WO1983004026A1 - Cytotoxic agent - Google Patents

Cytotoxic agent Download PDF

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Publication number
WO1983004026A1
WO1983004026A1 PCT/CH1983/000061 CH8300061W WO8304026A1 WO 1983004026 A1 WO1983004026 A1 WO 1983004026A1 CH 8300061 W CH8300061 W CH 8300061W WO 8304026 A1 WO8304026 A1 WO 8304026A1
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Prior art keywords
protein
cytotoxic agent
staphylococcus
fragment
castor
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PCT/CH1983/000061
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French (fr)
Inventor
Patrice Boquet
Original Assignee
Genefusion S.A.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
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Publication date
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Publication of WO1983004026A1 publication Critical patent/WO1983004026A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/195—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from bacteria
    • C07K14/305—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from bacteria from Micrococcaceae (F)
    • C07K14/31—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from bacteria from Micrococcaceae (F) from Staphylococcus (G)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/62—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being a protein, peptide or polyamino acid
    • A61K47/64—Drug-peptide, drug-protein or drug-polyamino acid conjugates, i.e. the modifying agent being a peptide, protein or polyamino acid which is covalently bonded or complexed to a therapeutically active agent
    • A61K47/6415—Toxins or lectins, e.g. clostridial toxins or Pseudomonas exotoxins
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/415—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from plants
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K19/00—Hybrid peptides, i.e. peptides covalently bound to nucleic acids, or non-covalently bound protein-protein complexes
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides

Definitions

  • the present invention relates to a cytotoxic agent capable of entering cells by endocytosis.
  • a cytotoxic agent capable of entering cells by endocytosis.
  • immunological, embryological and cancer research it is known to use agents capable of selectively killing cells.
  • the present invention aims at a cytotoxic agent capable of penetrating endocytosis into cells, in order to kill the latter, in particular cancer cells.
  • the cytotoxic agent according to the invention is characterized in that it comprises the protein Has staphylococcus chemically coupled to at least one material having toxic activity on cells.
  • this staphylococcal protein A is coupled by a disulfide bond -SS- to the fragment A of the castor toxin.
  • Castor A fragment is a protein with enzymatic activity which, when introduced into the cytoplasm of a cell, inhibits protein synthesis, resulting in the death of that cell.
  • this fragment A of the castor toxin cannot by itself enter the cell. To do this, it must be associated with another protein, which has the property of attaching to the surface of cells. When castor A is thus attached to the surface of a cell, it can enter the latter by endocytosis.
  • Staphylococcus protein A is a molecule that specifically binds to the Fc fragments of immunoglobulins. (Sorolia et al., TIBS (1982) 74 et seq.) The interaction between Staphylococcus protein A and the immunoglobulins gives rise to a very stable complex.
  • this agent it is possible to first obtain this agent by fixing a mercapto group on protein A of Staphylococcus which does not have it in its natural state.
  • This reaction can be easily carried out using the SPDP reagent, namely N-succinimidyl -3- (2-pyridyldithio) -propionate (Carlson et al., Pharmacia
  • the unreacted starting materials can be separated from the desired final product by chromatography, in particular in the liquid phase, or by molecular sieving, or by any other method known in this field.
  • the castor toxin fragment A is prepared according to the method described by Olsnes et al., Biochemistry (1973) 12,
  • Staplrylococcus protein A is prepared and purified according to the method described by Sjoquest et al., Eur. J. Biochem. (1972)
  • a cytotoxic agent corresponding to the formula (protein A of staphylococcus) -SS- (fragment A of castor toxin).
  • This agent can be used in the following manner: Cells in culture, p. e. a mixed population of T and B lymphocytes are brought into contact with an antibody for a certain time, p. e. with anti-thymocyte which i attaches only to T lymphocytes of a certain species of cells. The cells are then washed to remove
  • the cytotoxic agent described above and obtained according to the preceding example is now added. This agent binds to the Fc part of anti-T antibodies present on the surface of T lymphocytes.
  • the complex thus formed will enter the T lymphocyte and the A fragment of the castor toxin will inhibit the synthesis of proteins, causing the death of this cell.
  • fragment A from staphylococcus was combined with fragment A from castor toxin. It is obvious that this fragment could be replaced by any material showing toxicity on a cell, eg by fragment A of the diphtheria toxin, of the toxin of Pseudomonas aeruginosa, of abrin, of modexin or of gelonin , or by a toxic synthetic compound.

