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Breakthrough In The Development Of A Novel Human Antibody Platform

July 23, 2009

Open Monoclonal Technology, Inc. (OMT), in collaboration with Sangamo BioSciences, Inc. (NASDAQ, SGMO), Sigma-Aldrich Corporation (NASDAQ: SIAL), The Medical College of Wisconsin, and INSERM, today announced the creation of the first targeted knockout rats as detailed in “Knockout Rats Produced via Embryo Microinjection of Designed Zinc Finger Nucleases,” published in the July 24th issue of Science. The creation of rats with permanent, heritable genetic mutations is a critical milestone in the development of OMT’s novel human monoclonal antibody platform.

“Creating a knockout rat was the biggest challenge OMT faced”, said Dr. Roland Buelow, CEO of OMT and senior author of the paper. “Inactivation of endogenous rat antibody expression is essential for human antibody expression in genetically engineered animals. To solve this problem, we explored a new application for Zinc Finger Nuclease (ZFN) technology, which enabled a technique that could revolutionize the genetic engineering of animals.”

In the study, OMT scientists and its collaborators used ZFNs developed by Sangamo BioSciences, Inc. to knockout a gene encoding rat immunoglobulin. The mutations in rat immunoglobulin caused no off-target effects in other genes, and offspring of the ZFN-edited rats carried the mutated genes. Together, these results demonstrate the ability to generate heritable, specific and permanent modifications in a mammal using standard microinjection techniques and engineered ZFNs in early-stage embryos.

With antibody sales expected to reach $50 billion within five years, many companies have entered the biologics market through acquiring antibody technologies or licensing/fee for service arrangements. Currently, the mouse is the only genetically engineered animal commercially available for the generation of human monoclonal antibodies, and many targets are licensed already. The expense and limitations of the mouse technology create an opportunity for OMT and its new monoclonal antibody platform with unrestricted development options.

OMT’s human antibody technology is the result of an improved understanding of B-cell development and a novel approach to the inactivation of endogenous antibody expression described in the “Science” article. Previously, it took either embryonic stem cells or nuclear transfer cloning — techniques that are not available for the genetic engineering of rats ““ to create a knockout, OMT used a new ZFN-mediated technique to generate immunoglobulin knockout rats. ZFNs are engineered proteins that induce double-strand breaks at specific sites in an organism’s DNA. Such double-strand breaks stimulate the cell’s natural DNA-repair pathways and can result in site- specific changes in the DNA sequence. Up to now, ZFNs have been used to edit specific genes in fruit flies, worms (C. elegans), cultured cells and zebrafish embryos, but this is the first example of successful, permanent, heritable gene-editing in a mammal.

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