U.S. patent application number 13/527233 was filed with the patent office on 2012-10-11 for compositions and methods for the systemic treatment of arthritis.
This patent application is currently assigned to BAYLOR RESEARCH INSTITUTE. Invention is credited to Jacques Banchereau, Virginia Pascual.
Application Number | 20120258120 13/527233 |
Document ID | / |
Family ID | 34910974 |
Filed Date | 2012-10-11 |
United States Patent
Application |
20120258120 |
Kind Code |
A1 |
Banchereau; Jacques ; et
al. |
October 11, 2012 |
COMPOSITIONS AND METHODS FOR THE SYSTEMIC TREATMENT OF
ARTHRITIS
Abstract
The present invention includes compositions and methods for
treating arthritic joints found in patients with auto-inflammation,
e.g., systemic onset juvenile idiopathic arthritis, by
administering at the site of inflammation a therapeutically
effective amount of at least one agent that reduces or blocks
IL-1.beta. receptors.
Inventors: |
Banchereau; Jacques;
(Montclair, NJ) ; Pascual; Virginia; (Dallas,
TX) |
Assignee: |
BAYLOR RESEARCH INSTITUTE
Dallas
TX
|
Family ID: |
34910974 |
Appl. No.: |
13/527233 |
Filed: |
June 19, 2012 |
Related U.S. Patent Documents
|
|
|
|
|
|
Application
Number |
Filing Date |
Patent Number |
|
|
12578332 |
Oct 13, 2009 |
8221748 |
|
|
13527233 |
|
|
|
|
11067335 |
Feb 25, 2005 |
7615212 |
|
|
12578332 |
|
|
|
|
60548033 |
Feb 26, 2004 |
|
|
|
Current U.S.
Class: |
424/158.1 ;
424/172.1; 514/16.8; 514/44A; 514/44R; 514/458; 514/560 |
Current CPC
Class: |
A61P 19/02 20180101;
A61P 43/00 20180101; A61K 38/2006 20130101; A61P 29/00 20180101;
C07K 14/545 20130101; A61P 37/00 20180101; G01N 33/6869 20130101;
A61K 38/1709 20130101; C07K 16/245 20130101; A61K 39/395 20130101;
A61P 19/00 20180101; Y10S 514/825 20130101 |
Class at
Publication: |
424/158.1 ;
514/44.R; 514/44.A; 514/16.8; 424/172.1; 514/458; 514/560 |
International
Class: |
A61K 31/7088 20060101
A61K031/7088; A61K 38/02 20060101 A61K038/02; A61P 19/02 20060101
A61P019/02; A61K 31/355 20060101 A61K031/355; A61K 31/557 20060101
A61K031/557; A61K 38/16 20060101 A61K038/16; A61K 39/395 20060101
A61K039/395 |
Claims
1. A method for treating a joint with systemic onset juvenile
idiopathic arthritis comprising administering to the joint a
composition comprising a therapeutically effective amount of one or
more active agents that reduces the bioavailability of
interleukin-1 .beta. by blocking one or more IL-1.beta.
receptors.
2. The method of claim 1, wherein the active agent comprises a
single-stranded RNA molecule, a double-stranded RNA molecule, an
antisense RNA molecule, a small inhibitory RNA (siRNA) molecule, or
an inhibitory RNA molecule (RNAi) designed to encode an agent that
blocks one or more IL-1.beta. receptors.
3. The method of claim 1, wherein the active agent is provided at
between about 1 to 250 mg per day.
4. The method of claim 1, wherein the one or more active agents
reduces the fever, rash, arthritis and white blood cell count of a
SOJIA patient.
5. A method for treating a patient with systemic onset juvenile
idiopathic arthritis comprising administering to the patient a
composition comprising an effective amount of at least one agent
capable of reducing or blocking the bioavailability of an
interleukin-1.beta. by blocking one or more IL-1.beta.
receptors.
6. The method of claim 5, wherein the composition reduces the
fever, rash, arthritis and white blood cell count of a SOJIA
patient.
7. The method of claim 5, wherein the one or more active agents are
selected from: one or more modifiers of interleukin-1 beta
(IL-1.beta.) gene transcription; one or more modifiers of
IL-1.beta. gene translation; one or more siRNAs that target the
expression of IL-1.beta.; one or more IL-1.beta. receptors
blockers; one or more interleukin-1 receptor antagonist proteins;
one or more interleukin-1 receptor antagonist peptides; one or more
active agents that modify the release of IL-1.beta.; one or more
antibodies that neutralize IL-1.beta.; one or more antibodies that
blocks an IL-1.beta. receptor; one or more recombinant, naturally
occurring IL-1 receptor antagonists; one or more anion transport
inhibitors, lipoxins and alpha-tocopherol that inhibit the release
of IL-1.beta.; one or more opioids that inhibits a proteolytic
enzyme that converts the inactive IL-1.beta. precursor to its
mature, active form; one or more antibodies that neutralizes the
biological function of IL-1.beta., mixtures and combinations
thereof.
8. The method of claim 5, wherein the active agent comprises is
provided at between about 1 to 250 mg per day.
Description
REFERENCE TO RELATED APPLICATION
[0001] This application is a divisional of and claims priority to
U.S. patent application, Ser. No. 12/578,332, filed Oct. 13, 2009,
which is a divisional of and claims priority to U.S. Pat. No.
