Fritzberg, Alan R. (Olga, WA, US)
Abrams, Paul G. (Seattle, WA, US)
Tatalick, Lauren Marie (Redmond, WA, US)
Thoelke, Kent R. (Seattle, WA, US)
Bryan, James Kyle (Seattle, WA, US)
Hylarides, Mark D. (Stanwood, WA, US)
John, Elizabeth K. (San Diego, CA, US)

Plaque It! Sponsored by: Flash of Genius

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08/05/2008

06/30/2004

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Poniard Pharmaceuticals, Inc. (Seattle, WA, US)

424/9.1

534/15, 424/1.11, 424/1.65

C07F5/00

424/9, 424/1.81, 534/15, 424/1.37, 424/1.11, 424/1, 424/1.65, 514/836

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3032585	Process for the production of p-bis-(2-chloroethyl)-aminophenylalanine	May, 1962	Bergel et al.	260/518
3398198	Less than fully propylated (beta hydroxy propyl) ethylene diamine and method of preparation thereof	August, 1968	Kersnar et al.	260/584
3726912	SUBSTITUTED ALKANOLAMINE CHELATING AGENTS	April, 1973	McCrary et al.	260/513N
3852414	BONE SEEKING TECHNETIUM 99M STANNOUS PHOSPHATE COMPLEX	December, 1974	Adler et al.	424/1
3931396	Method of preparation of a composition having a base of 99.sup.m technetium for diagnosis by scintigraphy	January, 1976	Bardy et al.	424/1
3965254	Compositions for the treatment of calcific tumors	June, 1976	Tofe et al.	424/1
3974268	Bone-seeking technetium-99m imidodiphosphonate complex	August, 1976	Subramanian et al.	424/1
3989730	Bone-seeking technetium-99m complex	November, 1976	Subramanian et al.	260/429.7
4017596	Radiopharmaceutical chelates and method of external imaging	April, 1977	Loberg et al.	424/1
4058704	Coilable and severable heating element	November, 1977	Shimizu	219/528
4075314	Stannous pyrophosphate technetium-99m compositions	February, 1978	Wolfangel et al.	424/1
4104366	Compositions for preparation of aqueous solutions of low valence .sup.99 technitium salts	August, 1978	Schmidt-Dunker et al.	424/1
4187284	Skeletal imaging kit utilizing triethylene tetramine hexa (methylene phosphonic acid)	February, 1980	Rolleston et al.	424/1
4399817	Boron containing polyphosphonates for the treatment of calcific tumors	August, 1983	Benedict	406/20
4508625	Magnetic separation using chelated magnetic ions	April, 1985	Graham	210/695
4515767	Radioactive metals complexed with phosphonate derivatives of dicyclopentadienebis(methylamine)	May, 1985	Simon et al.	424/1.1
4560548	Bone seeking Tc-99m complexes of phosphonate derivatives of bis(aminoalkyl)piperazine	December, 1985	Simon et al.	424/1.1
4606907	Bone seeking Tc-99m complexes of phosphonate derivatives of polyamidoamines	August, 1986	Simon et al.	424/1.1
4639365	Gadolinium chelates as NMR contrast agents	January, 1987	Sherry	424/9
4647447	Diagnostic media	March, 1987	Gries et al.	424/9
4678667	Macrocyclic bifunctional chelating agents	July, 1987	Meares et al.	424/85
4707353	Radiographic imaging agents	November, 1987	Bugaj et al.	424/1.11
4752464	Treatment of arthritis, including rheumatoid arthritis, with radioactive isotopes	June, 1988	Lieberman et al.	424/1.1
4808541	Determination method utilizing reagents covalently labelled with essentially non-fluorescent lanthanide chelates in combination with time-resolved fluorescence spectroscopy and the reagents to be used in the method	February, 1989	Mikola et al.	436/501
4853209	Bone marrow suppressing agents	August, 1989	Kaplan et al.	424/1.77
4882142	Bone marrow suppressing agents	November, 1989	Simon et al.	424/1.22
4885363	1-substituted-1,4,7-triscarboxymethyl-1,4,7,10-tetraazacyclododecane and analogs	December, 1989	Tweedle et al.	540/465
4897254	Radioactive compositions for the treatment of calcific tumors	January, 1990	Simon et al.	424/1.1
4897255	Metal radionuclide labeled proteins for diagnosis and therapy	January, 1990	Fritzberg et al.	424/1.1
4898724	Organis amine phosphonic acid complexes for the treatment of calcific tumors	February, 1990	Simon et al.	424/1.1
4937333	Method for purifying aminomethylenephosphonic acids for pharmaceutical use	June, 1990	Garlich et al.	540/474
4957939	Sterile pharmaceutical compositions of gadolinium chelates useful enhancing NMR imaging	September, 1990	Gries et al.	514/492
4976950	Bone marrow suppressing agents	December, 1990	Simon et al.	424/1.1
5059412	Macrocyclic aminophosphonic acid complexes for the treatment of calcific tumors	October, 1991	Simon et al.	424/1.1
5064633	Macrocyclic aminophosphonic acid complexes, their formulations and use	November, 1991	Simon et al.	424/1.1
5066478	Radio labeled organic amine phosphonic acid complexes for the treatment of calcific tumors	November, 1991	Simon et al.	424/1.1
5089249	Conjugates for bone imaging and bone cancer therapy	February, 1992	Fritzberg et al.	424/1.1
5202109	Conjugates for bone imaging and bone cancer therapy	April, 1993	Fritzberg et al.	424/1.1
