Wednesday, May 21, 2008

The 3% (sialylated) Solution

Intravenous Immunoglobulin (IVIG) is an immune modulator and anti-inflammatory agent used to treat a wide range of diseases, including rheumatoid arthritis (see also: 1990 NIH consensus panel report). IVIG contains antibodies (immunoglobulins, Ig) pooled from the blood of hundreds or even thousands of donors; pooling raises the risks of infection and complicates standardization.

Here, Anthony and colleagues tested their idea that sialylation is required for the therapeutic activity of the invariant region of Ig called Fc (fragment crystallizable). Sialic acid can be linked through alpha 2,3 or alpha 2,6, which are distinguished by the location of the hydroxyl and methyl groups on the 6 member ring.
First, they looked for these linkages in a preparation of IVIG by comparing its mass spectrum with standards. Nearly all the sialylated IVIG was alpha 2,6 linked and treatment with an enzyme that selectively removed this linkage abolished the anti-inflammatory activity of IVIG. Of potentially enormous significance was their success in making Fc derived from cloned human IgG therapeutic by alpha 2,6 sialylation. The figure shows the clinical score of mice made arthritic by administration of K/BxN sera alone (top line), or also treated therapeutically with IVIG (second line), 1/30 as much sialylated-enriched Fc from IVIG (0.033 g/kg SNA IVIG, third line), or an equivalent amount of recombinant, sialylated Fc (bottom line). This finding could lead directly to the manufacture of much safer, much more consistent IVIG preparations.
Anthony RM, Nimmerjahn F, Ashline DJ, Reinhold VN, Paulson JC, Ravetch JV. Science. 2008 Apr 18;320(5874):373-6. "Recapitulation of IVIG anti-inflammatory activity with a recombinant IgG Fc".

1 comment:

Reuel said...

The complexity of biomolecules is greatly expanded by the addition of carbohydrates (sugars) to proteins. This work, and similar findings in cancer biology, demonstrate the physiological importance of modified carbohydrates, thereby adding a new layer of complexity.

So even though the genome encodes "only" 24,000 or so proteins, many can assume a myriad of physiologically distinct, mature forms.