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What s the Fuss about OGS? Breast Cancer Protein Findings Provide Clues

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Last week, Oxford GlycoSciences management spurned a takeover bid by UK biotech Celltech, signaling that the company’s merger with Cambridge Antibody Technology announced Jan. 23 is more likely to go forward.

David Ebsworth, CEO of OGS, spared no niceties, calling the offer “inadequate,” “opportunistic,” and “a spoiling tactic by Celltech.” He said in a statement that the cash offer “significantly undervalues OGS and provides our shareholders with no upside and no opportunity to share future benefits.” The decision is now in the hands of OGS shareholders as to whether to choose the hostile or the friendly suitor.

While this reaction is not a total surprise — CAT is the old steady, having collaborated with OGS since 2000 — the recent flurry of interest in Oxford GlycoSciences as an acquisition target may leave some observers wondering what all the fuss is about.

A Feb. 21 paper on novel breast cancer membrane proteins, published in the Journal of Biological Chemistry, may provide some clues as to just exactly why OGS is such a hot property. The paper, authored by OGS researchers and select academic collaborators, details their discovery of what is possibly the biggest collection of tumor-derived membrane proteins ever found — and a potential gold mine of targets for breast cancer therapeutics.

In the paper, “the proportion of membrane proteins [reported] is higher than anything else published,” said Jonathan Terrett, the OGS researcher who is the paper’s corresponding author. It “represents a leap forward to us in terms of the quality of the proteins you get at the other end.” Among the proteins, many “are looking like targets in terms of biology,” Terrett said.

With a breast cancer therapeutic market that forecasters have estimated at between $1.3 billion and $4 billion for 2003, this new set of protein targets related to breast cancer is likely to draw notice from more than just scientists. One only need note that recent oncology sensation Gleevec, as well as Herceptin, Panorex, and Iressa, all involve membrane proteins, to understand why these proteins are so important.

It’s in the Informatics

Together with researchers from the Cancer Research United Kingdom Molecular Oncology Laboratories, the Weatherall Institute of Molecular Medicine, and Paris proteomics company Hybrigenics, an OGS team went hunting in four breast cancer cell lines for novel cell surface antigens, as well as those involved in intracellular signal transduction, and secreted extracellular proteins.

They used a mix of 1D gels, MALDI-TOF mass spectrometry, and Hybrigenics’ yeast-two hybrid cloning analysis. They also used immunohistochemical analysis to determine location and expression of previously unknown proteins in breast cancer tissue.

The methods, Terrett said, were quite conventional, although the yeast-two-hybrid technology helped them to functionally validate some proteins for which the encoding sequence had no homology to sequences that encode proteins of known function.

But “the real difference came in the informatics,” Terrett said. “We designed the system to filter out at the informatics stage anything that was common and abundant and already known.” Importing data from SwissProt and GenBank, and making gene predictions from GeneScan, they assembled algorithms to create this informatics sieve.

The result was a unique database of over 500 breast cancer cell line proteins, 27 percent of which had unknown function. Of these unknown proteins, 20 to 25 percent (about 27 to 33 proteins) would be expected to be plasma membrane proteins. OGS has the rights to all of these proteins.

A Novel Tumor Suppressor Blocker

The authors described three of these proteins in their paper: BCMP11, which has sequence homologies to a secreted protein; BCMP84, a putative calcium binding protein; and BCMP101, a previously unknown plasma membrane protein that was highly upregulated in 85 percent of donor tissues, relative to normal tissue. They also found that BCMP101 interacted with alpha 1-catenin, which is believed to play a role in cell-cell adhesion.

“We can speculate that BCMP11 may play a role in breast tumor development by binding to alpha 1-catenin and blocking its tumor suppressor functions,” the authors wrote.

The company discovered other proteins, but has so far kept them close to its chest.

Meanwhile, the team has submitted another paper on BMCP101 and its oncogenic properties for publication in a journal.

But more importantly, Terrett said, OGS is working with its collaborator NeoGenesis Pharmaceuticals to screen these proteins for binding affinity to small molecules, and Medarex, which has transgenic mouse technology, for functionality and therapeutic antibody development.

NeoGenesis, of Cambridge, Mass., has developed the Automated Ligand Identification System, which can screen 300,000 lead compounds a day to identify the compounds that bind with a protein target. It has also created the neoMorph compound library, which contains over 10 million lead compounds.

Medarex of Princeton, NJ, has been collaborating with OGS since 2000 using its transgenic mouse UltiMab Human Antibody Development System to develop fully human monoclonal antibodies for protein targets that OGS supplies. Then in January 2002, the two announced a breast cancer-specific partnership, along with human antibody developer Genmab, of Copenhagen.

In this collaboration, Genmab and Medarex are developing human antibody therapeutics, as well as possible tumor vaccines, based on seven protein targets that OGS supplied from its work on breast cancer tumors. The companies have already discussed work on one of these targets, the hydrolytic enzyme heparanase I-which allows cancer cells to be invasive by dissolving the basement membranes of venules.

But, as this latest research indicates, heparanase I is just the tip of a potentially lucrative iceberg for OGS in oncology therapeutics.

Terret confirmed that OGS is “already well into the process” of putting the membrane protein targets reported on in the paper through the system, and has generated antibodies that it is starting to build into clinical lead compounds.

Additionally, the company has supplied antigen targets from this work to Bioinvent, another collaborator, Terrett said.

The CAT merger — or a hostile takeover by Celltech — could put the future of these projects into question. John Aston, CAT’s CEO, has indicated that it will fold OGS oncology business unit into its own drug discovery unit, while keeping its proteomics unit as a separate business entity. Analysts have said that Celltech would have to make significant cuts at OGS as well if it wants to profit from the acquisition.

Given the potential of these membrane protein targets, however, it is likely that the breast cancer drug discovery project is one that any acquiring company will want to nurture as it integrates OGS into its business.

— MMJ

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