U.S. patent number 4,946,674 [Application Number 06/782,221] was granted by the patent office on 1990-08-07 for process for treatment of rheumatic diseases.
This patent grant is currently assigned to Bioferon Biochemische Substanzen GmbH & Co.. Invention is credited to Franz Link, Hans-Joachim Obert, Johann-Friedrich von Eichborn.
United States Patent |
4,946,674 |
von Eichborn , et
al. |
August 7, 1990 |
**Please see images for:
( Certificate of Correction ) ** |
Process for treatment of rheumatic diseases
Abstract
This invention relates to the treatment of rheumatic diseases.
More particularly, this invention relates to processes and
compositions for treating rheumatic diseases by administering to a
patient a pharmaceutically effect amount of gamma interferon.
Inventors: |
von Eichborn; Johann-Friedrich
(Huttisheim, DE), Obert; Hans-Joachim (Laupheim,
DE), Link; Franz (Bad Abbach, DE) |
Assignee: |
Bioferon Biochemische Substanzen
GmbH & Co. (Laupheim, DE)
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Family
ID: |
27192401 |
Appl.
No.: |
06/782,221 |
Filed: |
September 30, 1985 |
Foreign Application Priority Data
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Oct 5, 1984 [DE] |
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3436638 |
Jun 18, 1985 [EP] |
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85107490.6 |
Sep 4, 1985 [EP] |
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85111183.1 |
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Current U.S.
Class: |
424/85.5;
424/85.4 |
Current CPC
Class: |
A61K
38/217 (20130101); A61P 29/00 (20180101); A61K
38/21 (20130101); A61K 38/00 (20130101); A61K
38/217 (20130101); A61K 2300/00 (20130101) |
Current International
Class: |
A61K
38/21 (20060101); A61K 037/66 () |
Field of
Search: |
;424/85,85.5,85.4 |
References Cited
[Referenced By]
U.S. Patent Documents
Foreign Patent Documents
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077063 |
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Apr 1983 |
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EP |
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77063 |
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Apr 1983 |
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EP |
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077670 |
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Apr 1983 |
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EP |
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87686 |
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Sep 1983 |
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EP |
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88540 |
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Sep 1983 |
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EP |
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107498 |
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May 1984 |
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0107498 |
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May 1984 |
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110044 |
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Jun 1984 |
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0110044 |
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Jun 1984 |
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EP |
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117470 |
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Sep 1984 |
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EP |
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8301198 |
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Apr 1983 |
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WO |
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Other References
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S. A. Jiminez et al., "Selective Inhibition of Human Diploid
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.
I. Mecs et al., "The Anti-Inflammatory Effect of Human Interferons
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C. M. Pearson et al., "Workshop IV. Aetiopathogenic Factors in
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C. M. Pearson et al., "Adjuvant Arthritis: Immune Responses and
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S. Pestka et al., "Definition and Classification of the
Interferons", Meth. Enzymol., 78, pp. 3-14, (1981). .
O. T. Preble et al., "Systemic Lupus Erythematosus: Presence in
Human Serum of an Unusual Acid-Lbile Leukocyte Interferon",
Science, 216, pp. 429-431, (1982). .
G. H. Reem et al., "Interleukin 2 Regulates Expression of Its
Receptor and Synthesis of Gamma Interferon by Human T Lymphocytes",
Science, 225, pp. 429-430, (1984). .
Scand. J. Rheumatol., Supplement 49, p. 59, (1983). .
M. L. Thoman et al., "Deficiency in Suppressor T Cell Activity in
Aged Animals", J. Exp. Med., 157, pp. 2184-2189, (1983). .
D. Wallach, "Regulation of Susceptibility to Natural Killer Cells'
Cytotoxicity and Regulation of HLA Synthesis . . . ", J. Interferon
Res., 2, pp. 329-338, (1982), [Wallach I]. .
D. Wallach, "Interferon-Induced Resistance to the Killing by NK
Cells: A Preferential Effect of IFN--", Cell. Immunol., 75, pp.
390-395, (1983), [Wallach II]..
|
Primary Examiner: Hazel; Blondel
Attorney, Agent or Firm: Haley, Jr.; James F. Yankwich; Leon
R. Marks; Andrew S.
Claims
We claim:
1. A process for treating rheumatic diseases comprising the step of
administering to a mammal a pharmaceutically acceptable composition
which comprises a pharmaceutically effective amount of
IFN-.sub..gamma..
2. The process according to claim 1, wherein the IFN-.sub..gamma.
is selected from the group consisting of natural IFN-.sub..gamma.,
recombinant IFN-.sub..gamma., and derivatives thereof which are
characterized by the biological activity of IFN-.sub..gamma.
against rheumatic diseases.
3. The process according to claim 1, wherein the rheumatic disease
to be treated is selected from the group consisting of inflammatory
rheumatism, degenerative rheumatism, extra-articular rheumatism and
collagen diseases.
4. The process according to claim 1, wherein the rheumatic disease
is selected from the group consisting of rheumatoid arthritis,
systemic lupus erythematosus, progressive systemic schleroderma,
dermatomyositis, chronic polyarhritis, psoriasis arthropathica,
muscular rheumatism, periarthritis humeroscapularis, panarthritis
nodosa, arthritis uratica, myositis, myogelosis, chondrocalcinosis
and juvenile chronic arthritis.
