Traces of pFc’ in IVIG interact with human IgG Fc domains and counteract aggregation

Dynamics of Inter-heavy Chain Interactions in Human Immunoglobulin G (IgG) Subclasses Studied by Kinetic Fab Arm Exchange

“…Thus, whether or not stabilization of IgG2 or IgG3 with a M397V mutation would affect the aggregation propensity in a positive or negative manner remains to be determined. Interestingly, heavy chain dissociation appears to be a critical step in some forms of aggregation, and the addition of IgG2 CH3 dimers was found to diminish acid-induced aggregation of a therapeutic immunoglobulin formulation, probably by acting as a scaffold (15). …”

“…Whereas a reasonable estimate of the strength of the CH3 interactions for IgG4 has been obtained in several studies ( K d between 2 and 4 n m ) (3–5), such data are lacking for the other subclasses. Indirect evidence suggests that the interactions between heavy chains may be weaker in the case of IgG2 compared with IgG1 (13–15), suggesting that subclass-specific determinants other than Lys/Arg-409 can affect the CH3 dimerization strength.…”

Interactions between immunoglobulin G molecules

“…Increasing IgG stability by site-directed mutagenesis has significant practical benefits and could improve the quality of these most important classes of pharmaceutical products. Using the pFc and C H 3 fragments as inhibitors of IgG aggregation constitutes another viable approach, as both fragments are able to block the interaction sites on the Fc portion [29]. Further experiments are needed to prove whether these methods can effectively stabilize immune globulin preparations especially during long-term storage.…”

“…This small fragment is nearly equal to the C H 3 domain. The pFc fragment and C H 3 can bind to the Fc portion and block contact sites on this part of IgG molecules that is responsible for the IgG aggregation [29]. There is a significant variation in the inhibition of Fc binding between fragments of IgG subclasses.…”

“…By Fab-Fab IgG dimers in immune globulins [4,5,41,42] IgG at high concentrations [8,9,13,14] By Fc-Fc In immune precipitates [16][17][18] IgG4 interactions [25,27] pFc -Fc interaction [29] In Fc crystals [32] could be found. In IG pools collected from 5000 donors, about 12% dimers were found; in pools from 10,000 donors 25% dimers were found, and in pools from 100,000 donors up to 40% dimers were found.…”