Drug – bio-affecting and body treating compositions – Lymphokine
Patent
1983-10-21
1986-04-15
Wiseman, Thomas G.
Drug, bio-affecting and body treating compositions
Lymphokine
260112B, 260112R, 514 2, 514 6, 424 88, A61K 3900, A61K 3700, A61K 3944, C07G 700
Patent
active
045827036
DESCRIPTION:
BRIEF SUMMARY
The present invention relates to medicaments comprising, in association, at least one immunotoxin and chloroquin.
In prior French patent applications, bearing particularly Nos. 78 27 838, 79 24 655, 81 07 596 and 81 21 836, there is described the preparation of so called conjugated anticancer products obtained by coupling, by covalent bonding, the A chain of ricin with antibodies or antibody fragments directed against an antigen borne by a cell to be destroyed. The products of this type are denoted in the present application under the generic name of immunotoxins.
As set forth in French Patent Application No. 78 27 838, the conjugate is 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:
this type of bond is the type which exists in the natural ricin molecule, and it can be expected to be particularly suitable for presenting the A chain in a conformation which facilitates its penetration into the cell, while at best retaining its fundamental biological property of inhibiting protein synthesis;
this type of bond is biochemically labile, which provides the A chain, coupled in this way, with the possibility of being liberated from its carrier protein in the contents of the cell;
the A chain of ricin possesses a single cysteine residue in its structure and hence only one 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
there are efficient methods which make it possible to produce such a 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 an
REFERENCES:
Houston et al., Cancer Res., vol. 41, pp. 3913-3917, Oct. 1981, "Cell-Specific Cytotoxicity Expressed by a Conjugate of Ricin and Murine Monoclonal Antibody Directed Against Thy 1.1 Antigen.
Ramakrishnan et al., Science, vol. 223, pp. 58-60, Jan. 6, 1984 "Inhibition of Human Acute Lymphoblastia Leukemia Cells by Immunotoxins: Potentiation by Chloroquine".
Leppla et al., J. Biol. Chem., vol. 255(6), Mar. 25, 1980, pp. 2247-2250, "Inhibition of Diphtheria Toxin Degradation and Cytotoxic Action by Chloroquine".
Schneider et al., Eur. J. Biochem., vol. 118(1), pp. 33-38, 1981, "Effect of Chloroquine and Methylamine on Endocytosis of Fluorescein-Labelled Control IgG and of Anti-Plasma Membrane . . . ".
Gilliland et al., J. Biol. Chem., vol. 256(24), Dec. 25, 1981, pp. 12731-12739, "Characterization and Hybrid Molecules Containing Binding Subunit of Ricin Toxin".
Gros Pierre
Jansen Franz
Sanofi
Teskin Robin Lyn
Wiseman Thomas G.
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