5219556	Stabilized therapeutic radiopharmaceutical complexes	June, 1993	Wolfangel	424/1.53
5286497	Diltiazem formulation	February, 1994	Hendrickson et al.	424/490
5300279	Organic amine phosphonic acid complexes for the treatment of calcific tumors	April, 1994	Simon et al.	424/1.77
5393512	Stable therapeutic radionuclide compositions and methods for preparation thereof	February, 1995	Vanderheyden et al.	424/1.53
5587451	Process for preparing polyazamacrocycles	December, 1996	Athey et al.	528/345
5621001	Methods for administration of taxol	April, 1997	Canetta et al.	514/449
5641803	Methods for administration of taxol	June, 1997	Canetta et al.	514/449
5665761	Methods for administration of taxol	September, 1997	Canetta et al.	514/449
5670537	Method for effecting tumor regression with a low dose, short infusion taxol regimen	September, 1997	Canetta et al.	514/449
5679318	Stable therapeutic radionuclide compositions and methods for preparation thereof	October, 1997	Vanderheyden et al.	424/1.11
5707610	Antibacterial mouthwash	January, 1998	Ibsen et al.	424/49
5708169	5-amidomethyl α,β-saturated and -unsaturated 3-aryl butyrolactone antibacterial agents	January, 1998	Hester, Jr. et al.	549/152
5712275	Antibacterial and antifouling oxathiazines and their oxides	January, 1998	Van Gestel	514/222.5
5714467	Antibacterial and antimalarial hybrid peptides	February, 1998	Boman et al.	514/12
5714504	Compositions	February, 1998	Lindberg et al.	514/338
5714604	Process for the preparation of azamacrocyclic or acyclic aminophosphonate ester derivatives	February, 1998	Kiefer	540/472
5756472	Antifungal agent obtained from hormonema	May, 1998	Liesch et al.	514/27
5756505	N-acylpiperazine derivative, antibacterial drug and anti-ulcer drug	May, 1998	Nishino et al.	514/253
5756685	Protein conjugate containing metal radionuclide labeled proteins	May, 1998	Fritzberg et al.	530/391.5
5756725	Carbapenem antibacterial compounds, compositions containing such compounds and methods of treatment	May, 1998	Wilkening et al.	540/302
5760063	Arylhydrazone derivatives useful as antibacterial agents	June, 1998	Lam et al.	514/355
5762907	Frozen radiopharmaceutical formulations	June, 1998	Simon et al.	424/1.77
5770617	Terbenzimidazoles useful as antifungal agents	June, 1998	LaVoie et al.	514/394
5773421	Antifungal fusacandins	June, 1998	Alder et al.	514/25
5773443	Triazole antifungal agents	June, 1998	Ray et al.	514/256
5773696	Antifungal polypeptide and methods for controlling plant pathogenic fungi	June, 1998	Liang et al.	800/205
5783570	Organic solvent-soluble mucopolysaccharide, antibacterial antithrombogenic composition and medical material	July, 1998	Yokota et al.	514/56
5786325	Cyclic peptide antifungal agents and methods of making and using	July, 1998	Borromeo et al.	514/11
5801172	Antifungal agent from sporomiella minimoides	September, 1998	Clapp-Shapiro et al.	514/250
5807854	Pyrimidone derivatives with antifungal activity	September, 1998	Bartroli et al.	514/248
5814634	Alkylenediamine derivative anti-ulcer drug and antibacterial drug	September, 1998	Nishino et al.	514/237.8
5824698	Antibacterial dibenzimidazole derivatives	October, 1998	Hasler et al.	514/394
5824874	Antifungal polypeptide and process for its production	October, 1998	Ulbrich et al.	800/205
5830855	Lipodepsipeptides as antifungal and fungicidal agents	November, 1998	Takemoto	514/11
5830889	Antibacterial penem esters derivatives	November, 1998	Iwata et al.	514/195
5837253	Preparation and use of Inula extracts as a fungicide for the control of plant diseases	November, 1998	Cohen	424/195.1
5837726	Antifungal agents derived from aspergillus fumigatus	November, 1998	Liu et al.	514/475
5849956	Antifungal terpene compounds and process for producing the same	December, 1998	Koga et al.	568/326
5854213	Antifungal cyclohexapeptides	December, 1998	Bouffard	514/11
5854280	Antifungal sordaridin derivatives	December, 1998	Gomez et al.	514/456
5856347	Antibacterial preparation or bactericide comprising 2-aminothiazole derivative and/or salt thereof	January, 1999	Hashiguchi et al.	514/390
5859032	Pyridine derivative, anti-ulcer drug, and antibacterial drug	January, 1999	Nishino et al.	514/352
5861430	Benzopyran phenol derivates for use as antibacterial, antiviral or immunostimulating agents	January, 1999	Markonius	514/456
5863773	Antifungal corynecandin	January, 1999	Gunawardana et al.	435/118
5866549	6-O-substituted ketolides having antibacterial activity	February, 1999	Or et al.	514/29
5872249	3-ammoniopropenyl cephalosporin compounds as antibacterial agents and process for preparing the same	February, 1999	Park et al.	540/225
5876738	Antifungal phyllosilicate	March, 1999	Ohno et al.	424/404
