Targeted alpha particle therapy using actinium-225 conjugates

• US 20020058007A1
• Filed: 09/14/2001
• Published: 05/16/2002
• Est. Priority Date: 09/15/2000
• Status: Active Grant

• Current Assignee: Sloan-Kettering Institute For Cancer Research (Memorial Sloan-Kettering Cancer Center)
• Original Assignee: Sloan-Kettering Institute For Cancer Research (Memorial Sloan-Kettering Cancer Center)
• Inventors: Ma, Dangshe, Borchardt, Paul, Scheinberg, David, McDevitt, Michael
• Granted Patent: US 6,683,162 B2
• Time in Patent Office: Days
• US Class Current: 424/1.65
• CPC Class Codes: A61K 51/1093 conjugates with carriers being antibodies
• CPC Class Codes: A61P 35/00 Antineoplastic agents

Abstract

The present invention provides functionalized chelants and a method of treating cancerous cells with alpha particles comprising the step of administering a pharmacologically effective dose of an ²²⁵Ac conjugate comprising a functionalized chelant

R is independently CHQCO₂X; Q is independently hydrogen; C1-C4 alkyl or (C1-C2 alkyl) phenyl; X is independently hydrogen; benzyl or C1-C4 alkyl; Z1 is (CH₂)_nY where n is 1-10 and Y is an electrophilic or nucleophilic moiety and Z2 is R; or, alternatively, Z1 is hydrogen and Z2 is a peptide linker composed of 1-10 amino acids; said Y or said peptide linker covalently attached to an antibody or fragment thereof, or other biologic molecule; or a pharmaceutically acceptable salt thereof, complexed with ²²⁵Ac. These biologic molecule binds to cancerous cells and ²²⁵Ac or its daughters emit alpha particles into said cancerous cells effecting treatment.

Claims

1. An ²²⁵Ac complex comprising a functionalized chelant compound having the structure

2. The ²²⁵Ac complex of claim 1, wherein R is CO₂H, Z1 is hydrogen and Z2 is a peptide linker composed of 1-10 amino acids.

3. A method of treating cancerous cells with alpha particles in an individual in need of such treatment comprising the step of:

administering a pharmacologically effective dose of an ²²⁵Ac conjugate comprising a functionalized chelant having the structure

wherein R is independently CHQCO₂X;

Q is independently hydrogen;

C1-C4 alkyl or (C1-C2 alkyl) phenyl;

X is independently hydrogen;

benzyl or C1-C4 alkyl;

Z1 is (CH₂)_nY wherein n is 1 to 10 and Y is an electrophilic or nucleophilic moiety and Z2 is R;

or, in the alternative,

Z1 is hydrogen and Z2 is a peptide linker composed of 1-10 amino acids;

said Y or said peptide linker covalently attached to an antibody or fragment thereof, or other biologic molecule;

or a pharmaceutically acceptable salt thereof, complexed with ²²⁵Ac;

wherein said antibody or fragment thereof, or other biologic molecule binds to said cancer cells, said ²²⁵Ac or its daughters emitting said alpha particles into said cancerous cells, wherein said alpha particles cause a cytotoxic effect on said cancerous cells, thereby effecting treatment of said individual.

4. The method of claim 3, wherein said electrophilic or nucleophilic moiety is selected from the group consisting of p-isothiocyanatobenzene, maleimides, vinylpyridine and NHS esters.

5. The method of claim 3, wherein in said chelant R and Z2 are CO₂H and Z1 is (CH₂)_nY.

6. The method of claim 5, wherein said chelant is 2-(p-isothiocyanatobenzyl)-1,4,7,10-tetraazocyclododecane-1,4,7,10-tetraacetic acid.

7. The method of claim 3, wherein said antibody is IgG.

8. The method of claim 3, wherein said antibody is a monoclonal antibody.

9. The method of claim 8, wherein said monoclonal antibody is an internalizing antibody.

10. The method of claim 9, wherein said internalizing monoclonal antibody is selected from the group consisting of HuM195, J591, B4 and 3F8.

11. The method of claim 3, wherein said cancerous cells comprise a disseminated cancer or a solid tumor cancer.

12. The method of claim 11, wherein said cancers are selected from the group consisting of prostate cancer, lymphoma, leukemia, neuroblastomas, breast cancer and ovarian cancer.

13. The method of claim 3, wherein said ²²⁵Ac conjugate is administered as a pharmaceutical composition comprising said ²²⁵Ac conjugate and a pharmaceutical carrier.

15. The method of claim 14, wherein said electrophilic or nucleophilic moiety is selected from the group consisting of p-isothiocyanatobenzene, maleimides, vinylpyridine and NHS esters.

16. The method of claim 14, wherein said chelant is 2-(p-isothiocyanatobenzyl)-1,4,7,10-tetraazocyclododecane-1,4,7,10-tetraacetic acid.

17. The method of claim 16, wherein said monoclonal antibody is selected from the group consisting of HuM195, J591, B4 and 3F8.

18. The method of claim 14, wherein said cancerous cells comprise a disseminated cancer or a solid tumor cancer.

19. The method of claim 18, wherein said cancers are selected from the group consisting of prostate cancer, lymphoma, leukemia, neuroblastomas, breast cancer and ovarian cancer.

20. The method of claim 14, wherein said ²²⁵Ac conjugate is administered as a pharmaceutical composition comprising said ²²⁵Ac conjugate and a pharmaceutical carrier.

14. A method of treating cancerous cells with alpha particles in an individual in need of such treatment comprising:

administering a pharmacologically effective dose of an ²²⁵Ac conjugate comprising a functionalized chelant having the structure

wherein R and Z2 are CO₂H; and

Z1 is (CH₂)_nY wherein n is 1 to 10 and Y is an electrophilic or nucleophilic moiety;

said Y covalently attached to a monoclonal antibody;

or a pharmaceutically acceptable salt thereof;

complexed with ²²⁵Ac;

binding said monoclonal antibody to said cancerous cells;

internalizing said ²²⁵Ac within said cancerous cells, and

emitting said alpha particles from said ²²⁵Ac or its daughters, said alpha particles remaining within said cancerous cells, wherein said alpha particles cause a cytoxic effect on said cancerous cells thereby effecting treatment of said individual.