Drug – bio-affecting and body treating compositions – Antigen – epitope – or other immunospecific immunoeffector – Hormone or other secreted growth regulatory factor,...
Reexamination Certificate
1999-12-13
2004-07-20
Carlson, Karen Cochrane (Department: 1653)
Drug, bio-affecting and body treating compositions
Antigen, epitope, or other immunospecific immunoeffector
Hormone or other secreted growth regulatory factor,...
C514S015800, C514S002600, C530S324000, C530S327000, C530S300000, C530S317000, C530S402000, C424S001210, C930S120000
Reexamination Certificate
active
06764683
ABSTRACT:
TECHNICAL FIELD OF THE INVENTION
The present invention provides a novel peptide that is derived from a loop or “lollipop” region of transforming growth factor alpha (TGF-&agr;) and is biologically active for causing stem cells to proliferate and migrate. The present invention further provides a method for augmenting hematopoiesis, particularly trilineage hematopoiesis, and a method for suppressing immune functioning associated with autoimmune diseases, and a method for suppressing inflammatory responses mediated (in part) by excessive histamine release, comprising administering an effective amount of a TGF-&agr; polypeptide or a fragment thereof, such as the lollipop region. The present invention further provides a method for treating or preventing mucositis and gastrointestinal side effects in patients undergoing cancer treatment, comprising administering an effective amount of a TGF-&agr; polypeptide or a fragment thereof, such as the lollipop region.
BACKGROUND OF THE INVENTION
There are several disease treatments that could significantly benefit by having cells regenerate after injury or lesion formation, particularly in the Central Nervous System (CNS), in the immune system and in the gastrointestinal tract. The expression of growth factors and their receptors on the preimplanted human embryo and maternal reproductive tract indicates that such factors influence growth and differentiation of embryonic cells in an autocrine and paracrine manner. Such growth factors are peptides that variously support survival, proliferation, differentiation, size and function of nerve cells and other lineages of ells. EGF (epidermal growth factor) is the first member found of the EGF family and characterized many years ago (Savage and Cohen,
J. Biol. Chem.
247:7609-7611, 1972; and Savage et al.;
J. Biol. Chem.
247:7612-7621, 1972). Additional members of the EGF family have been found and they include vaccina virus growth factor (VGF; Ventatesan et al.,
J. Virol.
44:637-646, 1982); myxomavirus growth factor (MGF; Upton et al.
J Virol.
61:1271-1275, 1987), Shope fibroma virus growth factor (SFGF; Chang et al.,
Mol. Cell. Biol.
7:535-540, 1987), amphiregulin (AR; Kimura et al.,
Nature
348:257-260, 1990), and heparin binding EGF-like factor (HB-EGF; Higashiyama et al.,
Science
251:936-939, 1991). A common structural feature of these polypeptides is the presence of six cysteine residues that form three disulfide cross links that support a conserved structure that binds to the EGF receptor.
Another member of the EGF family is TGF&agr; and it also binds to the EGF receptor (Todaro et al.,
Proc. Natl. Acad. Sci.
USA 77:5258-5262, 1980). TGF&agr; stimulates the EGF receptor's tyrosine kinase activity and has many cellular functions, such as stimulating a mitogenic response in a wide variety of cell types. TGF&agr; and EGF mRNAs reach their highest levels and relative abundance (compared to total RNA in the early postnatal period and decrease thereafter, suggesting a role in embryonic development. From a histological perspective, TGF&agr; acts on numerous cell types throughout the body. The active form of TGF&agr; is derived from a larger precursor and contains 50 amino acids. TGF&agr; shares only a 30% structural similarity with the 53-amino acid form of EGF, but including conservation of all six cysteine residues. TGF&agr; is highly conserved among species. For example, the rat and human polypeptides share about 90% homology as compared to a 70% homology as between the rat and human EGF polypeptide. The amino acid sequence of human TGF&agr; is shown in SEQ ID NO. 1. The sequence shows that a family consisting of vaccinia growth factor, amphiregulin precursor, betacellulin precursor, heparin binding EGF-like growth factor, epiregulin (rodent only), HUS 19878 and schwannoma derived growth factor have similar sequence motifs and can be considered as members of the same family based upon their shared cysteine disulfide bond structures.
