WO1999054954A2

WO1999054954A2 - Cd4 radio-immunological pharmaceuticals for the treatment of hiv infections

Info

Publication number: WO1999054954A2
Application number: PCT/DE1999/001177
Authority: WO
Inventors: Wolfgang Bergter; Ingrid Corinna Bergter
Original assignee: Wolfgang Bergter; Ingrid Corinna Bergter
Priority date: 1998-04-15
Filing date: 1999-04-15
Publication date: 1999-10-28
Also published as: JP2002512261A; AU4497199A; EP1071475A2; DE19980721D2; WO1999054954A3

Abstract

The disadvantages of standard HIV therapies are as follows: currently used medicaments must be taken in large quantities each day during an entire lifetime according to a strict timetable and have a large number of side effects. Traditional medicaments only manage to restrict virus replication. Host cells infected with HIV are not eliminated. For this reason it was not previously possible to cure HIV infections. The current application describes, as an additional application to PCT patent application (PCT/DE99/00598) dated 8.3.99, radio-immunological pharmaceuticals consisting of a CD4 molecule or a fragment derived therefrom and a radionuclide for in-vivo elimination of HIV replicating cells in HIV-1 and HIV-2 infected patients. The combination of HIV affine CD4 receptor molecules or fragments with radionuclides for therapeutic purposes, especially for use in radioimmunological anti-HIV therapy is totally novel. The radioimmunological pharmaceuticals are to be administered intravenously to HIV-1 or HIV-2 infected patients once or in several cycles in order to cause sustained damage to HIV replicating cells in a targeted manner so that the latter can be fully eliminated.

Description

description

CD4 radioimmunopharmaceuticals used to treat HIV infection

State of the art

According to WHO estimates, 30.6 million people were already infected with the human immunodeficiency virus HIV in December 1997 (http://www.who.org/ asd / issues / mar98.htm # th). Infection with HIV leads to a progressive immunodeficiency through loss of the CD4 receptor-carrying (CD4 +) T-lymphocytes infected with HIV. In patients with symptomatic HIV infection or in the clinical stage of HIV infection (AIDS), with a CD4 cell count below 350 cells / μl blood and / or a virus load with over 30,000 viral RA copies (vRNAVμl in serum is now an antiretroviral Therapy, preferably with an oral medicinal combination of three, consisting of two inhibitors of reverse transcriptase (RTI) and one protease inhibitor (PI) is recommended (Brodt et al. 1997), although the replication of the HI viruses is disrupted and slowed down by these preparations. However, HIV-infected host cells cannot be eliminated as a result, and the HIV infection persists as a life-threatening infection for the rest of the life.

CD4 molecules are integrated into the cell membrane of T-lymphocytes, have a molecular weight of 55,000 Daltons and, with their receptor component facing outwards, play an important role in fighting infection (Gaubin et al. 1996), but also in binding HIV to it Cells (Dalgeish et al. 1984). HI viruses use the CD4 receptor as a coupling site on the outside of the cell membrane. The exact location at which the viral gpl20 surface glycoprotein binds could be located at the amino-terminal end of the CD4 molecule and is referred to as the VI domain (Richardson et al. 1988. Arthos et al. 1989).

Based on this knowledge, a number of investigations have already been undertaken to clarify whether synthetic CD4 molecules or parts of this protein (peptides) can be used therapeutically. It could be shown that such molecules are the Occupy the CD4 binding site of the viral surface glycoprotein gpl20 and neutralize HI viruses (Deen et al. 1988, Byrn et al. 1989. Clapham et al. 1989. Watanabe et.al 1989). In this way, uninfected cells can be protected from infection with HIV. However, the application of such proteins or peptides alone is not sufficient for the therapy of an existing HIV infection because the HIV genome in the infected cells is not destroyed as a result and new HI viruses are replicated unimpeded.

Radiation therapy and radiopharmaceuticals are completely unknown in the treatment of HIV infection. In contrast, the treatment of benign and malignant thyroid diseases with radioisotopes, the so-called radioiodine therapy, has been the most important therapeutic method in nuclear medicine in Germany for over 50 years and has proven to be effective and has few side effects. To date, late complications, especially malignant induction, have not been detected (Moser 1996, Reiners 1997).

Newer therapeutic options with radioisotopes are now also available with ¹³¹ J-labeled meta-iodo-benzyl-guanidine (MIBG) in the treatment of metastatic pheochromocytomas and neuroblastomas, through the radiosynoviorthesis in rheumatoid arthritis, through intracavitary instillation of ⁹⁰ Y silicate in pleural or peritoneal cancer, palliative pain therapy for skeletal metastases with bone-affine substances such as ⁸⁹ Sr, or radiophosphorus treatment for polycythemia vera (Moser 1996).