Abstract

The cytotoxic agent is capable of penetrating a cell by endocytosis. To obtain such result, the protein A of staphylococcus is chemically coupled to at least one material having a toxic activity on cells. Such material is for example the fragment A of the ricin toxin.

Description

Agent cytotoxique Cytotoxic agent
La présente invention concerne un agent cytotoxique capable de pénétrer dans des cellules par endocytose. Dans la recherche immunologique, embryologique et cancéro logique, il est connu d'utiliser des agents capable de tuer sélectivement des cellules. Ansi par exemple, en immunologie cellulaire, pour étudier l'influence d'un type de lymphocyte sur la production d'anticorps, on supprime ce type de lympho cyte pour déterminer son rôle.The present invention relates to a cytotoxic agent capable of entering cells by endocytosis. In immunological, embryological and cancer research, it is known to use agents capable of selectively killing cells. Ansi for example, in cellular immunology, to study the influence of a type of lymphocyte on the production of antibodies, one suppresses this type of lymphocyte to determine its role.
D'autre part, pour sélectionner des cellules, il est connu de coupler un anticorps reconnaissant la surface d'un type de cellule (p.e. thymocytes avec des anticorps anti-thymocytes) avec une toxine microbienne ou végétale (toxinediphtérique, ricine ou abrine). Ce sont les immuno-toxines connues. Fondée sur cet état de la technique, la présente invention a pour but un agent cytotoxique capable de pénétrer par endocytose dans des cellules, afin de tuer ces dernières, notamment des cellules de cancer. L'agent cytotoxique selon l'invention est caractérisé par le fait qu'il comprend la protéine A du staphylocoque coupléechimiquement à au moins une matière possédant une activité toxique sur des cellules. En particulier, cette protéine A du staphylocoque est couplée par une liaison disulfure -S-S- au fragment A de la toxine de ricin. Le fragment A de ricin est une protéine douée d'activité enzymatique qui, lorsqu'elle est introduite dans le cytoplasme d'une cellule, inhibe la synthèse des protéines, ce qui abou tit à la mort de cette cellule. (Olsnes et Pihl, FEBS Letters (1972) 20, 327 et suiv.)On the other hand, to select cells, it is known to couple an antibody recognizing the surface of a cell type (eg thymocytes with anti-thymocyte antibodies) with a microbial or plant toxin (toxinediphtheria, ricin or abrin). These are the known immunotoxins. Based on this state of the art, the present invention aims at a cytotoxic agent capable of penetrating endocytosis into cells, in order to kill the latter, in particular cancer cells. The cytotoxic agent according to the invention is characterized in that it comprises the protein Has staphylococcus chemically coupled to at least one material having toxic activity on cells. In particular, this staphylococcal protein A is coupled by a disulfide bond -SS- to the fragment A of the castor toxin. Castor A fragment is a protein with enzymatic activity which, when introduced into the cytoplasm of a cell, inhibits protein synthesis, resulting in the death of that cell. (Olsnes and Pihl, FEBS Letters (1972) 20, 327 et seq.)
Toutefois, ce fragment A de la toxine de ricin ne peut par lui-même pénétrer dans la cellule. Il ëtoit pour cela être associé à une autre protéine qui, elle, a la propriété de se fixer à la surface des cellules. Lorsque le ricin A est ainsi fixé à la surface d'une cellule, il peut pénétrer dans cette dernière par endocytose.However, this fragment A of the castor toxin cannot by itself enter the cell. To do this, it must be associated with another protein, which has the property of attaching to the surface of cells. When castor A is thus attached to the surface of a cell, it can enter the latter by endocytosis.