7,615,212, which claims priority to U.S. Provisional Patent
Applications, Ser. No. 60,548,033, filed Feb. 26, 2004 the entire
content of each is incorporated herein by reference.
TECHNICAL FIELD OF INVENTION
[0002] The present invention relates to therapeutic use of a
bio-affecting and body-treating composition, and more particularly,
to compositions and methods for the systemic treatment of joint
inflammation.
BACKGROUND OF THE INVENTION
[0003] Juvenile idiopathic arthritis ("JIA"), also referred to as
juvenile rheumatoid arthritis ("JRA") or juvenile chronic arthritis
("JCA") is the most common rheumatic disease in childhood and an
important cause of both short and long-term disability. The term
"JIA" includes a heterogeneous group of diseases, each of which may
have a variety of causes and elicit a variety of host responses.
All are characterized, however, by the development of idiopathic
peripheral arthritis thought to be secondary to an
immuno-inflammatory pathogenesis, possibly triggered by contact
with external antigen(s). JIA is classified according to three
major types of disease presentation: (1) oligoarthritis; (2)
polyarthritis; and (3) systemic onset juvenile idiopathic arthritis
(hereinafter "SOJIA"). Each of these groups is defined by a
constellation of clinical signs and symptoms during the first six
months of illness.
[0004] Of the known JIA diseases, all three major groups based on
primary modes of onset have been considered to: (1) have an
"autoimmune etiology"; and (2) follow a complex, nonmendelian,
genetic trait. Evidence of underlying autoimmunity is mainly drawn
from the presence of autoantibodies and/or immune complexes in the
patient's sera. Anti-nuclear antibodies occur in a high proportion
of children with oligoarticular and, to a lesser extent,
polyarticular onset, and these antibodies confer a higher risk of
developing uveitis. Other autoantibodies directed against
cytoplasmic and extracellular components such as collagen have also
been described. Rheumatoid factors (RF) are detected in
approximately 3% of children with JIA, and the presence of these
autoantibodies defines a subgroup of polyarticular onset patients
whose disease is undistinguishable from adult onset rheumatoid
arthritis (Cassidy, JT and Ross, E. 2001. Textbook of Pediatric
Rheumatology, 4th ed, Books on Demand Publishers, Visby, Sweden; p.
218-321).
[0005] A variety of T cell alterations have been described mainly
in the blood and synovial fluid of children with oligoarthritis,
but a consistent pattern of cytokine production has not been found.
In both oligoarthritis and polyarthritis patients, increased
soluble IL-2R and IL-1.beta. have been found in the blood. In all
three forms of JIA, TNF-.alpha. and soluble TNF.alpha.R (p55/75)
have been found elevated in the serum and/or synovial fluid (SF).
In SOJIA patients, abnormal expression of IL-6 has been described,
especially in the blood prior to the febrile spikes, and IL-6
levels correlate with the systemic activity of the disease, with
the development of arthritis, and with the increase in acute phase
reactants (Yokata, S. 2003. "Interleukin 6 as a therapeutic target
in systemic-onset juvenile idiopathic arthritis," Curr Opin
Rheumatol 15:581-586). IL-6deregulation has also been proposed to
mediate the linear growth retardation, thrombocytosis and anemia
seen in SOJIA patients (de Benedetti F, et al., 1991. Arthritis
Rheum 34:1158-1163; Mangge H, et al. 1999. J Interferon Cytokine
Res 19:1005-1010; Ozen S, et al. 1997. Clin Rheumatol 16:173-178;
de Benedetti F, et al., 1999. J Rheumatol 26:425-431; Muller K, et
al. 1998. Br J Rheumatol 37:562-569; Shahin A, et al., 2002.
Rheumatol Int 22:84-88; de Benedetti F, et al., 1992. Clin Exp
Rheumatol 10:493-498; and Muzaffer M, et al., 2002. J Rheumatol
29:1071-1078).
[0006] Data on HLA segregation suggests a hereditary basis to the
complex etiopathogenesis of the disease(s) in cases of
oligoarticular and polyarticular onset JIA. Studies in SOJIA have
yielded, however, inconsistent results. Finally, both viruses and
bacteria have been described in association with chronic arthritis
in children. Rubella and Parvovirus B19 can cause chronic arthritis
secondary to persistence of the organism or by triggering an immune
reaction, as it has also been described in cases of
post-vaccination arthritis.
[0007] SOJIA represents about 10% of all the cases of JIA. The
course and prognosis of SOJIA is heterogeneous, as fifty per cent
of patients have a monophasic course with resolution of the
symptoms, while the remaining fifty per cent develop a chronic
relapsing and remitting course and a very severe form of
polyarticular chronic arthritis. Patients with SOJIA also display
an increased risk of developing hemophagocytic syndrome, a
potentially fatal complication (Cassidy, JT and Ross, E. 2001.
Textbook of Pediatric Rheumatology, 4th ed, Books on Demand
Publishers, Visby, Sweden; p. 218-321).
[0008] Children with SOJIA present with severe systemic symptoms
(fever and rash) that usually precede the development of arthritis
for weeks to years. The high spiking fever, which is the hallmark
of this disease, usually follows a quotidian pattern with 1-2
spikes/day. Patients look characteristically well when the fever is
not present, but become quite ill with the spikes. In many
patients, the fever is accompanied by a salmon-pink rash that
becomes more apparent with the fever. Additionally, children with
SOJIA may have hepatosplenomegaly, lymphadenopathy, pericarditis
and other manifestations of serositis. These systemic
manifestations may last from weeks to months and eventually tend to
subside to be followed by the development of chronic arthritis.
