Drug – bio-affecting and body treating compositions – Antigen – epitope – or other immunospecific immunoeffector – Bacterium or component thereof or substance produced by said...
Reexamination Certificate
1997-09-26
2002-04-09
Scheiner, Laurie (Department: 1648)
Drug, bio-affecting and body treating compositions
Antigen, epitope, or other immunospecific immunoeffector
Bacterium or component thereof or substance produced by said...
C424S257100, C424S258100
Reexamination Certificate
active
06368604
ABSTRACT:
TABLE OF CONTENTS
1. FIELD OF THE INVENTION
2. BACKGROUND OF THE INVENTION
2.1. THE HUMAN IMMUNODEFICIENCY VIRUS
2.2. HIV TREATMENT
2.3. LIPOPOLYSACCHARIDES
3. SUMMARY OF THE INVENTION
3.1. DEFINITIONS
4. DESCRIPTION OF THE FIGURES
5. DETAILED DESCRIPTION OF THE INVENTION
5.1. LIPOPOLYSACCHARIDE VARIANTS AND DERIVATIVES AND ANALOGS THEREOF WITH REDUCED OR ABSENT PYROGENICITY
5.2. SYNTHESIS AND ISOLATION OF LIPOPOLYSACCHARIDES
5.2.1 PURIFICATION OF LIPOPOLYSACCHARIDES FROM MICROORGANISMS
5.2.1.1 SOURCES OF LIPOPOLYSACCHARIDES
5.2.1.2 ISOLATION OF LIPOPOLYSACCHARIDES
5.2.2 SYNTHESIS OF LIPOPOLYSACCHARIDES
5.3 THERAPEUTIC USES
5.4 COMBINATION THERAPY
5.5 DEMONSTRATION OF THERAPEUTIC UTILITY
5.4.1 DETERMINING THE PYROGENICITY OF THE PREPARATION
5.4.2 DETERMINING THE ANTI-HIV ACTIVITY OF THE PREPARATION
5.6 THERAPEUTIC COMPOSITIONS AND METHODS OF ADMINISTRATION
6. EXAMPLE: NON-PYROGENIC LPS STIMULATES &bgr; CHEMOKINE SECRETION IN PBMC
6.1 MATERIALS AND METHODS
6.2 RESULTS
6.3 DISCUSSION
7. EXAMPLE: INHIBITION OF HIV-1 REPLICATION IN HUMAN PBMC-DERIVED MONOCYTES BY NON-PYROGENIC LPS
7.1 METHOD
7.2 RESULTS
8. EXAMPLES: SYNTHETIC LIPID IV
A
SUPPRESSES HIV REPLICATION WITHOUT INDUCING MEASURABLE LEVELS OF &bgr; CHEMOKINES
8.1 METHODS AND RESULTS
9. EXAMPLES: NON-PYROGENIC LPS SUPPRESSES HIV REPLICATION WITHOUT DISPLAYING LPS ANTAGONIST ACTIVITY
9.1 METHODS AND RESULTS
1. FIELD OF THE INVENTION
The present invention relates to lipopolysaccharide (LPS) or lipid A variants, derivatives, and analogs with non-pyrogenic and non-endotoxic properties as well as methods for treatment and prevention of immunodeficiency virus infection, in particular HIV infection, using these LPS or lipid A variants and analogs and derivatives. The present invention also relates to LPS and lipid A antagonists and their use as therapeutics in the treatment and prevention of HIV infection. The LPS and lipid A variants, derivatives, and analogs of the present invention preferably induce the secretion of &bgr; chemokines but exhibit decreased induction relative to LPS and lipid A of secretion of proinflammatory cytokines, such as IL-1&bgr;, IL-6 and TNF-&agr;. The present invention further relates to pharmaceutical compositions for the treatment and prevention of HIV infection.
2. BACKGROUND OF THE INVENTION
2.1. THE HUMAN IMMUNODEFICIENCY VIRUS
The human immunodeficiency virus (HIV) has been implicated as the primary cause of the slowly degenerative immune system disease termed acquired immune deficiency syndrome (AIDS) (Barre-Sinoussi, F., et al., 1983,
Science
220:868-870; Gallo, R., et al., 1984,
Science
224:500-503). There are at least two distinct types of HIV: HIV-1 (Barre-Sinoussi, F., et al., 1983,
Science
220:868-870; Gallo, R., et al., 1984,
Science
224:500-503) and HIV-2 (Clavel, F., et al., 1986,
Science
233:343-346; Guyader, M., et al., 1987,
Nature
326:662-669). Further, a large amount of genetic heterogeneity exists within populations of each of these types. In humans, HIV replication occurs prominently in CD4
+
T lymphocyte populations, and HIV infection leads to depletion of this cell type and eventually to immune incompetence, opportunistic infections, neurological dysfunctions, neoplastic growth, and ultimately death.