5888526	Antibacterial antifungal agent and fibrous material containing the same	March, 1999	Tsubai et al.	424/405
5888941	Carbozamides with antifungal activity	March, 1999	Bartroli et al.	504/262
5891890	Benzamide derivatives, anti-ulcer drug, and antibacterial drug	April, 1999	Nishino et al.	514/331
5908862	Water-miscible esters of mono--and diglycerides having antibacterial activity and their use in inhibiting infection	June, 1999	Wai Lee et al.	514/546
5910498	Pyridonecarboxylic acid derivatives or salts thereof and antibacterial agents comprising the same as active ingredient	June, 1999	Yazaki et al.	514/255
5917084	Antifungal agents	June, 1999	Jiang	560/174
5919438	Dermatological/cosmetic compositions comprising antifungal and antibacterial compounds and reduction of hair loss therewith	July, 1999	Saint-Leger	424/70.1
5919925	2-isocephem and oxacephem derivatives and use as antibacterial agents	July, 1999	Burton et al.	540/300
6005083	Bridged aromatic substituted amine ligands with donor atoms	December, 1999	Kasina	534/10
6177551	Bridged aromatic substituted amine ligands with donor atoms	January, 2001	Kasina	534/10
6187910	Bridged aromatic substituted amine ligands with donor atoms	February, 2001	Kasina	534/10
6241961	Radioimmuno conjugates for use in human therapy and method for their preparation	June, 2001	Benes et al.	424/1.49
6528627	Bridged aromatic substituted amine ligands with donor atoms	March, 2003	Kasina	534/10
6767531	High dose radionuclide complexes for bone marrow suppression	July, 2004	Fritzberg et al.	424/1.65
7070759	High dose radionuclide complexes for bone marrow suppression	July, 2006	Fritzberg et al.	424/1.65
7094885	Skeletal-targeted radiation to treat bone-associated pathologies	August, 2006	Fritzberg	534/15
7097823	High dose radionuclide complexes for bone marrow suppression	August, 2006	Fritzberg et al.	424/1.65
7115720	Therapeutic and diagnostic compounds, compositions, and methods	October, 2006	Fritzberg
20020176818	High dose radionuclide complexes for bone marrow suppression	November, 2002	Fritzberg et al.	424/1.11
20030118508	Treatment of osteomyelitis with radiopharmaceuticals	June, 2003	Simon et al.	424/1.77
20030158393	Bridged aromatic substituted amine ligands with donor atoms	August, 2003	Kasina	534/11
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20040126317	Skeletal-targeted radiation to treat bone-associated pathologies	July, 2004	Fritzberg
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CA1078731	June, 1980
EP0164843	December, 1985			Organic amine phosphonic acid complexes for the treatment of calcific tumors
EP0210043	January, 1987			Contrast agent for NMR scanning.
EP0232751	August, 1987			1-substituted-4,7,10-triscarboxymethyl-1,4,7,10-tetraazacyclododecane and analogs
EP0255471	February, 1988			1,4,7,10-Tetraazacyclododecane-derivatives
EP0258616	March, 1988			NMR Imaging with paramagnetic polyvalent metal salts of poly-(acid-alkylene-amino)-alkanes
EP0287465	October, 1988			Cyclic ligands containing nitrogen, metal complexes formed by these ligands, diagnostic compositions containing them and process for their preparation
EP0374501	June, 1990			Bone marrow suppressing agents
EP0382582	August, 1990			Tetra-aza macrocyles and processes for their preparation.
EP0408701	January, 1991			MACROCYCLIC AMINOPHOSPHONIC ACID COMPLEXES, THEIR PREPARATION, FORMULATIONS AND USE.
EP0411941	February, 1991			Process for purifying aminomethylenephosphonic acids.
EP0455380	November, 1991			Tetra-aza macrocycles; processes for their preparation, and their use in magnetic resonance imaging.
EP0698029	February, 1996			PROCESS FOR THE PREPARATION OF AZAMACROCYLCIC OR ACYCLIC AMINOPHOSPHONATE ESTER DERIVATIVES
EP0972528	January, 2000			Radioimmunoconjugate for use in human therapy and its preparation
FR2230374	December, 1974
WO/1984/003698	September, 1984			COMPOUND
WO-8403698	September, 1984
WO/1990/006776	June, 1990			MACROCYCLIC AMINOPHOSPHONIC ACID COMPLEXES, THEIR PREPARATION, FORMULATIONS AND USE
WO-9006776	June, 1990
WO/1991/016075	October, 1991			BONE MARROW TREATMENTS
WO-9116075	October, 1991
WO-9325240	December, 1993
WO/1993/025240	December, 1993			PRETARGETING METHODS AND COMPOUNDS
WO/1994/026753	November, 1994			PROCESS FOR THE PREPARATION OF AZAMACROCYLCIC OR ACYCLIC AMINOPHOSPHONATE ESTER DERIVATIVES
WO-9426753	November, 1994
WO-9510940	April, 1995
WO/1995/010940	April, 1995			IMPROVED ANTIMICROBIAL COMPOSITION
WO-9843678	October, 1998
WO/1998/043678	October, 1998			TETRAAZA- OR N2S2- COMPLEXANTS, AND THEIR USE IN RADIODIAGNOSTICS OR RADIOTHERAPY
WO/2001/091806	December, 2001			MEASUREMENT OF THE THERAPEUTIC DOSE FOR BONE MARROW ABLATION THERAPY
WO-0191806	December, 2001
WO/2002/062398	August, 2002			RADIOACTIVELY LABELLED CONJUGATES OF PHOSPHONATES
WO-02062398	August, 2002