La protéine A du staphylocoque est une molécule qui se fixe spécifiquement sur les fragments Fc des immunoglobulines. (Sorolia et al., TIBS (1982) 74 et suiv.) L'interaction entre protéine A du staphylocoque et les immunoglobulines donne lieu à un complexe très stable. Ainsi, selon un exemple préféré de l'invention, il est donc intéressant de coupler le fragment A de la toxine de ricin avec la protéine A du staphylocoque, par une liaison disulfure, afin d'obtenir un agent cytotoxique, De cette manière, on peut coupler très facilement n'importe quel type d'immunoglobuline avec ledit fragment A. Selon une forme d'exécution préférée de l'invention, on peut obtenir cet agent tout d'abord en fixant un groupe mercapto sur la protéine A du Staphylocoque qui en est dépourvu à l'état naturel. Cette réaction peut se faire facilement au moyen du réactif SPDP, soit le N-succinimidyl -3-(2-pyridyldithio)-propionate (Carlson et al., PharmaciaStaphylococcus protein A is a molecule that specifically binds to the Fc fragments of immunoglobulins. (Sorolia et al., TIBS (1982) 74 et seq.) The interaction between Staphylococcus protein A and the immunoglobulins gives rise to a very stable complex. Thus, according to a preferred example of the invention, it is therefore advantageous to couple the fragment A of castor toxin with protein A of staphylococcus, by a disulfide bond, in order to obtain a cytotoxic agent. In this way, we can very easily couple any type of immunoglobulin with said fragment A. According to a preferred embodiment of the invention, it is possible to first obtain this agent by fixing a mercapto group on protein A of Staphylococcus which does not have it in its natural state. This reaction can be easily carried out using the SPDP reagent, namely N-succinimidyl -3- (2-pyridyldithio) -propionate (Carlson et al., Pharmacia
Sweden (1978) 173 723 et suiv.).Sweden (1978) 173 723 et seq.).
Le fragment 2 du Ricin possédant un groupe mercapto, il suffit donc de mélanger la protéine A du Staphylocoque traitée par leSince the castor 2 fragment has a mercapto group, it suffices to mix the Staphylococcus protein A treated with
SPDP avec le Ricin A, afin de former une liaison disulfure entre les deux groupes mercapto.SPDP with Castor A, in order to form a disulfide bond between the two mercapto groups.
Les matières de départ n'ayant pas réagi peuvent être séparées du produit final désiré par chromatographie, notamment en phase liquide, ou par tamisage molculaire, ou encore par toute autre méthode connue dans ce domaine.The unreacted starting materials can be separated from the desired final product by chromatography, in particular in the liquid phase, or by molecular sieving, or by any other method known in this field.
ExempleExample
Le fragment A de la toxine de ricin est préparé selon le procédé décrit par Olsnes et al., Biochemistry (1973) 12,The castor toxin fragment A is prepared according to the method described by Olsnes et al., Biochemistry (1973) 12,
3121 et suiv.3121 et seq.
La protéine A du staplrylocoque est préparée et purifiée selon la méthode décrite par Sjoquest et al., Eur. J. Biochem. (1972)Staplrylococcus protein A is prepared and purified according to the method described by Sjoquest et al., Eur. J. Biochem. (1972)
