KR100414505B1 - Use of anti-TNF antibodies as a drug for the treatment of diseases with high serum levels of interleukin-6 - Google Patents

Abstract

The present invention relates to the use of TNF antagonists for the manufacture of drugs for the treatment of diseases characterized by high serum levels of interleukin-6.

Description

Use of anti-TNF antibodies as drugs for treating diseases with high serum levels of interleukin-6

The present invention relates to the use of anti-TNF antibodies in the treatment of diseases with high serum levels of interleukin-6.

The term tumor necrosis factor (TNF) is known to include two cytotoxic factors (TNF-α and TNF-β) mainly produced by activated lymphocytes and monocytes.

EP 260 610 describes inactivation of TNF for diseases associated with an increase in blood TNF levels, such as, for example, septic shock, graft rejection, allergies, autoimmune diseases, shock lungs, coagulation disorders or inflammatory bone disease. Anti-TNF antibodies that are said to be available are described.

Examples of diseases characterized by high serum levels of interleukin-6 in patients are the sequelae of transplantation, autoimmune diseases and, in particular, certain types of sepsis.

Sepsis is defined in the medical textbook as a generic clinical term for a condition where bacterial pathogens start from a lesion and enter the bloodstream and cause a wide range of subjective and objective pathological symptoms. In addition, clinical conditions have been found to vary widely depending on the type of pathogen, the responsiveness of the body, primary lesions and associated organs [Sturm et al., "Grundbegriffe der Inneren Medizin", 13th edition, 570, Gustav Fischer Verlag, Stuttgart, 1984].

Many cytokines have been proposed to be involved in the complex pathophysiological processes of sepsis. TNF is thought to play an important role in septic shock, especially based on animal experimental data (Beutler et al., Science 229 (1985) 869-871).

This eventually led to a clinical study of the treatment of sepsis patients using anti-TNF antibodies.

However, in a recently published multicenter Phase II study of the treatment of severe sepsis using rat monoclonal anti-TNF antibodies, the entire population (80 patients) benefits in terms of survival from treatment with the antibody. Turned out not to get. Only patients with high circulating TNF concentrations have been shown to benefit from the administration of high doses of anti-TNF antibodies in terms of viability [CJ Fisher et al., Critical Care Medicine, Vol. 21, No. 3, Pp. 318-327. The study also addresses the correlation between plasma levels of TNF and IL-6.

The role played by cytokine interleukin-6 (IL-6) in sepsis is unclear and contradictory. High serum levels of IL-6 have been found in some sepsis patients (Hack et al., Blood 74 (1989) 1704-1710).

Waage describes the correlation between their concentration and shock severity, although cytokines IL-6 and IL-8, alone or in combination with TNF, had no effect on mortality on the development of shock syndrome. [Wum, "Tumor Necrosis Factors", ed. B. Beutler, Raven Press, New York, 1992, pp. 275-283].

Some scientists have thought that IL-6 plays a beneficial role in septic shock because IL-6 inhibits LPS-induced TNF production in the form of negative feedback regulation (Lbert et al., "Tumor Necrosis Factor"). : Molecular and Cellular Biology and Clinical Relevance ", ed. W. Fiers, Karger, Basel, 1993, pp. 126-131].

The inventors have now surprisingly found that TNF antagonists can be used particularly successfully as drugs for the treatment of diseases characterized by high serum levels of interleukin-6.

Treatment of sepsis with a TNF antagonist according to the present invention is particularly successful, e.g., when the IL-6 level of the treated sepsis patient is at least 500 pg / ml at the start of treatment, e.g. a clear reduction in mortality. to be. Patients with IL-6 serum levels above 1000 pg / ml especially benefit from the treatment according to the invention.

The term high serum levels of IL-6 means at least 10 times higher levels than physiological serum levels in healthy subjects.

Serum levels of IL-6 up to 20,000 times the level of healthy subjects were found in sepsis patients.

“Normal” IL-6 serum levels are usually below the detection limit, which may vary slightly depending on the assay system used. However, its maximum is 20 pg / ml.

Serum concentrations of IL-6 can be measured by conventional detection methods such as RIA or ELISA. An example of a very suitable detection system is IL-6-EASIA provided by Medgenix.

IL-6 concentrations can also be determined by activity assays, for example, analyzing C-reactive proteins.

Suitable TNF antagonists include anti-TNF antibodies, TNF receptors and soluble fragments thereof, TNF binding proteins, or TNF derivatives that still bind to TNF receptors but have no TNF activity. These types of TNF antagonists have the property of capturing the formed TNF to prevent the captured TNF from reaching the TNF receptor or competing with the TNF for the receptor.

However, TNF antagonists which inhibit the formation or release of TNF are also suitable for use according to the invention. Such agents inhibit, for example, the release of TNF from the expression or precursor form of the TNF gene.

Such TNF-antagonistic activity has been described, for example, for xanthine derivatives, glucocorticoids, prostaglandin E2, thalidomide, interleukin-4, interleukin-10, granulocyte stimulating factor (G-CSF), cyclosporin and α-antitrypsin . Thus, these types of compounds are also suitable as TNF antagonists.

