Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Peptide containing doai
Reexamination Certificate
1999-12-29
2001-05-22
Davenport, Avis M. (Department: 1653)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Peptide containing doai
C514S002600, C514S012200, C514S013800, C514S014800, C530S300000, C530S324000, C530S325000, C530S326000, C530S327000, C530S328000, C424S185100
Reexamination Certificate
active
06235716
ABSTRACT:
BACKGROUND OF THE INVENTION
Anti-angiogenic therapies are potential treatments for a wide variety of diseases, including cancer, arteriosclerosis, obesity, arthritis, duodenal ulcers, cardiovascular disorders and abnormal ocular neovascularization caused, for example, by diabetes (Folkman,
Nature Medicine
1:27 (1995) and Folkman, Seminars in Medicine of the Beth Israel Hospital, Boston,
New England Journal of Medicine,
333:1757 (1995)). Anti-angiogenic therapies are thought to act by inhibiting the formation of new blood vessels.
Pro-angiogenic therapies are potential treatments for promoting wound healing and for stimulating the growth of new blood vessels to by-pass occluded ones. Thus, pro-angiogenic could potentially augment or replace by-pass surgeries and balloon angioplasty (PTCA).
The full potential of anti-angiogenic and pro-angiogenic therapies, together referred to as “angiogenic therapies”, has yet to be fully realized. One reason is because of the shortage of agents which modulate neovascularization when administered to a subject. Furthermore, known angiogenic agents suffer from a number of limitations. For example, a number of proteins, including thrombospondin 1 (hereinafter “TSP-
1
”), h-endostatin (hereinafter “endostatin”) and h-angiostatin (hereinafter “angiostatin”) are thought to have angiogenic activity. However, the cost of producing protein drugs can be prohibitively high. This concern is of a special relevance when a high dose is required in order to achieve therapeutic efficacy.
The full potential of angiogenic therapies is unlikely to be realized until the problems discussed hereinabove have been overcome.
SUMMARY OF THE INVENTION
This invention is based upon the discovery that angiogenic proteins have a region of about twenty-five amino acids which is substantially conserved among different angiogenic proteins. This region is included in the “angiogenic homology region”, also abbreviated as “AHR”. It has also been discovered that the angiogenic activity of this class of proteins is attributable, at least in part, to the AHR.
Applicant has also discovered that multivalent ligands comprising peptide derivatives of the AHR of angiogenic proteins modulate angiogenesis in mammals. A multivalent ligand has two or more peptides connected by a covalent bond or linker group to a multilinker backbone. For example, the multivalent ligands Tip-13.40 and Tip-12.40 suppress tumor growth in mice (Example 2). The peptides in Tip-13.40 are represented by SEQ ID NO. 8 and are derivatives of the AHR of TSP-1 (SEQ ID NO.: 1); the peptides in Tip-12.40 are represented by SEQ ID NO.: 7 and are derivatives of the AHR of endostatin (SEQ ID NO.: 2).
A further discovery, reported herein, is that multivalent ligands comprising peptides which are hybrids of the AHR of two different angiogenic proteins also modulate angiogenesis in mammals. For example, the multivalent ligands Tip-14.40, Tip-15.40, Tip-16.40, Tip-18.40 and Tip-19.40 suppress tumor growth in mice (Example 2). The hybrid peptides in Tip-14.40, Tip-15.40, Tip-16.40, Tip-18.40 and Tip-19.40 are represented by SEQ ID NOS.: 3, 4, 10, 11 and 12, respectively, and consist of a subsequence from the AHR of TSP-1 (SEQ ID NO.: 1) and a subsequence from the AHR of endostatin (SEQ ID NO.: 2). In contrast, the multivalent ligand Tip-17.40, which also contains hybrid peptides, stimulates tumor growth in mice.
The hybrid peptides in Tip-17.40 are represented by SEQ ID NO.: 9.
