Organic compounds -- part of the class 532-570 series – Organic compounds – Carbohydrates or derivatives
Reexamination Certificate
1997-11-20
2001-02-06
Degen, Nancy (Department: 1635)
Organic compounds -- part of the class 532-570 series
Organic compounds
Carbohydrates or derivatives
C536S024500, C536S024300, C536S023100, C435S091100, C514S04400A
Reexamination Certificate
active
06184372
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention pertains to a method for treating a patient with a disease in which the levels of interleukin-10 need to be down-regulated which comprises adminstering to the patient a therapeutically effective amount of an antisense oligodeoxynucleotide specific for interleukin-10 mRNA. The present invention also pertains to an antisense oligodeoxynucleotide specific for interleukin-10 mRNA having the formula 5′-TGGGTCTTGGTTCTCAGCTTGGGGCAT (SEQ ID NO: 1).
2. Description of the Background
The disclosures referred to herein to illustrate the background of the invention and to provide additional detail with respect to its practice are incorporated herein by reference and, for convenience, are numerically referenced in the following text and respectively grouped in the appended bibliography.
Growth Inhibition of Malignant CD5+B(B-1) Cells by Antisense Interleukin-10
The increased proliferation and longevity of malignant cells is, in part, due to increased production of, or response to, growth factors. Antisense oligodeoxynucleotides which interfere with mRNA translation of growth factors are an area of intensive investigation. Of particular interest is the role of antisense directed toward the cytokine interleukin-10 (IL-10), an important regulator of B cell growth and differentiation in malignant B-1 cells.
B-1 cells are thought to belong to a sub-population of B cells. These cells are usually of a larger size, CD5+ (B-1a) or CD5− (B-1b), according to the new nomenclature (1). Due to their long life span and self-renewal capabilities, B-1 cells have an increased ability to clonally expand and become malignant. The most striking example of malignant transformation of a B-1 cell is seen in human chronic lymphocytic leukemia (CLL), where the predominant malignant cell is a B-1 cell (2). Malignant clonal expansions of B-1 cells in aged NZB mice can serve as a model for human chronic lymphocytic leukemia (3, 4). NZB mice have similarities with chronic lymphocytic leukemia patients in that there is an age-dependent onset of clonal expansion of malignant B-1 cells, the indolent course, the presence of increased numbers of lymphocytes and “smudge” cells in the circulation, and the similar pathology with malignant cells infiltrating spleen, lymph nodes and bone marrow. In both the mouse model and patients with chronic lymphocytic leukemia, occasionally the malignancy can evolve into an aggressive diffuse large cell lymphoma termed Richter's syndrome (3). Both NZB malignant B-1 cells and human chronic lymphocytic leukemia cells have been found to express IL-10 mRNA (5-7). Genetic analysis of the NZB mice have revealed a strong correlation between high levels of IL-10 and B cell lymphoproliferative disease. IL-10 antisense was found to block cell growth in murine malignant NZB B-1 cells but have only a minimal effect on non-malignant B-1 cells (51).
IL-10 is a B cell growth regulatory cytokine that can be produced by many kinds of cells including Th2 cells, macrophages, monocytes, mast cells and B cells (8-11). Among murine B cells, B-1 cells are considered the main source of B cell derived murine interleukin-10 (mIL-10) (12) while in humans, B cells induced to produce human interleukin-10 (hIL-10) are associated with the mature B and preplasmocytic stages (13). IL-10 has been found to participate in the EBV transformation of human B cells and in the development of B cell lymphomas in AIDS patients (56-58). IL-10 not only functions as a potent growth and differentiation factor for activated human B lymphocytes but it also plays a regulatory role on human monocytes (14, 15). IL-10 can function alone or together with other cytokines (15-17). In addition, exogenous IL-10 down regulates the production of IFN-gamma (15).
