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CXR, Geron Wrap Up Alliance to Develop hESC Hepatocytes for ADME/Tox Assays

CXR Biosciences and Geron this week said they have concluded a research collaboration that focused on developing human embryonic stem cell-derived hepatocytes for use in ADME/Tox assays.
The companies are betting that their alliance will lead to a more reliable alternative to immortalized hepatocyte lines or primary human hepatocytes, which could attract drug makers.
Meantime, CXR has been working with Artemis Pharmaceuticals since February 2005 to create a strain of humanized mice that produce cytochrome p450s to determine the gene’s role in drug disposition.
“We are just finalizing some IP licenses that will allow us to market them,” CXR CEO Tom Shepherd told CBANews this week. “We’ve actually started discussions with some companies,” he said, explaining that the company intends to license the mice to companies rather than sell individual mice. “We expect to get more involved with that over the next few months.”
In terms of the Geron alliance, the program “is not yet at a commercial stage,” Shepherd said. “What it has done is demonstrated proof of concept for the differentiation of hESCs into hepatocytes, and we have some good data. It was basically a research project, however.”
Shepherd said the program resulted in an undisclosed number of US patent applications and other assets that Geron and CXR will share. (see CBA News, 5/25/2004) He declined to describe the nature of the IP, but said that CXR plans to use it to develop products for drug development.
Cell Differentiation
Shepherd said he feels that the potential market for hESC-derived hepatocytes is very large. Many problems inherent in the drug-development process are due to the biological differences between humans and the model organisms on which drug candidates are initially tested, he explained.
Also contributing to this challenge is the short shelf-life and variable quality of primary human hepatocytes.
Shepherd said that because hESC-derived hepatocytes are standardized, data comparison would be much easier. “An unlimited source of human hepatocytes would be a very big step forward” toward confronting this challenge,” he said. “The idea of having a human hepatocyte that you can use whenever you want and to whatever scale you want is very attractive to drug development companies and investigators.” (See related article, this issue)
Another option is to use immortalized hepatocyte lines. However, “one of the problems with immortalized hepatocytes is the very fact that you’ve immortalized them means there has been a significant genetic change,” said Shepherd.
By comparison, hESC-derived hepatocytes have not been genetically modified to make them immortal, meaning that researchers “could consider them closer to primary hepatocytes.”

“An unlimited source of human hepatocytes would be a very big step forward,” Shepherd said. The idea of having a human hepatocyte that you can use whenever you want and to whatever scale you want is very attractive.”

Generally speaking, hESC-derived hepatocyte technology would likely compete with animal hepatocytes, said Shepherd. It’s hard to say, though, how it would compete with other methods because it is not at the commercialization stage yet. It is also hard to estimate market size, but according to Shepherd, MultiCell thinks that this will be a very large market because all drugs are tested in hepatocytes during development.
Other Alliances
Shepherd also said CXR has been working with Millipore for about a year to use hESC-derived hepatocytes as reporter cells. He said the companies aim to create cell-based assays with reporter systems for toxicity that can be used in high-throughput screening applications.
“The original decision was actually to work with Upstate, which Millipore acquired last year,” Shepherd said. “Upstate had some HTS technology [the Luminex Tag-It p450 2D6] that was very compatible with our cells. We developed cell lines with reporter systems for various toxicities that were very compatible with this technology.”
Shepherd said that the cell lines are expected to reach the market in the “not too distant future.” He also mentioned that this collaboration involves research funding and royalties on sales.
CXR has also collaborated with Millipore to make a series of specialized antibodies to ADME/Tox enzymes, such as cytochromes. He said that those antibodies have already been commercialized through Millipore.

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