Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Peptide containing doai
Reexamination Certificate
1999-11-09
2004-07-27
Carlson, Karen Cochrane (Department: 1653)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Peptide containing doai
C514S012200, C514S311000, C514S016700, C530S350000, C530S300000, C435S007100, C435S006120
Reexamination Certificate
active
06767889
ABSTRACT:
FIELD OF THE INVENTION
The invention relates to therapeutic compounds and methods for inhibiting angiogenesis.
BACKGROUND OF THE INVENTION
Angiogenesis
Angiogenesis is the process in which new blood vessels grow into an area which lacks a sufficient blood supply. Angiogenesis commences with the erosion of the basement membrane surrounding endothelial cells and pericytes forming capillary blood vessels. Erosion of the basement membrane is triggered by enzymes released by endothelial cells and leukocytes. The endothelial cells then migrate through the eroded basement membrane when induced by angiogenic stimulants. The migrating cells form a “sprout” off the parent blood vessel. The migrating endothelial cells proliferate, and the sprouts merge to form capillary loops, thus forming a new blood vessel.
Angiogenesis can occur under certain normal conditions in mammals such as in wound healing, in fetal and embryonic development, and in the formation of the corpus luteum, endometrium and placenta. Angiogenesis also occurs in certain disease states such as in tumor formation and expansion, or in the retina of patients with certain ocular disorders. Angiogenesis can also occur in a rheumatoid joint, hastening joint destruction by allowing an influx of leukocytes with subsequent release of inflammatory mediators.
The evidence for the role of angiogenesis in tumor growth was extensively reviewed by O'Reilly and Folkman in U.S. Pat. No. 5,639,725, the entire disclosure of which is incorporated herein by reference. It is now generally accepted that the growth of tumors is critically dependent upon this process. Primary or metastatic tumor foci are unable to achieve a size of more than approximately 2 mm in the absence of neovascularization. Serial evaluation of transgenic mice predisposed to develop neoplasms has demonstrated that neovascularization of premalignant lesions precedes their evolution into tumors (Folkman et al.,
Nature
339:58-61, 1989), and that inhibition of angiogenesis delays the growth of such lesions, as well as their assumption of a malignant phenotype (Hanahan et al.,
Cell
86:353-364, 1996). In humans, several studies have demonstrated that increased density of microvessels within a tumor is associated with a poor clinical outcome (Weidner et al.,
J Natl Cancer Inst
84:1875-1887, 1992).
An emerging paradigm is that proteolytic fragments of plasma or extracellular matrix proteins regulate angiogenesis. To date, several polypeptides with such activities have been identified. These include angiostatin, which contains kringles 1-4 plasminogen (O'Reilly et al.,
Cell
79:315-328, 1994), endostatin, a 20 kD C-terminal fragment of collagen XVIII (O'Reilly et al.,
Cell
88:277-285, 1997), PEX, the hemopexin domain of matrix metalloprotease 2 (Brooks et al.,
Cell
92:391-400, 1998), the C-terminal 16 kD fragment of prolactin (Clapp et al.,
Endocrinol
133:1292-1299, 1993) and a 29 kD fragment of fibronectin (Homandberg et al.,
Am J Pathol
120:327-332; 1985). In addition, both intact thrombospondin 1 as well as peptides derived from its procollagen domain and properdin-like type-1 repeats express potent anti-angiogenic activity (Good et al.,
Proc Nat Acad Sci USA
87:6624-6628,1990); Tolsma et al.,
J Cell Biol
122:497-511, 1993. In preclinical models, several of these fragments inhibited tumor growth, and some induced tumor regression and dormancy (Boehm et al.,
Nature
390:404-407, 1997).
High Molecular Weight Kininogen
High molecular weight kininogen (HK) is a 120 kD glycoprotein containing heavy and light chains, comprised of domains 1 through 3, and 5 and 6, respectively (Kaplan et al.,
Blood
70:1-15, 1987). The heavy and light chains are linked by domain 4, which contains bradykinin, a nonapeptide which mediates several events including NO-dependent vasodilation (Weimer et al.,
J Pharm Exp Therapeutics
262:729-733, 1992). HK (also referred to as “single chain high molecular weight kininogen”) binds with high affinity to endothelial cells, where it is cleaved to two-chain high molecular weight kininogen (HK
a
) by plasma kallikrein. Bradykinin is released from HK through cleavage mediated by plasma kallikrein (Kaplan et al.,
Blood
70:1-15, 1987). This event occurs on the surface of endothelial cells following the activation of prekallikrein to kallikrein by an endothelial cell protease (Motta et al.,
Blood
91:515-528, 1998). Cleavage of HK to form HK
a
and release bradykinin occurs between Lys(362) and Arg(363). HK
a
contains a 62 kD heavy chain and a 56 kD light chain linked by a disulfide bond.