5. The process according to claim 1, wherein the mammal is a
human.
6. The process according to claim 1, wherein the composition which
comprises IFN-.sub..gamma. further comprises a compound selected
from the group consisting of interferons other than
IFN-.sub..gamma., interluekin-1, interleukin-2, tumor necrosis
factor, macrophage colony stimulating factor, macrophage mirgration
inhibitory factor, lymphotoxin, fibroblast growth factor, thymus
hormones and conventional anti-rheumatic therapeutic agents.
7. The process according to claim 1, wherein the composition is
administered intravenously, intramuscularly, subcutaneously,
intra-articularly, intrasynovially, intrathecally, periostally, by
infusion, orally or topically.
8. The process according to claim 1, wherein the composition is
administered at a dosage of between 200 International units (20 ng)
and 2000 million International units (200 mg).
9. The process according to claim 8, wherein the dosage is between
20,000 International units (2 .mu.g) and 2,000,000 International
units (200 .mu.g).
Description
TECHNICAL FIELD OF INVENTION
This invention relates to the treatment of rheumatic diseases. More
particularly, this invention relates to processes for treating
rheumatic diseases such as inflammatory rheumatism, degenerative
rheumatism, extra-articular rheumatism and collagen diseases.
According to this invention, natural or recombinant gamma
interferons are used for the treatment of these rheumatic
diseases.
BACKGROUND ART
Rheumatic diseases are a group of diseases that effect the
musculo-skeletal and connective tissues of the body. Such diseases
are characterized by chronic inflammation which often leads to
permanent tissue damage, deformity, atrophy and disability.
Rheumatoid arthritis, a progressive rheumatic disease, affects as
many as 1-2% of all adults [P. D. Utsinger et al., Rheumatoid
Arthritis, p. 140 (1985)].
Although their etiology is unknown, most rheumatic diseases are
thought to be autoimmune diseases caused by a patient's altered
immune response to as yet unidentified antigen or antigens [H.O.
McDevitt and B. Benacerraf, "Genetic Control Of Specific Immune
Responses", Adv. Immunol., 11, p. 31 (1969)].
Rheumatic diseases may affect the joints, spinal cord, soft tissue
or bone [H. Mathies, Rheuma ("Rheumatism") (1983)]and are
classified as inflammatory rheumatism, degenerative rheumatism,
extraarticular rheumatism or collagen diseases. Systemic lupus
erythematosus, progressive systemic scleroderma, dermatomyositis,
chronic polyarthritis, psoriasis arthropathica, muscular
rheumatism, periarthritis humeroscapularis, panarteriitis nodosa,
myositis, myogelosis, arthritis uratica and chondrocalcinosis are
also rheumatic diseases [W. Pschyrembel, Klinisches Worterbuch
("Medical Dictionary") (1982)]. Juvenile chronic arthritis, which
occurs in children and adolescents, differs from rheumatoid
arthritis as seen in adults and can lead to impaired development
and growth [B. Z. P. Anzell, "Juvenile Chronic Polyarthritis",
Arthr. Rheum. Supp., 20, pp. 176-80 (1977); H. Truckenbrodt, "Die
Juvenile Chronische Arthritis Und Ihre Subgruppen" ("Juvenile
Chronic Arthritis And Its Subgroups"), Munch. Med. Wschr., 126, pp.
1076-78 (1984). Upon serological examination, the majority of
patients diagnosed with clinical rheumatic disease test
seropositive for rheumatoid factor, an abnormal gamma-globulin [R.
B. Berkow et al. (Eds.), The Merck Manual (1982)].
Because the etiology of the majority of rheumatic diseases remains
unknown, no cure for these diseases exists and effective agents are
not conventionally available for treatment of a specific disease
[K. Kruger, "Neue Therapieprinzipien In Der Rheumatologie" ("New
Therapeutic Principles In Rheumatology"), Munch. Med. Wschr., 126,
pp. 1084-86 (1984)]. Moreover, these agents typically must be
administered over long periods of time and any therapeutic value is
often diminished by adverse side effects.
Therapeutics used in the treatment of rheumatic diseases fall into
two classes. The first class of therapeutics, symptomatic
anti-rheumatics, act on the symptoms of the disease, exerting
effects both upon and throughout the total course of
administration. Such symptomatic anti-rheumatics include salicylic
acid, glucocorticoids and non-steroidal anti-inflammatory agents,
such as inodomethacin. The second class of therapeutics, base
anti-rheumatics, act on the pathogenesis of the disease, exerting
their effects only after the initial weeks of administration yet
having effects lasting beyond the cessation of treatment. Such base
anti-rheumatics include gold compounds, D-penicillamine,
chloroquine, cortisones and immunosuppressants [H. Mathies, Rheuma,
infra, p. 1; R. C. Butler and D. H. Goddard, "Controversy In The
Treatment Of Rheumatoid Arthritis", Lancet, ii, pp. 278-79
(1984)].