Clinical testing is currently on therapy with ¹³¹ J-labeled anti-CEA IgG for colorectal cancer (Blumenthal et al. 1992, Blumenthal 1994) and B-cell lymphoma (Kaminski et al 1993, Press et al. 1993. Press et al. 1995, Press et al. 1995).

There is little experience with the effect of ionizing radiation on HIV replication. While low-dose gamma radiation can apparently result in increased HIV expression (Faure et al. 1995, Xu et al. 1996), there has been no acceleration of HIV replication as a result of therapeutic radiation from HIV-associated patients Tumors (Lotz et al. 1990, Plettenberg et al. 1991, Scheidegger et al. 1991, Stanley et al. 1991, Krain and Dieckmann 1994, Saran et al. 1995. Swift 1996, Saran et al. 1997). In animal experiments, the SlV infection of a macaque monkey showed that targeted lymph node irradiation can reduce the viral load in peripheral blood and halt disease progression (Fultz et al. 1995). Whole-body irradiation of HIV-infected patients is, however, only unspecifically effective and requires a high radiation dose. The effect is therefore fundamentally uncertain and the price due to undesirable radiation damage is high.

There are no scientific publications and patents on radioimmunotherapy for HIV infection. A search in the patent register only yields two publications in which, in addition to cytostatics and toxin conjugates, radionuclide conjugates are also mentioned. However, these conjugates are unsuitable for the treatment of HIV infection, which will be explained below.

In publication WO 94/04191 A1, a "therapy method" is described which is intended to cause not only the sick, HIV-infected T helper cells to be destroyed, but also, quite consciously, all healthy T helper cells. The authors want the HI virus the possibility of infecting new (ie healthy T helper cells) by conjugating monoclonal antibodies or gpl20 molecules against the CD4 receptor of the T helper cells with a cell poison or a radionuclide. the complete destruction of all T-helper cells carrying the CD4 receptor, especially the healthy cells!), however, represents a life-threatening intervention in the already severely impaired immune system of HIV-infected and AIDS patients. However, this is so worrying from a medical and ethical point of view that clinical trials would not even be approved by the ethics committee not commercially applicable.

The DNA structure of fusion proteins is described in publication WO 89/06690 AI. For this purpose, the authors want to fuse a DNA sequence of the CD4 receptor with the DNA sequence of the heavy chain of an immunoglobulin (claim 1). If necessary, the expressed fusion protein should also contain toxins or Radionuclides (without this being described and justified) conjugated. The fusion proteins are said to bind to HIV-infected cells via the CD4 portion of viral gpl20. The underlying idea is absurd. In immunodeficient patients, HIV-infected cells should be eliminated by activating the immune system via the immunoglobulin portion of the fusion protein (p. 15, par. 5).

The problem

The invention specified in claims 1 to 4 is based on the problem of developing HIV-binding proteins or peptides into cytotoxic agents in order to achieve a cure for HIV infection by deliberately killing all HIV-infected cells.

The solution

This problem is solved by the conjugation of CD4 molecules or fragments of CD4 molecules with radionuclides listed in claims 1 to 4 of this additional application, which represents a modification of the radioimmuno conjugates described in the main application (file number 198 09 785.9 of March 8, 1998).

The effects of radioactive radiation on cells and DNA have been sufficiently described (reviews in: Kauffmann et al. 1996, Sauer 1998). The basis of the radiation biological effects is the structural damage to the DNA. DNA modified in this way encodes defective proteins that lose their function. Not only do enzymes that are essential for HIV replication lose their function, but there are also metabolic changes in the HIV-infected cell. This leads to the elimination of HIV-infected cells through reproductive cell death or apoptosis. Production of the radioimmunoconjugate

CD4 molecules can be obtained on a large scale from tissue cultures (Deen et al. 1988, Glick and Pasternak 1995). The cleaning of the CD4 molecules is possible with the help of established molecular biological cleaning processes. For example, they can be isolated directly from the cell membrane by differential extraction using non-ionic detergents (Eckert and Kartenbeck 1997 '), by purification from tissue culture supernatants as in Deen et al. 1988 described by a biomagnetic separation (Deutsche Dynal GmbH, Hamburg) or other methods. The production of conjugates from proteins and radioactive isotopes can be carried out, for example, using the chloramine T method (Hunter and Greenwood 1962, Eckert and Kartenbeck 1997 ² ).

Another embodiment of the radioimmunoconjugate relates to the use of synthetic CD4 fragments with gp 120 affinity. Such fragments can be produced in large quantities in a prokaryotic host such as Escherichia coli or in a eukaryotic host such as Saccharomyces cerevisae (Wilcox and Studnicka 1988, Martin and Scheinbach 1989).