Based on the aforementioned discoveries, novel peptides which are peptide derivatives of the AHR of angiogenic peptides are disclosed. Also disclosed are novel peptides which are hybrids of the AHR of angiogenic proteins and peptide derivatives of said hybrids. Novel multivalent ligands which comprise these peptide derivatives and/or hybrid peptides and methods of modulating (inhibiting or stimulating) angiogenesis in a subject with these multivalent ligands are other aspects of the present invention.
One embodiment of the present invention is a multivalent ligand which has angiogenic activity and is represented by Structural Formula (I):
B is a multilinker backbone.
n is an integer from two to about twenty.
Each L is a covalent bond or linking group.
Each P is a peptide having from about 10 to about 30 amino acid residues. At least two of the peptides are peptide derivatives of an AHR of an angiogenic protein, a hybrid peptide or a peptide derivative of a hybrid peptide. Each P and each linker or covalent bond are independently chosen.
Another embodiment of the present invention is a polypeptide multivalent ligand having angiogenic activity. A “polypeptide multivalent ligand” is a tandem repeat polypeptide chain in which two or more peptides P are each separated by a peptide spacer. A polypeptide multivalent ligand is represented by Structural Formula (II):
m is an integer from zero to about twenty.
Each P is a peptide having from about ten to about forty amino acid residues. At least two of the peptides are peptide derivatives of an AHR of an angiogenic protein, a hybrid peptide or a peptide derivative of a hybrid peptide.
Each S is a peptide spacer having from about five to about thirty amino acids.
Each peptide P and each peptide spacer are independently chosen. The N-terminus and/or C-terminus of the polypeptide multivalent ligand is optionally substituted, as described below.
Another embodiment of the present invention is a method of modulating (stimulating or inhibiting) angiogenesis in a subject. The method comprises administering a therapeutically effective amount of a multivalent ligand represented by Structural Formula (I) or a polypeptide represented by Structural Formula (II).
The multivalent ligands of the present invention can be used to modulate angiogenesis in a subject. Thus, multivalent ligands which inhibit angiogenesis can be used to treat subjects with cancer and other diseases which respond favorably to drugs which inhibit angiogenesis. Mutlivalent ligands which stimulate angiogenesis can be used to promote wound healing or to stimulate the growth of new blood vessels to bypass, for example, blood vessel occlusions. Multivalent ligands are likely to be less expensive to produce than angiogenic protein drugs. Moreover, multivalent ligands might enable the administration of lower doses in order to achieve therapeutic efficacy, as compared with a univalent peptide chain. In addition, they can have long in vivo lifetimes and good biodistribution when administered orally or parenterally.
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patent: WO 97/15666 (1997-05-01), None
O'Reilly, M. S. et al., “Endostatin: An Endogenous Inhibitor of Angiogenesis and Tumor Growth,”Cell,88:277-285, (1997).
Kosfeld, M. D. et al., “Identification of Active Peptide Sequences in the Carboxyl-terminal Cell Bindin Domain of Human Thrombospondin-1,”The Journal of Biological Chemistry,267:16230-16236, (1992).
Kosfeld, M. D. et al., “Identification of a New Cell Adhesion Motif in Two Homologous Peptides from the COOH-terminal Cell Binding Domain of Human Thrombospondin,”The Journal of Biological Chemistry,268:8808-8814 (1993).
Tolsma, S.S. et al., “Peptides Derived from Two Separate Domains of the Matrix Protein Thrombospondin-1 Have Anti-Angiogenic Activity,”The Journal of Cell Biology,122:497-511 (1993).
Vogel, T. et al., “Modulation of Endothelial Cell Proliferation, Adhesion, and Motility by Recombinant Heparin-Binding Domain and Synthetic Peptides from the Type 1 Repeats of Thrombospondin,”Journal of Cellular Biochemistry 53:74-84 (1993).
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Children's Medical Center Corporation
Davenport Avis M.
Hamilton Brook Smith & Reynolds P.C.
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