Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Peptide containing doai
Reexamination Certificate
1997-04-03
2004-08-31
Saunders, David (Department: 1644)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Peptide containing doai
C435S355000, C435S372000, C435S375000, C514S013800, C514S014800, C514S015800, C514S016700, C514S017400, C514S018700, C514S282000, C530S326000, C530S327000, C530S328000, C530S329000, C530S330000, C530S385000
Reexamination Certificate
active
06784155
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to the use of modulators of stem cell proliferation for regulating stem cell cycle in the treatment of humans or animals with autoimmune diseases, aging, cancer, myelodysplasia, preleukemia, leukemia, psoriasis, acquired immune deficiency syndrome (AIDS), myelodysplastic syndromes, aplastic anemia or other diseases involving hyper- or hypo-proliferative conditions, as well as the use of such compounds for analgesia. The present invention also relates to a method of treatment for humans or animals anticipating or having undergone exposure to chemotherapeutic agents, other agents which damage cycling stem cells, or radiation exposure and for protection against such agents during ex vivo treatments. Finally, the present invention relates to the improvement of stem cell maintenance or expansion cultures for auto- and allo-transplantation procedures or for gene transfer, as well as for in vivo treatments to improve such procedures.
BACKGROUND OF THE INVENTION
Most end-stage cells in renewing systems are short-lived and must be replaced continuously throughout life. For example, blood cells originate from a self-renewing population of multipotent hematopoietic stem cells (HSC). Hematopojetic stem cells are a subpopulation of hematopoietic cells. Hematopoietic cells can be obtained, for example, from bone marrow, umbilical cord blood or peripheral blood (either unmobilized or mobilized with an agent such as G-CSF); hematopoietic cells include the stem cell population, progenitor cells, differentiated cells, accessory cells, stromal cells and other cells that contribute to the environment necessary for production of mature blood cells. Hematopoietic progenitor cells are a subset of stem cells which are more restricted in their developmental potency. Progenitor cells are able to differentiate into only one or two lineages (e.g., BFU-E and CFU-E which give rise only to erythrocytes or CFU-GM which give rise to granulocytes and macrophages) while stem cells (such as CFU-MIX or CFU-GEMM) can generate multiple lineages and/or other stem cells. Because the hematopoietic stem cells are necessary for the development of all of the mature cells of the hematopoietic and immune systems, their survival is essential in order to reestablish a fully functional host defense system in subjects treated with chemotherapy or other agents.
Hematopoietic cell production is regulated by a series of factors that stimulate growth and differentiation of hematopoietic cells, some of which, for example erythropoietin, GM-CSF and G-CSF, are currently used in clinical practice. One part of the control network which has not been extensively characterized, however, is the physiological mechanism that controls the cycling status of stem cells (Eaves et al. Blood 78:110-117, 1991; Lord, in
Stem Cells
(C. S. Potten, Ed.) pp 401-22, 1997 (Academic Press, NY)).
Early studies by Lord and coworkers showed the existence of soluble protein factors in normal and regenerating bone marrow extracts which could either inhibit or stimulate stem cell proliferation (reviewed in: Lord and Wright, Blood Cells 6:581-593, 1980; Wright and Lorimore, Cell Tissue Kinet. 20:191-203, 1987; Marshall and Lord, Int Rev. Cyt. 167:185-261, 1996). These activities were designated stem cell inhibitor (S CT) and stem cell stimulator (SCS), respectively.
