Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Peptide containing doai
Reexamination Certificate
2000-09-29
2003-07-22
Stucker, Jeffrey (Department: 1648)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Peptide containing doai
C424S545000, C530S350000, C530S325000, C530S326000, C530S327000
Reexamination Certificate
active
06596688
ABSTRACT:
1 FIELD OF THE INVENTION
The present invention relates to peptides of one or more portions of the human chorionic gonadotropin &bgr;-chain as well as methods for treatment and prevention of disease, including HIV infection, cancer and wasting syndrome, and methods of promoting hematopoiesis using human chorionic gonadotropin, employing the &bgr;-chain of human chorionic gonadotropin, peptides containing a sequence of one or more portions of the &bgr;-chain of human chorionic gonadotropin and derivatives and analogues thereof. The invention further relates to fractions of sources and or preparations of human chorionic gonadotropin, such as fractions of human early pregnancy urine, which fractions have anti-HIV activity, anti-cancer activity, anti-wasting activity, and/or pro-hematopoietic activity. The present invention further relates to pharmaceutical compositions for treating and/or preventing HIV infection, cancer, and/or wasting, and/or for promoting hematopoiesis.
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 human, HIV replication occurs prominently in CD4
+
T lymphocyte populations, and HIV infection leads to depletion of this cell type and eventually to immune incompetence, opportunisitic 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 compunds, 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., 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
+
T cells by some HIV-1 strains (Smith, D. H., et al., 1987
, Science
238:170-1707). Certain primary HIV-1 isolates, however, are relatively less sensitive to inhibition by recombinant CD4 (Daar, E., et al., 1990
, Proc. Natl. Acad. Sci. USA
87:6574-6579). In addition, recombinant soluble CD4 clinical trials have produced inconclusive results (Schooley, R., et al., 1990
, Ann. Int. Med.
112:247-253; Kahn, J. O., et al., 1990
, Ann. Int. Med.
112:254-261; Yarchoan, R., et al., 1989, Proc. Vth Int. Conf. on AIDS, p. 564, MCP 137).
The late stages of HIV replication, which involve crucial virus-specific processing of certain viral encoded proteins, have also been suggested as possible anti-HIV drug targets. Late stage processing is dependent on the activity of a viral protease, and drugs are being developed which inhibit this protease (Erickson, J., 1990
, Science
249:527-533).
Recently, chemokines produced by CD8
+
T cells have been implicated in suppression of HIV infection (Paul, W. E., 1994
, Cell
82:177; Bolognesi, D. P., 1993
, Semin. Immunol
. 5:203). The chemokines RANTES, MIP-1&agr; and MIP-1&bgr;, which are secreted by CD8
+
T cells, were shown to suppress HIV-1 p24 antigen production in cells infected with HIV-1 or HIV-2 isolates in vitro (Cocchi, F
Bryant Joseph
Gallo Robert C.
Lunardi-Iskandar Yanto
Hultquist Steven J.
Marianne Fuierer
Stucker Jeffrey
University of Maryland Biotechnology Institute
Yang Yongzhi
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