CN1163272C - Use of a TNF antagonist as a medicament for the treatment of septic diseases - Google Patents

Abstract

TNF antagonists were used to prepare drugs for treating septic diseases, wherein serum levels of interleukin-6 were elevated within a assay period of at least 30 minutes.

Description

Use of a TNF antagonist as a medicament for the treatment of septic diseases

The present invention relates to the use of TNF antagonists for treating septic diseases.

The well-known term tumor necrosis factor (TNF) includes two cytotoxic factors (TNF-α and TNF-β) produced in most cases by activated lymphocytes and monocytes.

For example, EP 260 610 describes the purported use of anti-TNF antibodies to inactivate TNF in diseases associated with elevated TNF in the blood, such as septic shock, graft rejection, anaphylaxis, autoimmune Immune disease, shock lung, blood clotting disorder, or bone inflammatory disease.

In medical textbooks, a septic disease is defined as a common term for a clinical situation in which an agent causing inflammation, such as bacteria, begins from a lesion and enters the bloodstream, which can trigger a wide range of subjective and objective pathological manifestations. It was further found that the clinical situation can vary significantly depending on the type of pathogen, the reactivity of the body, the primary lesion and the different complexities contained in the organ (Sturm et al. "Grundbegriffe der Inneren Medizin", 13th ed., p. 570, Gustav Fishcher Verlag, Stuttgart, 1984).

A number of cytokines have been implicated in the complex pathophysiology of sepsis. On the basis of data from animal experiments (Beutler et al., Science, 229 (1985) 869-871), it is believed that TNF plays an important role especially in septic shock.

This eventually led to clinical studies in the treatment of septic patients with anti-TNF antibodies.

However, in a recently published multicentre phase II study it was found that the entire group (80 patients) did not benefit from the use of the murine monoclonal anti-TNF antibody in terms of survival in severe sepsis. treatment plan. It appears that only patients with elevated TNF concentrations in the circulation benefit from the administration of high doses of anti-TNF antibodies in terms of survival probability (C.J. Fisher et al., Critical Care Medicine, Vol. 21 No. 3 318- 327). The correlation between plasma TNF level and IL-6 level was also involved in this study.

Part of the explanation for the cytokine interleukin-6 (IL-6) in sepsis is unclear and contradictory. Increased levels of IL-6 have been found in the serum of certain septic patients (Hack et al., Blood, 74, Issue 5 (1989) 1704-1710).

Waage described a correlation between the concentrations of the cytokines IL-6 and IL-8 and the severity of shock, but they neither act alone nor in combination with TNF on the shock syndrome in terms of mortality (Waage In "Tumor Necrosis Factors", edited by B. Beutler, Raven Press, New York, 1992, pp. 275-283).

Some scientists have attributed the beneficial role in septic shock to IL-6, because IL-6 can inhibit LPS-induced TNF production in the process of developing negative feedback control (Libert et al. in "Tumor Necrosis Factors: Molecular and Cellular Biology and Clinical Relevance", edited by W. Fiers, Karger, Basle, 1993, pp. 126-131).

TNF antagonists are disclosed in WO 95/00291 as drugs for the treatment of septic patients in whom serum levels of interleukin-6 are 500 pg/ml or higher.

However, it has been shown from clinical studies that the method of treatment disclosed in WO 95/00291 is not always successful.

Clearly there are cases where sepsis can be successfully treated with TNF antagonists, while in other cases treatment with TNF antagonists has been unsuccessful and is in fact contraindicated.

It is an object of the present invention to reliably and rapidly identify those patients suffering from sepsis who can be successfully treated with TNF antagonists.

We have found that this is accomplished by utilizing the following characteristics to identify patients who can be successfully treated for septic disease:

Elevated serum levels of interleukin-6, i.e., serum levels of interleukin-6 measured at a later time than the first measured serum level of interleukin-6 during an assay period of at least 30 minutes.

Patients with sepsis who fulfill this criterion are well suited for treatment with TNF antagonists.

Preferably, such treatment is administered to patients with serum levels of interleukin-6 of at least 500 pg/ml over the assay period. However, it can be significantly higher than this level and reach the range of several mg/ml.

To determine whether serum levels of interleukin-6 (IL-6) are elevated, it is necessary to perform at least two IL-6 assays.

A second, later measurement should be obtained within a period of 30 minutes to 48 hours after the first IL-6 measurement (measurement period).

The preferred measurement period is 2-24 hours, especially 4-10 hours.

Treated patients are often subjected to intensive therapy, which sometimes does not allow the strict assay period constraints on which it is based.

The extent to which IL-6 serum levels rise between the two assays is not critical to the use of the invention.

If the serum level of IL-6 does not increase or even decreases during the assay period, then the treatment regimen with TNF antagonists is not recommended.

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

The concentration of IL-6 can also be determined in an activity detection assay in which, for example, C-active protein is measured.

Since different assays or detection systems sometimes produce different results for the same assay, it is reasonable to use the same assay or detection system to measure IL-6 levels or, if different systems are used, to calibrate them against each other.

Suitable TNF antagonists are anti-TNF antibodies, TNF receptors or soluble fragments thereof, TNF binding proteins or those TNF derivatives which still have TNF receptor binding but no longer have any TNF activity. These types of TNF antagonists are characterized in that they either capture already produced TNF and do not make it to the TNF receptor or in that they compete with TNF for the receptor.