About 50% of patients will present oligoarticular involvement and
will eventually recover. The other half will evolve into a
polyarticular pattern, the prognosis of which correlates with the
number of joints involved six months into the disease course. Up to
48% of children with SOJIA will have active arthritis ten years
after the diagnosis is made (Cassidy, JT and Ross, E. 2001.
Textbook of Pediatric Rheumatology, 4th ed, Books on Demand
Publishers, Visby, Sweden; p. 218-321; and Lomater C, et al., 2000.
J Rheumatol 27:491-496).
[0009] There are no available specific tests to establish the
diagnosis of SOJIA, nor are there known prognostic indicators to
ascertain its clinical course. Fever, anemia, leukocytosis and
elevated erythrocyte sedimentation rate (ESR) are the main initial
features of the disease, sometimes lasting several months before
the diagnosis can be established. As these symptoms are nonspecific
and can mimic infections, malignancies, and other diseases,
patients undergo a series of very costly diagnostic tests and
prolonged hospitalizations.
[0010] One of the most serious complications in patients with SOJIA
is the development of hemophagocytic syndrome, also known as
macrophage activation syndrome (MAS) (Cassidy, JT and Ross, E.
2001. Textbook of Pediatric Rheumatology, 4th ed, Books on Demand
Publishers, Visby, Sweden; p. 218-321). The hemophagocytic
syndrome, which can occur as well in the context of infectious and
neoplastic diseases, is associated with serious morbidity and/or
death. Its etiology, especially in the context of SOJIA, is
unknown. Familial cases of MAS occur as the result of defective
viral killing due to mutations in genes like perforin (involved in
the release of granzyme by cytotoxic T cells/natural killer cells
to target cells) or Rab27 (involved in the control of granzyme
vesicle degranulation).
SUMMARY OF THE INVENTION
[0011] Therefore, SOJIA remains a chronic inflammatory disease of
unknown etiology for which a specific treatment has not been
determined. Despite extensive study, multi-drug treatment of
patients with SOJIA is similar to that of oligoarthritis and
polyarthritis, which depends on the phase (systemic phase versus
arthritic phase) of the disease and on the extent of involvement.
While a minority of patients does well with non-steroidal
anti-inflammatory drugs (NSAIDs), most children require the use of
oral and/or parenteral steroids as well as methotrexate to control
the symptoms. Intravenous immunoglobulin (IVIG) has been used in
recalcitrant cases. Most recently, anti-TNF therapy (e.g.,
etanercept and infliximab) is being added to these regimens.
Nevertheless, there are some limitations and risks associated with
these drugs. For example, long term treatment of these patients
with immunosuppressive drugs such as methotrexate and steroids have
been reportedly associated with an impaired ability of the patients
to eliminate viral infections. Intravenous immunoglobulin treatment
is accompanied by the risks associated with transfusions of
blood-derived products. The present inventors have found that SOJIA
patients do not respond as well and require higher doses of
anti-TNF agents to control the symptoms than any other type of JIA.
Therefore, there is a continuing need to identify effective drug
treatments for SOJIA disease.
[0012] Blocking IL-1 has been reported as an effective agent for
treating patients with inflammatory arthritis associated with
autoimmune diseases. Clinical studies have been preformed on adults
with rheumatoid arthritis and children with diverse forms of
juvenile arthritis. Anakinra (Kineret.RTM., made by Amgen), the
recombinant human IL-1 receptor antagonist has the ability to block
the interaction of IL-1 with its receptor, thus blocking the
cellular response of IL-1. A clinical trial using Anakinra has been
conducted with patients with severe rheumatoid arthritis. At 150 mg
per day, a 43% response rate based on the American College of
Rheumatology index was seen in comparison to 27% in placebo group.
Clinical studies using IL-1 antagonists, however, have never been
done in children or adults with Systemic Onset Arthritis during the
systemic phase of the disease, as defined by the presence of fever
and/or rash with or without arthritis. Furthermore, IL-1 has been
reported not to play a relevant role in SOJIA disease (de Benedetti
F, et al., 1995. "Circulating levels of interleukin 1 beta and of
interleukin 1 receptor antagonist in systemic juvenile chronic
arthritis," Clin Exp Rheumatol 13:779-84).
[0013] Autoinflammatory diseases are illnesses associated with
alterations of the innate immune system. Cells of the innate immune
system, e.g., neutrophils, monocytes, macrophages and NK cells, are
characterized by the lack of somatically generated receptors, the
clonal expansion of antigen-specific cells and their inability to
confer "immunological memory." Although autoinflammatory diseases
may clinically mimic autoimmune diseases, patients with
autoinflammation never develop autoantibodies, which are the
hallmark of many autoimmune diseases. On the other hand, most
autoinflammatory diseases cause fever, usually with an intermittent
or periodic pattern, and the skin and joints are frequently the
targets of inflammation. In the past five years, the genes
responsible for at least nine familial autoinflammatory diseases
have been described. These include Familial Mediterranean Fever
(FMF), Tumor Necrosis Factor-Associated Periodic Fever Syndrome
(TRAPS), Hyper IgD, Cyclic Neutropenia, Familial Cold Urticaria
(FCU), Muckle-Wells Syndrome, Chronic Inflammatory Neurologic and
Articular Syndrome (CINCA), Familial Granulomatous Disease (Blau's
Syndrome), and Crohn's disease (reviewed in Hull KM, et al., 2003.
