Diagnostic/therapeutic agents

• US 6,680,047 B2
• Filed: 08/10/2001
• Issued: 01/20/2004
• Est. Priority Date: 10/28/1996
• Status: Expired due to Fees

• Current Assignee: GE Healthcare As (GE Healthcare Technologies, Inc.)
• Original Assignee: Amersham Health (General Electric Company)
• Inventors: Nævestad, Anne, Løvhaug, Dagfinn, Rongved, Pål, Klaveness, Jo, Godal, Aslak, Hoff, Lars, Cuthbertson, Alan, Solbakken, Magne, Høgset, Anders, Tolleshaug, Helge, Hellebust, Halldis, Gogstad, Geir, Bryn, Klaus
• Primary Examiner(s): Hartley, Michael G.
• Application Number:
  US09/925,715
• Publication Number:
  US 20020102217A1
• Time in Patent Office: 893 Days
• Field of Search: 424/9.52, 424/9.51, 424/9.5, 424/1.21, 424/1.29, 424/1.49, 424/1.53, 424/1.69, 424/9.1, 424/9.3, 424/9.4, 424/9.6, 424/450, 424/489, 516/11, 516/77, 600/441, 600/458
• US Class Current: 424/9.52
• CPC Class Codes: A61K 47/542 Carboxylic acids, e.g. a fatty acid or an amino acid
• CPC Class Codes: A61K 47/62 the modifying agent being a protein, peptide or polyamino acid
• CPC Class Codes: A61K 47/6925 the form being a microcapsule, nanocapsule, microbubble or nanobubble
• CPC Class Codes: A61K 49/0002 General or multifunctional contrast agents, e.g. chelated agents
• CPC Class Codes: A61K 49/0043 Fluorescein, used in vivo
• CPC Class Codes: A61K 49/0047 Green fluorescent protein [GFP]
• CPC Class Codes: A61K 49/0054 Macromolecular compounds, i.e. oligomers, polymers, dendrimers
• CPC Class Codes: A61K 49/0056 Peptides, proteins, polyamino acids
• CPC Class Codes: A61K 49/0058 Antibodies
• CPC Class Codes: A61K 49/0091 Microparticle, microcapsule, microbubble, microsphere, microbead, i.e. having a size or diameter higher or equal to 1 micrometer
• CPC Class Codes: A61K 49/223 Microbubbles, hollow microspheres, free gas bubbles, gas microspheres
• CPC Class Codes: A61K 51/065 conjugates with carriers being macromolecules
• CPC Class Codes: A61K 51/1227 Micelles, e.g. phospholipidic or polymeric micelles
• CPC Class Codes: A61K 51/1255 Granulates, agglomerates, microspheres
• CPC Class Codes: Y10S 977/928 X-ray agent
• CPC Class Codes: Y10S 977/929 Ultrasound contrast agent
• CPC Class Codes: Y10S 977/93 MRI contrast agent

Abstract

Targetable diagnostic and/or therapeutically active agents, e.g. ultrasound contrast agents, comprising a suspension in an aqueous carrier liquid of a reporter comprising gas-containing or gas-generating material, said agent being capable of forming at least two types of binding pairs with a target.

Claims

1. A combined formulation comprising:

i) a first administrable composition comprising a first pre-targeting vector; and

ii) a second administrable composition comprising a targetable diagnostic and/or therapeutically active agent, said agent comprising a suspension in an aqueous carrier liquid of a reporter comprising gas-containing or gas-generating material, said reporter further comprising a moiety having affinity for said pre-targeting vector and a second vector, the first and second vectors binding to different targets on the same or different cells.

2. A combined formulation as claimed in claim 1 wherein the gas is selected from the group consisting of air, nitrogen, oxygen, carbon dioxide, hydrogen, an inert gas, a sulphur fluoride, selenium hexafluoride, a low molecular weight hydrocarbon, a ketone, an ester, a halogenated low molecular weight hydrocarbon and a mixture of any of the foregoing.

3. A combined formulation as claimed in claim 2 wherein the gas is selected from the group consisting of a perfluorinated ketone, a perfluorinated ether and a perfluorocarbon.

4. A combined formulation as claimed in claim 2 wherein the gas is selected from the group consisting of sulphur hexafluoride, perfluoropropane, perfluorobutane and perfluoropentane.

5. A combined formulation as claimed in claim 1 comprising gas microbubbles stabilised by a coalescence-resistant surface membrane, a filmogenic protein, a polymer material, a non-polymeric, non-polymerisable wall-forming material or a surfactant.

