Chemistry of carbon compounds – Miscellaneous organic carbon compounds – C-metal
Patent
1981-01-23
1982-08-31
Schain, Howard E.
Chemistry of carbon compounds
Miscellaneous organic carbon compounds
C-metal
424 85, A61K 39395, A61K 3944, C07G 700
Patent
active
043471790
DESCRIPTION:
BRIEF SUMMARY
TECHNICAL FIELD
The present invention relates to a process for the preparation of immunogammaglobulin. More particularly, the present invention relates to an improved process for the preparation of S-sulfonated immunogammaglobulin.
BACKGROUND ART
Immunoglobulin includes antibodies against a variety of diseases and is used for the prophylaxis and therapy of these diseases, however, the use of immunoglobulin preparation has been limited to intramuscular injection. Namely, when an immunoglobulin preparation is intravenously injected, the immunoglobulin binds with the complement to lower the serum complementary concentration and cause a side-effect called anticomplementary action, resulting in the observation of blood pressure drop, body temperature rise, disorder in circulatory system and others. Therefore, many studies have been made to attain the purpose of keeping immunoglobulin stable on intravenous administration.
The first method is to cut off the part that is thought to bind with the complement from human immunoglobulin by use of enzyme. For example, A. Nisonoff proposed to use pepsin as an enzyme [c.f. Science 132. 1770 (1970)] and another method using plasminogen in serum, cathepsin and others as an enzyme is described in the specification of Japanese Pat. No. 47-37529 (1972). However, these enzyme-treated immunoglobulins have defects that their half-life period is short and consequently the duration time of the efficacy is short as E. Merler and B. Jager showed in their articles of Vox Snag 13, 102 (1967) and Arch. Intora. Med. 119, 60 (1967) respectively.
The second method is to treat human immunoglobulin with a protein-acylating reagent. For example, Japanese Patent Laid-open 49-6119 (1974) described that the acylation of human immunoglobulin gave a modified immunoglobulin with reduced anticomplement activity-level. But the acylated immunoglobulin formed by this process has a danger of giving rise to antigenecity in human bodies and the administration in large amounts has been thought to be difficult.
The third method is to reduce the disulfide bonds in human immunoglobulin, followed by alkylation. For example, according to Japanese Patent Laid-open No. 48-103723 (1973), this method gave a modified immunoglobulin having the same apparent molecular weight as that of the unmodified immunoglobulin and a reduced anticomplement activity level. However, this method is a two-stepped process and the operations are considerably complicated, thus being industrially disadvantageous.
The fourth method is to S-sulfonate the interchain disulfide bonds in human immunoglobulin with tetrathionate ion and sulfite ion to give immunoglobulin derivatives suitably used for intravenous injection [c.f. Japanese Patent Laid-open Nos. 50-121421 (1975), 51-1630, 51-76418, and 51-112512 (1976)]. This method is the best in known ones. But, in this method unstable tetrathionate salt is used as an oxidant. Therefore, a large amount of the tetrathionate salt is required to promote the complete reaction, which oftentimes causes side-reactions and further produces the denaturation of the protein to inhibit the sufficient reduction in the anticomplement activity level as a defect to be improved. Further, the oxidation power of tetrathionate ion is relatively strong to have a possibility to break intrachain disulfide bonds as well as interchain disulfide bonds and sufficient caution is inconveniently required to control the reaction.
DISCLOSURE OF THE INVENTION
The present inventors focused their research of the improvement of such defects and have found that when trithionate ion, which has high stability and appropriate reactivity, and sulfite ion are together used as oxidants, interchain disulfide bonds in human immunoglobulin are cleaved and simultaneously the cleaved sulfur atoms are S-sulfonated (--S--SO.sub.3.sup.-) to prepare immunoglobulin derivatives that are suitably used for intravenous injection because of freeness of the above defects, thus attaining the present invention.
Namely, the present invention is a proce
REFERENCES:
patent: 4059571 (1977-11-01), Tomibe et al.
Chem. Abstracts, vol. 91, 1979, 145953b, Ono et al., effective date May 30, 1979.
Miura Shuzi
Ono Syoji
Yoshida Tsunemasa
Schain Howard E.
Teijin Limited
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