Curr Opin Rheumatol 15:61-69). Although most autoinflammatory
diseases are the result of single gene mutations, there are some
that follow complex genetic traits, like ulcerative colitis and
some forms of Crohn's disease, and yet some, like Behcet's, that
may not be genetic in origin.
[0014] Despite reports the contrary, the present inventors have
found that SOJIA is an autoinflammatory disease and reducing or
blocking the bioavailability of interleukin-1 beta (IL-1.beta.) is
an effective therapeutic treatment for SOJIA patients. In one
aspect, the present invention is a method for treating a patient
with systemic onset juvenile idiopathic arthritis by administering
to the patient a composition with an effective amount of at least
one agent capable of reducing or blocking the bioavailability of
interleukin-1 beta.
[0015] More particularly, the present invention includes
compositions and method for treating a joint undergoing
autoinflammation, e.g., having systemic onset juvenile idiopathic
arthritis, by administering to the joint a composition that
includes a therapeutically effective amount of one or more active
agents that reduces the bioavailability of interleukin-1 .beta..
The active agent may modify the transcription of the
interleukin-1.beta. gene or the translation of the
interleukin-1.beta. gene. Alternatively, the active agent may be a
single-stranded RNA molecule, a double-stranded RNA molecule, an
antisense RNA molecule, a small inhibitory RNA (siRNA) molecule, or
an inhibitory RNA molecule (RNAi) designed to reduce the expression
of interleukin-1.beta.. Another active agent may block IL-1.beta.
receptors, e.g., an interleukin-1 receptor antagonist protein or
peptide that blocks the interaction between IL-1.beta. and the
IL-1.beta. receptor.
[0016] Yet another active agent modifies the release of IL-1.beta.
or an antibody to an IL-1.beta. to reduce or neutralize IL-1.beta.,
or even an IL-1.beta. receptor. In one specific example, the active
agent may be a naturally occurring IL-1 receptor antagonist
provided at between about 1, 10, 15, 25, 50, 100, 125, 150, 175,
200 and even 250 mg per day. Often doses may be halved for
pediatric patients. The active agent may also be a single-stranded
RNA molecule, a double-stranded RNA molecule, an antisense RNA
molecule, a small inhibitory RNA (siRNA) molecule, or an inhibitory
RNA molecule (RNAi) designed to target and reduce the expression of
interleukin-1.beta. receptor. Examples of active agents that affect
or inhibit the release of IL-1.beta. include anion transport
inhibitors, e.g., lipoxins, and alpha-tocopherol. Other examples
include opioids that inhibit a proteolytic enzyme that converts the
inactive IL-1.beta. precursor to its mature, active form. Yet other
examples include antibodies that neutralize the biological function
of IL-1.beta..
[0017] Yet another example of the present invention is a method for
treating a patient with systemic onset juvenile idiopathic
arthritis by administering to the patient a composition having an
effective amount of at least one agent capable of reducing or
blocking the bioavailability of an interleukin-1.beta.. The
composition may include an effective amount of at least one agent
capable of reducing or blocking the bioavailability of an
interleukin-1.beta. receptor. For example, a composition for
treating SOJIA includes a therapeutically effective amount of one
or more active agents adapted for delivery to a joint that reduces
the inflammation of the joint affected with SOJIA. The composition
helps reduce one or more of the following symptoms: fever, rash,
arthritis and white blood cell count of a SOJIA patient. The
composition may include one or more active agents that are:
modifiers of interleukin-1 beta (IL-1.beta.) gene transcription;
modifiers of IL-1.beta. gene translation; siRNAs that target the
expression of IL-1.beta.; IL-1.beta. receptors blockers;
interleukin-1 receptor antagonist proteins; interleukin-1 receptor
antagonist peptides; active agents that modify the release of
IL-1.beta.; antibodies that neutralize IL-1.beta.; antibodies that
blocks an IL-1.beta. receptor; recombinant, naturally occurring
IL-1 receptor antagonists; anion transport inhibitors, lipoxins and
alpha-tocopherol that inhibit the release of IL-1.beta.; opioids
that inhibits a proteolytic enzyme that converts the inactive
IL-1.beta. precursor to its mature, active form; antibodies that
neutralizes the biological function of IL-1.beta., and mixtures or
combinations thereof. The pharmaceutical formulation may be adapted
to treat joint autoinflammation and may be a made available in a
variety of dosage forms, including, intravenous, intramuscular,
oral, nasal, rectal, peritoneal, sub-cutaneous, intra-cutaneous
(e.g., a patch), and the like.
[0018] The present invention also include a method of monitoring a
therapeutic response to an autoinflammatory diease, e.g., SOJIA by
monitoring the fever, rash, arthritis, white blood cell count
and/or the sedimentation rate of white blood cells after treatment
using the methods and compositions taught and disclosed herein. The
present invention will find utility in a wide variety of contexts,
e.g., treating an animal suffering from an autoinflammation by
administering a therapeutic agent to an animal suffering from
autoinflammation, wherein that agent including an antagonist of
Interleukin 1.beta. function in a pharmaceutically acceptable
carrier, wherein the antagonist suppresses the
autoinflammation.