29, 572 et suiv. Au moyen du réactif SPDP, un grcupement Mercapto est fixé sur la protéine A du Staphylocoque. L'excès de réactif SPDP (non fixé sur la protéine A du Staphylocoque) est éliminé par tamisage moléculaire. Le fragment A du Ricin sous forme réduite (S H) est mélangé à la protéine A du Staphylocoque traité par le SPDP, de préférence en milieu aqueux. La liaison disulfure -S-S- entre les deux matières de départ se forme ainsi facilement. Les matières de départ n'ayant pas réagi sont séparés du produit désiré par chromatographie d'exclusion sur Sephadex G75 (marque déposée) par exemple, en milieu liquide.29, 572 et seq. By means of the reagent SPDP, a Mercapto group is fixed on protein A of the Staphylococcus. The excess of SPDP reagent (not attached to protein A of the Staphylococcus) is eliminated by molecular sieving. The castor A fragment in reduced form (SH) is mixed with protein A of the Staphylococcus treated with SPDP, preferably in an aqueous medium. The disulfide bond -SS- between the two starting materials is thus easily formed. The unreacted starting materials are separated from the desired product by exclusion chromatography on Sephadex G75 (registered trademark) for example, in a liquid medium.
Ainsi , on obtient un agent cytotoxique répondant à la formule (protéine A du staphylocoque )-S-S- (fragment A de la toxine de ricin) . Cet agent peut être utilisé de la manière suivante : Des cellules en culture , p. e . une population mixte de lympho cytes T et B, sont mises en contact avec un anticorps pendant un certain temps , p. e . avec l ' anti-thymocyte
Figure imgf000006_0001
qu i se fixe uniquement sur les lymphocytes T d 'une certaine espèce de cellules . Les cellules sont ensuite lavées pour éli Thus, one obtains a cytotoxic agent corresponding to the formula (protein A of staphylococcus) -SS- (fragment A of castor toxin). This agent can be used in the following manner: Cells in culture, p. e. a mixed population of T and B lymphocytes are brought into contact with an antibody for a certain time, p. e. with anti-thymocyte
Figure imgf000006_0001
which i attaches only to T lymphocytes of a certain species of cells. The cells are then washed to remove
miner l'excès d'anticorps qui ne se sont pas fixés sur ces lymphocytes T. On ajoute maintenat fagent cytotoxique décrit ci-dessus et obtenu selon l'exemple précédant. Cet agent se fixe sur la partie Fc des anticorps anti-T présents à la surface des lymphocytes T.mining the excess of antibodies which have not fixed on these T lymphocytes. The cytotoxic agent described above and obtained according to the preceding example is now added. This agent binds to the Fc part of anti-T antibodies present on the surface of T lymphocytes.
Par endocytose, le complexe ainsi formé va pénétrer dans le lymphocyte T et le fragment A de la toxine de ricin va inhiber lpvsynthèse des protéines, provoquant la mort de cette cellule.By endocytosis, the complex thus formed will enter the T lymphocyte and the A fragment of the castor toxin will inhibit the synthesis of proteins, causing the death of this cell.
Dans l'exemple décrit, on a combiné la protéine A du staphylocoque avec le fragment A de la toxine de ricin. Il est évident que l'on pourrait remplacer ce fragment par toute matière montrant une toxicité sur une cellule, p.e. par le fragment A de la toxine diphthérique, de la toxine de Pseudomonas aeruginosa, de l'abrine, de la modexine ou de la gélonine, ou encore par un composé synthétique toxique. In the example described, protein A from staphylococcus was combined with fragment A from castor toxin. It is obvious that this fragment could be replaced by any material showing toxicity on a cell, eg by fragment A of the diphtheria toxin, of the toxin of Pseudomonas aeruginosa, of abrin, of modexin or of gelonin , or by a toxic synthetic compound.