To date, no candidate SCS molecules have been purified from bone marrow extracts prepared as described by Lord et al. (reviews referenced above). Purification of either SCS or SCI from primary sources was not accomplished due to the difficulties inherent in an in vivo assay requiring large numbers of irradiated mice. In an attempt to overcome these problems Pragnell and co-workers developed an in vitro assay for primitive hematopoietic cells (CFU-A) and screened cell lines as a source of the inhibitory activity (see Graham et al. Nature 344:442-444, 1990). As earlier studies had identified macrophages as possible sources for SCI (Lord et al. Blood Cells 6:581-593, 1980), a mouse macrophage cell line, J774.2, was selected (Graham et al. Nature 344:442-444, 1990). The conditioned medium from this cell line was used by Graham et al. for purification; an inhibitory peptide was isolated which proved to be identical to the previously described cytokine macrophage inflammatory protein 1-alpha (MEP1&agr;). Receptors for MIP-1&agr; have been cloned; like other chemokine receptors, these MIP-1&agr; receptors are seven-transmembrane domain (or “G-linked”) receptors which are coupled to guanine nucleotide (GTP) binding proteins of the G
inhibitory
subclass (“G
i
”) (reviewed in Murphy, Cytokine & Growth Factor Rev. 7:47-64, 1996). The “inhibitory” designation for the G
i
subclass refers to its inhibitory activity on adenylate cyclase.
MIP-1&agr; was isolated from a cell line, not from primary material. While Graham et al. observed that antibody to MIP-1&agr; abrogated the activity of a crude bone marrow extract, other workers have shown that other inhibitory activities are important. For example, Graham et al. (J. Exp. Med. 178:925-32, 1993) have suggested that TGF&bgr;, not MIP-1&agr;, is a primary inhibitor of hematopoietic stem cells. Further, Eaves et al. (PNAS 90:12015-19, 1993) have suggested that both MIP-1&agr; and TGF&bgr; are present at sub optimal levels in normal bone marrow and that inhibition requires a synergy between the two factors.
Recently, mice have been generated in which the MIP-1&agr; gene has been deleted by homologous recombination (Cook et al., Science 269:1583-5, 1995). Such mice have no obvious derangement of their hematopoietic system, calling into question the role of MIP-1&agr; as a physiological regulator of stem cell cycling under normal homeostatic conditions. Similarly, although transforming growth factor beta (TGF&bgr;) also has stem cell inhibitory activities, the long period of time it takes for stem cells to respond to this cytokine suggests that it is not the endogenous factor present in bone marrow extracts; further, neutralizing antibodies to TGF&bgr; do not abolish SCI activity in bone marrow supernatants (Hamnpson et al., Exp. Hemat. 19:245-249, 1991).
Other workers have described additional stem cell inhibitory factors. Frindel and coworkers have isolated a tetrapeptide from fetal calf marrow and from liver extracts which has stem cell inhibitory activities (Lenfant et al., PNAS 86:779-782, 1989). Paukovits et al. (Cancer Res. 50:328-332, 1990) have characterized a pentapeptide which, in its monomeric form, is an inhibitor and, in its dimeric form, is a stimulator of stem cell cycling. Other factors have also been claimed to be inhibitory in various in vitro systems (see Wright and Pragnell in
Bailliere's Clinical Haematology
v. 5, pp. 723-39, 1992 (Bailliere Tinadall, Paris); Marshall and Lord, Int Rev. Cyt. 167:185-261, 1996).
Tsyrlova et al., SU 1561261 A1, disclosed a purification process for a stem cell proliferation inhibitor.
Commonly owned applications WO 94/22915 and WO96/10634 disclose an inhibitor of stem cell proliferation, and are hereby incorporated by reference in their entirety.
To date, none of these factors have been approved for clinical use. However, the need exists for effective stem cell inhibitors. The major toxicity associated with chemotherapy or radiation treatment is the destruction of normal proliferating cells which can result in bone marrow suppression or gastrointestinal toxicity. An effective stem cell inhibitor will protect these cells and allow for the optimztion of these therapeutic regimens. Just as there is a proven need for a variety of stimulatory cytokines (i.e., cytokines such as IL-1, IL-2, IL-3, IL-4, IL-5, IL-6, IL-7, IL-9, IL-11, IL-13, IL-14, IL-15, G-CSF, GM-CSF, erythropoietin, thrombopoietin, stem cell factor, flk2/flt3 ligand, etc., which stimulate the cycling of hematopoietic cells) depending upon the clinical situation, so too it is likely that a variety of inhibitory factors will be needed to address divergent clinical needs.
Further, there is a need to
Tsyrlova Irena
Wolpe Stephen D.
Saunders David
Wellstat Therapeutics Corporation
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