JP2001521009A - Use of a TNF antagonist as a medicament for treating septic disease - Google Patents

Abstract

  (57) [Summary] The TNF antagonist is used to manufacture a medicament for treating sepsis in which the serum interleukin-6 level is increased during a measurement period of at least 30 minutes.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001] The present invention relates to the use of a TNF antagonist for treating septic disease.

It is known that the term tumor necrosis factor (TNF) includes two cytotoxic factors (TNF-α and TNF-β) produced primarily by activated lymphocytes and monocytes. .

[0003] EP 260610 describes, for example, diseases associated with an increase in TNF in the blood, such as septic shock, transplant rejection, allergies, autoimmune diseases, shock lung, coagulating diseases or Anti-TNF antibodies have been described that can be used to inactivate TNF in inflammatory bone diseases.

[0004] In medical books, septic disease is defined as the collective term for the clinical condition in which an agent that induces inflammation, such as bacteria, starts at a lesion and reaches the bloodstream, where the disease has widespread awareness. Initiate symptoms and objective pathological manifestations. Furthermore, it has been found that the clinical picture may vary widely, depending on the type of agent induced, the susceptibility of the organism, the initial lesions and the various interventions of the organs (Sturm et al. .), "Grundbegriffe der Inneren Medizin", 13th edition,
570, Gustav Fischer Verlag, Stuttgart, 1984).

[0005] Many complex cytokines have been shown to be involved in the complex pathophysiological processes of sepsis. In particular, TNF is based on data from animal experiments (Beutler et al.,
Science 229 (1985) 869-871), and is considered to play an important role in septic shock.

[0006] Eventually, this has led to clinical trials performed on the treatment of septic patients with anti-TNF antibodies.

[0007] However, in a multicentric Phase 2 trial for the treatment of severe sepsis in mice using a monoclonal anti-TNF antibody, all groups (80 patients)
Was found to be ineffective in terms of survival with treatment with the antibody. Only patients with elevated TNF concentrations in the bloodstream have been shown to benefit from high doses of anti-TNF antibodies in terms of survival (CJ Fisher et al., Critica
l Care Medicine, Vol. 21, No. 3, 318-327). The study also relates to a correlation between plasma TNF and IL-6 levels.

[0008] The part affected by the cytokine interleukin-6 (IL-6) in sepsis is ambiguous and contradictory. Elevated IL-6 levels have been found in the sera of some sepsis patients (Hack et al., Blood 74, N0.5, (1989) 1704-
1710).

[0009] Wage describes a correlation between the levels of the cytokines IL-6 and IL-8 and the severity of shock symptoms, however, these cytokines are involved in the development of shock syndrome. In terms of mortality above, alone or in combination with TNF has no effect (Waage in “Tumor Necro
sis Factors ", ed. B. Beutler, Raven Press, New York, 1992, 275-283).

[0010] Some scientists have suggested that IL-6 plays an advantageous role during septic shock because IL-6 suppresses LPS-induced TNF production in a negative feedback manner. (Libert et al. In “Tumor Necrosis Factor: Molecular
and Cellular Biology and Clinical Relevance ”, ed. W. Fiers, Karger, Bas
le, 1993, 126-131).

[0011] WO95 / 00291 discloses that the concentration of interleukin-6 in serum is 500 p.
TN as a medicament for treating sepsis in patients at or above g / ml
F antagonists have been disclosed.

However, clinical trials have shown that the treatment disclosed in WO 95/00291 does not always work.

[0013] While there are cases of sepsis that can be successfully treated with TNF antagonists,
Another case is apparent where treatment with an antagonist has been unsuccessful and is in fact contraindicated.

It is an object of the present invention to reliably and rapidly identify those patients with sepsis that can be successfully treated with a TNF antagonist.

This goal has been found to be achieved using the following features that identify patients with septic disease that can be successfully treated: increased levels of interleukin-6 in serum; That is, within a measurement period of at least 30 minutes, the subsequently measured concentration is higher than the initially measured concentration.

Patients suffering from sepsis and meeting this criterion are very suitable for treatment with TNF antagonists.

