A production process developed by Amersham Biosciences has enabled Isis Pharmaceuticals to produce the world's largest antisense oligonucleotide synthesis scale per single run.
Isis accomplished this pharmaceutical industry manufacturing first by using Amersham's OligoProcess synthesiser, coupled with Isis' proprietary synthesis methods and custom reactor column.
Using OligoProcess, Isis produced more than 4 kilograms (600-millimole scale) of high-quality crude 20mer oligonucleotide in approximately 5.3 hours, which equates to a production capacity of a metric ton of crude oligonucleotide on an annual basis.
Antisense oligonucleotides have been the subject of considerable research, but have not lived up to their initial promise as a broad-based platform for new therapeutics, mainly because of delivery and stability problems but also in part because they have tended to be difficult - and expensive - to manufacture.
At present, only one antisense therapeutic has reached the market, namely Isis' Vitravene (fomivirsen) for cytomegalovirus retinitis, an opportunistic infection that affects the eyes of people with immune suppression usually caused by HIV.
In its collaboration with Isis, Amersham designed a custom OligoProcess that could accommodate the antisense specialist's proprietary synthesis methods. OligoProcess operates on Amersham's Unicorn control platform and is an automated system of pumps that delivers the precise levels of solvents at appropriate intervals with high capacity, through a column packed with solid support, called Primer Support 200.
The solid support used by Isis to achieve the single run consisted of beads of polystyrene cross linked with divinylbenzene, with the first nucleoside attached at a density of 200 micromoles per gram. The high density of nucleoside loading on this solid support resulted in an elevated scale of synthesis per reaction volume.
"The advantage of this high synthesis scale is a reduction in the quantity of reagents consumed per run and an increased yield of full-length oligonucleotide," said the firm in a statement.
Isis noted that the current run achieved a 600 millimole-scale, and that it is planning to undertake an 800 millimole-scale run later this year.