Drug – bio-affecting and body treating compositions – Antigen – epitope – or other immunospecific immunoeffector – Amino acid sequence disclosed in whole or in part; or...
Patent
1997-09-08
2000-10-17
Stucker, Jeffrey
Drug, bio-affecting and body treating compositions
Antigen, epitope, or other immunospecific immunoeffector
Amino acid sequence disclosed in whole or in part; or...
4241841, 4241881, 4242071, 4242081, 4242781, 530350, 530403, 530826, C07K 100
Patent
active
061327212
DESCRIPTION:
BRIEF SUMMARY
The present invention relates to new retroviral immunogens which use retroviral regulatory proteins, the essential biological properties of which will have been inactivated beforehand such that their immunogenic properties are retained or increased, a process for their preparation and pharmaceutical compositions comprising them. These new "inactivated" immunogens can be used to induce active immunization in humans which is capable of preventing or correcting the deregulatory effects which the native proteins from which they are produced may help to produce.
The present invention also relates to new antibodies obtained by using these "inactivated" immunogens, processes for their preparation and pharmaceutical compositions for passive immunization which comprise them.
The Tat molecule is an HIV regulatory protein which is not found in the viral particle but is coded by the HIV-1 genome. Inside infected cells, this protein coded by the proviral DNA plays a transactivating role on viral or cell genes. However, this genetic regulatory protein can also be found outside cells in the circulating extracellular medium, excreted within the debris of dead cells in the native or fragmented state or by a secretion process. Its presence in the circulating medium explains the existence of anti-Tat antibodies detectable in some seropositive subjects. In this extracellular context of Tat, the terminal C segment which carries the RGD residues recognized by the integrins of the cell surface and the base region of the molecule (residues 45-70) enable it, as do bacterial toxins, to act on the non-infected cells of different tissues. The circulating Tat protein thus acts like a true viral toxin, can exert harmful effects on endothelial cells and, in combination with the growth factor BFGF, can contribute to the neoangiogenesis of Kaposi's sarcoma, which characterizes the AIDS disease. The circulating Tat protein can also aggravate the immunosuppression which becomes established progressively with AIDS, either by direct immunosuppressive action on the T cells or by helping to deregulate the production of interferon-.alpha. by the cells presenting the antigen, called APC (macrophages or dendrite cells).
Acquired immunodeficiency syndrome (AIDS) is defined clinically by opportunistic diseases due to immunosuppression or by Kaposi's sarcoma. Acquired immunosuppression, established progressively in the course of HIV infection, manifests itself biologically by the loss of immunological reactivity of T cells (cytostasis and the reduction in the production of IL2), after stimulation in the first instance by memory antigens, and then by alloantigens, and finally by mitogens (PHA). This immunosuppression is associated with excessive production of interferon-.alpha. and -.gamma..
The cytopathogenic mechanisms which induce immunosuppression are complex and involve various factors of viral origin, which act either directly on the immunity cells, T lymphocytes and APC, or indirectly via the cytokine system. The envelope protein gp120 which is carried by the HIV-1 particle and of which the extracellular presence is measured by the serum viral charge can thus induce anergy of T cells of phenotype CD4 directly. On their part, the HIV regulatory proteins, in particular Tat in its extracellular configuration of circulating viral toxin, also seem to induce a direct immunosuppression of T cells or other pathogenic effects, for example by the fact that in vitro T cells activated by a memory antigen or by anti-CD3 antibodies no longer proliferate in the presence of the Tat molecule. In addition, the circulating Tat protein seems to facilitate excessive production by the APC of interferon-.alpha., a cytostatic and apoptogenic cytokine which is capable of amplifying the immunosuppresion and apoptosis observed with the AIDS disease. In fact, the secretion of interferon-.alpha. by macrophages no longer seems halted in the presence of Tat by a retroregulation (feedback), which in the normal state controls this production of interferon-.alpha. (refractory p
REFERENCES:
Harlow et al. Antibodies: A Laboratory Manual. N.Y., Cold Spring Harbor, 1988. pp. 78, 79, 124, 130, and 131. QR186.7.A53.
Brake, David A. et al., "Identification of an Arg-Gly-Asp (RGD) cell adhesion site in human innumodeficiency virus type 1 transactivation protein, tat." Jour. Cell Biol., vol. 111, pp. 1275-1282 (Sep. 1990).
Brake, David A. et al., "Characterization of murine monoclonal antibodies to the tat protein from human immunodeficiency virus type 1.", Jour. Viro., vol. 64, No. 2, p. 962-965 (Feb. 1990).
Frankel, A.D., et al., "Cellular Uptake of the Tat Protein from Human Immunodeficiency Virus," Cell 55:1189-1193 (1988).
Bizzini Bernard
Zagury Daniel
Zagury Jean-Fran.cedilla.ois
NEOVACS
Stucker Jeffrey
LandOfFree
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