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AssigneeBoard of Trustees of the University of Arkansas
InventorQing Yi
Estimating the term…
The present invention describes the use of agents that interact with major histocompatibility complex (MHC) HLA class I molecules, such as β2-microglobulin, or antibodies that bind to β2-microglobulin, for the treatment and prevention of multiple myeloma and other types of cancer. The anti-cancer therapeutics of the present invention interact with MHC molecules on the surface of the tumor cell to increase apoptosis and inhibit cell growth and proliferation. For example, in an embodiment, anti-β2-microglobulin antibodies inhibit the growth of multiple myeloma cells by over 90%. Thus, the present invention describes a new class of anti-cancer therapeutics and methods of use.
A composition to reduce tumor growth or proliferation in an individual in need thereof comprising a pharmacologically effective amount of an agent that interacts with MHC β2-microglobulin HLA class I molecules located on the tumor cell surface in a pharmaceutically acceptable carrier, wherein a pharmacologically effective amount of said agent comprises sufficient agent to reduce proliferation of said tumor cells.
A composition to reduce tumor growth or proliferation in an individual in need thereof comprising a pharmacologically effective amount of an agent that binds to β2-microglobulin (β2m) in a pharmaceutically acceptable carrier, wherein a pharmacologically effective amount of said β2-microglobulin binding agent comprises sufficient agent to reduce proliferation of said tumor cells.
A method to reduce tumor growth or proliferation in an individual in need thereof comprising application of a pharmacologically effective amount of an agent that interacts with MHC β2-microglobulin HLA class I molecules located on the tumor cell surface in a pharmaceutically acceptable carrier to said individual, wherein a pharmacologically effective amount of said agent comprises sufficient agent to reduce proliferation of said tumor cells.
A method to reduce tumor growth or proliferation in an individual in need thereof comprising application of a pharmacologically effective amount of an agent that binds to β2-microglobulin (β2m) in a pharmaceutically acceptable carrier to said individual, wherein a pharmacologically effective amount of said β2-microglobulin binding agent comprises sufficient agent to reduce proliferation of said tumor cells.
A kit to reduce tumor growth or proliferation in an individual in need thereof comprising:
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Against the immunoglobulin superfamily: against MHC-molecules, e.g. HLA-molecules
Receptors; Cell surface antigens; Cell surface determinants: immunoglobulin superfamily
Medicinal preparations containing antigens or antibodies: comprising antibodies
Characterized by aspects of specificity or valency: specific for a neo-epitope on a complex, e.g. antibody-antigen or ligand-receptor
Term end not estimated
The present invention relates to the field of anti-cancer therapeutics. For example, the present invention describes the use of agents that interact with major histocompatibility complex (MHC) HLA class I molecules, such as antibodies that bind to β2-microglobulin, for the treatment and prevention of multiple myeloma and other types of cancer.
Cancer remains the second leading cause of death in the western hemisphere. While some types of cancer may be managed by surgery, radiation therapy and/or chemotherapy, other types of cancer are considered to be incurable.
For example, multiple myeloma (MM) is a B-cell neoplasm characterized by the accumulation of malignant plasma cells in the bone marrow. Multiple myeloma accounts for about 1% of all cancers and about 10% of all hematological malignancies. The American Cancer Society estimated that about 14,600 new cases of myeloma would be diagnosed and nearly 11,000 Americans would die from multiple myeloma in 2002. Although high-dose chemotherapy followed by autologous stem cell support may result in remission for about 50% of individuals with MM, relapses are still frequent (Barlogie B., et al., Blood, 93:55-65, 1999).
FIG. 1 illustrates the cellular effects of β2m on growth of myeloma cells in accordance with an embodiment of the present invention wherein (A) shows a dose-response of four Epstein Barr Virus (EBV)-negative cell lines in a 48-hour culture; (B) shows a time-response of the EBV-negative cell lines in cultures with or without the addition of 20 μg/ml β2m; and (C) shows a dose response of two EBV-positive cell lines in a 48-hour culture. Cell growth, determined by 3H-thymidine incorporation assay, is expressed as a percentage of control. Values are expressed as the mean ±SD of four experiments.
FIG. 2. illustrates the proliferation of primary myeloma cells from 5 patients in response to different concentrations of β2m in accordance with an embodiment of the present invention wherein 3H-thymidine incorporation assay was performed in a 24-hour culture and cell growth is expressed as a percentage of control.
FIG. 3 illustrates β2m-induced apoptosis in myeloma cells in accordance with an embodiment of the present invention wherein (A) shows representative dot plots showing apoptotic RPMI-8226 cells determined by propidium idodide (PI) and Annexin V staining; (B) shows representative histograms showing apoptotic RPMI-8226 cells determined by TUNEL assay using β2m at 40 μg/ml, where the percentage of apoptotic cells is indicated by the horizontal bar; (C) shows dose-dependent induction of apoptosis in RPMI-8226 myeloma cells by β2m; and (D) shows β2m-induced apoptosis in six myeloma cell-lines (□, control cells; ▪, cells treated with 40 μg/ml β2m). Values are expressed as the mean ±SD of 5 experiments.
The present invention describes the use of β2-microglobulin based therapeutics for the treatment and prevention of cancer. Thus, embodiments of the present invention recognize that β2-microglobulin interacts with other molecules of the major histocompatibility complex (MHC) class I to affect an individual's ability to resist and combat tumor development. In one embodiment, application of exogenous β2-microglobulin inhibits cancer cell growth and proliferation. In another embodiment, anti-β2-microglobulin antibodies inhibit cancer cell growth and proliferation. In yet another embodiment, β2-microglobulin enhances the ability of β2-microglobulin antibodies to inhibit cancer cell growth and proliferation. Thus, embodiments of the present invention recognize that antibodies to β2-microglobulin interact with β2-microglobulin to invoke a synergistic inhibition of cancer cell growth.
In one aspect, the present invention comprises a composition to reduce tumor growth or proliferation in an individual in need thereof comprising a pharmacologically effective amount of an agent that interacts with MHC β2-microglobulin HLA class I molecules located on the tumor cell surface in a pharmaceutically acceptable carrier, wherein a pharmacologically effective amount of the agent comprises sufficient agent to reduce proliferation of the tumor cells.
In an embodiment, the agent comprises β2-microglobulin. Alternatively, the agent may comprise an antibody that binds β2-microglobulin. In yet another embodiment, the agent comprises β2-microglobulin used in combination with an antibody that binds β2-microglobulin. Preferably, the use of both β2-microglobulin used in combination with an antibody that binds β2-microglobulin provides a greater than additive effect.