U.S. patent application number 09/782290 was filed with the patent office on 2001-08-02 for use of anti-tnf antibodies as drugs for the treatment of disorders with an elevated serum level of interleukin-6.
This patent application is currently assigned to Knoll Aktiengesellschaft. Invention is credited to Daum, Lothar, Kaul, Martin, Kempeni, Joachim, Raab, Christa, Schaefer, Sibylle, Stenzel, Roswitha.
Application Number | 20010010819 09/782290 |
Document ID | / |
Family ID | 25933592 |
Filed Date | 2001-08-02 |
United States Patent
Application |
20010010819 |
Kind Code |
A1 |
Stenzel, Roswitha ; et
al. |
August 2, 2001 |
Use of anti-TNF antibodies as drugs for the treatment of disorders
with an elevated serum level of interleukin-6
Abstract
The invention relates to the use of TNF antagonists for
producing drugs for the treatment of disorders characterized by
elevated serum levels of interleukin-6.
Inventors: |
Stenzel, Roswitha;
(Lampertheim, DE) ; Kaul, Martin; (Neustadt,
DE) ; Daum, Lothar; (Otterstadt, DE) ;
Kempeni, Joachim; (Neustadt, DE) ; Raab, Christa;
(Dannstadt-Schauernheim, DE) ; Schaefer, Sibylle;
(Walldorf, DE) |
Correspondence
Address: |
OBLON SPIVAK MCCLELLAND MAIER & NEUSTADT PC
FOURTH FLOOR
1755 JEFFERSON DAVIS HIGHWAY
ARLINGTON
VA
22202
US
|
Assignee: |
Knoll Aktiengesellschaft
Ludwigshafen
DE
67061
|
Family ID: |
25933592 |
Appl. No.: |
09/782290 |
Filed: |
February 14, 2001 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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09782290 |
Feb 14, 2001 |
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08687328 |
Aug 7, 1996 |
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6235281 |
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08687328 |
Aug 7, 1996 |
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PCT/EP95/00291 |
Jan 27, 1995 |
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Current U.S.
Class: |
424/145.1 |
Current CPC
Class: |
A61P 31/00 20180101;
A61P 37/00 20180101; A61P 31/04 20180101; C07K 16/241 20130101;
A61K 38/00 20130101 |
Class at
Publication: |
424/145.1 |
International
Class: |
A61K 039/395 |
Foreign Application Data
Date |
Code |
Application Number |
Feb 7, 1994 |
DE |
P 44 03 669.8 |
Mar 19, 1994 |
DE |
P 44 09 513.9 |
Claims
We claim:
1. The use of TNF antagonists for producing drugs for the treatment
of disorders characterized by serum levels of interleukin-6 which
are elevated at least ten-fold compared with physiological serum
levels in healthy subjects.
2. The use as claimed in claim 1, wherein the serum levels of
interleukin 6 are 500 pg/ml or above.
3. The use as claimed in claim 1, wherein the serum levels of
interleukin 6 are above 1000 pg/ml.
4. The use as claimed in claims 1 to 3, wherein the disorder is
septicemia.
5. The use as claimed in claim 1, wherein the TNF antagonists are
monoclonal anti-TNF antibodies.
6. The use as claimed in claim 5, wherein the anti-TNF antibodies
are humanized or human anti-TNF antibodies.
7. The use as claimed in claims 1 to 4, wherein the TNF antagonists
are TNF receptors or soluble fragments thereof.
Description
[0001] The present invention relates to the use of anti-TNF
antibodies in the treatment of disorders with an elevated serum
level of interleukin-6.
[0002] It is known that the term tumor necrosis factor (TNF)
embraces two cytotoxic factors (TNF-.alpha. and TNF-.beta.) which
are mostly produced by activated lymphocytes and monocytes.
[0003] EP 260 610 describes, for example, anti-TNF antibodies which
are said to be utilizable for disorders associated with an
increased level of TNF in the blood, such as septic shock,
transplant rejection, allergies, autoimmune diseases, shock lung,
coagulation disturbances or inflammatory bone diseases, to
inactivate TNF.
[0004] Examples of disorders characterized by elevated serum levels
of interleukin-6 in patients are the sequelae of transplantations,
autoimmune diseases and, in particular, certain types of
septicemia.
[0005] Septicemia is defined in medical textbooks as a collective
clinical term for conditions in which bacterial pathogens, starting
from a focus, enter the blood stream to induce a wide range of
subjective and objective pathological manifestations. It is
furthermore found that the clinical picture may vary widely
depending on the type of pathogen, the reactivity of the body, the
primary focus and the changes in organ involvement (Sturm et al.
