title: L-Proline reduces IgG dimer content and enhances the stability of intravenous immunoglobulin (IVIG) solutions.
abstract: Liquid intravenous immunoglobulin (IVIG) products offer improved convenience in preparation but often lack sufficient stability to allow room temperature storage. Furthermore, clinical tolerability may be affected due to formation of idiotype/anti-idiotype IgG dimers and/or aggregates. Here we report on the development of a 10% IVIG formulation with optimized stability achieved by the use of l-proline. The stability of concentrated liquid IVIG was strongly pH dependent. Aggregate formation, yellowish discoloration of the solution and loss of anti-hepatitis B surface antigen (HBs) antibody activity was minimal at intermediate pH (pH 4.8-5.3). Fragmentation of IgG was highest at low pH (pH 4.1). Idiotype/anti-idiotype IgG dimer formation was highest at neutral pH and was reduced with decreasing pH. The presence of L-proline further improved stability by inhibiting protein aggregation, reducing loss of anti-HBs antibody activity and decreasing coloring, particularly compared with glycine formulations. The IgG dimer content was up to 30% lower in solutions containing L-proline compared with those containing glycine or other stabilizers. In conclusion, a weakly acidic pH of approximately 5 and L-proline as stabilizer are optimal conditions for long-term stability of a liquid IVIG. L-proline, an amphiphilic, naturally occurring amino acid, is superior to glycine in restricting IgG dimer formation.
authors.affiliation: CSL Behring AG, Wankdorfstrasse 10, CH-3000 Bern 22, Switzerland. reinhard.bolli@cslbehring.com
authors.forename: Reinhard
authors.initials: R
authors.lastname: Bolli
authors.forename: Karin
authors.initials: K
authors.lastname: Woodtli
authors.forename: Michelle
authors.initials: M
authors.lastname: Bärtschi
authors.forename: Liane
authors.initials: L
authors.lastname: Höfferer
authors.forename: Peter
authors.initials: P
authors.lastname: Lerch
mesh_terms: D000906:Antibodies / Q000032:analysis; D011232:Chemical Precipitation / Q000187:drug effects; D002626:Chemistry, Pharmaceutical / Q000379:methods; D004339:Drug Compounding; D004353:Drug Evaluation, Preclinical; D004355:Drug Stability; D005079:Excipients / Q000494:pharmacology; D005998:Glycine / Q000494:pharmacology; D006514:Hepatitis B Surface Antigens / Q000276:immunology; D006801:Humans; D006863:Hydrogen-Ion Concentration; D007074:Immunoglobulin G / Q000187:drug effects* / Q000378:metabolism; D016756:Immunoglobulins, Intravenous; D010446:Peptide Fragments / Q000737:chemistry / Q000187:drug effects; D011392:Proline / Q000494:pharmacology*; D055503:Protein Multimerization / Q000187:drug effects*; D012996:Solutions
chemical_list: D000906:Antibodies; D005079:Excipients; D006514:Hepatitis B Surface Antigens; D007074:Immunoglobulin G; D016756:Immunoglobulins, Intravenous; D010446:Peptide Fragments; D012996:Solutions; D011392:Proline; D005998:Glycine