These prior therapeutic agents are often characterized by adverse
side effects. For example, those that are immunosuppressants may
increase the patient's susceptibility to infection. And, therapies
based on gold compounds, penicillamine or chloroquine may exert
toxic effects on the patient's system.
Alpha interferon has been reported to be ineffective in the
treatment of rheumatoid arthritis [A. Kajender et al., "Interferon
Treatment Of Rheumatoid Arthritis", Lancet, i, pp. 984-85 (1979)].
This lack of efficacy may not be surprising because certain
rheumatic diseases, such as rheumatoid arthritis, are characterized
by an endogenous formation of interferons to which no therapeutic
activity has been ascribed. Furthermore, in some cases, high
circulating levels of interferons have been suggested without real
clinical data as a factor contributing to the pathogenesis of
rheumatic diseases [J. J. Hooks et al., "Immune Interferon In The
Circulation Of Patients With Autoimmune Disease", N. Engl. J. Med.,
301, pp. 5-8 (1979); O. T. Preble et al., "Systemic Lupus
Erythematosus: Presence In Human Serum Of An Unusual Acid-Labile
Leukocyte Interferon", Science, 126, pp. 329-31 (1982); M. Degre et
al., "Immune Interferon In Serum And Synovial Fluid In Rheumatoid
Arthritis And Related Disorders", Ann. Rheumatic. Dis., 42, pp.
672-76 (1973); A. M. Arvin and J. J. Miller, "Acid Labile
.alpha.-Interferon In Sera And Synovial Fluids From Patients With
Juvenile Arthritis", Arthritis and Rheumatism, 27, pp. 582-85
(1984); T. 0. Rosenbach et al., "Interferon Triggers Experimental
Synovitis And May Potentiate Auto-Immune Disease In Humans", Clin.
Rheumatol., 3, pp. 361-64 (1984)].
To date therefore, conventional methods and therapeutic agents have
not proved to be effective in the treatment of rheumatic diseases.
Accordingly, the need exists for a process which avoids the
disadvantages of these conventional methods and agents while
providing effective treatment for rheumatic diseases.
DISCLOSURE OF THE INVENTION
The present invention solves the problems referred to above by
providing a process for the treatment of rheumatic diseases.
According to this invention, natural or recombinant gamma
interferons are used in processes and compositions for treating
rheumatic diseases. Advantageously, the processes and compositions
of this invention are effective and are not beset by the variety of
side effects which typically characterize conventional treatments
of rheumatic diseases.
BEST MODE OF CARRYING OUT THE INVENTION
In order that the invention herein described may be more fully
understood, the following detailed description is set forth.
In the description, the following terms are employed:
Gamma interferon or IFN-.sub..gamma. -- In accordance with the
interferon nomenclature announced in Nature, 286, p. 110 (1980) and
recommended by the Interferon Nomenclature Committee in Archives Of
Virology, 77, pp. 283-85 (1983). IFN-.sub..gamma. was originally
referred to as "immune interferon".
IFN-.sub..gamma. is a lymphokine which is naturally produced in
minute quantities together with other lymphokines by lymphocytes.
It is primarily produced by T-lymphocytes, spontaneously or in
response to various inducers such as mitogens, specific antigens or
specific antibodies [W. E. Stewart, II, The Interferon System, pp.
148-49 (1981)]. IFN-.sub..gamma. is a glycoprotein having a
molecular weight between 20,000 and 25,000 (or 17,000 in
non-glycosylated form). IFN-.sub..gamma. has also been cloned and
expressed in various host-vector systems. The nucleotide sequence
of cloned IFN-.sub..gamma. indicates that it is composed of 143-46
amino acids.
As used in this application and claims, "IFN-.sub..gamma. "
includes all proteins, polypeptides and peptides which are natural
or recombinant IFN-.sub..gamma. s, or derivatives thereof, and
which are characterized by the biological activity of those
IFN-.sub..gamma. s against rheumatic diseases. These include
IFN-.sub..gamma. -like compounds from a variety of sources such as
natural IFN-.sub..gamma. s, recombinant IFN-.sub..gamma. s, and
synthetic or semisynthetic IFN-.sub..gamma. s.
Rheumatic Disease -- Any disease which is (i) characterized by
inflammation or degeneration of musculo-skeletal or connective
tissue structures of the body, particularly the joints, and
including muscles, tendons, cartilage, synovia and fibrous tissues,
(ii) accompanied by pain, stiffness or impairment of locomotion or
function of those structures and, in some cases, (iii) often
accompanied by serological evidence of rheumatoid factor.
Rheumatic diseases include, but are not limited to, inflammatory
rheumatism, degenerative rheumatism, extra-articular rheumatism and
collagen diseases. Examples of such diseases are systemic lupus
erythematosus, rheumatoid arthritis or chronic polyarthritis,
progressive systemic scleroderma, dermatomyositis, psoriasis
arthropathica, muscular rheumatism, periarthritis humeroscapularis,
panarthritis nodosa, myositis, myogelosis, arthritis uratica,
chondrocalcinosis and juvenile chronic arthritis ("Stills
disease").
