Chemistry: natural resins or derivatives; peptides or proteins; – Proteins – i.e. – more than 100 amino acid residues – Blood proteins or globulins – e.g. – proteoglycans – platelet...
Reexamination Certificate
2000-10-10
2003-08-26
Housel, James (Department: 1648)
Chemistry: natural resins or derivatives; peptides or proteins;
Proteins, i.e., more than 100 amino acid residues
Blood proteins or globulins, e.g., proteoglycans, platelet...
C530S389100, C424S136100, C424S139100, C424S130100
Reexamination Certificate
active
06610834
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates generally to IgM autoantibodies and, more particularly, to a method of inhibiting disease progression.
2. Discussion of the Background
Chemokines, or chemotactic cytokines, are a class of cytokine molecules capable of chemotactically attracting migratory cells. Chemokines are essential in attracting cells to inflammatory sites irrespective of the aetiology, i.e., immunologic, infective, ischaemic, drug-induced, etc., causing the inflammation. Chemokines generally have small molecular weights in the range of about 8-10 kD.
Most chemokines can be divided into three major families, CC, CXC and CXXXC, based on the number of amino acids (referred to as “X”) separating the two cysteines (referred to as “C”) in the chemokine molecule. Within the CC and CXC families, chemokines are further grouped into related sub-families based on amino acid sequence similarity between them. CC chemokine sub-families include the monocyte chemoattractant protein (“MCP”) sub-family and the sub-family including macrophage inhibitory protein-1&agr; (“MIP-1&agr;”), macrophage inhibitory protein-1&bgr; (“MIP-1&bgr;”) and regulated on activation normal T cell expressed (“RANTES”). CXC chemokine sub-families include the IP-10 and Mig sub-family; the interleukin-8 (“IL-8”) sub-family; and the PF4 sub-family. The chemokines stromal cell-derived factor 1&agr; (“SDF-1&bgr;”) and stromal cell-derived factor 1&bgr; (“SDF-1&bgr;”) form a chemokine family that is approximately equally related by amino acid sequence similarity to the CC and CXC chemokine families. Close to 40 different chemokines have been described and cloned, each exerting a predominant functional effect. For example, RANTES attracts T lymphocytes to inflammatory sites, while IL-8 typically attracts neutrophils to inflammatory sites.
Chemokines exert their effect by binding to chemokine receptors. CC chemokines typically bind to members of the CCR class of receptors, while CXC chemokines generally bind to members of the CXCR class of receptors. These receptors are important in regulating the extent and nature of inflammation, and certain receptors tend to be localized in certain tissues and cells.
Chemokine receptors are involved in certain functions such as, for example, chemotaxis and interacting with viral proteins. The HIV-1 virus is known to bind to certain proteins on the surface of cells, i.e., the CD4 antigen on lymphocytes. However, in order to gain entrance into these cells and replicate, the HIV-1 virus must bind to another receptor, i.e., predominantly, CXCR4 and CCR5 chemokine receptors. Different HIV-1 viral strains use specific chemokine receptors, i.e., the X4 virus uses CXCR4 receptors, while the R5 virus uses CCR5 receptors.
Viral entry through chemokine receptors is of prime importance in influencing viral replication and disease progression after HIV-1 infection. For example, individuals with genetic defects in chemokine receptors have been associated with a prolonged latency period after HIV-1 infection, i.e., progression of HIV-1 to AIDS.
Researchers and pharmaceutical companies have begun looking into strategies to block or inactivate specific chemokine receptors in an effort to inhibit HIV-1 viral replication, especially because fresh human sera and their antibodies (including Immunoglobulin G (“IgG”) anti-HIV-1) have no direct lytic or neutralizing activity on the HIV-1 virus. Some of these strategies include the use of peptides and IgG monoclonal antibodies that will bind to specific chemokine receptors. Such strategies, however, have not been shown to be effective.