However, TNF antagonists which prevent the formation or release of TNF are also suitable for use according to the invention. Such substances may inhibit, for example, the expression of the TNF gene or the release of TNF from the precursor form. Examples of suitable TNF antagonists are inhibitors of TNF converting enzyme.

For example, TNF-resistant derivatives have been described, which are xanthine derivatives, glucocorticoids, prostaglandin E2, thalidomide, interleukin-4, interleukin-10, granulocyte-stimulating factor (G- CSF), cyclosporine and alpha-antitrypsin. Compounds of these types are therefore also suitable as TNF antagonists.

For example, Mariott et al., "DDT", Vol. 2, No. 7, July 1997, and references cited therein, describe TNF antagonists suitable for use according to the invention.

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

Anti-TNF antibodies suitable for use according to the invention are known (EP 260 610, EP 351789, EP 218 868). Both polyclonal and monoclonal antibodies can be used. Also suitable are TNF binding antibody fragments such as Fab or F(ab') ₂ or single chain Fv fragments.

Humanized or human anti-TNF or TNF-binding fragments thereof are also very suitable since these molecules should not produce any anti-mouse antigenicity in human patients.

Mixtures of various anti-TNF antibodies or mixtures of anti-TNF antibodies and TNF receptor fragments can also be used as active ingredients.

The invention includes pharmaceutical compositions comprising an anti-TNF antibody and a non-toxic, inert pharmaceutically suitable carrier and methods for preparing these compositions.

Anti-TNF antibodies are formulated in a conventional manner for the biotechnological production of active ingredients, usually as liquid formulations or lyophilizates (see, for example, Hagers Handbuch derpharmazeutischen Praxis, Vol. 2, 5th Edition, 1991, p. 720, ISBN 3-540-52459-2). The aforementioned pharmaceutical compositions are produced by known methods, in a conventional manner, for example by mixing the active ingredient with the carrier.

Generally it has proved to be suitable for the use according to the invention that the active ingredient is advantageously administered in a total amount of about 0.1 to about 100 mg/kg body weight/24 hours, preferably 0.1 to 10 mg/kg body weight/24 hours, if appropriate, in several divided doses. The administration may be administered as a single dose or as a continuous infusion; and, if appropriate, the desired result may be achieved over a treatment period of several days. Administration can be by brief intravenous infusion of a single dose over 24 hours or by long-term continuous infusion of daily doses. A single dose preferably contains from about 0.1 to about 10 mg/kg body weight of the active ingredient. However, it is necessary to deviate from the stated doses, depending inter alia on the age and size of the patient being treated and the nature and severity of the underlying disease, the nature of the composition and the nature of the drug administered and the period for which the administration is carried out.

The invention is further explained in the following examples.

Example

Septic patients were treated with a murine anti-TNF antibody fragment (F(ab') ₂ ) called MAK 195F (INN: AFELIMOMAB).

In conclusion, 251 patients with severe sepsis treated with an anti-TNF antibody fragment (afelimomab) or as controls were analyzed in a multicentre clinical study.

Among the 251 patients, 47 patients had elevated serum levels of IL-6, while 178 patients had decreased IL-6 serum levels.

The figure shows a reduction in mortality (55.6% mortality compared to 69% in the control group) achieved by the treatment group with elevated IL-6 levels.

Treatment with MAK 195F was not significantly successful in the group with decreased serum levels of IL-6; on the contrary, adverse effects of treatment were in fact marked (54.7% mortality compared to 50.6% in the control group).

In addition to standard care for sepsis, patients in the treatment group received a total of nine 15-minute short infusions of the trial product afelimomab over a 3-day period, each administered 8 hours apart, in a single dose of 1mg/kg body weight/time. In addition to the standard treatment for sepsis, patients in the control group received a pharmaceutically inactive sham product (placebo) administered in the same manner.

The results of this clinical study clearly demonstrate that the treatment of severe sepsis with anti-TNF antibodies is particularly successful when the treated septic patients have elevated serum levels of IL-6. Patients with reduced IL-6 serum levels should therefore not be treated with TNF antagonists.

Claims (6)

1.TNF antagonist is used for the treatment of those in the purposes aspect the medicine of the septic diseases of the serum levels rising of the mensuration time limit of 30 minutes to 48 hours interval words spoken by an actor from offstage cytokine-6 in preparation.

2. the purposes described in claim 1, wherein said is 500pg/ml and at this more than value at the serum levels of measuring time limit words spoken by an actor from offstage cytokine-6.

3. the purposes described in claim 1, wherein said test period is limited to 4-10 hour.

4. the purposes described in claim 1 is wherein with the F of monoclonal anti-TNF antibody (ab ') ₂Fragment is as the TNF antagonist.

5. one kind comprises that TNF antagonist and this TNF antagonist are used for the treatment of the commodity medicated bag of the operation instruction of the septic diseases that the serum levels at mensuration IL-6 in the time limit of 30 minutes to 48 hours interval raises.

6. the commodity medicated bag described in claim 5 wherein is used as the TNF antagonist with monoclonal anti-TNF antibody.

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