Reduction of Isoagglutinin in Intravenous Immunoglobulin (IVIG) Using Blood Group A- and B-Specific Immunoaffinity Chromatography: Industry-Scale Assessment.

Simon Gerber, Annette Gaida, Nicole Spiegl, Sandra Wymann, Adriano Marques Antunes, Ibrahim El Menyawi, Brigitte Zurbriggen, Alphonse Hubsch, Martin Imboden

BioDrugs : clinical immunotherapeutics, biopharmaceuticals and gene therapy 2016 Oct

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Hemolysis, a rare but potentially serious complication of intravenous immunoglobulin (IVIG) therapy, is associated with the presence of antibodies to blood groups A and B (isoagglutinins) in the IVIG product. An immunoaffinity chromatography (IAC) step in the production process could decrease isoagglutinin levels in IVIG. Our objectives were to compare isoagglutinin levels in a large number of IVIG (Privigen®) batches produced with or without IAC and to assess the feasibility of the production process with an IAC step on an industrial scale. The IAC column comprised a blend of anti-A and anti-B resins formed by coupling synthetic blood group antigens (A/B-trisaccharides) to a base bead matrix, and was introduced towards the end of the industrial-scale IVIG manufacturing process. Isoagglutinin levels in IVIG were determined by anti-A and anti-B hemagglutinin direct and indirect methods according to the European Pharmacopoeia (Ph. Eur.) and an isoagglutinin flow cytometry assay. IVIG product quality was assessed with respect to the retention of immunoglobulin G (IgG) subclasses, specific antibodies, and removal of IgM using standardized procedures. The IAC step reduced isoagglutinins in IVIG by two to three titer steps compared with lots produced without IAC. The median anti-A and anti-B titers with IAC were 1:8 and 1:4, respectively, when measured by the Ph. Eur. direct method, and 1:2 and <1, respectively, when measured by the Ph. Eur. indirect method. The isoagglutinin flow cytometry assay showed an 87-90 % reduction in isoagglutinins in post-IAC versus pre-IAC fractions. IAC alone reduced anti-A and anti-B of the IgMs isotype by 92.5-97.8 % and 95.4-99.2 %, respectively. Other product quality characteristics were similar with and without IAC. IAC is an effective method for reducing isoagglutinin levels in IVIG, and it is feasible on an industrial scale.

Citation

Simon Gerber, Annette Gaida, Nicole Spiegl, Sandra Wymann, Adriano Marques Antunes, Ibrahim El Menyawi, Brigitte Zurbriggen, Alphonse Hubsch, Martin Imboden. Reduction of Isoagglutinin in Intravenous Immunoglobulin (IVIG) Using Blood Group A- and B-Specific Immunoaffinity Chromatography: Industry-Scale Assessment. BioDrugs : clinical immunotherapeutics, biopharmaceuticals and gene therapy. 2016 Oct;30(5):441-451