Process for the preparation of intra-venously administered gamma

Details Process for the preparation of intra-venously administered gamma Process for the preparation of intra-venously administered gamma

1987-01-23

1989-10-17

Rosen, Sam

Chemistry: molecular biology and microbiology

Process of utilizing an enzyme or micro-organism to destroy...

Treating animal or plant material or micro-organism

435 68, 530387, 530388, 530412, C07K 312

Patent

active

048747084

DESCRIPTION:

BRIEF SUMMARY
This is why there have already been developed different preparation processes seeking to suppress, or at least to limit this drawback.
A first process seeks to eliminate the aggregates and consists of carrying out a pepsin digestion of the gamma-globulin preparation in such a way as to provoke a rupture of the heavy chains near to the junction of the Fab and Fc fractions. See, for example, the patent FR-A-No. 2,433,342.
Another process, which had been perfected by the applicant, consists of treating a preparation of gamma-globulins with plasmin, in such a way as to provoke a moderated digestion conserving a large proportion (from 30 to 50%) of the gamma-globulins intact and giving the Fab and Fc fragments. This preparation is active and very well tolerated.
A drawback of these different processes which seek to reduce the anti-complement power present is that they require a more or less extensive digestion of the gamma-globulins. Also, the processes seek a compromise between the innocuousness and the activity of the preparation.
One may equally cite diverse preparation processes forming chemically modified gamma-globulins: alkylation, reduction, sulfonation.
Patent FR-A-No. 2,301,266 recommends not carrying out enzymatic treatment, notably with pepsin, of the gamma-globulins and to carry out, instead, a polyethylene-glycol fractionation.
Thus, there has been perfected a process for the preparation of gamma-globulins by polyethylene-glycol (PEG) fractionation which presents the advantage of preventing the formation of aggregates or of eliminating them, while conserving the globulins intact.
In addition, although at diverse degrees, the different preparations described above may present shock factors by activating of the kallikreinbradykinin system. These shock factors appear linked to a residual content of prekallikrein activator.
Another technique, which allows the obtaining of gamma-globulins of good quality, consists of carrying out a treatment at an acid pH, in the presence of small quantities of pepsin. See, for example, J. J. Walsh: Purification of normal immmunoglobin for intravenous use. DEVELOP. BIOL. STAND. 1974, 27, 31-6. However, there still remain aggregates and dimers at a relatively high level.
One has equally proposed, in patent application EP-A-O No. 120 835, to avoid using treatments with pepsin or plasmin, that these enzymes be rendered insoluable or not, to propose a digestion with pancreatic enzymes accompanied by a treatment with polyethylene-glycol at a relatively high concentration. However, this gamma-globulin is not balanced in sub-classes.
The present invention proposes to furnish preparations of gamma-globulins administratable intravenously, at the same time deprived of aggregates and of dimers, deprived of anti-complement power and deprived of kallikrein and of prekallikrein activator and with a profile of sub-classes comparable to that of normal Human Serum.
Another objective of the invention is to furnish such a process which, applied to preparations of gamma-globulins prepared by fractionation with low levels of PEG or analog substances, ameliorates these preparations in diminishing notably the anti-complement power, the content of kallikrein and of prekallikrein activator, as well as the residual PEG.
The invention has for object a process for the preparation of gamma-globulins administratable intravenously, characterized in that it includes a fractionation step with polyethylene-glycol (PEG) or similar substances and a moderated enzymatic treatment step, in which the pH is dependent on the nature of the enzyme used, this being added preferably in the form of traces, the treatment being conducted so as to avoid an appreciable proteolysis.
The enzyme used is chosen from the group formed by the pepsins, fibrinolysins (plasmin), and papains.
The starting material is a fraction of serum origin rich in gamma-globulins such as Cohn's Technique 6.9 fraction II, known to give hepatitis-free products, or a fraction of placental origin such as the fraction of Cohn's technique 6.9 as mo

REFERENCES:
patent: 4093606 (1978-06-01), Coval
patent: 4312949 (1982-01-01), Ahrens
Walsh--13th Int. Congress of IABS--Develop. Biol. Standard, vol. 27 (1974), pp. 31-36.
Walsh--Chem. Abst., vol. 81 (1974), pp. 149961u.
Favreau et al--Experientia, vol. 39 (1983), pp. 483-487.

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