BRIEF DESCRIPTION OF THE DRAWINGS
[0019] For a more complete understanding of the features and
advantages of the present invention, reference is now made to the
detailed description of the invention along with the accompanying
figures and in which:
[0020] FIG. 1 is a graphic rendering of gene array data that
depicts genes upregulated (red), downregulated (blue) or unchanged
(yellow) upon incubation of PBMCs from four healthy volunteers with
either autologous serum (AS) or the sera from three SOJIA
patients;
[0021] FIG. 2A is a graph that compares the induction of
Interleukin 1-Beta (IL-b) protein secretion in healthy PBMCs
incubated with SOJIA sera;
[0022] FIG. 2B is a graph that compares the induction of IL-1b
protein secretion in SOJIA patients with and without systemic
symptoms; and
[0023] FIGS. 3A through F are graphs that shows the values of
temperature (FIG. 3A); active joint count (FIG. 3B); WBC (FIG. 3C);
hemoglobin (FIG. 3D); platelet count (FIG. 3E); and ESR in 9 SOJIA
patients (FIG. 3F).
DETAILED DESCRIPTION OF THE INVENTION
[0024] While the making and using of various embodiments of the
present invention are discussed in detail below, it should be
appreciated that the present invention provides many applicable
inventive concepts that can be embodied in a wide variety of
specific contexts. The specific embodiments discussed herein are
merely illustrative of specific ways to make and use the invention
and do not delimit the scope of the invention.
[0025] To facilitate the understanding of this invention, a number
of terms are defined below. Terms defined herein have meanings as
commonly understood by a person of ordinary skill in the areas
relevant to the present invention. Terms such as "a", "an" and
"the" are not intended to refer to only a singular entity, but
include the general class of which a specific example may be used
for illustration. As used in the claim(s), in conjunction with the
word "comprising," the words "a" or "an" may mean one or more than
one. As used herein, "another" may mean at least a second or more
of an item. The terminology herein is used to describe specific
embodiments of the invention, but their usage does not delimit the
invention, except as outlined in the claims.
[0026] As used herein, the term the "therapeutically effective" is
used to define the amount of a compound required to improve some
symptom associated with autoinflammatory disease, e.g., SOJIA. For
example, in the treatment of autoinflammation, the present
invention includes one or more active agents that improve the
health or movement of a joint to any degree or arrests any symptom
of a joint disease would be therapeutically effective. A
therapeutically effective amount of a compound is not required to
cure a disease but will provide a treatment for a disease.
[0027] As used herein, the phrase "a therapeutically effective
amount of one or more active agents that reduces the
bioavailability of interleukin-1.beta." is the amount of an
inhibitor of IL-1.beta. expression, translation, processing,
release or activity; an inhibitor of IL-1.beta. receptor
expression, translation, processing, release or activity; and/or
inhibitors of second messenger(s) expression, translation,
processing, release or activity that are downstream from the
IL-1.beta. receptor when administered at, to or about a joint, or
to an animal systemically or locally, that reduced the scope and
extent of autoinflammation.
[0028] As used herein the term, "interleukin-1.beta. receptor" is
used to describe the cognate receptor for interleukin-1.beta..
Non-limiting examples of agents that may specifically bind to,
whether causing activation of the receptor or not, include:
interleukin-1.beta., anti- interleukin-1.beta. receptor antibodies
or fragments thereof, peptides, proteins, glycoproteins,
lipoproteins, epitopes, lipids, lectins, carbohydrates,
multi-molecular structures, and specific conformation of one or
more molecules. A "receptor" is a naturally occurring molecule or
complex of molecules that is generally present on the surface of
cells of a target organ, tissue or cell type, e.g., a joint.
[0029] As used herein the term "modify" or "modifies" is meant to
include up or down regulation of the function of a gene or gene
product, e.g., affecting the transcription, translation,
processing, release or modification of a gene or gene product. The
active agent may modify the transcription of the
interleukin-1.beta. gene. Examples of modification include, e.g.,
transcriptional or post-transcriptional silencing, changes to
message stability and the like. Examples of post-translational
modifications include maturation of the gene product or protein,
post-translational modifications (e.g., glycosylation, di-sulfide
bonding, myristylation, protease cleavage, association with other
proteins, ubiquitination, etc.). The processing, transport and
release of the protein may also be modified, e.g., by placing in
storage organelles prior to release, by association with other
proteins that affect release and the like.
[0030] The present inventors have recognized that SOJIA is an
autoinflammatory disease rather than an autoimmune disease.
Therefore, one aspect of the present invention is treatment of
SOJIA aimed at targeting the cells (and the cell products) of the
innate immune system rather than the adaptive immune system.
[0031] According to the present invention, IL-1.beta. has now been
found to be a fundamental mediator of inflammation in
"autoinflammatory" diseases. Moreover, IL-1.beta. modulation can be
effective in treatment of autoinflammatory diseases including but
not limited to SOJIA.
