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

Abstract

BackgroundHemolysis, 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.ObjectivesOur 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.MethodsThe 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.ResultsThe 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.ConclusionsIAC is an effective method for reducing isoagglutinin levels in IVIG, and it is feasible on an industrial scale.

Hemolysis related to intravenous immunoglobulins is dependent on the presence of anti‐blood group A and B antibodies and individual susceptibility

“…The most promising tools for reducing the incidence of hemolysis appear to be measures to reduce isoagglutinins in IVIG products, such as specific immunoaffinity chromatography, which has now been instituted by CSL Behring and some other manufacturers. [39][40][41] Finally, in this study, 61% of patients reached the threshold PLT count required for a response according to the EMA guideline from 2010, 31 supporting the efficacy of Privigen in patients with ITP. It is worth mentioning that, although the response rate appears similar across blood groups, complete response occurred most frequently in patients with blood group A1.…”

“…The clinical significance is clearly influenced by additional, largely still poorly understood, factors. The most promising tools for reducing the incidence of hemolysis appear to be measures to reduce isoagglutinins in IVIG products, such as specific immunoaffinity chromatography, which has now been instituted by CSL Behring and some other manufacturers …”

Efficacy and safety of IVIG in CIDP: Combined data of the PRIMA and PATH studies

“…Hemolytic events were observed in both trials. The trials were undertaken before the implementation of an immunoaffinity chromatography step in the production process, which lowers isoagglutinin levels by 75% to 88%, and is expected to reduce the incidence of hemolytic events seen in future studies . The safety results from the combined analysis support that IgPro10 is a well‐tolerated treatment option when administered as induction and maintenance infusions to subjects with CIDP.…”

Impact of screening and exclusion of high anti‐A titer donors on the risk of hemolytic anemia with intravenous immunoglobulin treatment: A hospital‐based cohort study in the US

“…To reduce the isoagglutinin titers and the risk of hemolytic anemia with Privigen, a two-step approach was implemented: exclusion of donors with high anti-A titer donors introduced in mid-2013, 4 followed by an immunoaffinity chromatography step which started in Oct-2015. 5 We conducted a study to describe the risk of hemolytic anemia before and after the first step of exclusion of high anti-A titers donors from pooled plasma in the manufacturing of the IVIG Privigen. The primary outcome was hemolytic anemia within 30 days of IVIG administration assessed from manual review of patient summaries by a hematologist (TLS) for the assessment of all potential hemolytic anemia events, the date of hemolytic anemia and the indication for IVIG use.…”

“…Vaso-occlusive crisis (VOC) is the hallmark complication of sickle cell disease (SCD), and the majority of SCD-related healthcare costs in the United States, estimated at $2.4 billion annually, is attributed to frequent emergency department (ED) visits and hospitalizations due to recurrent VOC. 1-3 A day hospital (DH) dedicated to manage uncomplicated VOC has been shown to reduce admission rates, decrease inpatient length of stay (LOS), and save health care costs 4,5. The major-ity of DH programs have hours of operation from 9 am to 5 pm, and programs with extended hours beyond this are limited by a lack of sufficient resources.…”