Somatostatin analogs

Details Somatostatin analogs Somatostatin analogs

1999-09-16

2002-03-19

Jones, Dameron L. (Department: 1619)

Drug, bio-affecting and body treating compositions

Radionuclide or intended radionuclide containing; adjuvant...

In an organic compound

C424S001110, C424S001650, C424S009100, C530S311000, C530S317000, C530S329000, C534S010000, C534S014000

Reexamination Certificate

active

06358491

ABSTRACT:

This application relates to the field of cancer imaging and therapy using novel somatostatin analogs.
BACKGROUND OF THE INVENTION
Cancer is a leading cause of morbidity and mortality in developed countries. For example, approximately 1.4 million new cases of cancer and more than 0.5 million cancer deaths were reported in the U.S. in 1996. In 1995, the total annual cost of cancer care in the U.S., including direct and indirect costs, was estimated to be more than $96 billion. A great need exists for improved diagnostic and therapeutic tools to allow early detection and safe, cost-effective treatment of cancer.
Many tumors express receptors for the peptide hormone somatostatin. In particular, neuroendocrine tumors such as pituitary adenomas, pheochromocytomas, paragangliomas, some medullary thyroid carcinomas, and some small cell lung cancers express somatostatin receptors (SSTRs). In addition, cells of nervous system tumors such as astrocytomas and meningiomas display SSTRs on their surfaces. SSTR expression has also been found in human breast tumors, malignant lymphomas, and renal cell carcinomas, and some prostate tumors may be characterized by SSTR expression.
Binding studies performed with radiolabeled or iodinated somatostatin and its analogs have identified five SSTR subtypes (SSTRs
1-5
). The SSTR-bearing tumors described above express SSTR
2
and SSTR
5
most frequently, with SSTR
3
and SSTR
4
occurring less frequently, according to most authors. One group reports that SSTR
3
is expressed at very high levels in almost all human tumors (Virgolini (1997)
Eur. J. Clin. Invest.
27, 793-800). There is general agreement that most tumors typically express more than one SSTR subtype, and that varying densities of SSTRs may be expressed in the cells contained within a particular tumor. The availability of cloned SSTR subtype genes has allowed somatostatin analogs to be characterized by their affinities for SSTR
1-5
, and these studies have revealed considerable variability in SSTR subtype specificity among somatostatin analogs, as described in Raynor, et al. (1993)
Molecular Pharmacol.
43, 838-844 and in Patel, et al. (1997)
TEM
8, 398-404.
Until recently, three somatostatin analogs have been commercially available. Octreotide (Sandostatin®) binds to SSTR
2
, SSTR
3
, and SSTR
5
, and is marketed in the U.S. and Europe for treatment of acromegaly and control of symptoms associated with vipomas and metastatic carcinoid tumors. Lanreotide (Somatuline™) has a SSTR subtype profile similar to that of octreotide and is approved in several European countries for the same indications as octreotide. A radiolabeled form of octreotide,
111
In-pentetreotide (
111
In-DTPA-D-Phe
1
-octreotide or
111
In-OctreoScan®) has been approved in the U.S. and Europe for imaging neuroendocrine tumors.
Recently the U.S. Food and Drug Administration approved a new radiopharmaceutical, NeoTect™, a
99m
Tc-labeled form of the novel somatostatin analog depreotide (P829), for sale as an imaging agent. Blum, et al., (1999)
Chest
115, 224-232, describes the use of
99m
Tc-depreotide for evaluation of solitary pulmonary nodules of the lung.
99m
Tc-labeled depreotide has also been studied as an imaging agent for other somatostatin-receptor bearing tumors. For example, Handmaker (1998)
J. Nucl. Med.
39, 315P describes a comparison of
99m
Tc-depreotide and
99m
Tc-sestamibi for diagnosis of breast cancer. Depreotide is described in commonly assigned U.S. Pat. No. 6,051,206, in U.S. Ser. No. 08/253,973; and in WO 95/00553 and WO 95/33497.
A large body of literature exists relating to clinical uses of unlabeled octreotide and lanreotide. For example, as summarized in Lamberts, et al. (1996)
New England J. of Med.