6. A combined formulation as claimed in claim 5 wherein said surfactant comprises at least one phospholipid.

7. A combined formulation as claimed in claim 6 wherein at least 75% of the phospholipid suspended comprises phospholipid molecules individually bearing net overall charge.

8. A combined formulation as claimed in claim 7 wherein at least 75% of the phospholipids are selected from the group consisting of phosphatidylserines, phosphatidylglycerols, phosphatidylinositols, phosphatidic acids and cardiolipins.

9. A combined formulation as claimed in claim 8 wherein at least 80% of said phospholipids are phosphatidylserines.

10. A combined formulation as claimed in claim 1 wherein said gas-containing material further comprises moieties capable of binding to a receptor system so as to induce a therapeutic response.

11. A combined formulation as claimed in claim 1 wherein the vectors are selected from the group consisting of antibodies;

cell adhesion molecules;

cell adhesion molecule receptors;

cytokines;

growth factors;

peptide hormones;

non-bioactive binders of receptors for cell adhesion molecules, cytokines, growth factors and peptide hormones;

oligonucleotides and modified oligonucleotides;

DNA-binding drugs;

protease substrates/inhibitors; and

proteins and peptides which bind to cell-surface proteoglycans.

12. A combined formulation as claimed in claim 1 wherein the vectors have affinity for targets at a level such that the agent interacts with but does not fixedly bind to said targets.

13. A combined formulation as claimed in claim 12 wherein the vectors are selected from ligands for cell adhesion proteins and cell adhesion proteins which have corresponding ligands on endothelial cell surfaces.

14. A combined formulation as claimed in claim 1 wherein the vectors are sited such that they are not readily exposed to the target.

15. A combined formulation as claimed in claim 1 wherein the vectors are coupled or linked to the reporter by means of avidin-biotin and/or streptavidin-biotin interactions.

16. A combined formulation as claimed in claim 1 wherein the vectors may be covalently or non-covalently coupled or linked to the reporter.

17. A combined formulation as claimed in claim 1 wherein the vectors are coupled or linked to the reporter by means of electrostatic charge interaction.

18. A combined formulation as claimed in claim 1 which further contains moieties which are radioactive or are effective as X-ray contrast agents, light imaging probes or spin labels.

19. A combined formulation as claimed in claim 1 further comprising a therapeutic compound.

20. A combined formulation as claimed in claim 19 wherein said therapeutic compound is an antineoplastic agent, blood product, biological response modifier, antifungal agent, hormone or hormone analogue, vitamin, enzyme, antiallergic agent, tissue factor inhibitor, platelet inhibitor, coagulation protein target inhibitor, fibrin formation inhibitor, fibrinolysis promoter, antiangiogenic, circulatory drug, metabolic potentiator, antitubercular, antiviral, vasodilator, antibiotic, antiinflammatory, antiprotozoan, antirheumatic, narcotic, opiate, cardiac glycoside, neuromuscular blocker, sedative, local anaesthetic, general anaesthetic or genetic material.

21. A combined formulation as claimed in claim 19 wherein said therapeutic compound is covalently coupled or linked to the reporter through disulphide groups.

22. A combined formulation as claimed in claim 19 wherein a lipophilic or lipophilically-derivatised therapeutic compound is linked to the reporter through hydrophobic interactions.

23. A combined formulation as claimed in claim 1 wherein said pre-targeting vector comprises a monoclonal antibody.

24. A method of generating enhanced images of a human or non-human animal body which comprises administering to said body a combined formulation as claimed in claim 1 and generating an ultrasound, magnetic resonance, X-ray, radiographic or light image of at least a part of said body.

25. A method as claimed in claim 24 for generation of an ultrasound image.

26. A method as claimed in claim 24 which comprises the steps:

i) administering to said body a pre-targeting vector having affinity for a selected target; and

thereafter

ii) administering said agent comprising a vector having affinity for said pre-targeting vector.

27. A method as claimed in claim 26 wherein said pre-targeting vector comprises a monoclonal antibody.

28. A method as claimed in claim 24 which comprises the steps:

i) administering to said body a combined formulation; and

thereafter

ii) administering a substance capable of displacing or releasing said agent from its target.

29. A method as claimed in claim 24 wherein said agent further comprises a therapeutic compound.

30. A method as claimed in claim 29 wherein said therapeutic compound is covalently coupled or linked to the reporter through disulphide groups, and a composition comprising a reducing agent capable of reductively cleaving said disulphide groups is subsequently administered.