Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Peptide containing doai
Reexamination Certificate
1998-08-11
2001-06-26
Hendricks, Keith D. (Department: 1652)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Peptide containing doai
C514S012200, C514S013800, C514S014800, C514S015800, C514S016700, C514S017400, C530S300000, C530S324000, C530S326000, C530S327000, C530S328000, C530S329000, C530S330000, C530S350000, C530S380000, C530S381000
Reexamination Certificate
active
06251867
ABSTRACT:
TECHNICAL FIELD
The present invention relates to the field of peptide chemistry. More particularly, the invention relates to the preparation and use of peptides containing amino acid sequences substantially similar to the corresponding sequences of the kringle 5 region of mammalian plasminogen, pharmaceutical compositions containing the peptides, antibodies specific for the angiostatin receptor, means for angiostatin detection and measurement, cytotoxic agents linked to angiostatin proteins and treatment of diseases which arise from or are exacerbated by angiogenesis.
BACKGROUND OF THE INVENTION
Angiogenesis, the process by which new blood vessels are formed, is essential for normal body activities including reproduction, development and wound repair. Although the process is not completely understood, it is believed to involve a complex interplay of molecules which regulate the growth of endothelial cells (the primary cells of capillary blood vessels). Under normal conditions, these molecules appear to maintain the microvasculature in a quiescent state (i.e. one of no capillary growth) for prolonged periods which may last for as long as weeks or, in some cases, decades. When necessary (such as during wound repair), these same cells can undergo rapid proliferation and turnover within a 5 day period (Folkman, J. and Shing, Y.,
The Journal of Biological Chemistry,
267(16), 10931-10934, and Folkman, J. and Klagsbrun, M.,
Science,
235, 442-447 (1987).
Although angiogenesis is a highly regulated process under normal conditions, many diseases (characterized as angiogenic diseases) are driven by persistent unregulated angiogenesis. Otherwise stated, unregulated angiogenesis may either cause a particular disease directly or exascerbate an existing pathological condition. For example, ocular neovacularization has been implicated as the most common cause of blindness and dominates approximately 20 eye diseases. In certain existing conditions, such as arthritis, newly formed capillary blood vessels invade the joints and destroy cartilage. In diabetes, new capillaries formed in the retina invade the vitreous, bleed, and cause blindness. Growth and metastasis of solid tumors are also dependent on angiogenesis (Folkman, J.,
Cancer Research,
46, 467-473 (1986), Folkman, J.,
Journal of the National Cancer Institute,
82, 4-6 (1989). It has been shown, for example, that tumors which enlarge to greater than 2 mm must obtain their own blood supply and do so by inducing the growth of new capillary blood vessels. Once these new blood vessels become embedded in the tumor, they provide a means for tumor cells to enter the circulation and metastasize to distant sites such as liver, lung or bone (Weidner, N., et al.,
The New England Journal of Medicine,
324(1), 1-8 (1991).
To date, several naturally occurring angiogenic factors have been described and characterized (Fidler, J. I. and Ellis, L. M.,
Cell,
79, 185-189 (1994). Recently, O'Reilly, et al. have isolated and purified a 38 kilodalton (kDa) protein from serum and urine of tumor-bearing mice that inhibits endothelial cell proliferation (O'Reilly, M. et al.,
Cell,
79, 315-328 (1994) and International Application WO 95/29242, published Nov. 2, 1995. Microsequence analysis of this endothelial inhibitor showed 98% sequence homology to an internal fragment of murine plasminogen. Angiostatin, as the murine inhibitory fragment was named, was a peptide which included the first four kringle regions of murine plasminogen. A peptide fragment from the same region of human plasminogen (i.e. containing kringles 1-4) also strongly inhibited proliferation of capillary endothelial cells in vitro and in vivo. The intact plasminogen from which this peptide fragment was derived did not possess as potent an inhibitory effect.