[0017] The treatment is preferably performed in a patient whose serum interleukin-6 concentration during the measurement period is at least 500 pg / ml. However, it can also be significantly higher than this concentration and up to a few mg / ml.

[0018] At least two IL-6 measurements need to be performed to demonstrate whether the serum levels of interleukin-6 (IL-6) are increasing.

[0019] A second, subsequent measurement should be obtained within 30 minutes to 48 hours after the first IL-6 measurement (measurement time).

The measurement period is preferably 2 to 24 hours, particularly preferably 4 to 10 hours.

In general, the patient to be treated is one who is on strong pharmacotherapy, which often does not allow for a strict measurement period to be followed.

The extent of the increase in serum IL-6 concentration between the two measurements is less important for use according to the invention.

If serum IL-6 levels do not increase or even decrease during the measurement period, treatment with a TNF antagonist is not recommended.

[0024] The serum concentration of IL-6 may be measured by conventional detection methods, such as RIA or ELISA. An example of a very suitable detection system is Medgenix.
ix) provided by IL-6-EASIA.

The concentration of IL-6 may be determined by, for example, an activity measurement method in which the C-reactive protein of IL-6 is quantified.

Since different measurement methods or quantification systems often produce different results for the same measurement, either a similar measurement method or quantification system is used to measure IL-6 concentration, and different systems use If so, it is recommended to calibrate each other's results.

Suitable TNF antagonists are anti-TNF antibodies, TNF receptors or soluble fragments thereof, TNF binding proteins or derivatives of TNF that still have a TNF receptor binding site, but no longer have any TNF activity. . These types of TNF antagonists have the property of trapping already produced TNF and preventing it from reaching the TNF receptor or competing with the receptor for TNF.

However, TNF antagonists which prevent the formation or release of TNF are also suitable for use according to the invention. This type of substance suppresses, for example, the expression of the TNF gene or the release of TNF from its precursor form. An example of a suitable TNF antagonist is a TNF convertase inhibitor.

The TNF antagonistic activity includes, for example, xanthine derivative, glucocorticoid, prostaglandin E ₂ , thalidomide, interleukin-4, interleukin-10, granulocyte, stimulating factor (G-CSF), cyclosporin And α-antitrypsin. Therefore, these types of compounds are also suitable as TNF antagonists.

[0030] TNF antagonists suitable for use in accordance with the invention include, for example, Mariot et al.
t et al.), DDT, Vol. 2, No. 7, 1997, July, and in the references cited therein.

[0031] Anti-TNF antibodies and fragments thereof are particularly preferred for use according to the invention.

[0032] Anti-TNF antibodies suitable for use according to the invention are known (EP 26
0610, EP 351789, EP 218868). It is possible to use both polyclonal and monoclonal antibodies. Also suitable are TNF binding antibody fragments, such as Fab or F (ab ') ₂ fragments or single chain Fv fragments.

[0033] Also, humanized anti-TNF antibodies or human anti-TNF antibodies or TNF binding fragments thereof are very suitable as these molecules should not cause any anti-mouse antigenicity in human patients.

As an active ingredient, a mixture of various anti-TNF antibodies or an anti-TNF antibody and T
It is also possible to use mixtures with NF receptor fragments.

The present invention includes a pharmaceutical composition comprising an anti-TNF antibody in addition to a non-toxic and inert pharmaceutically suitable carrier, and a method of making the composition.

[0036] Anti-TNF antibodies are generally prepared in a conventional manner for bioengineered active ingredients as solutions or lyophilizates (eg, Hagers Handbuch der pharmazeut).
ischen Praxis, vol. 2, fifth edition, 1991, p. 720, ISBN 3-540-52459-2). The pharmaceutical composition shown above is manufactured by a known method, for example, by mixing an active ingredient (a plurality of active ingredients) with a carrier (a plurality of carriers).

