respond to of 1073

SAGE: A new tool for the discovery of improved cancer treatments The accuracy and sensitivity of our gene expression technology make it possible to identify genes expressed at very low levels, which is often the case with genes that control crucial biological processes and therefore represent potential drug targets. SAGE has identified many genes that were previously unknown. <Picture> SAGE is a patented, high-efficiency method of simultaneously detecting and measuring the levels of virtually all genes expressed in a cell at a given time. It can be used in a wide variety of applications to identify disease-related genes, analyze the effects of drugs on tissues, and provide insight into disease pathways. Genomics has the potential to revolutionize the life science development and discovery process by providing a wealth of new genes that help us understand disease pathways and by providing new targets for health and nutrition products. The critical question, however, is how to harness this wealth of information and synthesize it into a select group of relevant, prioritized targets. Gene expression analysis is a critical tool in this prioritization and selection process. Recognizing that, Genzyme Molecular Oncology (GMO) has recently acquired commercial rights to an extremely powerful expression analysis tool known as SAGE™ (Serial Analysis of Gene Expression). Not only has GMO positioned SAGE as the cornerstone of its own genomics and drug discovery efforts, but it is now providing interested companies with access to this remarkable technology. THE SAGE METHOD <Picture> SAGE is a patented proprietary sequence-based technology for gene identification and quantitation developed by Bert Vogelstein, Ken Kinzler, and Victor Velculescu at the Johns Hopkins University Oncology Center. (Patent No. 5,695,937) In order to use SAGE for transcript identification and quantitation, messenger RNA (mRNA) is first prepared from the desired cell or tissue sample. Complementary DNA (cDNA) is then synthesized from the mRNA using standard techniques. At this point, the entire population of cDNA molecules is treated using proprietary techniques to create a single unique "tag" from each cDNA. The sequence of the tags serves to identify each transcript. The number of times each tag occurs measures the number of copies of the mRNA originally present in the biological sample. GMO has developed proprietary software to perform tag identification and quantitation and uses its bioinformatics tools to create a relational database of the expression profile. THREE PRINCIPLES UNDERLIE THE SAGE TECHNOLOGY: • One short oligonucleotide sequence from a defined location within a transcript ("tag") allows accurate quantitation. • Tag size (10-14bp) is optimal for high throughput while maintaining accurate gene identification and quantitation. • The combined power of serial and parallel processing increases data throughput by orders of magnitude when compared to conventional approaches. These attributes combine to enable rapid, accurate analysis of gene expression patterns.1 THE SAGE ADVANTAGE SAGE is highly efficient, able to detect low abundance genes, very accurate, and extremely sensitive. The SAGE method avoids bias inherent in PCR-based transcript amplification processes. The serial analysis of short oligonucleotide tags enables approximately 50 fold more SAGE tags than ESTs to be sequenced using comparable sequencing effort. This allows greater depth of analysis which results in quantitation at high confidence levels and significantly increases the probability of detecting low abundance genes. The data from each tissue is immortalized in an electronic database which allows multiple comparisons with other tissues without repetitive wet lab procedures. <Picture> SAGE Compares Favorably to Other Gene Expression Methods SAGE provides expression information directly as sequence - the gold standard for genetic research. The key attributes of SAGE derive from the short tags offering high efficiency sequencing and therefore dramatically improved productivity and considerably reduced research costs over non-tag methods. Compared to Oligo Arrays (gene chips): SAGE is more efficient. Oligo arrays must hybridize many oligomers to assure an interpretable sequence. This limits the number of sequences that can be arrayed on any one chip. With short tags and parallel processing, SAGE is able to achieve a greater depth of tags, avoiding that problem. Furthermore, oligo arrays are incapable of discovering novel genes and are not yet readily available. Compared to cDNA arrays (DNA chips): SAGE is much less biased since SAGE avoids numerous PCR amplification and hybridization steps which may introduce and compound errors. Furthermore, SAGE is able to quantitate expression level differences in multiple experiments over time without requiring additional wet lab procedures. This is not true of cDNA arrays. Compared to Transcript Imaging (EST's): SAGE unequivocally offers a much more in-depth, comprehensive analysis where the interpretation of the results (differential expression) is backed-up with statistical significance, thereby essentially giving results that are more believable and "confirmable" by other means. Compared to Differential Display (DD or reverse transcriptase PCR): SAGE provides immortal data that can be queried as many times as one wishes. The big drawback with DD is non-quantitative results and a high frequency of false leads, both of which are overcome when performing a SAGE analysis. For confirmation of these wonderful attributes you may refer to recent publications which document and demonstrate SAGE's capabilities. SAGE allows you to work smart by saving valuable time and effort.

To: scaram(o)uche who wrote (250)	11/20/1998 3:44:00 PM
From: mike mulhearn	Respond to of 1073

Small molecule drugs are chemical compounds that offer manufacturing and delivery advantages over other forms of treatment. Potential therapies are identified by evaluating compounds using screens that represent therapeutic targets. With the new technologies available today, research that formerly required years of effort and significant expense can now be accomplished in several days. Genzyme Molecular Oncology has established a valuable infrastructure in this area. Our resources include robotically-driven combinatorial chemistry technology, high-throughput screens, and a diverse library of over one million compounds. Our drug development efforts are focused on inhibiting the blood vessel formation that feeds tumor growth, on preventing the spread of tumors throughout the body, and on modulating cancer cell proliferation and death. In 1997, we established collaborations with the National Cancer Institute, Novalon Pharmaceutical Corp., and Acadia Pharmaceuticals Inc. to evaluate our compound library against their panels of cancer screens. In addition, we licensed an important cancer screen to Merck & Co. In the future we plan to utilize the SAGE technology in our drug discovery efforts by translating SAGE data into novel cancer screens. Collaborators & Partners Merck & Co. Acadia Pharmaceuticals Georgetown University Novalon Pharmaceutical Corp. ArQule Inc. National Cancer Institute Johns Hopkins University