[0032] In one embodiment of the invention the formulation will
include a therapeutically effective amount of one or more IL-1
inhibitors, such as type I or type II IL-1 receptor (e.g., IL-1
binding fragments of type II IL-1 receptor, see e.g., U.S. Patent
No. 5,350,683, relevant portions incorporated herein by reference);
IL-1 binding and IL-1 inhibitory fragments of type I IL-1 receptor;
IL-1 receptor antagonist, IL-1 beta converting enzyme (ICE)
inhibitors, antibodies to IL-1, including IL-1 alpha and IL-1 beta
and other IL-1 family members, and therapeutics known as IL-1 traps
and antagonistic type I IL-1 receptor antibodies. Other specific
IL-1 inhibitors for use with the present invention include IL-1 RA
and variants or fragments thereof (see e.g., U.S. Pat. No.
5,922,573, relevant portions incorporated herein by reference). Yet
another active agent is an IL-1 beta converting enzyme (ICE)
inhibitor, e.g., peptidyl and small molecule ICE inhibitors
including those described in PCT patent application WO 93/16710;
and European patent application 0 547 699, relevant portions
incorporated herein by reference). Non-peptidyl compounds (see
e.g., U.S. Pat. No. 6,121,266, relevant portions incorporated
herein by reference) and ICE (see e.g., U.S. Pat. No. 6,204,261,
relevant portions incorporated herein by reference). Other IL-1
antagonists include chimeric proteins that include portions of both
an antibody molecule and an IL-1 antagonist molecule, chimeras and
multimers thereof, and IL-1 antagonists such as peptides derived
from IL-1 that are capable of binding competitively to the IL-1
signaling receptor, IL-1 RI and/or IL-1 RI.
[0033] In particular, it has now been found that administering an
agent to significantly reduce or effectively block the
bioavailability of interleukin-1 beta (IL-1.beta. is a therapeutic
option for SOJIA patients. As used herein, significant reduction of
the bioavailability of IL-1.beta. is defined as a sufficient
reduction of bioavailable IL-1.beta. to effect a reduction in
symptoms and/or disease progression in SOJIA patients. In the
present invention, at least one agent capable of significantly
reducing or effectively blocking the bioavailability of IL-1.beta.
is administered to a patient diagnosed with SOJIA to effect a
reduction in symptoms and disease progression. It is contemplated
that more than one agent capable of reducing or blocking the
bioavailability of (IL-1.beta.) can be administered to an SOJIA
patient either concomitantly or sequentially. It is further
contemplated that one or more agents capable of reducing or
blocking the bioavailability of (IL-1.beta.) can be administered to
an SOJIA patient in combination with other drug treatments either
concomitantly or sequentially.
[0034] Techniques and compositions for making useful dosage forms
using the present invention are described in one or more of the
following references: United States Pharmacopeia (USP # 24 NF19)
(Hardcover Text w/ 3 Supplements)(United States Pharmacopeial
2002). Remington: The Science and Practice of Pharmacy, (21st
Edition, formerly, Remington's Pharmaceutical Sciences), Mack
Publishing Co, 2005); Advances in Pharmaceutical Sciences (David
Ganderton, Trevor Jones, Eds., 1992), and the like, relevant
portions incorporated herein by reference.
[0035] Generally, the therapeutic formulations of the present
invention will be provided to a person in need of preventive or
therapeutic intervention in water, a suitable oil, saline, aqueous
dextrose (e.g., glucose, lactose and related sugar solutions) and
glycols (e.g., propylene glycol or polyethylene glycols) or other
suitable carriers for intravenous or parenteral administration.
Solutions for parenteral administration include generally, a water
soluble salt of the active ingredient, suitable stabilizing agents,
and if necessary, buffering salts. Citric acid and its salts and/or
sodium EDTA may also be included to increase stability.
Antioxidizing agents, e.g., sodium bisulfite, sodium sulfite and/or
ascorbic acid, either alone or in combination, are suitable
stabilizing agents. In addition, the solutions may include
pharmaceutically acceptable preservatives, e.g., benzalkonium
chloride, methyl- or propyl-paraben, and/or chlorobutanol. Suitable
pharmaceutical carriers are described in Remington's (supra).
[0036] In one embodiment, treatment of SOJIA includes administering
an amount of at least one agent to significantly reduce or
effectively block the transcription of the interleukin-1 beta
(IL-1.beta.) gene. Exemplary agents for the present invention
suitable for blocking the transcription of the interleukin-1 beta
(IL-1.beta.) gene include but are not limited to anti-sense RNA
compounds (Mehta RC, et al. 2000. "Intercellular adhesion
molecule-1 suppression in skin by topical delivery of anti-sense
oligonucleotides," J Invest Dermatol 115):805-812; Frankel AE, et
al. 2001. "Novel therapeutics for chemotherapy-resistant acute
myeloid leukaemia," BioDrugs 15:55-57; Lorenz HM and Kalden JR.
2001. "New therapy developments in rheumatoid arthritis," Z
Rheumatol 60:326-32.; Ideo G and Bellobuono A. 2002. "New therapies
for the treatment of chronic hepatitis C," Curr Pharm Des
8:959-966; Sandborn W J and Targan S R. 2002. "Biologic therapy of
inflammatory bowel disease," Gastroenterology 122:1592-1608).
[0037] In another embodiment, treatment of SOJIA includes
administering an amount of at least one agent to significantly
reduce or effectively block IL-1.beta. receptors, including
interleukin-1 receptor antagonist proteins or peptides. Exemplary
agents for the present invention suitable for block IL-1.beta.
receptors include but are not limited to an isolated naturally
occurring IL-1 receptor antagonist. One such agent is commercially
available Anakinra (Kineret.RTM., made by Amgen), a recombinant
form of the naturally occurring IL-1 receptor antagonist.
