Non-human sugars could compromise biologic drugs
pharmafile | July 28, 2010 | News story | Manufacturing and Production |Â Â biologicals, biologics, manufacturingÂ
Many of the biologic drugs on the market today contain sugar molecule components that in some patients could undermine their effectiveness and cause chronic inflammation, according to US researchers.
Making simple changes to the manufacturing process for the drugs, however, could alleviate the problem, say the scientists from the University of California, San Diego.
The sugar molecule under scrutiny – sialic acid N-glycolylneuraminic acid (Neu5Gc) – is found in other primate species such as chimpanzees and gorillas but not in humans. Recombinant glycoprotein therapeutics produced in non-human mammalian cell lines, and particularly those produced using animal serum, are often modified with non-human Neu5Gc.
Research has indicated that all humans have Neu5Gc-specific antibodies because of exposure to the sugar in their diet. “But this immune response varies greatly in people, with some developing antibodies at high levels,” according to Ajit Varki, professor of medicine and cellular and molecular medicine at UCSD.
In these people the presence of Neu5Gc in biologic drugs could compromise their half-life and efficacy and stimulate an unwanted immunological response, he said.
Varki’s team have shown that mice which are genetically modified to have a human-like version of sialic acid react when treated with Merck KGaA/Bristol-Myers Squibb’s monoclonal antibody drug Erbitux (cetuximab), raising antibodies which lead to the drug being cleared from the body at a faster rate.
Neu5Gc contamination is unavoidable using current production methods because many biotherapeutics such as antibodies, clotting factors or hormones are produced using cells, tissues or serum from mammalian sources, which naturally contain the non-human sialic acid.
This contamination has however generally been ignored in drug development because healthy individuals were not thought to react to Neu5Gc.
Varki and colleagues studied several biotherapeutic agents currently in clinical use, and found the non-human sialic acid in almost all of them, although in varying amounts.
There is a simple solution to the problem. If the human version of sialic acid (Neu5Ac) is added to the culture medium used in the drug-making process it competes with the Gc version, reducing the chances of the Gc version making it into the final product.
“In our initial tests, it removes low-level Gc contamination in drugs,” said Varki, who notes the change to the production process should only require ‘minor’ regulatory approval.
“We think that while we’ve identified a problem, we’ve also come up with an answer, at least for some drugs.”
The study is published in the online edition Nature Biotechnology.
Phil Tayor
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