Drug – bio-affecting and body treating compositions – Radionuclide or intended radionuclide containing; adjuvant... – In an organic compound
Reissue Patent
2000-05-18
2002-05-21
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, C530S300000, C530S328000, C530S313000, C534S010000, C534S014000
Reissue Patent
active
RE037710
ABSTRACT:
BACKGROUND OF THE INVENTION
This invention relates to derivatives of leutenizing hormone releasing hormones (LHRH) in which one or more of the amino acid side chains contain chelating moieties that can tightly bind radionuclides.
Luteinizing hormone-releasing hormone (LHRH) is a decapeptide having the structure (<G)HWSYGLRPG-NH
2
, (SEQ ID NO:1) where <G is pyroglutamic acid. LHRH controls pituitary synthesis of the gonadotropins luteinizing hormone (LH) and follicle stimulating hormone (FSH). LH and FSH control the synthesis of sex steroids in the gonads. It has been shown that analogues of LHRH, when substituted in position 6, 10, or both, display both greater and more sustained bioactivity than native LHRH. More than 3000 LHRH peptides have been evaluated both in vitro and in vivo. See, for example, Schally et al., BASIC ASPECTS; GNRH ANALOGUES IN CANCER AND IN HUMAN REPRODUCTION, Vickery & Lunenfeld eds. Vol. 1, pp. 5-31, (Kluwer Academic Publishers, Dordecht, 1989); Schally et al., ADVANCES IN GYNECOLOGY AND OBSTETRICS, GENERAL GYNECOLOGY, Belfort et al. eds., Vol. 6, pp. 3-20 (Parthenon Publishers, Carnforth, UK, 1989); Vickery et al., Endocrine Rev. 7: 115 (1986); Dutta et al., Drugs of the Future, 13:761 (1988). Several of these analogues have been used clinically, including: [D-Leu
6
, NH-Et
10
] LHRH (Vilchez-Martinez et al., Biochem. Biophys. Res. Commun. 59:1226 (1974); [D-Trp
6
] LHRH (Coy et al., J. Med. Chem. 19:423 (1976); [D-Ser(tBu)
6
, NH-Et
10
] LHRH (Koenig et al., In: PROCEEDINGS OF THE FOURTH AMERICAN PEPTIDE SYMPOSIUM, Walter and Meienhofer eds., 883-888 (1975)); [D-Ser(tBu)
6
, NH—NH—CO—NH
2
10
] LHRH (Dutta et. al., J. Med. Chem. 21:1018 (1978); [D-Nal(2)
6
]LHRH (Nestor et al., J. Med. Chem. 25:795 (1982)).
In addition, changes in position 1, 2, 3, 6 and optionally in positions 5 and 10 of the LHRH molecule can give rise to powerful antagonists. See Karten M. J. et al., Endocrine Review 7:44 (1986) and Bajusz, S. et al., Int. J. Pept. Prot. Res. 32:425 (1988). These antagonists inhibit the release of LH and FSH from the pituitary and as such, have potential as clinical agents in the imaging, diagnosis and treatment of hormone dependent cancers such as prostate, breast, ovarian, endometrial and pancreatic cancers.
The mechanism of LHRH analogue action is related, at least in part, to the fact that the density of the LHRH receptors of human tumors may be substantially greater than the LHRH receptor density of normal cells. Furthermore, the LHRH receptors of tumor cells possess a high affinity for LHRH peptides. For example, 80% of epithelial ovarian cancers have upregulated LHRH receptor densities and the receptors also have high affinities for the LHRH peptides. See Emons et al., Cancer Res. 53:5439 (1993); Irmer et al., Cancer Res. 55:817 (1955). Similarly, LHRH receptors have also been shown to be upregulated in breast cancer tumors (Fekete et al., Endocrinol. 124:946 (1989); Fekete et al., J. Clin. Lab. Anal. 3:137 (1989), endometrial cancers (Srkalovic et al., Cancer Res. 50:1841 (1990)), prostate tumors (Srkalovic et al., Endocrinol. 127:3052 (1990)), and pancreatic cancers (Schally et al., J. Steroid Biochem. Molec. Biol. 37: 1061 (1990)).