[0038] In yet another embodiment, treatment of SOJIA includes
administering an effective amount of at least one agent to
significantly reduce or effectively block the release of
IL-1.beta..
[0039] Exemplary agents include anion transport inhibitors,
lipoxins, and alpha-tocopherol. In yet another embodiment,
treatment of SOJIA includes administering an effective amount of at
least one agent to significantly reduce or effectively block the
activity of IL-1.beta. converting enzyme, a proteolytic enzyme that
converts the inactive IL-1.beta. precursor to its mature, active
form. Exemplary agents include morphine and other opioids.
[0040] It is further contemplated that the present invention
includes the administration of an antibody to IL-1.beta.. The
antibody to IL-1.beta. can be made by any means known in the art.
For example, monoclonal antibodies can be generated by immunizing
mice with recombinant IL-1.beta. or one or several synthetic
peptides including epitopes that are regarded as highly antigenic.
Alternatively, polyclonal antibodies can also be raised by
immunizing rabbits using the above described antigens. The
generated antibodies are examined to determine their ability to
interact with IL-1 protein and their ability to block IL-1 mediated
cellular responses. Once generated using hybridoma technology, the
monoclonal antibodies are then humanized by swapping mouse and
human framework and constant regions. According to the present
invention, antibodies that block the biological effect of
IL-1.beta. block the IL-1-induced release of IL-8 from fibroblasts
as described by Kaplanski G et al. 1994. "Interleukin-1 induces
interleukin-8 secretion from endothelial cells by a juxtacrine
mechanism," Blood 84:4242-4248. The IL-1.beta. antibodies are then
administered intravenously or subcutaneously to SOJIA patients in
an effective amount to significantly reduce or effectively
neutralize the biological function of IL-1.beta..
[0041] According to the present invention, the therapeutic response
of SOJIA patients is monitored by assessing the patient's clinical
improvement, i.e., disappearance and/or improvement of the fever,
rash and arthritis, as well as normalization of the white blood
cell count and the sedimentation rate.
[0042] Based on the finding that culturing SOJIA patient's sera
with healthy blood mononuclear cells (PBMCs) in vitro results in
significant induction of IL-1 beta (IL-1.beta.) transcription
(Example 1), two patients with persistently active disease for over
1 year in spite of more conventional aggressive treatment were
treated with a commercially available anti-IL-1 medication
(Anakinra, Amgen Inc., Thousand Oaks, Calif.), known to neutralize
the biological activity of IL-1. As illustrated in Example 2 and 3,
both patients became asymptomatic the day after initiation of
therapy and remained asymptomatic for over 3 months.
[0043] Example 1: Incubation of healthy PBMCs with SOJIA serum
induces the transcriptional upregulation of Interleukin 1.beta..
The gene expression profile was analyzed for healthy donor PBMCs
before and after incubation with autologous serum or serum from two
untreated and two treated SOJIA patients for six hours in vitro.
After incubation with the serum, the PBMCs were processed to
extract the RNA, and the RNA was hybridized to Affymetrix U133 A
and B microarray chips. In this way, a wide array of genes whose
transcription would be up-regulated or down-regulated with the
SOJIA serum was screened.
[0044] Patient Population. PBMCs and sera from 23 SOJIA patients
(15 females, 8 males, average age 7.1 years) fulfilling the ACR
diagnostic criteria .sup.34 were collected on repeated occasions.
Patients were classified as active if they had systemic symptoms
(fever and/or rash) and/or active arthritis (swollen and/or tender
and limited joints). The control population consisted of 12
children (average 14 years) and 7 adults (average 35 years). The
sera from healthy controls were cultured on repeated occasions with
autologous and heterologous PBMCs. Patients and pediatric controls
were recruited at Texas Scottish Rite Hospital for Children in
Dallas. The study was approved by the Institutional Review Boards
of UT Southwestern Medical Center, Texas Scottish Rite Hospital and
Baylor Health Care System (IRB #0199017, 0701-513) and informed
consent was obtained from parents or legal guardians.
[0045] PBMC cultures and RNA extraction. PBMCs were obtained by
Ficoll-Histopaque gradient centrifugation of 20 ml of blood. PBMCs
were cultured (10.sup.6/ml) in RPMI 1640 supplemented with 20%
autologous or SOJIA patient's serum for 6 hrs. RNA was extracted
using RNAeasy kit (Qiagen, Valencia, Calif.) and assessed using an
Agilent 2100 Bioanalyzer (Agilent, Palo Alto, Calif.). Supernatants
were frozen at -80.degree. C. PBMCs were cultured with RPMI 1640
and 10% fetal calf serum with PMA (50 ng/ml)-Ionomycin (1 .mu.g/ml)
for 24 hrs. Cells were harvested and the RNA extracted as above.
Supernatants were frozen at -80.degree. C.
[0046] Microarrays and Real-time PCR. Samples for microarray
analysis were processed as described .sup.18 and hybridized to the
HG U133A Affymetrix GeneChip array containing 22,283 probe sets
(Affymetrix Inc., Santa Clara, Calif.) at 45.degree. C. for 16
hours. GeneChip arrays were washed stained and scanned according to
protocols described in the GeneChip Expression Analysis Technical
Manual (Affymetrix). Scanned GeneChips were visually inspected for
abnormalities or irregularities.
