Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Peptide containing doai
Reexamination Certificate
1998-07-10
2003-10-28
Romeo, David S. (Department: 1647)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Peptide containing doai
C514S014800, C514S015800, C514S016700, C514S018700, C514S019300, C530S326000, C530S328000, C530S329000, C530S330000, C530S331000
Reexamination Certificate
active
06638912
ABSTRACT:
FIELD OF THE INVENTION
The invention generally relates to compositions of biologically active components useful for therapeutic applications, such as cancer therapy, and more particularly to compositions including small peptides having (or mimicking) TGF&bgr;, activity and collagen receptor agonists.
BACKGROUND OF THE INVENTION
Cancer is a cellular proliferative disease that is characterized by failure at the level of DNA of normal regulation of growth and/or differentiation. Generally, after an initiating event, there are two stages of the disease. The first is tumorigenesis, the establishment of a cancerous growth. This amplification of cancerous cell populations is supported by increased angiogenesis, which nurtures the growth by enhancing vascular perfusion. Tumorigenesis and angiogenesis seem always to occur together. Later in the natural history of the disease metastasis, in which the cancer spreads to other tissue sites, often occurs. Metastasis results from release and migration of aberrant cells from the primary site of tumorigenesis and their subsequent attachment at distal sites where the processes of tumorigenesis and angiogenesis begin anew.
The major pathobiological processes in tumorigenesis and metastasis can be classified into three categories: cell proliferation leading to cancerous cell amplification and angiogenic cell propagation; integrin-mediated processes of cell attachment and migration, crucial components of both angiogenesis and metastasis; and metalloproteinase-mediated processes that underlie both the release of cancer cells and angiogenesis. Metalloproteinases release aberrant cells from their connective tissue anchorage, facilitating metastatic migration. Angiogenesis depends upon metalloproteinases to clear a path for migrating cells at the advancing capillary front.
Most current approaches to cancer therapy, such as standard chemotherapy and irradiation, are attempts to kill cancer cells. However, the discovery of peptides that inhibit proliferation of cancer cells or inhibit endothelial cell proliferation have raised hopes for new therapeutic modalities. For example, members of the transforming growth factor p family (TGF-&bgr;) are among the peptides known to have a number of biological activities related to tumorigenesis (including angiogenesis) and metastasis. TGF-&bgr; inhibits the proliferation of many cell types including capillary endothelial cells and smooth muscle cells. TGF-&bgr; downregulates integrin expression (&agr;1&bgr;1, &agr;2&bgr;1, &agr;&agr;v&bgr;3 involved in endothelial cell migration). Integrins are involved in the migration of all cells, including metastatic ones. TGF-&bgr; downregulates matrix metalloproteinase expression needed for both angiogenesis and metastasis. TGF-&bgr; induces plasminogen activator inhibitor, which inhibits a proteinase cascade needed for angiogenesis and metastasis. TGF-&bgr; induces normal cells to inhibit transformed cells.
Transforming growth factor-&bgr;s were originally named for their ability to transform normal fibroblasts to cells capable of anchorage-independent growth. The effects of TGF-&bgr;s on cells are generally classified as proliferative and non-proliferative. As originally established with the first experiments on fibroblasts, TGF-&bgr;s are bona fide growth factors. Two important cell types in which proliferation is enhanced by TGF-&bgr; are osteoblasts and Schwann cells of the peripheral nervous system. However, in many cells, TGF-&bgr;s are potent inhibitors of cell proliferation. This negative growth control may be the regulatory mechanism that checks regeneration of certain tissues and may play a role in the initiation of carcinogenesis.
The most important non-proliferative function of TGF-&bgr;s are in enhancing the formation of extracellular matrices. Although this is achieved primarily through the increased transcription of both collagen and fibronectin, the inhibition of the proteases from degrading the matrix also contributes to its stability. Degradation of the extracellular matrix is inhibited by the decrease in the secretion of the proteases themselves and the simultaneous increase in the levels of protease inhibitors.
Because of the wide applicability of TGF-&bgr;s in clinical therapies, they have been the focus of much research. Although much of the research involved in vitro uses, recent in vivo studies have confirmed some of the more promising in vitro effects.
The natural members of the transforming growth factor-&bgr;family range upwards of 25 KDa molecular weight. Clinical uses of growth factors, including TGF-&bgr;s, may be limited because of their size, which can cause immune responses. For example, human TGF-&bgr;1 is a 25,000 dalton homodimeric protein. In addition to possible adverse immunological responses, large proteins are not often the best candidates for drugs because of the difficulties in administration and delivery.
Consequently, small peptide mimics of a natural growth factor such as TGF-&bgr; would be desirable. It would also be advantageous to have small peptides mimicking the biological activity of a large, natural protein such as TGF-&bgr; since small peptides on a mole per mole basis would require much smaller net amounts for administration, and topical applications would be more feasible. Also, quite small peptides would tend to have little or no adverse immunological responses, and could be synthesized easily using simple peptide chemistry procedures.
As earlier noted, tumoregenesis and metastasis are integrin-mediated processes of cell attachment and migration. Further, matrix metalloproteinase 1 (MMP-1) processes underlie both the release of cancer cells and angiogenesis. Thus, inhibitors of MMP-1 should interfere with angiogenesis, since it is dependent on the lysis of collagenous matrices in the release of migrating cells in metastasis.
Several recent reports have suggested amelioration of cancer by synthetic versions of endogenous peptides: Cao et al., “Expression of Angiostatin cDNA in a Murine Fibrosarcoma Suppresses Primary Tumor Growth and Produces Long-term Dormancy of Metastases,”
J. Clin. Invest.,
101, (1998), 1055-1063; Boehm et al., “Antiangiogenic Therapy of Experimental Cancer Does Not Induce Acquired Drug Resistance,”
Nature,
390 (1997), 404-407; and Wu et al., “Suppression of Tumor Growth with Recombinant Murine Angiostatin,”
Biochem. Biophys. Res. Commun.,
236(1997), 651-654.
SUMMARY OF THE INVENTION
In one aspect of the present invention, compositions suitable for pharmaceutical administration are provided in which one compound is a small peptide mimic of TGF-&bgr;. More preferably, pharmaceutical compositions of the present invention are formulated as combinations of two components, wherein one component includes a peptide mimic for TGF-&bgr; and the other component includes compounds that are structurally or biologically analogous to a small region of collagen and mimic the conformation recognized by collagen binding species.
A feature for TGF-&bgr; activity believed critical is the peptide's ability to adopt a particular structure, when bound to a TGF-&bgr; receptor, that places certain side-chain functional groups in the appropriate relative positions and orientations. The TGF-&bgr; mimics of the present invention are sometimes herein referred to as “&bgr;-bend peptides,” or “extended-bend peptides.” The appropriate functional groups are represented, in many cases, within the following initial amino acid sequence, AA
i
-AA
i+1
-AA
i+2
wherein AA, is alanine, asparagine, or leucine, AA
i+1
is valine or isoleucine, and AA
i+2
is alanine. Of particular importance is the relatively positioning of the side-chains of AA
i+1
and AA
i+2.
The correct positioning of these amino acids can be achieved if AA
i+1
and AA
i+2
are in either of two backbone conformations: a &bgr;-bend or an “extended-bend” conformation with the backbone (&phgr;,&PSgr;) angles of AA
i+1
equal to approximately (−60, +135) and those of AA
i+2
equal to approximately (&
Bhatnagar Rajendra S.
Gough Craig
Qian Jing Jing
Bozicevic Field & Francis LLP
Francis Carol L.
Romeo David S.
The Regents of the University of California
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