Evaluation of the presence of RF-like activities in immunoglobulin preparations for intravenous use. I. IgG anti-IgE in intravenous Ig.

We have studied the IgG anti-IgE antibody content of 8 IgG preparations for intravenous administration that we use in our Day Hospital as replacement therapy for patients with hypogammaglobulinemia. In all preparations we found the presence of both IgE and IgG anti-IgE as monomers and oligomers after fractionation with ultracentrifugation on sucrose gradient. This RF-like activity seem to be an essential constituent of low m.w. aggregates, disappearing at acid pH. We suggest that its presence could be responsible for the enrichment of IgE in Ig preparations for therapeutic use and perhaps for immediate and long-term adverse reactions.

Evaluation of the presence of RF-like activities in immunoglobulin preparations for intravenous use. II. IgG and IgA anti-IgG in intravenous Ig.

IgG- and IgA-rheumatoid factor like activities have been found in 4 out of 8 i.v. Ig preparations and in 1 i.m. Ig studied as control. In 2 i.v. Igs as well as in the 1 i.m., these RF-like activities were both present. These RF-like activities seem to be essential constituents of low m.w. aggregates, disappearing at acid pH. Their presence could perhaps be responsible for the enrichment of IgA in Ig preparations for therapeutic use and theoretically for the side-effects occurring "in vivo" after injection.

Evaluating the quality of immunoglobulin G preparations for intravenous therapy.

The major function of immunoglobulins is recognition of the antigen that has caused their formation with subsequent antigen binding and removal through antigen nonspecific recognition systems of the body. Such clearance for detrimental antigens depends on a complex system of now clearly characterized single features of the immunoglobulin molecule, such as antigen-binding capacity, viral neutralization, complement activation, fixation to receptors on the reticuloendothelial system, and maintenance of an optimal half-life in circulation before antigen removal. When gamma-globulins are used therapeutically, the producer must choose a purification procedure that aims at fully maintaining these features. In fact, isolation of any protein from its natural plasma protein environment may induce subtle losses of function that do not appear when such variables as molecular weight or subunit size are applied as the only quality criteria.

A rapid radioassay for human IgG produced in lymphocyte in vitro culture systems.

Protein A bearing Staphylococcus aureus was used to develop a solid-phase radioassay for IgG immunoglobulins. The assay was specifically optimised for use with in vitro human lymphocyte culture work. Compared with a solid-phase radioimmunoassay for IgG produced in lymphocyte culture, this assay had similar performance profile and the advantages of rapidly and technical ease.

Preparation of a stable intravenous gamma-globulin: process design and scale-up.

Intravenous gamma-globulin has been prepared on a pilot scale by the process of reduction with dithiothreitol and alkylation with iodoacetamide. The spent reagents are removed by diafiltration followed by ultrafiltration. The product is stabilized with maltose to minimize precipitation. Process design concepts as well as product characteristics are discussed.

[Immunologic properties, aggregate content and half-life of various human i.v. gamma globulin preparations]. / Immunologische Eigenschaften, Aggregatgehalt und Halbwertszeit verschiedener i.v. Human-Gamma-Globulinpräparate.

Anticomplementary activity, aggregate content, and elimination of i.v. human gamma globulin (HGG). During storage of HGG globulin aggregate formation increases leading to anticomplementary activity. Seventeen patients suffering from postoperative sepsis showed significantly faster elimination rates of HGG than 6 healthy controls, while there was no difference in albumin elimination.

[Effect of gamma globulin on reactivity of the organism. V. Types of biological activity of gamma globulin preparations]. / Vliianie gamma-globulina na reaktivnost' organizma. Soobshchenie V. Izuchenie nekotorykh vidov biologicheskoi aktivnosti preparatov gamma-globulina

Biological activity of 110 series of commercial gamma-globulin preparations was studied; they were found to contain placental antigens, group-specific blood substances, gonadotropic hormones and antibodies to them. Placental antigens were found in 12% of placental and abortive gamma-globulin batches in titres of 1 : 2--1 : 16; no placental protein was revealed in donor gamma-globulin. There were group-specific blood substances in all the batches of placental and abortive gamma-globulin studied (in titres of 1 : 138--A, 1 : 112 B in the placental gamma-globulin and in titres of 1 : 48.9--A, 1 : 32--B in the abortive gamma-globulin). In the preparations from the venous blood group-specific substances were either absent or present in lowe titres only (1 : 2). The value of gonadotropic hormones in the placental gamma-globulin batches constituted 873+/-157, and in the abortive--991.4+/-147 IU/l; no gonadotropins were revealed in donor gamma-globulin. The mean titres of antibodies to gonadotropin hormone in the gamma-globulin preparations made of placental blood constituted 1 : 236+/-32, of abortive--1 : 131+/-16.6, and of the venous blood--1 : 46+/-24.7. The presence of biologically-active substances in the gamma-globulin preparations pointed to the necessity of increased requirement of their quality; additional requirements to its standardization proved to be also necessary.

Clinical tolerance and catabolism of plasmin-treated gamma-globulin for intravenous application.

Plasmin-treated gamma-globulin of placental origin was tested in clinical and laboratory studies and found to be suitable for intravenous use both for prophylactic and therapeutic purposes. Plasmin treatment of gamma-globulin (IgG) results in proteolytic cleavage of 60-70% of the molecules into Fab and Fc fragments whereas 30-40% of the molecules are plasmin resistant. The antibody spectrum of plasmin-treated gamma-globulin is similar to that of standard gamma-globulin. Catabolic properties of the plasmin-resistant portion of this preparation and of standard gamma-globulin are identical. Plasmin-treated gamma-globulin has no anticomplementary activity and its intravenous administration is well tolerated even by highly sensitive immunodeficient patients.