Aprotinin from plants could end supply shortage

Large Scale Biology Corp has solved the problem of supplying large
quantities of aprotinin - widely used in the manufacture of
biologic drugs - by developing a recombinant form that is made in
tobacco plants.

Aprotinin is a vital reagent in the manufacture of biologic drugs such as antibodies and vaccines, but is currently extracted from bovine lung tissue as a by-product of the meat industry. LSBC claims that it can deliver its alternative source - at a competitive price - and do away with the supply problems.

The recombinant form also sidesteps concerns about the use of animal-derived products in human-use medicines that followed in the wake of the mad cow disease issue, recently resurfaced with a new case of the disease in the US.

Daniel Tuse, LSBC's vice president of business development, told In-Pharmatechnologist.com that biotechnology companies use aprotinin 'by the shovelful' to improve the yield of their biological products made in cell culture. The compound acts as a non-specific protease inhibitor, and is added to the culture medium to prevent breakdown of the desired product by proteases secreted by the very cells it is being made in.

There are three or four suppliers of extracted aprotinin who are selling to end-users, he noted, and while the supplies are often adequate, they are subject to degree of seasonality that can cause shortages.

Moreover, aprotinin is also used as a therapeutic in its own right - Germany's Bayer sells its for the prevention of blood loss during heart surgery as Trasylol - and it is being tested in new uses that if approved could put added strain on supplies. It is also used as a reagent in R&D laboratories.

LSBC's solution to making a ready supply of aprotinin has been to place the genetic sequence coding for the compound into a virus that infects tobacco plants. This tobacco mosaic virus is based on RNA, so it does not combine with the tobacco plant's genetic material. This does away with the need to genetically modify the plant, avoiding the high cost and length of time taken to develop transgenics and also bypassing environmental concerns about GM material.

Using LSBC's process, regular tobacco is planted and sprayed with the virus once the plants have emerged. The tobacco is then harvested as normal, and further processing takes place to extract and purify the aprotinin.

The aprotinin produced via this process is purer than the bovine lung extracts, which tend to have a number of other protein contaminants, according to Tuse. Also, because LSBC's process makes for relatively easy extraction from the plants, the company expects to provide aprotinin to wholesalers at an equivalent cost or cheaper than its rivals when it launches commercial supplies in the middle of this year.

Tuse noted that there is little data around on the value of the aprotinin market. The prescription-grade product Trasylol has annual sales of around $120 million (€94m), but the market for the research-grade version used in bioproduction is less, perhaps a tenth of that total.

One potential obstacle to the company's plans is that regulators might ask companies who switch to using LSBC's aprotinin to prove that their drugs are equivalent to those made using the animal-derived version. Tuse acknowledged this possibility but said he believed the level of clinical work required to show equivalence would likely be 'a minimal amount'.

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