This invention relates to processes and compositions for treating
rheumatic diseases. The process of this invention comprises the
step of treating a mammal in a pharmaceutically acceptable manner
with a pharmaceutically effective amount of IFN-.sub..gamma. for a
period of time sufficient to reduce the symptoms of the specific
rheumatic disease.
The IFN-.sub..gamma. s used in the processes and compositions of
this invention may be produced by purification from natural sources
using conventional techniques or produced by recombinant
techniques.
For example, some established or transformed cell lines produce
natural IFN-.sub..gamma. constitutively in vitro [N. Fujii et al.,
"Spontaneous Production Of .gamma.-Interferon In Cultures Of T
Lymphocytes Obtained From Patients With Behcet's Disease", J.
Immunol., 130, pp. 1683-86 (1983)]. A T cell hybridoma variant
clone was also found to produce IFN-.sub..gamma., together with
other lymphokines, in response to stimulation with concanavalin A
[A. Zlotnick et al., "Coordinate Production By A T Cell Hybridoma
Of Gamma Interferon And Three Other Lymphokine Activities: Multiple
Activities Of A Single Lymphokine?", J. Immunol., 131, pp. 794-80
(1983)].
Among the IFN-.sub..gamma. s useful in the processes of this
invention are also the IFN-.sub..gamma. s produced in vitro by a
variety of cells in response to various interferon inducers. For
example, these IFN-.sub..gamma. s include IFN-.sub..gamma. s
produced in human buffy-coat leukocytes after exposure to
phytohemagglutinin P, concanavalin A and staphylococcal enterotoxin
A ("SEA"), M. deLey et al., "Interferon Induced In Human Leukocytes
By Mitogens: Production, Partial Purification And
Characterization", Eur. J. Immunol., 10, pp. 877-83 (1980); in
human splenocytes after stimulation with SEA, R. Devos et al.,
"Isolation And Characterization of IFN-Gamma mRNA Derived From
Mitogen-Induced Human Splenocytes", J. Interferon Res., 2, pp.
409-20 (1982); by an IL-2independent murine T cell line after
stimulation by phorbol 12-myristate 13-acetate, W. R. Benjamin et
al., "Production of Immune Interferon By An Interleukin
2-Independent Murine T Cell Line", Proc. Natl. Acad. Sci. USA, 79,
pp. 5379-83 (1982); in lymphoid cells by using calcium ionophore
A-23187, F. Dianzani et al., "Human Immune Interferon: Induction in
Lymphoid Cells By A Calcium Ionophore", Infection And Immunity, 29,
pp. 561-63 (1980); and in thymocytes, G. H. Reem et al., "Gamma
Interferon Induction In Human Thymocytes Activated By Lectins and B
Cell Lines", Infection And Immunity, 37, pp. 216-21 (1982). See
also, Y. R. Yip et al., "Stimulation Of Human Gamma Interferon
Production By Diterpene Esters", Infection And Immunity, 34, pp.
131-39 (1981); U.S. Pat. Nos. 4,376,821; 4,376,822 and 4,460,685
and European patent application No. 63,482.
These natural IFN-.sub..gamma. s have been subsequently purified to
some extent and partially characterized. See, for example, U.S.
Pat. Nos. 4,289,690, 4,314,935 and 4,382,027; European patent
application No. 87,686; O'Malley, "Affinity Chromatography Of Human
Immune Interferon", Methods in Enzymology, 78, pp. 540-45 (1981),
and Y. K. Yip et al., "Partial Purification and Characterization of
Human .gamma. (Immune) Interferon", Proc. Natl. Acad. Sci. USA, 78,
pp. 1601-05 (1981).
IFN-.sub..gamma. s useful in the processes of this invention may
also be produced in large amounts by cloning and expression in
various host/vector systems using recombinant DNA technology. See,
e.g., European patent application No. 88,540; R. Derynck et al.,
"Human Interferon .gamma. Is Encoded By A Single Class Of mRNA",
Nucleic Acids Research, 10, pp. 3605-13 (1982); R. Derynck et al.,
"Expression Of The Human Interferon-.lambda. DNA In Yeast", Nucleic
Acids Res., 11, pp. 1819-37 (1983); R. Devos et al., "In Vitro
Translation And Characterization Of Human IFN-.sub..gamma. mRNA",
J. Clin. Hemator. Oncol., 11(4), p. 114 (1981); R. Devos et al.,
"Molecular Cloning Of Human Immune Interferon cDNA And Its
Expression In Eukaryotic Cells", Nucleic Acids Research, 10(8), pp.
2487-501 (1982). See also, G. Simons et al., Gene, 28, pp. 55-64
(1984); S. J. Schaill et al., Proc. Acad. Sci. USA, 80, pp. 4654-58
(1983) and P. W. Gray et al., Nature, 295, pp. 503-08 (1982).
As a result of some of these methods, IFN-.sub..gamma. is present
in the culture medium up to a concentration of more than 100,000
International reference units per milliliter (I.U./ml) or it is
concentrated in the host itself, constituting up to 25% of the
protein content of the cell.