TGF&agr; is an acid and heat stable polypeptide of about 5.6 kDa molecular weight. It is synthesized as a larger 30-35 kDa molecular weight glycosylated and membrane-bound precursor protein wherein the soluble 5.6 kDa active form is released following specific cleavage by an elastase-like protease. TGF&agr; binds with high affinity in the nanomolar range and induces autophosphorylation to transduce signal with the EGF receptor. TGF&agr; is 50 amino acids in length and has three disulfide bonds to forms its tertiary configuration. All three disulfide bonds must be present for activity. TGF&agr; is stored in precursor form in alpha granules of secretory cells. Moreover, the primary amino acid sequence is highly conserved among various species examined, such as more than 92% homology at the amino acid level as between human and rat TGF&agr; polypeptides.
TGF&agr; has been investigated extensively and has recently been identified as useful for treating a patient with a neurological deficit. This mechanism is thought to stimulate proliferation and migration of neural-origin stem cells to those sites or lesions in a deficit. For example, Parkinson's Disease is characterized by resting tremor, rigidity, inability to initiate movement (akinesia) and slowness of movement (bradykinesia). The motor deficits are associated with progressive degeneration of the dopaminergic innervation to the nucleus accumbens and degeneration of noradrenergic cells of the locus ceruleus and serotonergic neurons of the raphe. Up to 80% of nigral dopamine neurons can be lost before significant motor deficits are manifest. TGF&agr; (full polypeptide) was shown, when infused into rat brains, was useful for the treatment of neurodegenerative disorders. Intracerebroventricular (ICV) or intrastriatal infusions of TGF&agr; induced neuronal stem cell proliferation, but degenerating or damaged or otherwise abnormal cells needed to be present to facilitate migration of the neuronal stem cells to a site of injury on a scale sufficient to impact recovery from an associated neurological deficit. Forebrain neural stem cells, that give rise to migrating progenitor cells that affect treatment and recovery from a neurological deficit disorder, are the migrating cells that affect treatment recovery from a neural deficit disorder (e.g., Parkinson's Disease, Huntington's Disease, Alzheimer's Disease and the like).
Neural stem cells have been found in subependyma throughout the adult rodent CNS (Ray et al.
Soc. Neurosci.
22:394.5, 1996) and in the subependyma of adult human forebrain (Kirschenbaum et al.,
Cerebral Cortex
4:576-589, 1994). Thus, the discovery that TGF&agr; stimulates proliferation of neural stem cells and promotes migration to a site of injury or deficit has led to its investigation for the treatment of a neurodegenerative disorder (Alzheimer's Disease, Huntington's Disease and Parkinson's Disease) or CNS traumatic injury (e.g., spinal chord injury), demyelinating disease, CNS inflammatory disease, CNS autoimmune disease (e.g., multiple sclerosis) or CNS ischemic disease (e.g., stroke or brain attack).
A CNS stem cell has the potential to differentiate into neurons, astrocytes and to exhibit replication of itself to provide a resource for self-renewal. Both neurons and glial cells seem to be derived from a common fetal precursor cell. In the vertebrate CNS, multipotential cells have been identified in vitro and in vivo. Certain mitogens, such as TGF&agr;, can cause proliferation of CNS mutipotential cells in vitro and this is the basis for a procedure to harvest such cell, treat them ex vivo to stimulate proliferation in culture and then readminister such cells. Immunohistochemical analysis in the human brain supports the notion that TGF&agr; is widely distributed in neurons and glial cells both during development and during adulthood. In mice genetically altered to lack expression of functioning TGF&agr;, there was a decrease in neural progenitor cell proliferation in forebrain subependyma, providing evidence for TGF&agr; as a proliferative fact
Felker Thomas S.
Paskell Stefan
Twardzik Daniel R.
Carlson Karen Cochrane
Gray Cary Ware & Freidenrich LLP
Haile Lisa A.
Kaleidos Pharma, Inc.
Liu Samuel Wei
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