Drug – bio-affecting and body treating compositions – Immunoglobulin – antiserum – antibody – or antibody fragment,...
Reexamination Certificate
2000-02-01
2002-10-22
Caputa, Anthony C. (Department: 1640)
Drug, bio-affecting and body treating compositions
Immunoglobulin, antiserum, antibody, or antibody fragment,...
C424S133100, C424S141100, C424S142100, C424S143100, C424S144100, C424S145100, C514S04400A, C530S387100, C530S387300, C530S388150, C530S388220, C530S388230, C536S024500
Reexamination Certificate
active
06468528
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates generally to materials and methods for inhibition of Hodgkin and Reed Sternberg cell proliferation.
BACKGROUND OF THE INVENTION
Hodgkin's disease (HD) is unique among human lymphomas in that the tumor cells, known as Hodgkin and Reed Sternberg (H/RS) cells, are exceedingly rare, generally representing 0.1-1% of the total cell population within lymphoma tissue [Drexler,
Leukemia and Lymphoma
8:283-313 (1992); Drexler,
Leukemia and Lymphoma
9:1-25 (1993); Kadin,
Current Opinion in Oncology
6:456:463 (1994); Cossman, et al.,
Lab. Invest
78:229-235 (1998)]. As a result, investigation of HRS cells has been impeded by their low frequency. PCR-based assays of DNA from single H/RS cells have revealed rearranged immunoglobulin genes and somatic mutations, suggesting that H/RS cells are clonal and may be derived from germinal center B cells [Kanzler, et al.,
J Exp Med
184:1495-505 (1996); Kyppers, et al.,
Annu Rev Immunol
16:471-93 (1998)]. The precise pathogenesis of HD, however, remains to be determined.
Previous observations suggest that the proliferation and survival of HD-derived cells depends on cytokine signaling. It is well established that the unique histology and eosinophilia of HD tissues, and secondary symptoms in the patient such as fever, weight loss, and night sweats, are induced by a pathological pattern of cytokine secretion [Drexler,
Leukemia and Lymphoma.
8:283-313 (1992); Drexler,
Leukemia and Lymphoma
9:1-25 (1993)]. For example, overexpression of IL-5 in H/RS cells has been previously demonstrated by in situ hybridization, but only in HD patients exhibiting eosinophilia [Samoszuk, et al.,
Blood
75:13-16 (1990); Samoszuk,
Blood
79:1518-22 (1992)]. To date, no cytokine has been consistently reported as being overexpressed in HD-derived cell lines or in primary H/RS cells.
Evidence for a role for IL-13 in the etiology of HD is indirect. IgE is elevated in HD tissues and serum samples from HD patients [Samoszuk,
Blood
79:1518-22 (1992); Thomas, et al.,
Ann Allergy
37:416-19 (1976)], and IL13 is known to promote Ig class switching to IgE. IL13-deficient mice exhibit lower basal levels of serum IgE [McKenzie, et al.,
Immunity
9:423432 (1998)]. Furthermore, studies of IL-4 deficient, IL-13 transgenic mice have demonstrated that IL-13 can promote class switching to IgE independently of IL-4[Emson, et al.,
J Exp. Med
188:399404 (1998)], emphasizing that IL-4 and IL-13 have distinct roles in regulating B cell functions.
IL-13 is a T cell-derived cytokine with immunomodulatory and anti-inflammatory properties [Minty, et al.,
Nature
362:248-250 (1993)]. The biological effects of IL-13 on B cells, macrophages, and monocytes are very similar to those of IL-4, probably because the IL-4 and IL-13 receptors share a common a chain. In B cells, IL-13 promotes proliferation, differentiation, and Ig heavy chain class switching to IgE and IgG4 [Zurawski, et al.,
Immunology Today
15:19-26 (1994)]. Proliferation results from a signaling pathway in which the engagement of the IL-13 receptor activates JAK1, which in turn activates STAT6 [Lin, et al.,
Immunity
2:331-339 (1995)].