The purification of IFN-.sub..gamma. from the preparations produced
according to the above-described processes may be effected by means
of one or a combination of the following conventional methods:
controlled pore glass (CPG) or silica gel
gel filtration (AcA 54 or Sephacel S200, for example)
ion-exchange chromatography (CM-Sepharose, phospho-cellulose or
DEAE-cellulose)
affinity chromatography (Con-A-Sepharose, Poly-U-Sepharose or
CU-chelate-Sepharose)
immune affinity chromatography using an anti-IFN-.sub..gamma.
Sepharose column
HPLC (with reverse phase materials, for example).
Other purification methods are described in Y. K. Yip et al.,
"Partial Purification And Characterization Of Human Gamma (Immune)
Interferon", Proc. Natl. Acad. Sci. USA, 78, pp. 1601-05 (1981), D.
Novick et al., "Monoclonal Antibodies To Human Interferon-.gamma.:
Production, Affinity Purification And Radioimmunoassay", EMBO
Journal, 2, pp. 1527-30 (1983) or West German patent DE No. 3136166
Al.
By means of such methods, alone or in any combination thereof,
purification up to electrophoretic homogeneity is possible. While
the average IFN-.sub..gamma. specific activity of such purified
substances ranges between about 10 and 50 million International
units per mg of protein, it is possible to obtain specific
activities of up to 100 million to 200 million International units
per mg of protein.
Clinical preparations used in the processes of this invention may
contain between about 100,000 to 200,000,000 I.U. per mg of protein
(1 .mu.g of active substance contains up to 200,000 International
reference units).
The processes and compositions of this invention may be used to
treat any mammal, including humans. According to this invention,
mammals are treated by the pharmaceutically acceptable
administration of IFN-.sub..gamma. in a pharmaceutically effective
dosage and for a period of time sufficient to reduce the symptoms
of the specific rheumatic disease or to prevent their
recurrence.
According to this invention, IFN-.sub..gamma. may be administered
to the patient in any pharmaceutically acceptable dosage form
including those which may be administered to a patient
intravenously as bolus or by continuous infusion over a period of
hours, days, weeks or months, intramuscularly -- including
paravertebrally and periarticularly -- subcutaneously,
intracutaneously, intra-articularly, intrasynovially,
intrathecally, periostally, or by oral or topical routes.
Such dosage forms may include pharmaceutically acceptable carriers
and adjuvants which are known to those of skill of the art. These
carriers and adjuvants include, for example, ion exchangers,
alumina, aluminum stearate, lecithin, serum proteins, such as human
serum albumin, buffer substances such as phosphates, glycine,
sorbic acid, potassium sorbate, partial glyceride mixtures of
saturated vegetable fatty acids, water, salts or electrolytes such
as protamine sulfate, disodium hydrogen phosphate, potassium
hydrogen phosphate, sodium chloride, zinc salts, colloidal silica,
magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based
substances and polyethylene glycol. Adjuvants for topical or gel
base forms of IFN-.sub..gamma. may be selected from the group
consisting of sodium carboxymethylcellulose, polyacrylates,
polyoxyethylene-polyoxypropyleneblock polymers, polyethylene glycol
and wood wax alcohols. For all administrations, conventional depot
forms may be used. Such forms include, for example, nano-capsules,
micro-capsules, liposomes and plasters.
The most effective mode of administration and dosage regimen of
IFN-.sub..gamma. will depend upon the type of rheumatic disease to
be treated, the severity and course of that disease, previous
therapy, the patient's health status and response to
IFN-.sub..gamma. and the judgment of the treating physician.
IFN-.sub..gamma. may be administered to the patient at one time or
over a series of treatments.
Depending on the severity of the disease, 200 I.U. (20 ng) to 2,000
million 1.U. (10 mg) may be administered to the patient over the
course of treatment. Generally, therapy is commenced with low doses
of IFN-.sub..gamma.. For example, an initial dose of
IFN-.sub..gamma. is administered to the patient by, for example,
injection or infusion. That initial dose should contain between
about 20,000 to 2,000,000 I.U. (about 2 .mu.g to 200 .mu.g) of
IFN-.sub..gamma.. For repeated administrations over several days,
dosages may be administered on successive days, every two to six
days, once a week, every two to four weeks or once a month, until a
desired suppression of disease symptoms is observed. However, other
dosage regimens are also useful. When the symptoms have been
alleviated to the desired level, treatment may cease. Patients may,
however, require intermittent treatment on a long term basis upon
recurrence of disease symptoms.
In cases of severe rheumatic disease, an initial dose of 50,000
1.U. (approximately 5 .mu.g) of IFN-.sub..gamma. may be
administered to the patient daily, over the course of between about
1 to 12 weeks, until the patient's condition improves. In the
absence of improvement, this initial daily dose may be doubled
after every 3 to 5 days of administration.
Once improvement in the patient's condition has occurred, a
maintenance dose of about 2,000,000 I.U. (approximately 200 .mu.g)
is administered about 3 times a week. Subsequently, the dosage
and/or frequency of administrations is reduced, as a function of
the symptoms, to a level at which the improved condition is
retained. Typically, such a maintenance schedule may involve the
administration of about 500,000 I.U. (approximately 50 .mu.g) to
the patient once or twice a week.
