Ligand/lytic peptide compositions and methods of use

Details Ligand/lytic peptide compositions and methods of use Ligand/lytic peptide compositions and methods of use

1999-09-24

2003-10-21

Low, Christopher S. F. (Department: 1653)

Chemistry: natural resins or derivatives; peptides or proteins;

Peptides of 3 to 100 amino acid residues

25 or more amino acid residues in defined sequence

C530S325000, C530S326000, C530S327000, C514S012200, C514S013800, C514S014800, C514S015800

Reexamination Certificate

active

06635740

ABSTRACT:

TECHNICAL FIELD
This invention pertains to compositions and methods for specifically inhibiting cells that are driven by or are dependent on specific ligand interactions. Examples are compositions and methods for long-term contraception or sterilization; compositions and methods for inhibiting or killing malignant and non-malignant, hormone-dependent tumors; compositions and methods for selectively killing virally infected cells; and compositions and methods for selectively destroying lymphocytes responsible for autoimmune disorders.
BACKGROUND ART
Compositions that have sometimes been used for long-term contraception include those based upon natural or synthetic steroidal hormones to “trick” the female reproductive tract into a “false pregnancy.” These steroidal hormones must be administered repeatedly to prevent completion of the estrous cycle and conception. Steroids have side effects that can be potentially dangerous.
P. Olson et al., “Endocrine Regulation of the Corpus Luteum of the Bitch as a Potential Target for Altering Fertility,”
J. Reprod. Fert. Suppl
., vol. 39, pp. 27-40 (1989) discusses the luteal phase and its regulation in bitches. The following discussion appears at page 37: “Specific toxins can be linked to an antibody or hormone and carried to a specific target cell (or cells) which is then killed by the toxin. The idea of developing a ‘magic bullet’ has been discussed for decades but is now gaining renewed recognition as a potential, highly selective method for destroying specific tissues while leaving other tissues unharmed. For many years it was impossible to develop large quantities of antibodies which would react specifically with only single antigenic determinants. However, with the advent of monoclonal antibodies, this problem has been largely overcome. Antibodies can be developed to specific hormone receptors (such as the LH receptor) and then coupled to a toxin. All cells with LH receptors should then be destroyed. Although various cell types have not been characterized in dog corpora lutea, destruction of any luteal cell type could potentially result in luteolysis if cell types communicate.” (citations omitted)
P. Olson et al., “New Developments in Small Animal Population Control,”
JAVMA
, vol. 202, pp. 904-909 (1993) gives an overview of methods for preventing or terminating unwanted pregnancies in small animals. The following discussion appears at page 905: “Tissue-specific cytotoxins—Permanent contraception in females and males might be achieved by administration of a cytotoxin that is linked to gonadotropin-releasing hormone (GnRH) and that selectively destroys gonadotropin-secreting pituitary cells. Similarly, a cytotoxin linked to antibodies against gonadotropin receptors could be targeted to alter gonadal function. Toxins would need to be carefully targeted to specific cells, yet be safe for all other body tissues.” (citation omitted).
T. Janaky et al., “Short Chain Analogs of Luteinizing Hormone-Releasing Hormone Containing Cytotoxic Moieties,”
Proc. Natl. Acad. Sci. USA
, vol. 89, pp. 10203-10207 (1992) discloses the use of certain hexapeptide and heptapeptide analogs of GnRH as carriers for certain alkylating nitrogen mustards, certain anthraquinone derivatives, antimetabolite, and cisplatin-like platinum complex. The authors reported that several of the compounds exerted some cytotoxic effects on the MCF-7 breast cancer cell line.
D. Fitzgerald et al., “Targeted Toxin Therapy for the Treatment of Cancer,”
J. Natl. Cancer Inst
., vol. 81, pp. 1455-1463 (1989), reviewed targeted toxin therapies for cancers, including conjugating toxins such as Pseudomonas exotoxin, diphtheria toxin, and ricin to a cell-binding protein such as a monoclonal antibody or a growth factor. The conjugates are then internalized into cytoplasm, where the toxin disrupts cellular activity.