Conversion of HK to HK
a
is accompanied by a dramatic structural rearrangement, which has been demonstrated using rotary shadowing electron microscopy (Weisel et al.
J. Biol Chem
269:10100-10106, 1994). HK
a
, but not HK, has been shown to inhibit the adhesion of endothelial and other cell types to vitronectin (Asakura,
J. Cell Biol
116:465-476, 1992).
Although the binding of HK to endothelial cells has been well characterized, comparatively little attention has been devoted to endothelial cell binding of H
a
. Furthermore, although binding of bradykinin to endothelial cells induces well-defined responses, functional consequences of the direct binding of HK
a
have not been reported.
SUMMARY OF THE INVENTION
The compounds of the present invention are in the form of peptides which possess anti-angiogenic activity.
In all embodiments, the peptide may optionally comprise an amino-terminal and/or carboxy-terminal protecting group.
A compound of the formula X
1
-His-Lys-X-Lys-X
2
(hereinafter “X
1
-His-Lys-X-Lys-X
2
peptide”) is provided wherein
X is any amino acid,
X
1
is from zero to twelve amino acids, more preferably from zero to six amino acids, most preferably from zero to three amino acids, and
X
2
is from zero to twelve amino acids, more preferably from zero to six amino acids, most preferably from zero to three amino acids.
Preferably, X is an amino acid having a nonpolar side chain, i.e., Ala, Leu, Ile, Val, Pro, Phe, Trp, or Met; or X is an amino acid having a polar side group which is uncharged at pH 6.0 to 7.0, the zone of physiological pH, i.e., Ser, Thr, Tyr, Asn, Gln, Cys, or Gly. Most preferably, X is Asn, Phe or His.
Preferred compounds comprise fragments of HK. In one group of such preferred compounds,
X
1
is
(i) zero amino acids, or
(ii) the segment His-Gly-His-Glu-Gln-Gln-His-Gly-Leu-Gly-His-Gly (SEQ ID NO:1) or N-terminal truncation fragment thereof containing at least one amino acid, and
X
2
is
(i) zero amino acids, or
(ii) the segment Leu-Asp-Asp-Asp-Leu-Glu-His-Gln-Gly-Gly-His-Val (SEQ ID NO:2), or C-terminal truncation fragment thereof containing at least one amino acid.
In another group of such preferred compounds,
X
1
is
(i) zero amino acids, or
(ii) the segment Gly-His-Lys-His-Lys-His-Gly-His-Gly-His-Gly-Lys (SEQ ID NO:3) or N-terminal truncation fragment thereof containing at least one amino acid, and
X
2
is
(i) zero amino acids, or
(ii) the segment Gly-Lys-Lys-Asn-Gly-Lys-His-Asn-Gly-Trp-Lys-Thr (SEQ ID NO:4) or C-terminal truncation fragment thereof containing at least one amino acid.
According to a further preferred embodiment of the invention, the compound has a substantial amino acid homology to either the amino acid sequence His-Gly-His-Glu-Gln-Gln-His-Gly-Leu-Gly-His-Gly-His-Lys-Phe-Lys-Leu-Asp-Asp-Asp-Leu-Glu-His-Gln-Gly-Gly-His-Val (SEQ ID NO:5), or the amino acid sequence Gly-His-Lys-His-Lys-His-Gly-His-Gly-His-Gly-Lys-His-Lys-Asn-Lys-Gly-Lys-Lys-Asn-Gly-Lys-His-Asn-Gly-Trp-Lys-Thr (SEQ ID NO:6).
Exemplary and preferred compounds include:
(a) His-Gly-His-Glu-Gln-Gln-His-Gly-Leu-Gly-His-Gly-His-Lys-Phe-Lys-Leu-Asp-Asp-Asp-Leu-Glu-His-Gln-Gly-Gly-His-Val (SEQ ID NO:5);
(b) Gly-His-Lys-Phe-Lys-Leu-Asp-Asp-Asp-Leu-Glu-His-Gln-Gly-Gly-His (SEQ ID NO:7);
(c) Gly-His-Lys-His-Lys-His-Gly-His-Gly-His-Gly-Lys-His-Lys-Asn-Lys-Gly-Lys-Lys-Asn-Gly-Lys-His-Asn-Gly-Trp-Lys-Thr (SEQ ID NO:6);
(d) Lys-His-Gly-His-Gly-His-Gly-Lys-His-Lys-Asn-Lys-Gly-Lys-Lys-Asn (SEQ ID NO:8); and
(e) His-Lys-Asn-Lys-Gly-Lys-Lys-
Carlson Karen Cochrane
Drinker Riddle & Reath LLP
Robinson Hope A.
Temple University of the Commonwealth System of Higher Education
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