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Columns : Mar 1, 2012 ( )
New Drug Conjugates Work at Cell Surface
Centrose Exploits Its EDC Platform to Target Cells with Goal of Avoiding Toxic Side Effects!--h2>
Centrose is developing advanced types of antibody-drug conjugates (ADCs) called extracellular drug conjugates (EDCs). Like ADCs, EDCs use monoclonal antibodies to target a drug to a particular type of cell, such as those found in tumors. But unlike ADCs, the antibody and drug component of the EDC are not internalized. Instead, they work synergistically on proteins on the cell surface.
This feature overcomes several technical limitations that have plagued ADCs in the past, according to the firm. With ADCs, if the antibody’s target is also present on normal cells, toxicity becomes a problem. In addition, after the ADC antibody binds to a cell, the entire ADC must be internalized and the drug enzymatically released from the antibody to become activated inside the cell. This internalization process is somewhat inefficient and requires the use of highly toxic drugs to insure activity. Consequently, ADCs often cause off-target side effects.
In the Centrose EDC system, the drug acts to kill the cell only in specific disease stages and when the antibody and drug targets are present in close proximity. Both the drug and antibody act together on selected cell surface targets to generate signals that are transmitted into the cell, leading to apoptosis and/or necrosis. This specificity prevents toxic side effects, the firm says. The EDC platform allows for the construction of drugs that can target not only cancerous cells, but also other disease conditions.
James Prudent, Ph.D., CEO and president, started Centrose along with two professors in the School of Pharmacy at the University of Wisconsin, Madison: Jon Thorson, Ph.D., and the late C. Richard Hutchinson, Ph.D. They developed CarboConnect®, the company’s carbohydrate linkage technology that binds the antibody to the drug.
“We synthetically make sugars with tags on them, typically amines. These amino sugars can be synthesized on a variety of small molecule drugs, which are screened for activity,” says Dr. Prudent. Subtle changes in the sugar linkages can greatly alter EDC potency. The company’s name reflects the importance of sugars as linkers in the technology platform.
Centrose researchers are screening for new leads to use in the EDC platform. The company’s first EDCs are built around approved steroidal drugs that show anticancer activity, but are too toxic to combat cancer. Centrose’s EDC technology allows these drugs to bind their targets only when involved in a disease-related complex. The drug then acts specifically on diseased cells with few or no side effects, the firm claims.
Identified drug leads so far show a 50% rate of success when combined with Centrose’s monoclonal antibodies and linker system. By increasing the number and types of antibody and drug combinations, Dr. Prudent hopes to uncover many more EDCs for preclinical testing.
Currently, Centrose has seven EDC drug candidates and 32 additional prescreened leads in its pipeline. The first class of EDCs targets the sodium/potassium ATPase, which is usually considered an ion channel and is highly expressed in multiple cancers. However, research at Centrose and elsewhere suggests that this cell surface protein functions as more than an ion pump.
“It’s a membrane spanning protein that complexes with proteins inside and is involved in cell proliferation and death. We don’t fully understand all of its implications, but the target appears to be a central player in multiple disease states,” says Dr. Prudent.
A main target of the sodium/potassium ATPase is Src kinase. When an EDC binds and changes the conformation of the ATPase, Src kinase is activated, which, in turn, phosphorylates proteins that trigger cell death. Other proteins are likely involved, such as IP3 (inositol triphosphate) and PI3Ks, a family of intracellular signal transducers involved in cancer.
Centrose’s lead candidate, EDC1, is effective against non-small-cell lung cancer (NSCLC), one of the most aggressive tumor types known, the firm notes. NSCLC accounts for 85% of lung cancer, and more than half of cases present at an advanced stage with little hope for survival.
EDC1 complexes to FXYD5 (also known as dysadherin), a recognized subunit of the sodium/potassium ATPase. Late-stage metastatic cancer cells express high levels of FXYD5, and it is considered a sole prognostic indicator for poor cancer outcomes.
The second program, EDC2, complexes with CD147, a protein highly expressed on the cell surface of carcinoma cells. EDC2 shows strong efficacy against several cancer types. Other EDCs found to date are selective for a variety of specific disease complexes. “We typically use antibodies with some disease significance, mainly oncology,” says Dr. Prudent.
Centrose is building a portfolio of EDCs to license to pharmaceutical companies for further testing. The revenue raised will be used to develop, test, and move to market other EDCs in house.
“We’re in negotiations with several pharmaceutical companies for access to our lead programs and core technology,” says Dr. Prudent. The EDC system could be a way to resurrect drugs that were shelved because they lack specificity or efficacy.
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