In less severe cases of rheumatic disease, an initial dose of 1 or
2 injections of between about 50,000 and 1,000,000 I.U.
(approximately 5 to 100 .mu.g) of IFN-.sub..gamma. typically
provides effective symptomatic treatment.
According to an alternate embodiment of this invention, the
effectiveness of the IFN-.sub..gamma. may be increased by
administration serially or in combination with other interferons
derived from natural sources or produced by recombinant techniques,
other cell mediators formed by leukocytes or produced by
recombinant techniques such as, for example, inter-leukin-1,
interleukin-2, tumor necrosis factor, macrophage colony stimulating
factor, macrophage migration inhibitory factor, macrophage
activation factor, lymphotoxin and fibroblast growth factor.
Alteratively, IFN-.sub..gamma. may be administered serially or in
combination with conventional anti-rheumatic therapeutic agents or
drugs such as, for example, thymus hormones.
In order that the invention described herein may be more fully
understood, the following examples are set forth. It should be
understood that these examples are for illustrative purposes only
and are not to be construed as limiting this invention in any
manner.
In the following examples, the IFN-.sub..gamma. s used in the
treatment of rheumatic diseases were either natural human
IFN-.sub..gamma. or human IFN-.sub..gamma. produced by recombinant
DNA techniques. The specific activity of the natural human
IFN-.sub..gamma. was in the range of 2-20 .times.106 I.U./mg of
protein. Recombinant human IFN-.sub..gamma. was supplied by Biogen
S.A., Geneva, for clinical testing. The specific activity of
Biogen's recombinant human IFN-.sub..gamma. was in the range of
10-20.times.10.sup.6 I.U./mg of protein.
These examples represent the results of treatment of various
rheumatic diseases using natural or recombinant IFN-.sub..gamma.
according to the processes of this invention. As demonstrated in
these examples, the use of IFN-.sub..gamma. according to this
invention was therapeutically effective in the treatment of
inflammatory rheumatism, extra-articular rheumatism, degenerative
rheumatism and collagen diseases.
These examples demonstrate that the administration of compositions
comprising either natural or recombinant IFN-.sub..gamma. to
patients afflicted with rheumatic disease effected significant and
lasting decreases in or elimination of symptoms, such as pain, and
led to considerable improvements in the motor responses of those
patients. These results were unexpected based upon previous
clinical studies of interferons generally and due to prior beliefs
that interferon therapy was contraindicated in the treatment of
rheumatic diseases.
EXAMPLE 1
In this example, the patient was a 49 year old male who weighed 79
kg and who was 172 cm tall. He had been suffering from severe
chronic polyarthritis for more than ten years, his condition
leading to deformities of the hands and feet. Upon admission to the
hospital for treatment, he was incapable of movement and no
improvement in his symptoms had resulted from conventional
therapies.
The patient was treated with an aqueous solution comprising 0.1,
0.5 or 1.0.times.10.sup.6 I.U./ml natural human IFN-.sub..gamma.,
prepared from human leukocytes, mg human serum albumin, 150
milli-molar sodium chloride and phosphate buffer according to
Sorensen, Biochem. Z., 21, p. 131 (1909) and Biochem. Z., 22, p.
352 (1909). The concentration of IFN-.sub..gamma. was
0.1-2.0.times.10.sup.6 /ml.
The patient received subcutaneous injections of the
IFN-.sub..gamma. composition according to the following dosage
schedule and regimen:
______________________________________ Treatment Day Dosage
______________________________________ 1 0.1 .times. 10.sup.6 I.U.
2 0.5 .times. 10.sup.6 I.U. 3 0.5 .times. 10.sup.6 I.U. 4 1.0
.times. 10.sup.6 I.U. 5 1.0 .times. 10.sup.6 I.U. 6 0 7 0 8 1.5
.times. 10.sup.6 I.U. 9 1.5 .times. 10.sup.6 I.U. 10 1.5 .times.
10.sup.6 I.U. 11 1.5 .times. 10.sup.6 I.U.
______________________________________
By the 6th day of treatment, the patient had experienced a
substantial decrease in pains in the lower extremities. From day 11
of treatment, the patient could walk and climb steps without pain
and all tenderness on percussion had disappeared. These
improvements lasted without the need for further treatments.
EXAMPLE 2
In this example, the patient was a 54 year old male weighing 75 kg
and who was 181 cm tall. At the time of hospitalization, he
suffered from severe chronic polyarthritis which led to deformity
of both
The patient was treated with a natural human IFN-.sub..gamma.
composition prepared from human leukocytes as described in Example
1. He received subcutaneous injections of the IFN-.sub..gamma.
composition according to the following dosage regimen:
______________________________________ Treatment Day Dosage
______________________________________ 1 0.5 .times. 10.sup.6 I.U.
2 0.5 .times. 10.sup.6 I.U. 3 0.5 .times. 10.sup.6 I.U. 4 0.5
.times. 10.sup.6 I.U. 5 0.5 .times. 10.sup.6 I.U. 6 0 7 0 8 1.0
.times. 10.sup.6 I.U. 9 1.0 .times. 10.sup.6 I.U. 10 1.0 .times.