Claims

RevendicationsClaims
1) Agent cytotoxique caractérisé par le fait qu'il comprend la protéine A du Staphylocoque couplée chimiquement à au moins une matière possédant une activité toxique sur des cellules.1) Cytotoxic agent characterized by the fact that it comprises Staphylococcus protein A chemically coupled to at least one material having a toxic activity on cells.
2) Agent cytotoxique selon la revendication 1, caractérisé par le fait que la protéine A du Staphylocoque est couplée par une liaison disulfure -S-S au fragment A de la toxine de Ricin.2) Cytotoxic agent according to claim 1, characterized in that the protein A of Staphylococcus is coupled by a disulfide -S-S bond to fragment A of the castor toxin.
3) Procédé de fabrication de l'agent cytotoxique selon la revendication 2, caractérisé par le fait que l'on fait agir le réactif SPDP sur la protéine A du Staphylocoque, de façon à créer un groupement Mercapto (S H) sur la protéine A (qui en est dépourvue à l'état naturel).3) Process for manufacturing the cytotoxic agent according to claim 2, characterized in that the SPDP reagent is made to act on protein A of the Staphylococcus, so as to create a Mercapto group (SH) on protein A ( which is devoid of it in its natural state).
4) Procédé de fabrication de l'agent cytotoxique selon la revendication 3, caractérisé par le fait que l'on fait réagir le groupement Mercapto créé par le réactif SPDP sur la protéine A du Staphylocoque avec le groupement Mercapto du Fragment A de la toxine du Ricin, afin de former une liaison disulfure entre les deux groupes Mercapto.4) A method of manufacturing the cytotoxic agent according to claim 3, characterized in that the Mercapto group created by the reagent SPDP is reacted on protein A of Staphylococcus with the Mercapto group of Fragment A of the toxin of Castor oil, to form a disulfide bond between the two Mercapto groups.
5) Procédé selon la revendication 4, caractérisé par le fait que les produits de départ (Protéine A et Ricin A) n'ayant pas réagi sont séparés du produit final par chrornatographie en phase liquide, ou par tamisage moléculaire. 5) Method according to claim 4, characterized in that the starting products (Protein A and Castor A) which have not reacted are separated from the final product by chrornatography in liquid phase, or by molecular sieving.
PCT/CH1983/000061 1982-05-11 1983-05-10 Cytotoxic agent WO1983004026A1 (en)

Applications Claiming Priority (2)

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CH2910/82-2 1982-05-11
CH291082 1982-05-11

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1998034956A1 (en) * 1997-02-07 1998-08-13 Commissariat A L'energie Atomique Non-covalent complex comprising at least an antibody and element binding with immunoglobulins associated with an active substance, method of preparing and applications

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2437213A1 (en) * 1978-09-28 1980-04-25 Cm Ind CYTOTOXIC PRODUCTS FORMED BY COVALENT BINDING OF THE CHAIN TO RICIN WITH AN ANTIBODY AND THEIR PREPARATION METHOD
EP0023401A2 (en) * 1979-07-20 1981-02-04 Teijin Limited Antitumor protein hybrid and process for the preparation thereof
EP0044167A2 (en) * 1980-07-14 1982-01-20 The Regents Of The University Of California Antibody targeted cytotoxic agent

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2437213A1 (en) * 1978-09-28 1980-04-25 Cm Ind CYTOTOXIC PRODUCTS FORMED BY COVALENT BINDING OF THE CHAIN TO RICIN WITH AN ANTIBODY AND THEIR PREPARATION METHOD
EP0023401A2 (en) * 1979-07-20 1981-02-04 Teijin Limited Antitumor protein hybrid and process for the preparation thereof
EP0044167A2 (en) * 1980-07-14 1982-01-20 The Regents Of The University Of California Antibody targeted cytotoxic agent

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1998034956A1 (en) * 1997-02-07 1998-08-13 Commissariat A L'energie Atomique Non-covalent complex comprising at least an antibody and element binding with immunoglobulins associated with an active substance, method of preparing and applications
FR2759296A1 (en) * 1997-02-07 1998-08-14 Commissariat Energie Atomique NON-COVALENT COMPLEX COMPRISING AT LEAST ONE ANTIBODY AND ONE IMMUNOGLOBULIN-BINDING ELEMENT ASSOCIATED WITH AN ACTIVE SUBSTANCE, METHOD FOR PREPARING IT AND ITS APPLICATIONS

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