Selective Exclusion of High Titer Donor Plasma and Immunoadsorption Chromatography As Steps to Reduce Isoagglutinin Titers in IVIG

Hemolysis is a rare but potentially serious complication of high-dose IVIG therapy. Isoagglutinins originating in donor plasma are believed to play a major role in these reactions, but host factors are also important. We determined the effects of excluding plasma from donors with high isoagglutinin titers from the pools used to prepare IVIG, and of specific anti-A/B immunoaffinity chromatography (IAC), on the anti-A and anti-B titers of IVIG products prepared using the process for Privigen/Hizentra. A high-throughput assay was used to identify plasma donors with the highest anti-A titers. The effects of addition of IAC with A/B-trisaccharide-coupled resins into the manufacturing process were also studied. Anti-A/B isoagglutinin titers in the resulting IVIG preparations were measured by indirect agglutination and flow cytometry. Exclusion of the 5% of plasma donors with the highest anti-A titers reduced both anti-A and anti-B isoagglutinins in the final product by approx. 50% (a single 2-fold dilution step, i.e. reduction of the titer from 1:16 to 1:8, and 1:8 to 1:4, respectively. N=30 lots). Specific IAC reduced anti-A and anti-B titers by at least two 2-fold dilution steps in the final product (>80% reduction shown by flow cytometry on standard red cells), while the content of antibodies against common microbial antigens remained unchanged. Anti-A/B isoagglutinin reduction in IVIG products is feasible using screening and exclusion of a small percentage of high anti-A titer donors and with specific IAC. These approaches may reduce the risk of hemolysis in IgG therapy.