"Grundbegriffe der Inneren Medizin", 13th edition, page 570, Gustav
Fischer Verlag, Stuttgart, 1984).
[0006] A number of cytokines have been suggested to be involved in
the complex pathophysiological process of septicemia. TNF in
particular is ascribed with an important role in septic shock on
the basis of data from animal experiments (Beutler et al., Science
229 (1985) 869-871).
[0007] This has eventually led to clinical studies of the treatment
of septicemic patients with anti-TNF antibodies.
[0008] In a recently published multicenter phase II study on the
treatment of severe septicemia with a murine monoclonal anti-TNF
antibody, however, it was found that the overall population (80
patients) did not profit in terms of survival rate from the
treatment with the antibody. Only the patients with elevated
circulating TNF concentrations appeared to profit, in terms of
probability of survival, from high-dose anti-TNF antibody
administration (C. J. Fisher et al., Critical Care Medicine, vol.
21, No. 3, pages 318-327). Furthermore, reference is made in this
study to a correlation of the plasma levels of TNF and Il-6.
[0009] The part played by the cytokine interleukin-6 (Il-6) in
septicemia is unclear and contradictory. Elevated serum levels of
Il-6 have been found in some septicemic patients (Hack et al.,
Blood 74 (1989) 1704-1710).
[0010] Waage describes a correlation between the concentrations of
the cytokines Il-6 and Il-8 with the severity of the shock,
although they had no effect, either alone or in combination with
TNF, on the development of a shock syndrome in terms of mortality
(Waage in "Tumor Necrosis Factors", ed. B. Beutler, Raven Press,
New York, 1992, pages 275-283).
[0011] Some scientists have ascribed a beneficial role to Il-6 in
septic shock because Il-6 inhibits, in the form of negative
feedback control, the LPS-induced TNF production (Libert et al. in
"Tumor Necrosis Factor: Molecular and Cellular Biology and Clinical
Relevance", ed. W. Fiers, Karger, Basel, 1993, pages 126-131).
[0012] We have now found, surprisingly, that TNF antagonists can be
used particularly successfully as drugs for the treatment of
disorders characterized by elevated serum levels of
interleukin-6.
[0013] The treatment of septicemia with TNF antagonists is
particularly successful according to this invention, for example
measured by a distinct reduction in mortality, when the septicemic
patients who are treated have Il-6 levels of 500 pg/ml or more at
the start of treatment. Patients who have Il-6 serum levels above
1000 pg/ml profit particularly well from the treatment according to
the invention.
[0014] Elevated serum levels of Il-6 mean levels which are elevated
at least ten-fold compared with physiological serum levels in
healthy subjects.
[0015] Serum concentrations of Il-6 up to 20,000 times the levels
in healthy subjects have been found in septicemic patients.
[0016] The "normal" Il-6 serum levels are usually below the
detection limit, which may vary slightly depending on the assay
system used. Their maximum is, however, 20 pg/ml.
[0017] The serum concentrations of Il-6 can be determined by
conventional detection methods such as RIA or ELISA. An example of
a very suitable detection system is the Il-6-EASIA supplied by
Medgenix.
[0018] The Il-6 concentration can also be determined by an activity
assay in which, for example, C-reactive protein is assayed.
[0019] Suitable TNF antagonists are anti-TNF antibodies, TNF
receptors and soluble fragments thereof, TNF binding proteins or
those TNF derivatives which still bind to TNF receptors but have no
TNF activity. TNF antagonists of these types have the
characteristic that they trap TNF which has been formed and do not
allow it to reach the TNF receptor or that they compete with TNF
for the receptor.
[0020] However, TNF antagonists which prevent the formation or
release of TNF are also suitable for the use according to the
invention. Such substances inhibit for example TNF gene expression
or release of TNF from precursor forms.
[0021] Such TNF-antagonistic activities have been described for
example for xanthine derivatives, glucocorticoids, prostaglandin
E2, thalidomide, interleukin-4, interleukin-10,
granulocyte-stimulating factor (G-CSF), cyclosporin and
.alpha.-antitrypsin. Hence compounds of these types are also
suitable as TNF antagonists.
[0022] Anti-TNF antibodies are particularly preferred for the use
according to the invention.
[0023] The anti-TNF antibodies suitable for the use according to
the invention are known (EP 260 610, EP 351 789, EP 218 868). Both
polyclonal and monoclonal antibodies can be used. Furthermore,
TNF-binding antibody fragments such as Fab or F(ab').sub.2
fragments or single-chain Fv fragments are also suitable.