Finally, the CD4 fragments can be additionally modified by targeted mutagenesis (Jones et al. 1990) and optimized for therapeutic use with regard to their pharmacokinetics, gp 120 affinity and CSF passage. Knowledge of the role of amino acids in the functional peptide is a prerequisite for targeted mutagenesis. These can be obtained by genetic analysis, X-ray structure analysis of the three-dimensional peptide structure and simulated and analyzed with the help of computer-aided examinations on the computer.

Nuclear medical aspects

The short half-life of the therapeutically usable radionuclides such as ¹³¹ J, ³² P, ⁹⁰ Y and ⁸⁹ Sr requires preparation close to the center or rapid transport of the radioimmunoconjugate. Prerequisite for the therapy of HIV patients with Short-lived radionuclides are therefore the provision of specialized interdisciplinary centers, in which, in addition to professional therapy for HIV-infected people, the timely application of the radioimmuno-conjugate is also guaranteed under radiation protection law aspects.

Therapeutic use of the radioimmunoconjugate

A successful therapy with a radioimmunoconjugate is likely to reduce the viral load by pretreating the patient with one of the currently recommended antiretroviral or highly active antiretroviral therapies (ART, HAART). As a result, a higher dose of the radioimmunopharmaceutical acts on the HIV-infected cells, which would otherwise be intercepted by free virus particles and could not develop its cytotoxic effect on the infected cells.

Before ^{applying a} preparation based on iodine (eg ^I31 J), thyroid ^diagnostics and thyroid ^blockage must also be carried out according to a known scheme.

The preparation can be administered peripherally or centrally as a bolus, short infusion or continuous therapy over several days with a dose of probably 100 - 300 mCi. The dose is given once or in the form of cycles at intervals of several weeks. Generally, hospitalization over several days is required to shield the patient from the environment until the radiation has decayed.

A stem cell transplantation may also be necessary due to the potential damage to the bone marrow due to the effects of the radioimmuno-pharmaceutical.

The advantages achieved with these radioimmuno-conjugates

The most significant advantage of therapy with radioimmuno-conjugates described in this patent application compared to current antiretroviral therapy is that that not only is HIV replication hindered, but rather HIV-infected cells are completely eliminated, thereby opening up the chance of a complete cure for HIV infection for the first time.

A second advantage is. that the HIV-infected cells are selectively damaged. The radioimmunoconjugates bind specifically to the CD4-specific epitope with the protein or peptide portion of the CDV-specific epitope of retroviral gpl20 surface glycoprotein, which are exposed on the outer cytoplasmic membrane of HIV-replicating cells for virus budding and emit their radiation directly to the cell.

Another advantage of the conjugates described here is that they are suitable for the treatment of a wide range of strains of HIV-1 and even HIV-2. This is extremely important given the willingness to mutate the HI viruses and the associated development of resistance to conventional antiretroviral substances. The gpl20 epitopes relevant for CD4 receptor binding are in fact very similar in all HIV-1 and HIV-2 isolates (Sattentau et al. 1988) and are essential for infectivity.

Another advantage of synthetic and possibly further modified peptides with the smallest possible size but still having gpl20 specificity is that they can easily cross the blood-brain barrier. Such conjugates are therefore also suitable for the elimination of infected cells of the CNS.

Finally, there is a great advantage in the subjective tolerance, which is comparatively good in comparison to the usual antiretroviral therapy, and the objective lack of side effects of radioimmunological therapies. It is known that the radiation energy of an α or β emitter such as ¹³¹ J has a range of up to 40 cell diameters. Malignant transformations of healthy cells as a result of radiation damage are extremely rare and can hardly be recorded statistically. If a healthy cell is damaged, it also loses its ability to divide in most cases and reproductive or programmed cell death (apoptosis) occurs. The radiation of surrounding healthy cells also plays a subordinate role in the radioimmunotherapy of HIV-infected T lymphocytes because these cells predominantly in the circulation and therefore healthy cells are only exposed to radiation for a short time.

Even if temporary hematological side effects and an increased risk of opportunistic infections have to be expected after application of the radioimmunopharmaceutical, this is primarily the loss of HIV-infected T4 helper cells, which are already impaired in their normal function, which is already explained Therapy goal is. For this reason, however, radioimmunotherapy should be combined with a stem cell transplant. However, since T4 progenitor cells are not infected with HIV due to the lack of CD4 receptors and naive T helper cells are not affected either, regeneration of the T4 helper cell population can be expected. This assumption is also supported by an animal experiment already mentioned (Fultz et al. 1995).

Novel, i.e. The fact that a CD4 molecule or a part of the CD4 molecule is coupled with a radionuclide in order to treat HIV infection with the aim of eliminating virus-infected cells is not part of the prior art. Another radioimmune drug for the therapy of HIV infection, composed of an HIV-specific monoclonal antibody and a radioisotope, was already registered by the inventor on March 8, 1998 with the German Patent and Trademark Office in Munich (file number 198 09 785.9). In view of the uniformity of the inventions, however, this additional application is made for the CD4 radio protein or CD4 radio peptide pharmaceutical described above.