Conventional targeted toxin therapies have several drawbacks. There is a small window for treatment with a particular targeted toxin (on the order of two weeks) before the recipient's immune system mounts an antibody response to the targeted toxin. These antibodies will neutralize the toxin; or worse, may result in deposition of the toxin in reticuloendothelial tissues (e.g., liver, spleen, lymph nodes, lungs, bone marrow), where they may damage otherwise healthy tissue. Aside from this drawback, the toxin must be internalized by the targeted cell and translocated into the cytoplasm to have effect.
A related approach is to link a monoclonal antibody to an enzyme. This conjugate is directed specifically to a tumor cell surface antigen. A prodrug is then administered to the patient. The prodrug is substantially less toxic than the drug that results from activation of the drug at the tumor site by the conjugated enzyme. The activated drug then erectively attacks tumor cells. See, e.g., D. Kerr et al., “Regressions and Cures of Melanoma Xenografts following Treatment with Monoclonal Antibody &bgr;-Lactamase Conjugates in Combination with Anticancer Prodrugs,”
Cancer Research
, vol. 55, pp. 3558-3563 (1995); and H. Svensson et al., “In Vitro and In Vivo Activities of a Doxorubicin Prodrug in Combination with Monoclonal Antibody &bgr;-Lactamase Conjugates,”
Cancer Research
, vol. 55, pp. 2357-2365 (1995).
S. Sealfon et al., “Molecular mechanisms of ligand interaction with the gonadotropin-releasing hormone receptor,”
Endocrine Reviews
, vol. 18, pp. 180-205 (1997) provides a review of research concerning the interaction between GnRH and its receptor.
F. Hu et al., “Theophylline and Melanocyte-Stimulating Hormone Effects on Gamma-Glutamyl Transpeptidase and DOPA Reactions in Cultured Melanoma Cells,”
J. Investigative Dermatology
, vol. 79, pp. 57-61 (1982) disclosed that theophylline and melanocyte-stimulating hormone (MSH) both enhanced pigmentation in murine melanoma cells, apparently by different mechanisms. J. Murphy et al., “Genetic Construction, Expression, and Melanoma-Selective Cytotoxicity of a Diphtheria Toxin-Related &agr;-Melanocyte-Stimulating Hormone Fusion Peptide,”
Proc. Natl. Acad. Sci. USA
, vol. 83, pp. 8258-8262 (1986) discloses selective activity against melanoma cells in vitro by an MSH-diphtheria toxin conjugate. See also D. Bard, “An Improved Imaging Agent for Malignant Melanoma, Based on [Nle
4
, D-Phe
7
]&agr;-Melanocyte Stimulating Hormone,”
Nucl. Med. Comm
., vol. 16, pp. 860-866 (1995).
W. Siegrist et al., “Homologous and Heterologous Regulation of &agr;-Melanocyte-Stimulating Hormone Receptors in Human and Mouse Melanoma Cell Lines,”
Cancer Research
, vol. 54, pp. 2604-2610 (1994) reports that it is well-established that human melanoma cells possess specific high affinity receptors for &agr;-MSH. See also J. Tatro et al., “Melanotropin Receptors Demonstrated In Situ in Human Melanoma,”
J. Clin. Invest
., vol. 85, pp. 1825-1832 (1990).
P. Bacha et al., “Thyrotropin-Releasing Hormone-Diphtheria Toxin-related Polypeptide Conjugates,”
J. Biol. Chem
., vol. 258, pp. 1565-1570 (1983) discloses conjugates of thyrotropin-releasing hormone (TRH) with two diphtheria toxins; one of these conjugates caused a 50% inhibition of protein synthesis in rat GH
3
pituitary cells at 3×10
−9
M concentration. See also P. Bacha et al., “Organ-Specific Binding of a Thyrotropin-Releasing Hormone-Diphtheria Toxin Complex after Intravenous Administration to Rats,”
Endocrinology
, vol. 113, pp. 1072-1076 (1983).
V. Chaudhary, “Activity of a Recombinant Fusion Protein between Transforming Growth Factor Type &agr; and Pseudomonas toxin,”
Proc. Natl. Acad. Sci. USA
, vol. 84, pp. 4538-4542 (1987) discloses that a fusion protein of a modified Pseudomotias toxin and transforming growth factor type &agr; selectively kills cells expressing epidermal growth factor receptors. See also D. Cawley et al., “Epidermal Growth Factor-Toxin A Chain Conjugates: EGF-Ricin
1
s a Potent Toxin while EGF-Diphtheria Fragment A is Nontoxic,”
Cell
, vol. 22, pp. 563-570 (1980).
E. Viterta et al., “Redesigning Nature's Poisons to Create Anti-Tumor Reagents,”
Sci

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