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Jones D. L.

Schwegman, Lundberg & Woessner, P.A.

RELATED APPLICATION

This is a divisional of U.S. patent application Ser. No. 10/784,476, filed Feb. 23, 2004, now U.S. Pat. No. 7,097,823 entitled HIGH DOSE RADIONUCLIDE COMPLEXES FOR BONE MARROW SUPPRESSION, which is a continuation application of U.S. patent application Ser. No. 10/159,245, filed May 29, 2002, entitled HIGH DOSE RADIONUCLIDE COMPLEXES FOR BONE MARROW SUPPRESSION abandoned, which is a divisional application of U.S. patent application Ser. No. 10/014,335, filed Dec. 11, 2001, entitled HIGH DOSE RADIONUCLIDE COMPLEXES FOR BONE MARROW SUPPRESSION now U.S. Pat. No. 6,767,531, which is a continuation under 35 USC § 111(a) of PCT Application Ser. No. PCT/US00/16052, filed on Jun. 12, 2000 and published as WO 00/76556 on Dec. 21, 2000, which claims priority from provisional U.S. patent application Ser. No. 60/139,065, filed Jun. 11, 1999, Ser. No. 60/143,780, filed Jul. 13, 1999 and Ser. No. 60/149,821, filed Aug. 19, 1999, all of which are incorporated herein by reference.

What is claimed is:

1. A therapeutic method for treating a bone-associated cancer comprising: (a) parenterally administering a dose of ¹⁵³Sm-EDTMP to said patient in an aqueous vehicle comprising an effective antiradiolytic amount of a pharmaceutically acceptable radioprotectant; and (c) administering to said patient an effective amount of chemotherapeutic agent in conjunction with ¹⁵³Sm-EDTMP wherein the patient is not subjected to total body irradiation or stem cell transplantation in conjunction with the therapeutic method.

2. The method of claim 1 wherein the cancer is multiple myeloma.

3. The method of claims 1 or 2 wherein the patient is treated with chemotherapy prior to step (a).

4. The method of claims 1 or 2 wherein the patient is treated with chemotherapy after step (c).

5. The method of claim 1 wherein the radioprotectant is ascorbic acid or gentistic acid.

6. The method of claim 5 wherein the concentration of ascorbic acid is about 35-75 mg/ml.

7. The method of claim 1 wherein the vehicle is buffered to about pH 7-8.

8. The method of claim 1 where the cancer is metastatic breast or prostate cancer.

9. The method of claim 1 wherein the dose is subablative.

10. The method of claim 8 or 9 wherein the chemotherapeutic agent is a bisphosphonate.

11. The method of claim 3 wherein the chemotherapeutic agent is a bisphosphonate.

12. The method of claim 4 wherein the chemotherapeutic agent is a bisphosphonate.

13. A therapeutic method for treating a bone-associated cancer comprising: (a) parenterally administering a dose of ¹⁵³Sm-EDTMP to said patient in an aqueous vehicle; and (c) administering to said patient an effective amount of a bisphosphonate in conjunction with said ¹⁵³Sm-EDTMP wherein the patient is not subjected to total body irradiation or stem cell transplantation in conjunction with the therapeutic method.

14. The method of claim 13 wherein the cancer is metastatic prostate cancer or metastatic breast cancer.

15. The method of claims 13 or 14 wherein the patient is treated with the bisphosphonate prior to step (a).

16. The method of claims 13 or 14 wherein the patient is treated with the bisphosphonate after step (a).

17. The method of claims 13 or 14 wherein the bisphosphonate is pamidronate, clodronate, zoledronate, etidronate, tiludronate or alerdronate.

18. The method of claims 13 or 14 wherein the aqueous vehicle further comprises an effective antiradiolytic amount of a pharmaceutically acceptable radioprotectant.