Anti-TNF antibodies are particularly preferred for the use according to the invention.

Anti-TNF antibodies suitable for use according to the invention are known (EP 260 610, EP 351 789, EP 218 868). Both polyclonal and monoclonal antibodies can be used. Also suitable are TNF-binding antibody fragments or single-chain Fv fragments, such as Fab or F (ab ') ₂ fragments.

Moreover, humanized or human anti-TNF antibodies or TNF-binding fragments thereof are also very suitable because these molecules do not cause any anti-mouse antigenicity in human patients.

It is also possible to use mixtures of various anti-TNF antibodies or mixtures of anti-TNF antibodies and TNF receptor fragments as active substances.

The present invention includes pharmaceutical compositions containing anti-TNF antibodies in addition to pharmaceutically suitable non-toxic inert vehicles and methods of making these compositions.

Anti-TNF antibodies are generally formulated as liquid formulations or lyophilisates in conventional methods for biotechnically produced active substances (see, eg, Hagers Handbuch der pharmazeutischen Praxis, Vol. 2, Fifth Edition, 1991, pp. 720, ISBN 3-540-52459-2). The pharmaceutical composition described above is produced in a conventional manner, for example by mixing the active substance (s) with the vehicle (s).

In general, the active substance (s) suitable for the use according to the invention are suitable, in a total amount of about 0.1 to about 1000 mg / kg body weight, preferably 0.1 to 10 mg / kg body weight, every 24 hours. To several individual dosage forms or as a continuous infusion, and suitably over several days of treatment has proved advantageous to achieve the desired result. Administration can be carried out as a short-term intravenous infusion of a single dose or as a continuous long-term infusion of the daily dose over 24 hours. The single dosage preferably contains the active substance (s) in an amount of about 0.1 to about 10 mg / kg body weight. However, it may be necessary to deviate from the above-mentioned dosage ranges, depending essentially on the age and physique of the patient being treated and the nature and severity of the underlying disease, the type of composition and type of drug administration, and the duration or interval of administration. The following examples further illustrate the invention.

<Example>

Treatment of Sepsis Patients Using Rat Anti-TNF Antibody Fragments (F (ab ') ₂ )

A total of 122 patients with severe sepsis were treated in a multicenter clinical study using various doses of anti-TNF antibody fragments or placebo.

The four treatment methods studied differed only at the single dose level of the anti-TNF antibody fragment. Dosage levels were 0.1 mg / kg body weight, 0.3 mg / kg body weight or 1.0 mg / kg body weight. Patients in group 4 were subjected to “sham treatment” (placebo) for comparison. Patients were randomly assigned to one of four therapies using anti-TNF antibody fragments. The treatment described above, in addition to standard treatment of sepsis patients, was administered as a total of 9 (9 ×) (ie, 3 days) short-term infusions at 8-hour intervals after diagnosis (see criteria for inclusion in this study). Matches). A total of 122 patients were included for this study, 34 patients were assigned to the 0.1 mg / kg dose group, 30 patients to the 0.3 mg / kg dose group, 29 patients to the 1.0 mg / kg dose group, Twenty nine patients were assigned to the placebo group.

119 of 122 patients were able to measure IL-6 serum concentrations prior to initiation of treatment. Serum levels of IL-6 were higher than 1000 pg / ml in 36 patients (> 1000 pg / ml) and serum levels of IL-6 were lower than 1000 pg / ml in 83 patients (<1000 pg / ml).

1A shows mortality of populations with IL-6> 1000 pg / ml in various treatment groups (Placebo, 0.1, 0.3 and 1.0 mg / kg body weight).

1B shows mortality of the population with IL-6 <1000 pg / ml in various treatment groups (placebo, 0.1, 0.3 and 1.0 mg / kg body weight).

In patients with IL-6> 1000 pg / ml, mortality in treatment with anti-TNF antibody fragments was dose dependently reduced from 80.0% (= placebo group) to 36.4% (1.0 mg / kg of antibody) (FIG. 1A ).

In patients with IL-6 <1000 pg / ml, treatment with anti-TNF antibody fragments did not reduce mortality but increased slightly (1.0 mg / kg of antibody compared to 30.4% for placebo). 38.9% for the group) (FIG. 1B).

As a result of this clinical study, treatment of severe sepsis with anti-TNF antibody is only successful if the sepsis patient being treated only has a serum level of IL-6 above 1000 pg / ml; It has been clearly demonstrated that treating patients with serum levels of IL-6 below 1000 pg / ml is not successful and sometimes even contraindicated.

Claims (4)

A pharmaceutical composition for the treatment of sepsis in a patient with a serum level of interleukin-6 greater than 1000 pg / ml, containing a TNF antagonist with a pharmaceutically suitable non-toxic inert vehicle. The pharmaceutical composition of claim 1, wherein the TNF antagonist is a monoclonal anti-TNF antibody. The pharmaceutical composition of claim 2, wherein the anti-TNF antibody is a humanized or human anti-TNF antibody. The pharmaceutical composition of claim 1, wherein the TNF antagonist is a TNF receptor or a soluble fragment thereof.