The active ingredient (s) suitable for use according to the invention are generally comprised of 1 kg body weight
About 0.1 to about 100 mg, preferably 0.1 to 10 mg, every 24 hours, where appropriate in the form of several individual doses or as a continuous infusion, and Where appropriate, administration over a treatment period of several days to achieve the desired result was advantageous. Administration may be as a single short-term intravenous infusion or as a long-term continuous infusion of daily doses over a 24-hour period. One dose is
Preferably the active ingredient (several active ingredients) is present in an amount of about 0.1 to about 10 per kg body weight.
Contains in mg amount. However, it may also be necessary to deviate from the stated doses, in particular as a function of the age and physique of the patient to be treated and depending on the type and severity of the underlying disease, the type of composition and the dosage form and the duration of administration. It may be.

The present invention is illustrated in detail in the following examples.

EXAMPLE Treatment of sepsis patients with a mouse anti-TNF antibody fragment (F (ab ') ₂ ) designated MAb 195F (INN: AFFLIMOMAB).

A total of 251 patients with severe sepsis treated with an anti-TNF antibody fragment (afelimomab) or treated as a control patient were analyzed in a multicentric clinical trial.

Forty-seven of the 251 patients had increased serum levels of IL-6 and 178 had decreased levels of serum IL-6.

There is no evidence that treatment with MAb 195F is successful in the serum IL-6 reduced group; on the contrary, further side effects of the treatment were evident (mortality 50.6% in control group). 54.7%).

The treatment group includes the usual treatment of sepsis plus the test product afelimomab (afe
limomab) for a total of 9 15-minute short-term infusions over 3 days
Each dose was given at a dose of 1 mg / kg body weight at intervals of 8 hours. The control group received a pharmaceutically inactive placebo (placebo) administered in a similar manner in addition to the usual treatment of sepsis.

The results of this clinical trial clearly show that treatment of severe sepsis with anti-TNF antibodies works particularly when the serum levels of IL-6 in treated sepsis patients are increased. Therefore, patients with reduced serum levels of IL-6 should not be treated with TNF antagonists.

[Brief description of the drawings]

FIG. 1 is a bar graph showing that reduction in mortality can be achieved by treatment in the IL-6 concentration increasing group (55.6% vs. 69% in the control group).

──────────────────────────────────────────────────続 き Continuation of front page (81) Designated country EP (AT, BE, CH, CY, DE, DK, ES, FI, FR, GB, GR, IE, IT, LU, MC, NL, PT, SE ), EA (AM, AZ, BY, KG, KZ, MD, RU, TJ, TM), AL, AU, BG, BR, BY, CA, CN, CZ, GE, HU, ID, IL, JP, KR , KZ, LT, LV, MK, MX, NO, NZ, PL, RO, RU, SG, SI, SK, TR, UA, US (72) Inventor Jürgen Iselstein Weisenheim am Vinn, Germany Goertsberg 26 (72) Inventor Rotar Daum Germany C 25 (72) Inventor Joachim Kempeni, Germany Neustadt Gin Meldinger Strasse 75 F-term (reference) 4C084 AA17 NA14 ZB262 ZB352 ZC022 4C085 AA14 BB01 CC05 EE03

Claims (7)

[Claims] 1. TNF for the manufacture of a medicament for treating a septic disease wherein the serum interleukin-6 concentration is increased during a measurement period of at least 30 minutes.
Use of antagonists. 2. The serum concentration of interleukin-6 was 500 p during the measurement period.
The use according to claim 1, which is in g / ml and above. 3. Use according to claim 1, wherein the measuring period is between 4 and 10 hours. 4. Use according to claim 1, wherein the F (ab ') ₂ fragment of the monoclonal anti-TNF antibody is used as a TNF antagonist. 5. Use of a TNF antagonist for treating a septic disease in which serum IL-6 levels are increased during the measurement period of at least 30 minutes, together with instructions for using said TNF antagonist A commercially available package having: 6. The commercial package according to claim 5, wherein a monoclonal anti-TNF antibody is used as a TNF antagonist. 7. A method for proving whether to treat a patient with TNF antagonists suffering from sepsis, following steps: a) measuring the interleukin-6 concentration in the serum of a patient in the initial t _1, b ) interleukin-6 in serum in the initial t ₁ for the second time t ₂ for at least 30 minutes after
Measure the concentration and ratio C) a method for proving whether to treat with a TNF antagonist, characterized in that if V is greater than 1, it is treated with a TNF antagonist.