10.sup.6 I.U. ______________________________________
As a result of treatments with 0.5 x 106 I.U. on days 1-5 of
therapy, the amount of pain experienced by the patient decreased
progressively. After treatments with 1.0.times.10.sup.6 I U. of the
IFN-.sub..gamma. composition on days 8-10 of therapy, the patient
was entirely free of pain. Before treatment with the
IFN-.sub..gamma. composition, the patient could exercise, at most,
for 4 minutes on a stationary bicycle. As of the 9th day of
treatment, he could exercise on the stationary bicycle twice a day
for a period of 20 minutes per exercise trial.
Seventeen days after the start of treatment, the patient was
discharged from the hospital. At the time of discharge, he was not
experiencing any pain, his mobility was excellent and he was no
longer sensitive to percussion over the joints. These improvements
lasted without the need for continued treatment. The patient feels
well and no longer requires cortisone therapy.
EXAMPLE 3
In this example, the patient, a 37 year old female, weighed 66 kg
and was 167 cm in height. She had been diagnosed as suffering from
seronegative rheumatic polyarthritis accompanied by anemia,
psoriasis and local nodal hyperplasia of the liver.
The patient was treated with an aqueous solution comprising 100
.mu.g/ml recombinant human IFN-.sub..gamma., 6 mg human serum
albumin, 8 mg sodium chloride, 0.2 mg potassium dihydrogen
phosphate and 1.4 mg disodium hydrogen phosphate. The concentration
of IFN-.sub..gamma. was 100 g/ml. She received intramuscular
injections of the recombinant IFN-.sub..gamma. composition
according to the following regimen:
______________________________________ Treatment Day Dosage
______________________________________ 1 100 .mu.g active substance
2 100 .mu.g active substance 3 100 .mu.g active substance 4 100
.mu.g active substance 5 100 .mu.g active substance 6 100 .mu.g
active substance 7 100 .mu.g active substance 8 100 .mu.g active
substance 9 0 10 0 11 175 .mu.g active substance 12 175 .mu.g
active substance 13 50 .mu.g active substance 14 50 .mu.g active
substance ______________________________________
During days 1-3 of treatment, the patient experienced an increase
in pain. She was free of pain for the first time on the 4th day of
therapy. Upon further treatment, the patient experienced some pain
for short periods of time. For over one year, the patient continued
to receive 10 .mu.g of active substance by intramuscular injection
-- initially, once a week and subsequently, once every two weeks.
She tolerated the treatments well and has not experienced any
further pain.
EXAMPLE 4
In this example, the patient was a male suffering from extremely
painful myogelosis over a six-month period.
The patient was treated with a natural human IFN-.sub..gamma.
composition prepared from human leukocytes, as described in Example
1. He received a single dose, 0.5.times.10.sup.6 I.U., of the human
IFN-.sub..gamma. composition by intramuscular injection. Within a
few minutes of the injection, the patient no longer experienced any
pain and he has remained pain free since the treatment.
EXAMPLE 5
In this example, the patient, a 60 year old female, was diagnosed
as having established rhematoid arthritis affecting the hands,
hips, knees, ankles and metatarsal phalangeal joints. She had
suffered from the disease for four years and was non-responsive to
therapy with either gold salts or prednisolone.
The patient was treated with a composition comprising recombinant
human IFN-.sub..gamma., as described in Example 3. She received
subcutaneous injections of the recombinant IFN-.sub..gamma.
composition according to the following treatment schedule:
______________________________________ Treatment Day Dosage
______________________________________ Days 1-16 2 injections of
250 .mu.g active substance per injection Days 17-22 2 injections of
100 .mu.g active substance per injection Days 23-38 1 injection of
100 .mu.g twice a week ______________________________________
After the first 5 days of treatment, the patient did not experience
any pain and she could move about freely. As a result of subsequent
maintenance therapy, the clinical picture of rheumatoid arthritis
continued to improve and the patient remained free of pain.
EXAMPLE 6
In this example, the patient, a 50 year old female, weighed 68 kg
and was 172 cm tall. She had suffered from severe chronic
polyarthritis for 19 years. Her symptoms did not respond to
treatments with non-steroidal drugs and she did not tolerate gold
or penicillamine therapy.
The patient was treated with a composition comprising recombinant
human IFN-.sub..gamma., of Example 3. She received subcutaneous
injections of the recombinant IFN-.sub..gamma. composition
according to the following regimen:
______________________________________ Treatment Day Dosage
______________________________________ 1-20 .mu.g active substance
21 + 20 .mu.g active substance (4 month administered twice per
period) week ______________________________________
After 20 days of treatment, the patient's general symptoms were
substantially diminished. A significant decrease in sensitivity of
the joints also resulted -- as reflected by over an 80% decrease in
the Ritchie Index, the articular index for assessment of joint
tenderness, measured for the patient. In addition, the level of
pain upon movement was reduced by 2.5 WHO degrees.
EXAMPLE 7
In this example, the patient was a female suffering from
periarthritis humeroscapularis over a 1 week period. She was
treated with a natural human IFN-.sub..gamma. composition prepared
from human leukocytes as described in Example 1.