Several angiogenesis inhibitors are currently under development for use in treating angiogenic diseases (Gasparini, G. and Harris, A. L.,
J. Clin. Oncol.,
13(3): 765-782, (1995), but there are disadvantages associated with these compounds. Suramin, for example, is a potent angiogenesis inhibitor but causes severe systemic toxicity in humans at doses required for antitumor activity. Compounds such as retinoids, interferons and antiestrogens are safe for human use but have weak antiangiogenic effects.
Thus, there is a need for compounds useful in treating angiogenic diseases in mammals. More specifically, there is a need for angiogenesis inhibitors which are safe for therapeutic use and which exhibit selective toxicity with respect to the pathological condition such as by selectively inhibiting the proliferation of cancer cells while exhibiting no or a low degree of toxicity to normal (ie. non-cancerous) cells. Such compounds should also be easily and cost-effectively made.
SUMMARY OF THE INVENTION
In its principle embodiment, the present invention provides a kringle 5 peptide fragment represented by the structural formula
A-B-C-X-Y (I),
or a pharmaceutically acceptible salt thereof, wherein
A is absent or a nitrogen protecting group;
Y is absent or a carboxylic acid protecting group;
B is absent, a naturally-occuring amino acid residue or a peptide of between 2 and 197 amino acids (inclusive), the &agr;-N-terminal optionally capped with A, the &agr;-C-terminal optionally capped with Y and a substantial sequence homology to the corresponding amino acid sequence from Asp
334
to Arg
530
(inclusive) of SEQ ID NO: 1;
C is absent or R
1
-R
2
-R
3
-R
4
wherein
R
1
is lysyl,
R
2
is selected from leucyl and arginyl,
R
3
is selected from tyrosyl, 3-I-tyrosyl and phenylalanyl and
R
4
is aspartyl,
with the proviso that at least one of B or C is present, and
X is absent, a naturally occuring amino acid residue or a peptide of between 2 and 11 amino acids (inclusive), the &agr;-N-terminal optionally capped with A, the &agr;-C-terminal optionally capped with Y and a substantial sequence homology to the corresponding amino acid sequence beginning at Tyr
535
and ending at Phe
546
of SEQ ID NO: 1.
The present invention also includes a method for treating a patient in need of antiangiogenesis therapy comprising adminstering to the patient a compound containing a kringle 5 peptide fragment.
The present invention also includes a composition for treating a patient in need of anti-angiogenesis therapy comprising a compound containing a kringle 5 peptide fragment, kringle 5 antisera, kringle 5 receptor agonists and antagonists and kringle 5 antagonists linked to cytotoxic agents either alone or in combination with a pharmaceutically acceptible excipient and/or optionally sustained release compounds to form a therapeutic composition.
The present invention also includes a composition for the treatment of a disease selected from the group consisting of cancer, arthritis, macular degeneration and diabetic retinopathy comprising a compound containing a kringle 5 peptide fragment.
The present invention also includes a composition comprising an isolated single or double-stranded polynucleotide sequence that encodes a kringle 5 peptide fragment or kringle 5 peptide fragment conjugate. Such a polynucleotide is preferably a DNA molecule. The present invention also includes a vector containing a DNA sequence encoding a kringle 5 peptide fragment or kringle 5 peptide fragment conjugate wherein the vector is capable of expressing a kringle 5 peptide fragment or kringle 5 peptide conjugate when present in a cell and a composition comprising a cell containing a vector wherein the vector contains a DNA sequence encoding a kringle 5 peptide fragment or kringle 5 peptide conjugate. The present invention further encompasses gene therapy methods whereby DNA sequences encoding a kringle 5 peptide fragment or kringle 5 peptide fragment conjugate are introduced into a patient to modify in vivo kringle 5 levels.
The present invention also includes a method of making a kringle 5 peptide fragment comprising the steps of: (a) exposing mammalian plasminogen to human or porcine elastase at a ratio of about 1:100 to about 1:300 to form a mixture of
Abbott Laboratories
Casuto Dianne
Hendricks Keith D.
Steele Gregory W.
Stole Einar
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