19. The method of claim 13 wherein the vehicle is buffered to about pH 7-8.

20. The method of claim 13 or 14 wherein the dose is subablative.

BACKGROUND OF THE INVENTION

The use of agents which cause partial or total suppression or eradication of bone marrow has become an accepted part of certain procedures used to treat patients with cancers such as leukemias, lymphomas, myelomas and Hodgkin's disease as well as in the treatment of patients suffering from hematopoietic disorders such as sickle cell anemia and thalassemia. In situations where the patient is suffering from a hematopoietic disorder such as thalassemia or sickle cell anemia, bone marrow transplantation may offer the possibility of a cure. If the abnormal bone marrow of an individual suffering from sickle cell anemia or thalassemia can be eradicated and then replaced with a bone marrow that takes and is reproduced and capable of producing normal red cells with normal hemoglobin, the individual may be cured.

Multiple myeloma is a disease of abnormal plasma cell proliferation that can result in anemia, pathologic fractures, renal failure, and death. Complete eradication of the abnormal plasma cells and precursor abnormal cells that may differentiate into abnormal plasma cells can prevent the progression, reverse or even cure the disease.

Current therapy is high dose chemotherapy (melphalan or combinations such as thiotepa/busulfan/cyclophosphamide) with or without total body irradiation (TBI). Treatment with melphalan 140 mg/m ² of body-surface area given intravenously can induce complete remissions in about 20-30% of patients. However, it causes severe and sometimes irreversible myelosuppression. For example, see B. Barlogie et al., Blood , 72, 2015 (1989); (1998); D. Cunningham et al., J. Clin. Oncol ., 12, 764 (1994); R. Bataille et al., New Engl. J. Med ., 336, 1657 (1997).

Furthermore, when radiation is combined with other cytotoxic therapies, such as chemotherapy, the toxicity can be additive or synergistic. In addition, patients who undergo bone marrow suppression or ablation, sufficient to require either growth factor support, transfusion support or stem cell reinfusion, may encounter toxicities from the chemotherapy, from TBI, or both.

The dose of chemotherapy and radiotherapy that can be administered to an individual patient is often limited by patient age or overall health. Some patients who could benefit from high dose chemotherapy and radiotherapy do not receive it because they are considered to old or have other concomitant diseases which make them unsuitable candidates because of the non-target organ toxicity currently associated with these therapies. Higher doses of radiation may increase the percentage of tumor cells that are killed, and, with ionizing radiation, there comes a point where small increments in radiation can have a major impact on the percentage of cells killed.

The use of complexed radionuclides for bone marrow suppression is discussed in U.S. Pat. No. 4,853,209, where the use of Samarium-153 ( ¹⁵³ Sm), Gadolinium-159 ( ¹⁵⁹ Gd), or Holmium-166 ( ¹⁶⁶ Ho) complexed with a ligand selected from ethylenediaminetetramethylenephosphonic acid (EDTMP), diethylenetriaminepentamethylenephosphonic acid (DTPMP), hydroxyethylethylenediaminetrimethylenephosphonic acid (HEEDTMP), nitrilotrimethylenephosphonic acid (NTMP), or tris(2-aminoethyl)aminehexamethylenephosphonic acid (TTHMP) is disclosed. Phosphonic acid-containing chelators are selected due to their ability to target the radionuclide to the bone.

U.S. Pat. Nos. 4,882,142, and 5,059,412 are directed to a method for the suppression of bone marrow and to a composition for use in the method. The method comprises administering to a mammal in need of such treatment a bone marrow suppressing amount of at least one composition comprised of a radionuclide ¹⁵³ Sm, ¹⁵⁹ Gd, or ¹⁶⁶ Ho complexed with 1,4,7,10-tetraazacyclododecanemethylenephosphonic acid as the macrocyclic chelating moiety. The method of bone marrow suppression described therein may be used in combination with chemotherapeutic drugs and/or external radiation. The compositions comprise the radionuclides in dosages comprising from about 18 to 1850 megabecquerels per kilogram of body weight of the target mammal. The amount of radioactivity delivered to the bone is necessarily lower, and was not determined.

Therefore, a continuing need exists for methodologies and agents useful for selective bone marrow suppression and/or for adequate tumor cell killing, that is, wherein the bone marrow is suppressed and/or tumor cells killed with only minimal damage to non-target soft tissues, for example, liver, urinary bladder, and kidney. There is also a need for a means of delivering high radiation doses to sites of disease in or near bone, with standard or high dose chemotherapy without increasing toxicity to non-target organs. For those situations where bone marrow support can aid in therapy or cure, it would be desirable to have a means of first selectively suppressing the abnormal or diseased bone marrow independent of, or with limited, total body irradiation.

SUMMARY OF THE INVENTION

The present invention provides a method for selectively, rapidly, and effectively suppressing bone marrow or to treat a pathology associated with (in or near) the bone or bone marrow. In one aspect, the method comprises administering to a mammal in need of such treatment a high dosage of a complex of a bone marrow suppressing radionuclide with a bone targeting ligand, such as an aminophosphonic acid. Such pathologies include cancer, autoimmune diseases, certain infections and certain hematopoietic genetic disorders.

Preferably, the radionuclide is ¹⁶⁶ Ho and the ligand is a macrocyclic aminophosphonic acid such as DOTMP. The complex is preferably administered in a single treatment dose effective to deliver at least 20 Gy to the bone marrow of the subject. The present invention also provides aqueous compositions comprising ¹⁶⁶ Ho-DOTMP and a radioprotectant that are stable for at least about 72 hours under ambient conditions.