HIV is a member of the lentivirus family of retroviruses (Teich, N., et al., 1984,
RNA Tumor Viruses,
Weiss, R., et al., eds., CSH-Press, pp. 949-956). Retroviruses are small enveloped viruses that contain a single-stranded RNA genome, and replicate via a DNA intermediate produced by a virally-encoded reverse transcriptase, an RNA-dependent DNA polymerase (Varmus, H., 1988,
Science
240:1427-1439).
The HIV viral particle comprises a viral core, composed in part of capsid proteins, together with the viral RNA genome and those enzymes required for early replicative events. Myristylated gag protein forms an outer shell around the viral core, which is, in turn, surrounded by a lipid membrane envelope derived from the infected cell membrane. The HIV envelope surface glycoproteins are synthesized as a single 160 kilodalton precursor protein which is cleaved by a cellular protease during viral budding into two glycoproteins, gp41 and gp120. gp41 is a transmembrane glycoprotein and gp120 is an extracellular glycoprotein which remains non-covalently associated with gp41, possibly in a trimeric or multimeric form (Hammarskjold, M., & Rekosh, D., 1989,
Biochem. Biophys. Acta
989:269-280).
HIV is targeted to CD4
+
cells because a CD4 cell surface protein (CD4) acts as the cellular receptor for the HIV-1 virus (Dalgleish, A., et al., 1984, Nature 312:763-767; Klatzmann et al., 1984,
Nature
312:767-768; Maddon et al., 1986,
Cell
47:333-348). Viral entry into cells is dependent upon gp120 binding the cellular CD4 receptor molecules (McDougal, J. S., et al., 1986,
Science
231:382-385; Maddon, P. J., et al., 1986,
Cell
47:333-348), explaining HIV's tropism for CD4
+
cells, while gp41 anchors the envelope glycoprotein complex in the viral membrane. While these virus:cell interactions are necessary for infection, there is evidence that additional virus:cell interactions are also required.
2.2. HIV TREATMENT
HIV infection is pandemic and HIV-associated diseases represent a major world health problem. Although considerable effort is being put into the design of effective therapeutics, currently no curative anti-retroviral drugs against AIDS exist. In attempts to develop such drugs, several stages of the HIV life cycle have been considered as targets for therapeutic intervention (Mitsuya, H., et al., 1991,
FASEB J.
5:2369-2381). Many viral targets for intervention with HIV life cycle have been suggested, as the prevailing view is that interference with a host cell protein would have deleterious side effects. For example, virally encoded reverse transcriptase has been one focus of drug development. A number of reverse-transcriptase-targeted drugs, including 2′,3′-dideoxynucleoside analogs such as AZT, ddI, ddC, and d4T have been developed which have been shown to been active against HIV (Mitsuya, H., et al., 1991,
Science
249:1533-1544).
The new treatment regimens for HIV-1 show that a combination of anti-HIV compounds, which target reverse transcriptase (RT), such as azidothymidine (AZT), lamivudine (3TC), dideoxyinosine (ddI), dideoxycytidine (ddC) used in combination with an HIV-1 protease inhibitor have a far greater effect (2 to 3 logs reduction) on viral load compared to AZT alone (about 1 log reduction). For example, impressive results have recently been obtained with a combination of AZT, ddI, 3TC and ritonavir (Perelson, A. S., et al., 1996,
Science
15:1582-1586). However, it is likely that long-term use of combinations of these chemicals will lead to toxicity, especially to the bone marrow. Long-term cytotoxic therapy may also lead to suppression of CD8
+
T cells, which are essential to the control of HIV, via killer cell activity (Blazevic, V., et al., 1995,
AIDS Res. Hum. Retroviruses
11:1335-1342) and by the release of suppressive factors, notably the chemokines Rantes, MIP-1&agr; and MIP-1&bgr; (Cocchi, F., et al., 1995,
Science
270:1811-1815). Another major concern in long-term chemical anti-retroviral therapy is the development of HIV mutations with partial or complete resistance (Lange, J. M., 1995,
AIDS Res. Hum. Retroviruses
10:S77-82). It is thought that such mutations may be an inevitable consequence of anti-viral therapy. The pattern of disappearance of wild-type virus and appearance of mutant virus due to treatment, combined with coincidental decline in CD4
+
T cell numbers strongly suggests that, at least with some compounds, the appearance of viral mutants is a major underlying factor in the failure of AIDS therapy.
Attempts are also being made to develop drugs which can inhibit viral entry into the cell, the earliest stage of HIV infection. Here, the focus has thus far been on CD4, the cell surface receptor for HIV. Recombinant soluble CD4, for example, has been shown to inhibit infection of CD4
Crowley Richard
Hone David M.
Lewis George
Fuierer Marianne
Hultquist Stephen J.
Parkin Jeffrey S.
Scheiner Laurie
University of Maryland Biotechnology Institute
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