The subject of this patent application is also based on an inventive step, as, to the best of the inventor's knowledge, the therapeutic importance of the CD4 molecule for HIV binding to T helper cells 15 years ago (Dalgeish et al. 1984) has so far not been radioactive conjugated CD4 molecules (except in the context of fusion proteins, see above) was considered. The comments on the above-mentioned publications also show that the idea for this invention does not in any way arise from the prior art in an obvious manner. Ultimately, the nuclear medical treatment of an infectious disease is a previously unknown and not state of the art procedure. The The benefit of a nuclear medical therapy for HIV infections results solely from the fact that this viral infection is, compared to other viral infections, a dangerous, chronic and probably in almost all cases fatal infection with lentiviruses, which with the usual pharmaceuticals cannot be cured. In addition, since there is no reliable vaccine available against HIV infection in the long term (Gallo, Reuters News, May 1997) and HIV strains that have become resistant to conventional antiretroviral drugs have become single and multiple resistant (Erickson and Burt 1996, Imrie et al . 1997), novel therapy strategies like this gain great importance.

The subject of the patent is industrially applicable as a pharmaceutical. The conjugates can be prepared using the methods described in this patent application and, after in-vitro analysis on HIV-replicating cell cultures and successful animal experimentation with HIV-infected chimpanzees, can be used in the foreseeable future for the therapy of HIV-infected people. This could give the over 30 million HIV-infected people worldwide a chance to be cured.

The processes for obtaining CD4 molecules, developing CD4 fragments with gp 120 affinity using recombinant DNA techniques and for labeling soluble proteins with radioisotopes in vitro are state of the art. The following example illustrates the conjugation of radioisotopes to CD4 molecules or corresponding CD4 fragments.

example

Preparation of CD4-radionuclide conjugates

CD4 molecules can be produced, for example, using the chloramine T method (Hunter and Greenwood 1962) according to the instructions of Eckert and Kartenbeck 1997 (pages 237-240), in which a radioisotope such as ¹³¹ J is briefly replaced by that of chloramine T ( N-chloro-p-toluen-4-sulfonamide, Na salt) is oxidized hypochlorite released in aqueous medium. The strongly electrophilic radioisotope then binds in this state preferably to the benzene rings of the tyrosine contained in the CD4 molecule. To protect the proteins, this reaction is ended after a short incubation period with an excess of bisulfite, the remaining chloramine T and also oxidized but still unbound radioisotopes being reduced and thus inactivated. The CD4 radioisotope conjugate can finally be isolated by gel electrophoresis and processed for intravenous use with appropriate auxiliaries.

literature

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Claims

claims

1. Radioimmunoconjugate for the in vivo elimination of virus-replicating cells in HIV-infected patients, characterized.

that it contains, as an immunologically active component, a CD4 receptor molecule with affinity for an epitope on the surface glycoprotein gpl20 of HIV-1 and / or HIV-2 together with pharmaceutical carriers and / or excipients, or a fragment of the CD4 molecule with affinity for one Contains epitope on the surface glycoprotein gpl20 of HΓV-1 and / or HIV-2 together with pharmaceutical carriers and / or excipients, or a fragment of the CD4 molecule modified by random or targeted mutagenesis with affinity for an epitope on the surface glycoprotein gpl20 of HIV- 1 and / or HIV-2 together with pharmaceutical carriers and / or excipients,

and that as radioactive component it contains a radionuclide suitable for therapeutic purposes, such as contains ¹³¹ J, or contains ³² P, or contains ⁹⁰ Y, or contains ⁸⁹ Sr.

2. Production of the radioimmunoconjugate according to claim 1, characterized in that

that CD4 molecules or their fragments are produced for therapeutic conjugation with radioisotopes and brought to expression in cell culture systems and that, if necessary, targeted improvement of the gp 120 affinity, pharmacodynamics,

CSF and compatibility with computer-aided molecular designs and molecular biological techniques can be carried out on the CD4 molecule or its synthetic fragments.

3. Use of the radioimmunoconjugate according to claims 1 and 2 for the therapy of HIV-1 and / or HIV-2 infection. characterized in that the radioimmunoconjugate is administered intravenously under one to several days of stationary radiation shielding with a total body dose, preferably between 50 to 300 mCi, once or in several cycles.

4. Use of the radioimmunoconjugate according to claims 1, 2 and 3, characterized in that

that treatment may follow or during standard antiretroviral triple therapy, and / or under the protection of a stem cell transplant, and / or under the protection of a thyroid block.