Organ protection in PSMA-targeted radionuclide therapy of prostate cancer

• US 9,956,305 B2
• Filed: 09/04/2015
• Issued: 05/01/2018
• Est. Priority Date: 09/08/2014
• Status: Active Grant

• Current Assignee: Molecular Insight Pharmaceuticals Incorporated (Lantheus Holdings, Inc.)
• Original Assignee: Molecular Insight Pharmaceuticals Incorporated (Lantheus Holdings, Inc.)
• Inventors: Babich, John W., Hillier, Shawn, Joyal, John
• Primary Examiner(s): Hartley, Michael G
• Assistant Examiner(s): SAMALA, JAGADISHWAR RAO
• Application Number:
  US14/846,252
• Publication Number:
  US 20160067361A1
• Time in Patent Office: 970 Days
• CPC Class Codes: A61K 31/555 containing heavy metals, e.g. hemin, hematin, melarsoprol
• CPC Class Codes: A61K 51/0461 having six-membered rings with three nitrogens as the only ring hetero atoms, e.g. chlorazanil, melamine melarsoprol A61K51/0472
• CPC Class Codes: A61K 51/0497 conjugates with a carrier being an organic compounds
• CPC Class Codes: A61K 51/12 characterised by a special physical form, e.g. emulsion, microcapsules, liposomes , characterized by a special physical form, e.g. emulsions, dispersions, microcapsules liposomes A61K51/1234
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 35/04 specific for metastasis
• CPC Class Codes: A61P 39/00 General protective or antinoxious agents

Abstract

A method of reducing radiation exposure of a non-cancerous tissue of a patient diagnosed with a cancer includes administering to the patient an agent capable of competing for binding sites on a surface of the non-cancerous tissue, provided that the administration is carried out after a waiting period that follows administration of a compound including a radionuclide to the patient, the compound having affinity for both a cancerous tissue and the non-cancerous tissue, and, further provided that the binding sites have an affinity for both the agent and the compound.

Claims

1. A method of reducing radiation exposure of a non-cancerous tissue of a patient diagnosed with prostate cancer, the method comprising:

administering to the patient a compound comprising a radionuclide and a recognition moiety for Prostate Specific Membrane Antigen (“

PSMA”

), the compound binding to both cancerous prostate tissue and the non-cancerous tissue, and,

after a waiting period of 1 hour to 60 hours, administering an agent in an amount sufficient to cause a displacement of the bound compound from the binding sites in the non-cancerous tissue by binding of the agent thereto while retaining the radionuclide in the cancerous tissue thereby reducing the exposure of the non-cancerous tissue to the radionuclide;

wherein;

the binding sites are attached to both the agent and the compound, and

the agent has a different chemical structure from the compound, or

the agent has the same chemical structure as the compound absent the radionuclide, and

the agent comprises a recognition moiety for PSMA;

the compound is a Glu-urea-based PSMA ligand; and

the agent comprises a Glu-urea-based PSMA ligand, a phosphinyl containing moiety, 7-(L-2-amino-2-carboxyethylthio)-2-(2,2-dimethylcyclopropanecarboxamide)-2-heptenoic acid, 2-(phosphonomethyl)pentanedioic acid, or 2-(3-mercaptopropyl)pentanedioic acid (2-MPPA).

2. The method of claim 1, wherein the non-cancerous tissue is kidney tissue, salivary gland tissue, lacrimal gland tissue, parotid gland tissue, or small intestine tissue.

3. The method of claim 1, wherein the radionuclide is a radioactive isotope of Ga, I, Y, Lu, Bi, Ac, Re, In, Th, or Tc.

4. The method of claim 1, wherein the compound is MIP-1555, MIP-1519, MIP-1545, MIP-1427, MIP-1428, MIP-1379, MIP-1072, MIP-1095, MIP-1558, MIP-1405, or MIP-1404;

wherein;

5. The method of claim 1, wherein the agent comprises:

2-[[methylhydroxyphosphinyl]methyl]pentanedioic acid;

2-[[ethylhydroxyphosphinyl]methyl]pentanedioic acid;

2-[[propylhydroxyphosphinyl]methyl]pentanedioic acid;

2-[[butylhydroxyphosphinyl]methyl]pentanedioic acid;

2-[[cyclohexylhydroxyphosphinyl]methyl]pentanedioic acid;

2-[[phenylhydroxyphosphinyl]methyl]pentanedioic acid;

2-[[(phenylmethyl)hydroxyphosphinyl]methyl]pentanedioic acid;

2-[[((2-phenylethyl)methyl)hydroxyphosphinyl]methyl]pentanedioic acid;

2-[[((3-phenylpropyl)methyl)hydroxyphosphinyl]methyl]pentanedioic acid;

2-[[((3-phenylbutyl)methyl)hydroxyphosphinyl]methyl]pentanedioic acid;

2-[[((2-phenylbutyl)methyl)hydroxyphosphinyl]methyl]pentanedioic acid;

2-[[(4-phenylbutyl)hydroxyphosphinyl]methyl]pentanedioic acid;

2-[[(aminomethyl)hydroxyphosphinyl]methyl]pentanedioic acid;

7-(L-2-amino-2-carboxyethylthio)-2-(2,2-dimethylcyclopropanecarboxamide)-2-heptenoic acid;

2-(phosphonomethyl)pentanedioic acid;

N-[methylhydroxyphosphinyl]glutamic acid;

N-[ethylhydroxyphosphinyl]glutamic acid;

N-[propylhydroxyphosphinyl]glutamic acid;

N-[butylhydroxyphosphinyl]glutamic acid;

N-[phenylhydroxyphosphinyl]glutamic acid;

N-[(phenylmethyl)hydroxyphosphinyl]glutamic acid;

N-[((2-phenylethyl)methyl)hydroxyphosphinyl]glutamic acid;

N-methyl-N-[phenylhydroxyphosphinyl]glutamic acid;

2-(3-mercaptopropyl)pentanedioic acid (2-MPPA), a pharmaceutically acceptable salt thereof;

or a mixture of any two or more thereof.

6. The method of claim 1, wherein the agent is cold MIP-1555, cold MIP-1519, cold MIP-1545, cold MIP-1427, cold MIP-1428, cold MIP-1379, cold MIP-1072, cold MIP-1095, cold MIP-1558, cold MIP-1405, or cold MIP-1404;

wherein;

7. The method of claim 1, wherein the compound is administered to the subject from about 0.2 mg/kg to about 100 mg/kg.

8. The method of claim 1, wherein the agent is administered to the subject from about 0.2 mg/kg to about 100 mg/kg.

9. The method of claim 1, wherein the compound is represented as:

10. The method of claim 1, wherein the agent is represented as