Other aspects of the HD phenotype may also be attributable to the effects of IL-13. A recent study of IL-13-deficient mice has shown that cultures of type 2 helper T (Th2) cells from these animals produce significantly reduced levels of IL-4, IL-5, and IL-10 compared to the wild type, suggesting an important role for IL-13 as a regulator of Th2 cell commitment [McKenzie, et al,
Immunity
9:423-432 (1998)]. If IL-13 is also important for promoting the differentiation of Th2 cells in humans, it could explain why H/RS cells (which secrete IL-13) are surrounded by Th2 cells in HD biopsies. In addition, because fibroblasts express the IL-13 receptor and can be activated by IL-13 [Doucet, et al.,
J Clin Invest
101:2129-2139 (1998)], the secretion of IL-13 by H/RS cells may underlie the pathogenesis of the fibrosis observed in nodular sclerosis HD.
Thus, there exists a need in the art to identify specific growth factors that participate in the pathogenesis of HD. In particular, identification of cytokines that stimulate H/RS cell proliferation will facilitate development of methods for therapeutic invention, by way of (i) modulating expression of the cytokine(s), (ii) modulating biological activity of the cytokine(s), and (iii) modulating both expression and biological activity.
SUMMARY OF THE INVENTION
The present invention provides materials and methods for inhibiting proliferation of cell types associated with Hodgkin's disease. In particular, the invention contemplates inhibiting proliferation of Reed Sternberg cells found in individuals suffering from Hodgkin disease. Reed Sternberg cells associated with Hodgkin's disease are referred to herein as H/RS cells.
The invention comprehends various methods by which proliferation of H/RS cells can be modulated, preferably through mechanisms that modulate expression, secretion, stimulation, activation, and/or biological activity of IL-13 and/or its cognate IL-13 receptor, as well as components in signal transduction pathways associated with IL-13 and the IL-13 receptor. In one aspect, the invention provides methods for inhibiting IL-13 dependent proliferation of Hodgkin and Reed Sternberg (H/RS) cell types comprising the step of contacting the H/RS cells with a compound that inhibits biological activity of IL-13. In a preferred embodiment, methods are provided wherein the compound that inhibits IL-13 biological activity is an antibody. It is preferred that the antibody is a monoclonal-antibody that specifically recognizes and binds to IL-13, and most preferably, the monoclonal antibody is a human antibody, however, humanized antibodies and non-human antibodies are also comprehended by the invention.
Get a PCT Publication for Humanized Antibodies
The term “specifically recognizes or binds” as used herein indicates antibodies of the invention bind to only IL-3, IL-13 receptor, or naturally occurring variants thereof, despite any sequence similarity, homology, or identity conserved in other polypeptides.
In another aspect, the invention provides methods for inhibiting IL-13 dependent proliferation of Hodgkin and Reed Sternberg (H/RS) cell types comprising the step of contacting the H/RS cell types with a compound that inhibits biological activity of IL-13 receptors expressed on the H/RS cell types. In a preferred embodiment, methods are provided wherein the compound that inhibits IL-13 receptor biological activity is an antibody. It is preferred that the antibody is a monoclonal antibody that specifically recognizes and binds to the IL-13 receptor, and most preferably, the monoclonal antibody is a human antibody, however, humanized antibodies and non-human antibodies are also comprehended by the invention.
Alternatively, the invention provides methods for inhibiting IL-13 dependent proliferation of Hodgkin and Reed Sternberg (H/RS) cell types comprising the step of contacting the H/RS cells with a compound that inhibits expression of IL-13. In a preferred embodiment, methods of the invention are provided wherein the compound that inhibits IL-13 expression is an antisense polynucleotide that specifically recognizes a polynucleotide encoding IL-13. In another preferred embodiment, methods are provided wherein the compound that inhibits IL-13 expression is a ribozyme that binds to and acts specifically on polynucleotides encoding IL-13. The terms “act specifically on” and “specifically recognizes or binds” as used herein indicates that anti-sense and ribozymes of the invention bind to and act only on polynucleotides that encode IL-13, the IL-13 receptor, or naturally occurring variants thereof despite any sequence similarity, homology, or identity conserved in polynucleotides encoding other polypeptides.
Similarly, the invention also provides methods for inhibi
Kapp Ursula
Mak Tak W.
Amgen Canada Inc.
Canella Karen A.
Caputa Anthony C.
Marshall Gerstein & Borun
LandOfFree
Materials and methods to inhibit Hodgkin and Reed Sternberg... does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Materials and methods to inhibit Hodgkin and Reed Sternberg..., we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Materials and methods to inhibit Hodgkin and Reed Sternberg... will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-2951541