Drug – bio-affecting and body treating compositions – Lymphokine
Patent
1983-11-09
1986-09-30
Kight, John
Drug, bio-affecting and body treating compositions
Lymphokine
530390, A61K 3900
Patent
active
046146504
DESCRIPTION:
BRIEF SUMMARY
The present invention relates to cytotoxic drugs comprising at least one immunotoxin and one amine of formula R.sub.1 NHR.sub.2 in which R.sub.1 represents hydrogen or a lower alkyl group (having 1 to 4 carbon atoms), R.sub.2 represents a lower alkyl group or the group R.sub.1 NHR.sub.2 represents 1-amino adamantane.
Earlier French Patent Applications, particularly Nos. 78 27838, 79 24655, 81 07596 and 81 21836, describe the preparation of so-called conjugate anti-cancerous products obtained by coupling, by covalent bond, of the chain A of ricin with antibodies or fragments of antibodies directed against an antigen carried by a cell to be destroyed. The products of this type are designated in the present Application under the generic name of immunotoxins.
Chain A of ricin/antibody conjugates are prepared by associating by means of a covalent bond of the disulphide type, on the one hand, an immunoglobulin which is specific for a given antigen, or any fragment of this molecule which possesses the capacity of specific recognition with respect to the antigen, with, on the other hand, the A chain of ricin. The choice of a disulphide bond between the A chain and the immunoglobulin is based on the following arguments: and it can be expected to be particularly suitable for presenting the A chain in a conformation which facilitates its penetration into the cell, whilst at best retaining its fundamental biological property of inhibiting protein synthesis, coupled in this way, with the possibility of being liberated, from its carrier protein, in the contents of the cell, and hence only the SH group capable of creating a disulphide bond. Consequently, the conjugates formed by involving this SH group in a disulphide bridge will be chemically well defined and will in no way modify the structure of the A chain, thus ensuring the integral retention of its biological activity, and disulphide bond under conditions which are sufficiently mild to ensure the integrity of the biological properties of the protein constituents of the conjugates formed.
In order to produce such conjugates, the proteins to be coupled must each carry at least one sulphur atom which is naturally capable, or is artificially rendered capable, of creating the desired disulphide bond, whether these sulphur atoms already exist in the proteins or have been chemically introduced into these proteins. As indicated above, the A chain of ricin naturally possesses only one sulphur atom permitting the desired coupling. This is the sulphur atom in the thiol group of the single cysteine residue incorporated in the A chain. As regards the immunoglobulin or its fragments, several cases must be considered:
(1) In the case of an entire immunoglobulin, neither a free thiol group nor other sulphur atoms capable of being used for the coupling exist naturally in these proteins. It will therefore be necessary, in this case, to introduce one or more sulphur atoms into the immunoglobulin molecule artificially so that: impaired, and the disulphide bond to be established with one or more molecules of the A chain of ricin.
(2) In the case of a Fab fragment, the situation is absolutely identical to that described above.
(3) If a fragment of the Fab' type is employed, it is possible to use the sulphur atom present in the free thiol group to carry out the coupling to the A chain. However, it is also possible to use the artificial introduction of one or more sulphur atoms; in this case, it is necessary to block the free thiol group in a stable manner beforehand, for example by alkylation.
(4) Finally, if it is desired to couple a F(ab').sub.2 fragment of immunoglobulin, it is necessary, as in the case of the whole immunoglobulin, to introduce one or more sulphur-containing groups into F(ab').sub.2 artificially.
In all the cases in which one or more sulphur-containing radicals are introduced into the immunoglobulin or its fragments, it is necessary to avoid any substitution in the site for recognition of the antigen or in its immediate environment, which substitution could disturb th
REFERENCES:
patent: 4485093 (1984-11-01), Runje
patent: 4489710 (1984-12-01), Spitter
patent: 4490362 (1984-10-01), Shionoya et al.
Biological Abstracts vol. 73, 1982 Schneider et al, Effect G . . . Fibroblast.
Biological Abstracts, vol. 73, 1982 (Philadelphia, Pa.) Y. J. Schneider et al.: "Effect of Chloroquine and Methylamine on Endocytosis of Fluorescein-Labelled Control Immunoglobulin G and of Anti-Plasma Membrane Immunoglobulin G by Cultured Fibroblasts", voir resume 78102, Eur. J. Biochem. 1981, 118(1), 33-38.
Gros Pierre
Jansen Franz
Draper Garnette D.
Kight John
Sanofi
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