[0024] Furthermore, humanized or human anti-TNF antibodies or their
TNF-binding fragments are also very suitable because these
molecules ought not to cause any anti-mouse antigenicity in human
patients.
[0025] It is also possible to use mixtures of various anti-TNF
antibodies or of anti-TNF antibodies and TNF receptor fragments as
active substance.
[0026] The present invention includes pharmaceutical compositions
which, besides non-toxic, inert, pharmaceutically suitable
vehicles, contain the anti-TNF antibodies, and processes for the
production of these compositions.
[0027] The anti-TNF antibodies are formulated in the conventional
way for biotechnologically produced active substances, as a rule as
liquid formulation or lyophilisate (see, for example, Hagers
Handbuch der pharmazeutischen Praxis, vol. 2, 5.sup.th edition,
1991, p. 720, ISBN 3-540-52459-2). The abovementioned
pharmaceutical compositions are produced in a conventional way by
conventional methods, eg. by mixing the active substance or
substances with the vehicle or vehicles.
[0028] In general, it has proven advantageous to administer the
active substance or substances which are suitable for the use
according to the invention in total amounts of about 0.1 to about
1000, preferably 0.1 to 10, mg/kg of body weight every 24 hours,
where appropriate in the form of several individual doses or as
continuous infusion and, where appropriate, over a therapy period
of several days to achieve the desired results. Administration can
take place as brief intravenous infusion of the single doses or as
continuous long-term infusion of the daily dose over 24 hours. A
single dose preferably contains the active substance or substances
in amounts of about 0.1 to about 10 mg/kg of body weight. However,
it may be necessary to deviate from the stated dosages,
specifically depending on the age and size of the patient to be
treated and on the nature and severity of the fundamental disorder,
the type of composition and of administration of the drug, and the
period or interval over which administration takes place. The
invention is illustrated further in the following Example.
EXAMPLE
[0029] Treatment of Septicemic Patients with a Murine Anti-TNF
Antibody Fragment (F(ab').sub.2).
[0030] A total of 122 patients with severe septicemia were treated
in a multicenter clinical study with anti-TNF antibody fragment in
various dosages or with placebo.
[0031] The four therapeutic methods investigated differed only in
the level of the single dose of the anti-TNF antibody fragment.
This was either 0.1 mg/kg of body weight, 0.3 mg/kg of body weight
or 1.0 mg/kg of body weight. The patients in the fourth group
received a "sham therapy" (placebo) for comparison. The patients
were assigned at random to one of the four therapeutic regimens
with anti-TNF antibody fragment. The described therapy, which was
given in addition to the standard therapy of septicemic patients,
was administered as brief infusion a total of nine times (9.times.)
at intervals of 8 hours (ie. for three days) after diagnosis
(=compliance with criteria for inclusion in the study). A total of
122 patients was recruited for the study, with 34 patients being
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 and 29 patients
to the placebo group.
[0032] It was possible to measure Il-6 serum concentrations before
the start of therapy in 119 of the 122 patients. The serum levels
of Il-6 were >1000 pg/ml in 36 patients and <1000 pg/ml in 83
patients.
[0033] FIG. 1A shows the mortality in the population with
Il-6>1000 pg/ml in the various treatment groups (placebo, 0.1,
0.3 and 1.0 mg of antibody per kg of body weight).
[0034] FIG. 1B shows the mortality in the population with
Il-6<1000 pg/ml in the various treatment groups (placebo, 0.1,
0.3 and 1.0 mg of antibody per kg of body weight).
[0035] In the patients with Il-6>1000 pg/ml there was a
dose-dependent reduction in the mortality on treatment with
anti-TNF antibody fragment from 80.0% (=placebo group) to 36.4%
(1.0 mg/kg antibody) (FIG. 1A).
[0036] In the patients with Il-6<1000 pg/ml, the mortality was
not reduced by treatment with anti-TNF antibody fragment, on the
contrary it was slightly increased (30.4% in the placebo group
compared with 38.9% in the group with 1.0 mg/kg antibody) (FIG.
1B).
[0037] The result of this clinical study clearly proves that
treatment of severe septicemia with anti-TNF antibodies is
successful only when the treated septicemic patients have a serum
level of Il-6>1000 pg/ml; treatment of patients with serum
levels of Il-6<1000 pg/ml is unsuccessful and sometimes even
contraindicated.
* * * * *