A preferred embodiment of the invention provides a method to increase the efficacy of chemotherapy, particularly high dose or intensive chemotherapy, without a substantial increase in total side effects, and more preferably, without the need for TBI. This method comprises administering an effective bone marrow suppressing amount of a radionuclide-amino phosphonate complex to a subject in need of such treatment in conjunction with one or more chemotherapeutic agents, while maintaining an acceptable level of tolerance of the subject to the total therapeutic regimen. For example, it has been unexpectedly found that a high dosage of radiation can be delivered to the bone marrow of a subject afflicted with a bone-associated neoplasm (cancer) or non-cancerous myeloproliferative disorder in conjunction with high dose chemotherapy, such as melphalan in the case of myeloma, while not substantially increasing the side effects as compared to the side effects associated with the high dose chemotherapy alone.

For example, the use of at least about 200 mg/m ² melphalan to treat multiple myeloma can be combined with a dosage of a ¹⁶⁶ Ho aminophosphonate complex effective to deliver about 20-60 Gy, preferably about 30-50 Gy, to the bone marrow of the afflicted subject without substantially increasing the side effects over those associated with melphalan therapy alone at about 140 mg/m ² or about 200 mg/m ² . Such treatment has the advantage of providing efficacy comparable to that obtained from treatment with a combination of melphalan and TBI, without the side effects associated with TBI.

The efficacy of conventional melphalan therapy (i.e., 70-120 mg/m ² can also be enhanced by administration of the present complexes, thus improving the outcome for older patients. Therefore, the efficacy of current treatment regimens to treat multiple myeloma, e.g., 140 mg/m ² melphalan plus TBI or 200 mg/m ² melphalan alone, can be substantially enhanced without substantial increase in side effects, e.g., those due to melphalan and/or TBI used without the complex.

The preferred radionuclide compositions employed in the method of the present invention are capable of delivering a significant portion, preferably greater than about 15%, e.g., about 25-35% of the radioactivity present in the composition to bone tissue while not deleteriously affecting non-target soft tissues. Therefore, for those disease states where the treatment regimen requires bone marrow suppression, the present invention is particularly advantageous since it provides a means of achieving selective reduction in the hemopoietic cell population, without having to resort to external irradiation of the subject, e.g., to TBI, resulting in minimal damage to non-target tissues. The reduction in the radiation dose delivered to non-target tissues (as compared to the use of TBI alone), provides the opportunity to use the same or increased amounts of conventional chemotherapeutic regimens, particularly non-radioactive antineoplastic (“anti-cancer”) agents that per se suppress bone marrow, such as alkylating agents.

It may be possible to completely eliminate the use of targeted radiation or TBI in certain patient populations, such as those under 55 years of age, while retaining equivalent efficacy. It may also be possible to increase the efficacy of regimens in which TBI is desirable, but too hazardous to use, as in older patients (>55 years of age). However, if it is desirable to employ targeted irradiation or TBI in conjunction with the bone marrow suppression method described herein, for example, in the treatment of leukemia, it can be possible to reduce the radiation dosage used for the total body irradiation and still obtain the same or higher level of reduction of leukemic cells.

Preferred radionuclide complexes comprise radionuclides that exhibit half-lives of sufficient length so that they can deliver preselected high doses of radiation after bone-targeting and soft tissue clearance, but which exhibit half-lives sufficiently short so that they decay in a relatively short time to allow safe bone marrow or stem cell transplantation or other therapy. For example, ¹⁶⁶ Ho has an energetic beta-particle with a long path length. Yet, despite increasing the dose of ¹⁶⁶ Ho from about 20 Gy to about 50 Gy to the marrow along with moderately high or very high doses of chemotherapy, there has been surprisingly no increase in toxicity to other organs beyond that expected from the chemotherapy itself and, surprisingly, no evidence of delay or difficulty in engraftment of marrow or stem cell transplant due to direct toxicity to the bone marrow space. The rapid radioactive decay also unexpectedly permits subsequent use of high dose chemotherapy, since cumulative effects are avoided or lessened. Thus, the present method provides the basis for a potent combination therapy, particularly with respect to cancers that are associated with bone, because additive toxic side effects are readily avoided.

In one aspect of the invention, the complex of the macrocyclic aminophosphonic acid, 1,4,7,10-tetraazacyclododecane, and ¹⁶⁶ Ho was found to deliver higher doses of radiation to the bone or to adjacent areas than previously thought possible, without undue deleterious side effects. A preferred ratio of DOTMP to ¹⁶⁶ Ho is above 3; preferably about 3.5-5, most preferably about 3.5.

Furthermore, it was unexpectedly found that bone marrow can be ablated effectively with a single dose or with closely spaced dosing regimens, further reducing the handler's exposure to radiation. As used herein, the term “single dosage” or “single dose” means that the total dosage of radionuclide complex is administered in one (1) or more doses within a short period of time, e.g., less than about 24 hours. Preferably the doses will be administered within about 12 hours, more preferably within about 8 hours. Most preferably the doses will be administered within about 0.1-4 hours. Preferably the dose will be also administered as a single infusion or injection.