Gene sequencing has revealed that hIL-10 has homology to BCRF1 of Epstein-Barr virus (EBV) ard the BCRF1 expressed protein has IL-10 activity (18). Furthermore, EBV transformed B lymphocytes constitutively secrete IL-10 and there is a relationship between IL-10 production by human malignant B cell lines and EBV expression (13, 19). Therefore, B cell transformation and abnormal proliferation is related to BEV infection and the consequent elevated IL-10 expression. Addition of viral IL-10 antisense prevented EBV induced B cell transformation (20). Evidence that IL-10 plays a role in malignant B cell transformation is found in AIDS associated B cell lymphomas in which increased hIL-10 has been found (19). Recently, the use of antisense in the treatment of diseases has been extensively investigated as a potential therapy (19-21). IL-10 antisense has been shown to inhibit the cell growth of non-Hodgkin's lymphoma from AIDS patients (21). Sirtilarly, antisense IL-6 has also been shown to have growth inhibitory effects on c ells from Hairy cell leukemia and various other malignancies, such as ovarian cancer, renal cancer, and myeloma cells (22-25).
Antisense Interleukin-10 Effects on Chronic Lymphocytic Leukemia Cell Growth
In the human malignancy, B-chronic lymphocytic leukemia (B-CLL), the malignant cell is a CD5+B cell. Morphological evidence as well as the phenotypic features of the circulating malignant cell in B-chronic lymphocytic leukemia suggest that the norrnal equivalent population is represented by resting CD5+B cells (43). In adult lymphoid tissues, CD5+B cells, or B-1 cells as they are referred to, are located at the edge of the germinal centers and within the mantle zone of secondary follicles. Like their normal B-1 counterparts, B-chronic lymphocytic leukemia cells coexpress CD5 and low levels of sIg, produce polyreactive antibodies and are capable of capping surface Ig. However, other features of B-chronic lymphorytic leukemia such as poor response to mitogenic stimuli, spontaneous proliferative responses to IL-2 and induction of apoptosis via Ig crosslinking are characteristic of an “activated” phenotype.
The increased proliferation and longevity of malignant cells is partly due to increased production of, or response to, growth factors. Additionally, failure to undergo programmed cell death may be due to abnormal expression of bcl-2 which plays a role in the accumulation of malignant CD5+B cells (44, 45). Consequently, antisense oligodeoxynucleotides that interfere with mRNA translation of growth factors, are candidates for therapy to regulate malignant cell growth.
SUMMARY OF THE INVENTION
The present invention pertains to a method for treating a patient with a disease in which the levels of interleukin-10 need to be down-regulated, such as diseases in which interleukin-10 is an autocrine growth factor for malignant cells or diseases wherein the inflammatory response is suppressed. The method for treating a patient with a disease wherein elevated levels of interleukin-10 has a detrimental effect, such as aquired inmmunodeficiency syndrome (AIDS), comprises adminstering to the patient a therapeutically effective amount of an antisense oligodeoxynucleotide specific for interleukin-10 mRNA.
The present invention also pertains to a method for treating a patient with chronic lymphocytic leukemia which comprises administering to the patient a therapeutically effective amount of an antisense oligodeoxynucleotide specific for interleukin-10 mRNA.
The present invention further pertains to an antisense oligodeoxynucleotide specific for interleukin-10 mRNA having the formula 5′-TGGGTCTTGGTTCTCAGCTTGGGGCAT (SEQ ID NO: 1).
REFERENCES:
patent: 5776451 (1994-07-01), Hsu et al.
Crooke, S., Basic Principles of Antisense Therapeutics, Springer-Verlag Berlin Heidelberg New York, Jul. 1998.
Gura T., Antisense Has Growing Pains, Science, vol. 270, pp. 575-577, Oct. 1995.
Crooke, S. et al., Antisense '97: A roundtable on the state of the industry, Nature Biotechnology, vol. 15, p.522, Jun. 1997.
Branch, A., A good antisense molecule is hard to find, TIBS vol. 23, pp. 47-49, Feb. 1998.
Degen Nancy
Epps Janet L.
Muccino Richard R.
University of Medicine & Dentistry of New Jersey
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