334, 246-254, octreotide has been investigated for use in treating thyrotropin-secreting pituitary adenomas, nonsecretory pituitary adenomas, and corticotropin-secreting pituitary adenomas such as bronchial and thymic carcinoids, medullary thyroid carcinomas and pancreatic islet cell tumors, but not those not associated with Cushing's disease. Lamberts, et al. discloses that in general, octreotide treatment only occasionally resulted in transient inhibition of tumor growth. Lamberts, et al. further discloses that octreotide has also been studied for use in gastrointestinal and pancreatic diseases, with variable results: for example, octreotide was not effective in treating bleeding from peptic ulcers, but was effective in controlling bleeding from esophageal varices. Lamberts, et al. describes octreotide as being ineffective in the treatment of acute pancreatitis, but efficacious in reducing fluid production by pancreatic fistulas and pseudocysts. Clinical trials of octreotide for treatment of watery diarrhea in AIDS patients were also described in Lamberts, et al. Octreotide has also been studied as an anti-angiogenic agent, as summarized in Woltering, et al. (1997)
Investigational New Drugs
15, 77-86. Lanreotide has been applied to surgical wounds induced in tumor-implanted mice to study its effect on wound-induced acceleration of tumor growth, and its use has been suggested as an endocrine antisecretogogue in cytoreductive cancer treatment, in Bogden, et al. (1997)
Brit. J. Cancer
75, 1021-1027.
Despite the commercial availability of octreotide, lanreotide, and pentetreotide, a large number of somatostatin analogs have been proposed for use as imaging and/or therapeutic agents to detect and/or treat cancer and other somatostatin-responsive disease states. Patel, et al., supra, discloses the need for second generation somatostatin analogs which bind more selectively, i.e., with higher affinity, to SSTRs generally and to SSTR subtypes, in particular to SSTR
1
, SSTR
3
, and SSTR
4
. Higher affinity analogs for SSTR
2
and SSTR
5
are also desirable, so that lower dosages of somatostatin analogs may be administered to obtain a clinical response.
Second generation somatostatin analogs are described, for example, in commonly assigned U.S. Pat. Nos. 5,620,675; 5,716,596; 5,783,170; 5,814,298; 5,820,845; 5,833,942; 5,843,401; 5,871,711; 5,932,189; allowed U.S. Ser. Nos. 08/592,323; 08/586,670; 08/776,160; 08/931,095; 09/039,062; 09/039,116; 09/042,224 and 09/042,315; and copending U.S. Ser. No. 08/092,355. U.S. Pat. No. 5,597,894 discloses somatostatin analogs containing additional N-terminal amino acids. U.S. Pat. Nos. 4,310,518 and 4,486,415 and EP 143 307 and EP 222 578 disclose cyclic hexapeptide somatostatin analogs which are cyclized through peptide linkages. U.S. Pat. No. 5,708,135 discloses somatostatin analogs which are cyclized through a disulfide bond between the N-terminal residue and the C-terminal residue. U.S. Pat. No. 5,776,894 discloses somatostatin peptides having a chelating group covalently linked to an N-terminal amino group. U.S. Pat. No. 5,770,687 discloses conformationally constrained backbone cyclized somatostatin analogs. U.S. Pat. No. 5,830,431 discloses radiolabeled somatostatin analogs having carboxyl termini in the carboxylic acid form. EP 714 911 discloses DOTA-conjugated octreotide analogs. WO 96/37239 discloses
188
Re-labeled vapreotide. WO 97/01579 discloses cyclic hexapeptide somatostatin analogs having a chelating group attached to a side chain amino group of a designated amino acid. Even in light of the large number of second generation somatostatin analogs which has been proposed, research continues for somatostatin analogs with improved binding properties.
Radiolabeled forms of octreotide and lanreotide have been investigated for use as radiotherapeutic agents in preclinical and clinical studies. For example, Anderson, et al. (1996)
J. Nucl. Med.
37, 128P-129P, discloses a study of
64
Cu-labeled TETA-octreotide as a radiotherapeutic in a tumor-bearing rat model. Stolz, et al. (1996)
Digestion
57 (suppl. 1) 17-21, discloses
90
Y-DTPA-benzyl-acetamido-D-Phe
1
, Tyr
3
-octreotide in a tumor-bearing mouse model. Otte, et al. (1997)
Eur. J. Nucl. Med.
24, 792-795, discloses use of
90
Y-labeled DOTA-D-Phe
1
, Tyr
3
-octreotide to treat metast

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