Preferably, an effective bone marrow suppressing dose of a radionuclide aminophosphonic acid complex, such as ¹⁶⁶ Ho-DOTMP will administer a total dose of 20-60 Gy, preferably about 30-50 Gy and, most preferably, about 37-45 Gy of radiation to the bone/bone marrow of the subject. At about 30% uptake, e.g., for a human subject, total therapy dose to bone marrow is about 500-4000 mCi (about 18.5-148 GBq).

Because the actual percentage of the administered dose of radiation that reaches the bone/bone marrow necessarily varies from subject to subject, the present method also preferably comprises the steps of first administering a dose (the “diagnostic or dosimetry dose”) of a radionuclide complex effective to determine the dosage required to subsequently deliver an effective therapy dose or doses, and then determining the percent uptake of the diagnostic or dosimetry dose by the bone of the subject, e.g., via whole body retention measurements. Although a radionuclide other than the intended therapeutic radionuclide can be used for dosimetry measurements, it is preferable to use the same radionuclide for dosimetry measurements and for therapy.

The administered dosage can, in some cases where patients have relatively low uptake in the skeleton, contain from about 2000 to about 2750 megabecquerels (MBq) per kilogram of body weight of said mammal. The most preferred dosage contains from about 2000 to about 2500 megabecquerels per kilogram of body weight of said mammal.

The dosing is preferably accomplished with a radionuclide complex emitting a beta energy of >0.5 MeV and having a radionuclide half-life of less than 5 days, most preferably <3 days, at a beta energy of >1 MeV. Preferred radionuclides include radionuclides selected from the group consisting of ¹⁵³ Sm, ⁹⁰ Y, ¹⁵⁹ Gd, ¹⁸⁶ Re, ¹⁸⁸ Re, and ¹⁶⁶ Ho (half-life 26.8 hr.) complexed with a bone targeting complexing ligand.

The radionuclide complexes can be administered alone or in combination with adjuvant bioactive agents, that act in conjunction with the localized complex in order to treat diseases, such as disease or pathologies associated with (at or near) mammalian bone (including bone marrow and associated tissue or cells). Such agents include antineoplastic chemotherapeutic agents known to the art. The complex can be delivered at a dose that itself is effective without the use of a chemotherapeutic agent or irradiation from an external source. Such regimens are particularly effective to treat cancers such as leukemia, myeloma, metastatic breast or metastatic prostate cancer, Hodgkin's lymphoma, osteosarcoma, Ewing's sarcoma or Paget's disease.

Following treatment with an amount of the present complexes, and, optionally, with external irradiation, growth factor support, chemotherapy, hormone therapy, or immunosuppressive therapy, the subject's bone marrow can be augmented by blood marrow restoration, or regenerated, as by transplantation with purged autologous or matched allogeneic bone marrow (including peripheral blood stem cells), and/or by treatment with bone marrow-stimulating agents.

The preferred chelating agents useful for practicing the present invention are polyaminophosphonic acid chelators, such as, for example, ethylenediaminetetramethylenephosphonic acid (EDTMP), diethylenetriaminepentamethylenephosphonic acid (DTPMP), hydroxyethylethylenediaminetrimethylenephosphonic acid (HEEDTMP), nitrilotrimethylenephosphonic acid (NTMP), 1,4,7,10-tetraazacyclododecanetetramethylenephosphonic acid (DOTMP), tris(2-aminoethyl)aminehexamethylenephosphonic acid (TTHMP), 1-carboxyethylenediamine-tetramethylenephosphonic acid (CEDTMP), hydroxyethylidene diphosphonate (HEDP), bis(aminoethylpiperazine)tetramethylenephosphonic acid (AEPTMP), N-methylethylenediaminetrimethylenephosphonic acid (MEDTMP), N-isopropylethylenediaminetriemthylenephosphonic acid (IEDTMP), N-benzylethylenediaminetrimethylenephosphonic acid (BzEDTMP), methylene diphosphonate, hydroxymethylene diphosphonate, ethane-1-hydroxy-1,1-diphosphonic acid, and the like. Other useful chelating agents for radionuclides are generally disclosed in U.S. Pat. Nos. 5,059,412, 5,066,478, 5,300,279 and 4,897,254.

Preferred macrocyclic aminophosphonic acids are of the structure:

wherein substituents A, B, C, and D are independently selected from hydrogen, hydrocarbon radicals having from 1-8 carbon atoms,

and physiologically acceptable salts of the acid radicals wherein X and Y are independently selected from the group consisting of hydrogen, hydroxyl, carboxyl, phosphonic, and hydrocarbon radicals having from 1-8 carbon atoms and physiologically acceptable salts of the acid radicals, and n is 1-3 with the proviso that when n>1, each X and Y may be the same as or different from the X and Y of any other carbon atom; X′ and Y′ are independently hydrogen, methyl, or ethyl radicals, and n′ is 2 or 3, with the proviso that at least two of said nitrogen substituents is a phosphorus containing group, i.e., wherein N and P are connected by alkylene or substituted alkylene.

