US-12617842-B2 - Antiviral immunotherapy by membrane receptor ligation

US12617842B2US 12617842 B2US12617842 B2US 12617842B2US-12617842-B2

Abstract

The present invention relates to a cytotoxic agent for the prophylaxis and/or treatment of a viral infection which is configured for the selective binding to a membrane receptor of virus-infected T lymphocytes, a pharmaceutical composition containing said cytotoxic agent, the use of the cytotoxic agent for the prophylaxis and/or treatment of viral infections, a method of finding cytotoxic agents, the use of a membrane receptor of virus-infected T lymphocytes which is overexpressed in comparison to non-infected T lymphocytes for the diagnosis of a viral infection.

Inventors

Michael Schindler
Marius Codrea
Sven Nahnsen
Herwig Koppensteiner
Gundram Jung
Martin Hofmann

Assignees

EBERHARD KARLS UNIVERSITAET TUEBINGEN MEDIZINISCHE FAKULTAET

Dates

Publication Date: 20260505
Application Date: 20211202
Priority Date: 20160318

Claims (8)

1 . A method for the treatment of HIV infection, comprising the administration to a living being in need in a therapeutically effective amount of a cytotoxic agent, and wherein said cytotoxic agent comprises an agonistic antibody, or a fragment thereof, that selective binds to CD134, and said cytotoxic agent is used alone.
2 . The method of claim 1 , wherein the cytotoxic agent comprises an agonistic antibody that selective binds to the CD134.
3 . The method of claim 1 , wherein the cytotoxic agent comprises a fragment of an agonistic antibody that selective binds to the CD134.
4 . The method of claim 1 , wherein the agonistic antibody is selected from the group consisting of: MEDI6469 (9B12), MEDI6383, MEDI0562, and Hu106-222/Hu119-122 (UTMDACC).
5 . The method of claim 1 , wherein said cytotoxic agent comprises a cytostatic agent.
6 . The method of claim 5 , wherein the cytostatic agent is selected from the group consisting of: alkylating agents, platinum analogues, intercalants, antibiotics, mitosis inhibitors, and taxanes.
7 . The method of claim 1 , wherein said cytotoxic agent comprises a virostatic agent.
8 . The method of claim 1 , wherein the cytotoxic agent consists of an agonistic antibody, or a fragment thereof, that selective binds to the CD134.

Description

CROSS REFERENCES TO RELATED APPLICATIONS This application is a continuation application of U.S. patent application Ser. No. 16/131,325, filed on Sep. 14, 2018, entitled “ANTIVIRAL IMMUNOTHERAPY BY MEMBRANE RECEPTOR LIGATION”, now allowed, which is a continuation of copending international patent application PCT/EP2017/056443 filed on 17 Mar. 2017 and designating the U.S., which has been published in German, and claims priority from German patent application DE 10 2016 105 069.5 filed on 18 Mar. 2016. The entire contents of these prior applications are incorporated herein by reference in their entireties for all purposes. FIELD The present invention relates to a cytotoxic agent for the prophylaxis and/or treatment of a viral infection, which is configured for the selective binding to a membrane receptor of virus-infected T lymphocytes, a pharmaceutical composition containing said cytotoxic agent, the use of the cytotoxic agent for the prophylaxis and/or treatment of viral infections, a method of finding cytotoxic agents, the use of a membrane receptor of virus-infected T lymphocytes, which is overexpressed in comparison to non-infected T lymphocytes, for the diagnosis of a viral infection. BACKGROUND Viral infections are one of the great challenges of the present to science and medicine. One of the human pathogenic viruses in focus is the human immunodeficiency virus (HIV). HIV is an enveloped virus belonging to the family of the retroviruses and to the genus of the lentiviruses. An untreated HIV infection usually leads to AIDS (acquired immunodeficiency syndrome) after a latency phase of varying lengths free of symptoms, usually lasting several years. The worldwide HIV prevalence in adults at the age of 15 to 49 years was 0.8 percent in the year 2010. For Central and Western Europe, it was 0.2 percent. It was above average in Subsaharian Africa (5.0 percent) and the Caribbean (0.9 percent). In some states, such as Swaziland, Botswana or Lesotho, about one quarter of the 15 to 49 years old are infected with the HI virus. In Germany, the HIV prevalence in the year 2009 was approximately 0.1 percent. For the proliferation, the HI virus requires host cells carrying the so-called CD4 receptor on the surface. These are mainly CD4 bearing T helper cells, so-called CD4+ cells or CD4+ lymphocytes. The main reservoir for the HI viruses is the follicular T helper cells in the body's lymphoid follicles, which make up about 2% of the CD4+ cells. Latent infected, resting CD4+ T cells or T memory cells, respectively, represent long lasting reservoirs for HIV. These cells are held responsible for the fact that despite the currently available antiretroviral drugs HIV cannot be eradicated yet and that recurrences occur repeatedly after discontinuation of the therapy. Since the proliferation of the viruses takes place inside of normal cells and is closely linked to the central biochemical cell mechanisms, the antiviral agents in question must either prevent the penetration of the virions into the host cells, intervene in the cell metabolism to the detriment of the virus proliferation or, after a possible virus proliferation in the cells, prevent the new viruses from escaping from the cells. On the other hand, however, these sought-after active agents must also be tolerable to the body's metabolism, the cell structure and/or the internal cell metabolism as a whole, as otherwise not only the virus proliferation in the cells but in the worst case also the (cellular) life of the entire treated organism comes to a standstill. Because these conditions are very difficult to reconcile, some of the antiviral drugs developed so far are often associated with serious side effect risks. The current therapy of choice for an HIV infection and AIDS is called highly active antiretroviral therapy (HAART). HAART is a combined drug therapy consisting of at least three antiretroviral agents. Several classes of active ingredients are currently used: Nucleoside and nucleotide analogues (NRTI), non-nucleoside reverse transcriptase inhibitors (NNRTI), HIV protease inhibitors (PI), entry and fusion inhibitors and integrase inhibitors. Some of the afore-mentioned active agents are referred to as ‘direct acting antiviral drugs’ (DAA). DAA specifically inhibit viral proteins, but not cellular proteins of the host. This principle of action should lead to fewer side effects. However, it is precisely in DAA that the viruses to be attacked also develop resistance, which they are well able to do so because of their extremely fast reproduction cycle and the biochemical characteristics of this replication. Furthermore, a disadvantage of the currently used antiviral agents is that they are virostatic, but not virotoxic. They inhibit the proliferation of the viruses, but do not kill them. SUMMARY Against this background, it is an object of the present invention to provide a novel antiviral agent with which the disadvantages of the currently available antiviral ag