She received a single subcutaneous injection, 0.5.times.10.sup.6
I.U., of the IFN-.sub..gamma. composition. Within a few minutes,
the patient was free of pain. Since then, the patient has not
experienced any further pain.
EXAMPLE 8
In this example, the patient was a male who had been diagnosed as
having ischialgia L.sub.5 /S.sub.1 right (i.e., located at the
lumbar 5 and sacral 1 disc of the spine) and osteoporosis over a 3
week period. He was treated with a natural human IFN-.sub..gamma.
composition prepared from human leukocytes, as described in Example
1.
The patient received two paravertebral injections of the
IFN-.sub..gamma. composition as follows:
______________________________________ Treatment Day Dosage
______________________________________ 1 0.5 .times. 10.sup.6 I.U.
21 0.5 .times. 10.sup.6 I.U.
______________________________________
The first injection alleviated the patient's pain over a 5 day
period. After the second injection, the patient remained pain-free
and to date, nine months after the first treatment, he has not
experienced further pain.
EXAMPLE 9
In this example, the patient, a 58 year old female, weighed 49 kg
and was 163 cm in height. For four years, she suffered from classic
rheumatoid arthritis, as defined by the diagnostic criteria
established by the American Rheumatism Association see The Merck
Manual, supra, p. 2, at 1179).
The patient was treated with a composition comprising recombinant
human IFN-.sub..gamma., of Example 3. She received subcutaneous
injections of the recombinant IFN-.sub..gamma. composition
according to the following regimen:
______________________________________ Treatment Day Dosage
______________________________________ 1-20 50 .mu.g active
substance twice daily 21 + gradual reduction of dosage and
frequency of administration to 50 .mu.g active substance
administered twice weekly
______________________________________
After 20 days of treatment, the patient's general symptoms and
motor responses clearly improved. The Ritchie Index measured for
the patient (see Example 6) decreased from 43 to 33. Pain at rest
was reduced by three WHO degrees and pain on movement was reduced
by one WHO degree. This improvement has lasted five months up to
the present time.
EXAMPLE 10
In this example, the patient, a 60 year old female weighed 61 kg
and was 164 cm in height. She suffered from classic rheumatoid
arthritis for eleven years.
The patient was treated with a composition comprising recombinant
human IFN-.sub..gamma., of Example 3. She received subcutaneous
injections of the recombinant IFN-.sub..gamma. composition
according to the following regimen:
______________________________________ Treatment Day Dosage
______________________________________ 1-20 50 .mu.g active
substance twice daily 21 + gradual reduction of dosage and
frequency of administration to 50 .mu.g active substance
administered twice weekly
______________________________________
After 20 days of treatment, the patient's general symptoms and
motor responses clearly improved. The Ritchie Index measured for
the patient (see Example 6) decreased by 35%. Pain on waking, at
rest and on motion were each reduced by one WHO degree. This
improvement has lasted six months until the present.
EXAMPLE 11
In this example, the patient, a 65 year old female, weighed 65 kg
and was 160 cm tall. For ten years, she suffered from definite
rheumatoid arthritis, as defined by the diagnostic criteria
established by the American Rheumatism Association (see The Merck
Manual, supra, p. 19).
The patient was treated with a composition comprising recombinant
human IFN-.sub..gamma., of Example 3. She received subcutaneous
injections of the recombinant IFN-.sub..gamma. composition
according to the following regimen:
______________________________________ Treatment Day Dosage
______________________________________ 1-20 50 .mu.g active
substance twice daily 21 + gradual reduction of dosage and
frequency of administration to 50 .mu.g active substance
administered twice weekly
______________________________________
After 20 days of treatment, the patient's general symptoms and
motor responses clearly improved. The Ritchie Index measured for
the patient (see Example 6) decreased by 40%. The patient's grip
strength was improved and the duration of morning stiffness
decreased. This improvement has lasted for four months until the
present time.
EXAMPLE 12
In this example, the patient, a 44 year old male, weighed 72 kg and
was 183 cm in height. He suffered from definite rheumatoid
arthritis for eight months.
The patient was treated with a composition comprising recombinant
human IFN-.sub..gamma., of Example 3. He received subcutaneous
injections of the recombinant IFN-.sub..gamma. composition
according to the following regimen:
______________________________________ Treatment Day Dosage
______________________________________ 1-20 50 .mu.g active
substance 20 + 50 .mu.g active substance administered three times a
week ______________________________________
After 20 days of treatment, although the patient showed no
improvement in clinical symptoms, his blood sedimentation rate
("BSR") was reduced from 130 mm to 66 mm (read after one hour).
During the continued course of therapy, the BSR decreased further,
the patient's motor responses improved and the patient's morning
stiffness decreased. As a result of this treatment, the patient was
able to return to work. The improved has lasted four months up to
the present time.
While we have hereinbefore presented a number of embodiments of
this invention, it is apparent that our basic construction can be
altered to provide other embodiments which utilize the processes
and compositions of this invention. Therefore, it will be
appreciated that the scope of this invention is to be defined by
the claims appended hereto rather than by the specific embodiments
which have been presented hereinbefore by way of example.
* * * * *