Normal (i.e., non-infected) individuals have in their blood low levels of circulating Immunoglobulin M (“IgM”) antibodies that bind to their own leukocytes such as, for example, B and T lymphocytes, without causing cell lysis at 37° C. Such IgM antibodies are, therefore, typically referred to as “anti-lymphocyte autoantibodies.” These antibodies may also be referred to herein as “IgM anti-leukocyte antibodies” or “IgM anti-leukocyte autoantibodies” because they bind to macrophages and neutrophils in addition to lymphocytes and, furthermore, because they bind to allogenic leukocytes in addition to autologous leukocytes. Very little is known about the leukocyte or lymphocyte antigens or receptors that bind to IgM autoantibodies. Levels of such anti-leukocyte autoantibodies increase during inflammatory states, including autoimmune diseases and infectious diseases (i.e., virus-mediated diseases) such as, for example, systemic lupus erythematosus (“SLE”), sarcoidosis, HIV-1, malaria, Epstein-Barr virus (“EBV”) and cytomegalovirus (“CMV”). Individuals with asymptomatic HIV-1, therefore, have high levels of IgM anti-leukocyte autoantibodies. The inventor's studies show, however, that chemokine receptors are one of the cell membrane receptors that bind to these IgM autoantibodies and that, through this mechanism, such IgM autoantibodies inhibit HIV-1 from infecting cells. The inventor's studies also show that IgM autoantibodies that bind to chemokine receptors are heterogeneous and that only some of these antibodies have the ability to inhibit HIV-1 from infecting cells. Levels of IgM antibodies that inhibit HIV-1 from infecting cells are very low or are undetectable in patients with AIDS. Thus, while individuals with asymptomatic HIV-1 infection have increased levels of IgM autoantibodies that inhibit HIV-1 infectivity, these levels, however, significantly decrease as the disease progress to AIDS. Total serum IgM does not decrease, however, as the disease progresses to AIDS.
The physiological and pathological functions of IgM autoantibodies that bind lymphocytes remain unknown because, in part, very little is known about which membrane receptors are recognized and are bound by these IgM autoantibodies. It is unresolved, therefore, whether the increased production of these IgM autoantibodies after a viral infection is merely a non-specific response resulting from direct polyclonal activation of B cell precursors by EBV and/or the gp120 glycoprotein or is designed for a specific purpose, i.e., to function as protective antibodies. That the normal B cell repertoire has a high frequency (about 3 to 10%) of B cells committed to the production of IgM autoantibodies supports the theory that such increased production of IgM autoantibodies is designed for a specific purpose.
SUMMARY OF THE INVENTION
Normal individuals have naturally occurring IgM autoantibodies (referred to as IgM NAA), which are present at birth. IgM NAA are mostly polyreactive and do not lyse cells at body temperature. While the presence of IgM anti-leucocyte NAA has previously been described, there is no prior art identifying the leukocyte receptors targeted by IgM, nor is there prior art showing that IgM anti-leukocyte NAA can alter cell function or inhibit viral infectivity of leukocytes
In the present invention, applicant has discovered that some of these non-lytic IgM anti-leukocyte NAA obtained from normal human sera specifically inhibit binding of chemokines to their receptors, enhance or inhibit chemotaxis and inhibit HIV-1 from infecting cells. IgM autoantibodies that inhibit HIV-1 from infecting cells are depleted in patients with AIDS but not in asymptomatic HIV-1 infected individuals or in normal individuals. Moreover, IgM anti-leukocyte NAA are a heterogenous group of antibodies that bind to other non-chemokine receptors on the leukocyte.
Accordingly, one object of the present invention is to provide a method of inhibiting virus-mediated disease progression through use of IgM anti-leucocyte NAA.
The above and other objects, advantages and features of the present invention will become more apparent from the following detailed description of the presently preferred embodiments, when considered in conjunction with the figures, and to the appended claims.
REFERENCES:
patent: 5606026 (1997-02-01), Rodman
patent: 5837242 (1998-11-01), Holliger et al.
patent: 5959085 (1999-09-01), Garrone et al.
patent: 596
Housel James
Lucas Zachariah
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