It has been shown that analogues of LHRH will selectively bind to hormone-sensitive tumors which are characterized by an overexpression of hormone receptors on the cell surface. When LHRH responsive tumors are treated with LHRH peptide analogues the analogues bind to the receptors on the cell surface and are then internalized. See Jackson et al., Cancer Treat. Rev. 16:161 (1989). Some studies have been carried out in which LHRH agonist and antagonist derivatives containing cytotoxic moieties attached to the targeting LHRH peptide have been used to deliver the cytotoxin into the cell. LHRH analogues modified with specific cytotoxic moieties may, therefore, be useful as carriers for chemotherapeutic agents. See, for example, EP 0 450 461 A2 and EP 0 364 819 A2. It has further been shown that, provided the analogues are lipophilic, various substituents can be attached to the side chain of the amino acid at position 6 of LHRH while still retaining its activity both in vitro and in vivo. (Janaky, T. et al. Proc. Natl. Acad. Sci. USA 89:972 (1992). Cytotoxic metal complexes containing platinum, nickel, and copper attached to the side chain of lysine at position 6 have demonstrated high in vitro activity in human breast tumor cells. See Bajusz, S. et al. Proc. Natl. Acad. Sci. USA 86:6313 (1989).
Some peptides either directly possesses, or are amenable to the introduction of residues that allow direct binding of radiometals to the peptide. For example, somatostatin contains a disulfide bond that, upon reduction, provides two sulfhydryl-containing cysteine side chains that can directly bind
99m
Tc. See U.S. Pat. No. 5,225,180. See also WO 94/28942, WO 93/21962 and WO 94/23758. Complexes of this type tend, however, to be heterogeneous and unstable and, moreover, the use of free sulfhydryls in this manner limits the radiometals which can be used to label the peptide to those that tightly bind free S—H groups. This methods also suffers from the problem that direct binding of the metal to an amino acid side chain can greatly influence the peptide conformation, thereby deleteriously altering the receptor binding properties of the compound.
Alternatively, chelating agents can be introduced into peptide side chains by means of site-selective reactions involving particular amino acid residues. For example, the lysine residue at position 6 of LHRH has been directly acylated with a chelating group. Bajusz et al. supra. This method is inherently limited by the lack of selectivity available when more than one side chain can potentially react with the chelator, or when the peptide sequence does not contain an amino acid that can be derivatized in this way.
Most peptides either do not contain a metal-binding sequence motif or, for various reasons such as those described supra, are not amenable to suitable sequence modifications that would permit introduction of such a motif. Some means of rendering the peptide capable of binding radiometals must therefore be introduced into the peptide. A preferred approach is to attach a metal binding ligand to the peptide so that a single, stable complex is formed. The ligands used to bind metals often contain a variety of heteroatoms such as nitrogen, sulfur, phosphorous, and oxygen that have a high affinity for metals.
These ligands are typically attached at the N-terminus of the desired peptide. This allows the peptide chain to be constructed using conventional methods of peptide synthesis, followed by addition of the ligand once peptide synthesis is complete. For example, Maina et al. have described the coupling of a tetra-amine chelator to the N-terminus of a somatostatin analogue, which then allowed
99m
Tc labeling of the peptide. See J. Nucl. Biol. Med. 38:452 (1994). Once again, however, application of this method is limited to those circumstances in which the N-terminus of the peptide can accommodate the presence of a (usually bulky) chelator without deleteriously affecting the binding properties of the peptide.
Bajusz et al., supra also describe the incorporation of a protected, chelate-derivatized lysine residue into a growing peptide chain during peptide synthesis. This method, however, requires the preparation of a suitably derivatized lysine derivative that also bears an &agr;-amino protecting group that is compatible with peptide synthesis. It would clearly be preferable to be able to use protected amino acids derivatives that are commercially available for use in peptide synthesis, and to subsequently deprotect and derivatize appropriate amino acid side chains in a selective fashion.
It is apparent, therefore, that a means of attaching a chelating moiety to any predetermined position within a peptide is greatly to be desired. It is also desirable to have access to a method that would allow this chelating moiety to be coupl
Griffiths Gary L.
Karacay Habibe
McBride William J.
Foley & Lardner
Immunomedics Inc.
Jones Dameron L.
LandOfFree
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