Combination of necrosis-inducing substances with substances which are activated by necroses for the selective therapy of tumors and inflammatory disorders

• US 5,710,134 A
• Filed: 05/19/1995
• Issued: 01/20/1998
• Est. Priority Date: 05/20/1994
• Status: Expired due to Term

• Current Assignee: Behringwerke Aktiengesellschaft (Sanofi )
• Original Assignee: Behringwerke Aktiengesellschaft (Sanofi )
• Inventors: Bosslet, Klaus, Czech, Jorg, Hoffmann, Dieter
• Primary Examiner(s): Reamer, James H.
• Application Number:
  US08/446,211
• Time in Patent Office: 977 Days
• Field of Search: 514/34, 536/6.4
• US Class Current: 514/34
• CPC Class Codes: A61K 2300/00 Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• CPC Class Codes: A61K 31/00 Medicinal preparations containing organic active ingredients
• CPC Class Codes: A61K 39/395 Antibodies agglutinins A61K38/36 ; as drug carriers A61K47/50; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
• CPC Class Codes: A61P 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 35/00 Antineoplastic agents

Abstract

The invention relates to a combination of substances (component I) inducing necrosis in tumors or inflamed tissue with other nontoxic substances ("prodrugs", component II). The enzymes set free by necrotic processes then cleave the nontoxic "prodrug" into the toxic "drug", which leads to massive tumor cell death and/or remission of inflammation.

Claims

1. A pharmaceutical composition for use in cytostatic or immunotherapy, comprising a component I and a component II, wherein said component I comprises at least one compound that produces necroses a in tumor or in an inflammatory process, said necroses resulting in the release of at least one enzyme, and component II comprises one or more compounds that are converted by said at least one enzyme released by said necroses into a cytotoxic drug.

2. A composition according to claim 1, wherein said component I comprises at least one substance selected from the group consisting of a cytolytic or apoptotic monoclonal antibody, an immunoconjugate, a receptor ligand toxin specific for proliferating endothelium, and a tumor cell or endothelial cell metabolism inhibitor substance.

3. A composition according to claim 1, wherein said component I comprises at least one monoclonal antibody or one receptor ligand that is specific for proliferating endothelium.

4. A composition according to claim 3, wherein said receptor-ligand is specific for the VEGF/VEGF receptor complex.

5. A composition according to claim 1, wherein said component I comprises at least one monoclonal antibody, receptor ligand or an antagonist against an apoptosis-mediating antigen occurring on proliferating endothelial cells.

6. A composition according to claim 5, wherein said antigen comprises the α

_v β

₃ integrin.

7. A composition according to claim 1, wherein said component I comprises at least one cytotoxic immunoconjugate.

8. A composition according to claim 1, wherein said component I comprises at least one ligand receptor toxin.

9. A composition according to claim 1, wherein said component I comprises at least one tumor cell or endothelial cell metabolism inhibiting substance.

10. A composition according to claim 1, wherein said component II comprises a prodrug.

11. A composition according to claim 10, wherein said prodrug is N-(4-β

-glucuronyl-3-nitrobenzylcarbonyl) doxorubicin.

12. A process for treating a subject bearing a solid tumor or inflammatory process, comprising administering to said subject an effective amount of a composition of claim 1 in a suitable pharmaceutical vehicle.

13. A pharmaceutical composition comprising a first component and a second component, said first component comprising a tissue necrosis factor and a second component comprising a prodrug activated by a product of the action of said first component, said first component consisting of a monoclonal antibody specific for the VEGF/VEGF receptor complex, and said second component consisting of N-(4-β

-glucuronyl-3-nitrobenzylcarbonyl) doxorubicin.

14. A method of tumoristatic or immunoregulatory therapy in a patient requiring same, comprising the steps of administering to said patient an effective amount of the composition according to claim 13 for an effective period of time.