A more preferred macrocyclic aminophosphonic acid ligand is 1,4,7,10-tetraazacyclododecanetetramethylenephosphonic acid (DOTMP). See, e.g., U.S. Pat. Nos. 4,973,333 and 5,714,604.

The present method can also be employed to treat pathologies other than cancer associated with (at or near) mammalian bone, that can be ameliorated by partial bone marrow suppression or by complete bone marrow ablation followed by bone marrow transplantation. The treatment can be accomplished by delivering i.e., 250-3000 megabecquerels per kg of body weight of the complex to the subject to be treated. Such pathologies include, but are not limited to, immunological disorders such as autoimmune diseases, e.g., Crohn's disease, rheumatoid arthritis or multiple sclerosis; metabolic diseases, such as osteoporosis or osteopenia; infections and infectious disease such as tuberculosis or blastomycoses, inflammatory diseases such as osteomyelitis or Paget's disease; hematopoietic disorders, and conditions treatable with stem cell transplantation, with or without gene therapy, that utilize bone marrow ablation, such as sickle cell anemia and lysosomal and peroxisomal storage diseases.

The present invention also provides novel liquid compositions, preferably aqueous compositions, comprising ¹⁶⁶ Ho-DOTMP combined with an effective stabilizing amount of ascorbic acid, gentisic acid, or other radio-stable stabilizing agent buffered to pH 7-8, as well as methods for preparing the compositions. The ascorbic acid, gentisic acid, and the like, maintain the radionuclide complex stability and reduces the amount of free radionuclide delivered in vivo. For example, ascorbic acid or gentisic acid may be present in the unit dosage forms useful in the practice of the present invention at about 35-75 mg/ml of composition. Stabilization unexpectedly inhibits radiolytic degradation of the complexes, i.e., so high (300 mCi/ml (12 GBq/ml)) levels of ¹⁶⁶ Ho-DOTMP can be maintained in the dosage forms, and thus allows distribution to hospitals at high levels of purity, with high levels of ¹⁶⁶ Ho-DOTMP.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 is a graphical representation of the uptake of ¹⁶⁶ Ho-DOTMP in bones and non-target organs.

FIGS. 2-4 are graphical representations of a comparison of the uptake of ¹⁶⁶ Ho-DOTMP in bones and non-target organs when using a stabilizer.

DETAILED DESCRIPTION OF THE INVENTION

As used herein, the term “mammal” means a warm blooded mammal, including humans, and is meant to encompass mammals in need of bone marrow suppression, especially humans; thus in some instances the term “patient” or “subject” is alternatively used for mammal.

The term “disease” includes pathologies and deleterious conditions, such as inflammatory responses, cancer, autoimmune, and genetic disorders.

The term “bone marrow restoration” includes partial or complete regeneration or augmentation of the bone marrow by marrow transplantation or hematopoietic stem cell transplantation and/or stimulation of bone marrow regeneration by administration of growth factors such as cytokines, glycoproteins and the like.

As used herein, the term “bone marrow transplant (BMT)” includes autologous, allogenic, xenogeneic marrow transplantation and stem cell transplantation.

The term “bone marrow suppression” refers to partial or essentially total eradication (“ablation” or “myeloablation”) of the bone marrow, in particular a temporary or permanent reduction of the hemopoietic stem cell population.

A sub-ablative therapy is one that does not completely eradicate bone marrow, e.g., the marrow may recover, particularly if hematopoietic cell growth factors are administered.

As used herein, the term that external irradiation (targeted or TBI) is not used “in conjunction with” the radionuclide complex and, optionally, chemotherapy, is intended to mean that external irradiation is not employed as part of the same treatment protocol. For example, a patient could have received external radiation treatment as part of a previous treatment protocol and still be considered not to have received external radiation “in conjunction with” treatment with the radionuclide complex. Thus, the term “inconjunction with” is intended to mean administration as part of the same protocol radionuclide complex, in order to accomplish the recited therapeutic effect, e.g., bone marrow suppression.

As used herein, the term “substantial” when used with respect to the side effects of chemotherapy or radiation therapy is to be understood by reference to the art-recognized definitions and scales employed in the working examples.

As used herein, the term “high dose” refers to a dose that is in the upper range of the dose used in conventional therapy to treat a particular pathology, as recognized by the art. As defined in Example 10, this can include the MTD+10%. The dose range and highest typical dose for certain chemotherapeutic agents is given herein below for illustration.

The present invention is directed to compositions and methods for suppressing bone marrow and/or treating a disease in or near the bone or bone marrow that is ameliorated by said suppression. The present invention has significant benefits in that it permits rapid and selective bone marrow suppression (the bone marrow can be suppressed with only minimal damage to non-target soft tissues, such as, for example, lung, liver, stomach, mucosal linings and the like) without the need for sustained exposure to radiation or for exposure to a large, >about 15-20:1, molar ratio of chelating agent to radionuclide. The complexes of the invention can also be administered prophylatically or in an adjuvant setting with little evidence of disease but likelihood of recurrence from minimal disease presence, e.g., to minimize the probability of metastases of established cancer.

As will be more fully discussed later herein, the properties of the radionuclide, and of the radionuclide aminophosphonic acid complex are important c