Treatment of HIV

Details Treatment of HIV Treatment of HIV

2000-01-18

2003-01-07

Fay, Zohren (Department: 1614)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Peptide containing doai

C514S018700, C514S408000

Reexamination Certificate

active

06503882

ABSTRACT:

BACKGROUND OF THE INVENTION
This invention relates to treatment of HIV.
One of the classic markers of full-blown AIDS resulting from long-term infection with HIV-1 is a severe depletion of CD4
+
T-cells, which are a key component of the immune system. Attempts have been made to increase the CD4
+
counts of AIDS patients, and some of these efforts, notably treatment with HIV protease inhibitors, have met with considerable success. Other approaches, e.g., stimulation of the immune response by vaccination with viral peptides, have been less successful. The reasons for CD4
+
depletion in AIDS, and resistance of CD4
+
cells to stimulation by some therapies, are not fully understood.
SUMMARY OF THE INVENTION
The invention provides a new and highly advantageous method of potentiating the immune response in HIV-infected patients, employing extremely low concentrations of compounds which, at these concentrations, act as stimulatory, rather than inhibitory, molecules. The very low concentrations employed according to the invention allow treatment with minimal side effects and toxicity. The specificity of the treatments according to the invention also helps avoid these adverse effects, which are seen, for example, in treatment with immune stimulatory compounds such as Interleukin-2.
The invention involves the unexpected finding that certain compounds, which at relatively low concentrations (e.g. 10
−4
-10
−6
) are cytotoxic to T-cells, nevertheless have immune stimulatory properties at extremely low concentrations (e.g. 10
−10
-10
14
). Even more surprising, this stimulation occurs even though the HIV-infected patient's T-cells are otherwise unable to respond to T-cell proliferation-inducing stimuli. The effects of these low concentrations are paraxodical because T-cells from non-HIV-infected individuals, which respond to T-cell proliferation-inducing stimuli, do not seem to respond in the same fashion as T-cells from an HIV-infected patient when treated with the extremely low concentrations of compounds according to the invention.
The invention thus provides a method for treating the T-cells of a human subject infected with human immunodeficiency virus. The subject's T-cells are contacted with a molecule that inhibits CD26 and that stimulates immune function of the T-cells in an amount effective to stimulate immune function of the T-cells, said amount being below a concentration which causes detectable cytotoxicity of the T-cells. In one embodiment, the molecule stimulates proliferation of T-cells at the effective concentration. In other embodiments, the molecule stimulates the production of cytokines or increases cytotoxic T-lymphocyte or antibody activity.
The T-cells can be contacted in vitro or in vivo. In certain embodiments, the effective amount is below 10
−8
M and may be between 10
−10
and 10
−16
M. Molarity is measured as a function of final concentration in vitro and as a function of blood concentration in vivo.
According to another aspect of the invention, the molecule can be administered in conjunction with a different therapeutic agent that increases the CD4
+
count of HIV-infected subjects. In this manner, treatment with effective amounts of the molecule according to the invention can enhance the therapeutic effect of other AIDS drugs. Specifically contemplated is use of the molecules according to the invention with non CD26 protease inhibitors. It has been determined that the effects of the treatments according to the invention are particularly good in patients whose CD4
+
count is above about 400. In one embodiment, subjects may be treated with therapeutic agents or regimens to increase T-cell count to above 400 where the count initially is below 400. The subjects then are believed to be better candidates for treatment according to the invention. Thus, the invention contemplates the use of the molecules according to the invention to provide optimal combination AIDS therapies. Particularly contemplated for use in conjunction with the molecules of the invention are therapeutics which inhibit HIV replication by, for example, inhibiting reverse transcriptase or by inhibiting HIV protease activity. Exemplary therapeutics include the antiretroviral drugs: AZT (3′ azido-2′,3′ dideoxythymidine), ddI (2′,3′ dideoxyinosine), (2′,3′ dideoxycytidine), ddt (2′,3′ didehydro-3′-deoxythymidine) and other nucleoside and non-nucleoside reverse transcriptase inhibitors and HIV-1 protease inhibitors: Indinavir, Ritonavir, Saquinavir. Combination therapies include the administration of one or more of these or other antiretroviral therapeutics, alone or together with therapeutics that are intended to treat the secondary infections associated with HIV and/or cytokines (e.g., GM-CSF, G-CSF, interferons, interleukins)
According to another aspect of the invention, the molecules of the invention are contacted with T-cells of a human subject infected with HIV, which T-cells are unable, prior to treatment according to the invention to respond normally to T-cell proliferation-inducing stimuli. In one particularly important embodiment, the molecules of the invention are administered in conjunction with an antigen. Ordinarily, such HIV-infected patients do not respond well to antigens because of an HIV-induced defect in the T-cell stimulation pathway. Use of the molecules according to the invention as adjuvants can render such T-cells responsive to stimulation or vaccination with antigens. The invention permits immunization of HIV-infected patients with antigens characteristic of HIV, antigens characteristic of other pathogens, antigens characteristic of cancer cells and the like. Peptide antigens in particular are contemplated.
Compounds useful in the invention inhibit CD26 and stimulate proliferation of T-cells of HIV-infected subjects in the assays and at the concentrations described below. CD26 is also referred to as “dipeptidyl-aminopeptidase type-IV” or “DP-IV”. CD26 is a post-prolyl cleaving enzyme with a specificity for removing Xaa-Pro (where Xaa represents any amino acid) dipeptides from the amino terminus of a polypeptide substrate.
Peptides which reportedly have demonstrated utility for inhibiting post-prolyl cleaving enzymes and which, if coupled to a reactive group, form a covalent complex with a functional group in the reactive site of a post-prolyl cleaving enzyme are described in U.S. Pat. No. 4,935,493, “Protease Inhibitors”, issued to Bachovchin et al. (“Bachovchin '493”); U.S. Pat. No. 5,462,928, “Inhibitors of Dipeptidyl-aminopeptidase Type IV”, issued to Bachovchin et al. (“Bachovchin '928”); U.S. Pat. No. 5,543,396, “Proline Phosphonate Derivatives”, issued to Powers et al., (“Powers '396”); U.S. Pat. No. 5,296,604, “Proline Derivatives and Compositions for Their Use as Inhibitors of HIV Protease”, issued to Hanko et al., (“Hanko '604”); PCT/US92/09845, “Method for Making a Prolineboronate Ester”, and its U.S. priority applications (U.S. Ser. Nos. 07/796,148 and 07/936,198), Applicant Boehringer Ingelheim Pharmaceuticals, Inc. (“Boehringer”). Representative structures of the transition-state analog-based inhibitors Xaa-Boo-Pro, include Lys-boroPro, Pro-boroPro, Val-boroPro and Ala-boroPro in which “boroPro” refers to the analog of proline in which the carboxylate group (COOH) is replaced with a boronyl group (B) (OH
2
).
In general, the molecules useful according to the invention can have a first targeting moiety for binding a post-prolyl cleaving enzyme such as CD26 covalently coupled to a first reactive group. As used herein, a reactive group is capable of reacting with a functional group in a post-prolyl cleaving enzyme such as CD26. By reacting, it is meant that the reactive group forms a bond with a functional group of a post-prolyl cleaving enzyme such as CD26. Reactive groups that are embraced within the invention include the reactive groups referred to as group “T” in U.S. Pat. No. 4,935,493, “Protease Inhibit

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