[0047] FIG. 1 is a depiction of a gene array for cytokine-cytokine
expression. Incubation of healthy PBMCs with autologous serum (AS)
or with the serum from 4 SOJIA patients for 6 hr in vitro. SOJIA
serum was found to induce the upregulation of transcription of
members of the IL-1 family. Asterisk indicates that gene
transcription is significantly upregulated in vivo in SOJIA
patients PBMCs.
[0048] Data Analysis. Intensity values were scaled to 500 using
global scaling in MAS 5.0 and data were exported in MS Excel for
import into GeneSpring software (Silicon Genetics, Redwood City,
Calif.) for gene expression analyses. No "per chip" normalization
was performed as global scaling had been applied in MAS 5.0. Global
scaling adjusts for chip-to chip variations in hybridization
intensities. Subsequent samples were normalized to pediatric
healthy controls and/or to the median of all samples. Statistical
comparisons were performed in GeneSpring using both parametric
(Welch's approximate t-test) and non-parametric (Mann-Whitney
U-test) methods. Unsupervised hierarchical clustering was performed
to visualize transcripts that had a control signal of 50 or above
(above the background intensity) and that were identified as
"present" according to MAS 5.0 in 15% of all samples. Statistical
comparisons were performed in GeneSpring using both parametric
(Welch's approximate t-test) and non-parametric (Mann-Whitney
U-test) methods. Unsupervised hierarchical clustering was performed
to visualize transcript/sample relationships using standard
correlation, Pearson correlation or Euclidian distance where
indicated.
[0049] Two-step RT-PCR was performed using Applied Biosystems
TaqMan Assays on Demand probe and primer sets according to the
manufacturer's instructions and the ABI Prism 7700 Sequence
detection System (Applied Biosystems). The endogenous GAPDH gene
and/or 18S RNA were used for correcting the results with the
comparative threshold cycle (C.sub.T) method for relative
quantification as described by the manufacturer.
[0050] Multiplex Analysis (Luminex). Culture supernatants were
analyzed for 6 cytokines and chemokines using the FluorikineMAP
cytokine assay kit (R&D Systems, Minneapolis, MN) as per
manufacturer's protocol.
[0051] FIG. 2A is a graph that compares the induction of
Interleukin 1-Beta (IL-b) protein secretion in healthy PBMCs
incubated with SOJIA sera. Supernatants from 6 hr incubation of
healthy PBMCs with 12 SOJIA sera and 3 healthy controls were
assayed for IL-1b production by Luminex.
[0052] FIG. 2B is a graph that compares the induction of IL-1b
protein secretion in SOJIA patients with and without systemic
symptoms. IL-1b protein secretion is preferentially induced by sera
from SOJIA patients experiencing systemic symptoms (SOJIA1, n=5)
over those patients with only active arthritis (SOJIA2, n=7). All
results were analyzed using non-parametric tests
(Mann-Whitney).
[0053] FIGS. 3A through F are graphs that shows the values of
temperature (FIG. 3A); active joint count (FIG. 3B); WBC (FIG. 3C);
hemoglobin (FIG. 3D); platelet count (FIG. 3E); and ESR in 9 SOJIA
patients (FIG. 3F). X values represent months prior (-2) to
starting of Anakinra treatment (0) and up to 2-12 months of follow
up (average 6.6. months). Arrows indicate the time of treatment
initiation. P values were calculated at time 0 and at 2 month
follow-up (paired, two-tailed t test).
[0054] Example 2: Interleukin 1.beta. treatment of SOJIA patient. A
17 year old Hispanic female diagnosed with SOJIA at the age of 15
was treated according to the method of the present invention. She
presented with persistent (>2 month) daily fever, a generalized
pruritic rash and joint pain. On exam, she had swelling and
limitation of the radio-carpal and carpal-metacarpal joints
bilaterally. Her laboratory tests revealed high white blood cell
count (WBC), low hemoglobin (Hgb), high platelets (Plts) and
elevated erythrocyte sedimentation rate (ESR). An extensive
infectious disease work up yielded negative results. The patient
received oral and IV high dose methyl prednisolone and eventually
was placed on methotrexate. Her symptoms improved, and the patient
was asymptomatic for several months during which the steroid
treatment was slowly tapered. A few months later the symptoms
recurred. Steroids were reinitiated without success. Anti-TNF IV
therapy (Infliximab) was tried at a dose of 5 mg/kg every month for
approximately 6 months without any significant effect. After the
patient had been symptomatic for over one year, IL-1 antagonist was
administered in the form of Anakinra, 100 mg (1 cc) as a
subcutaneous daily injection. The day after the first subcutaneous
injection, the patient was asymptomatic, with the disappearance of
fever, rash and joint swelling. Two follow-up visits confirmed that
she remained asymptomatic at 2 and 3 months post-initiation of
therapy. Laboratory tests also reflected this response, as WBC,
Hgb, Plt number and ESR were within normal limits.
[0055] Example 3: Interleukin 1.beta. treatment of SOJIA patient. A
9 year old Hispanic male was diagnosed with SOJIA at the age of 7,
when he presented with prolonged daily spiking fever, rash,
pericarditis and joint and muscle pain. Laboratory tests showed
high WBC, low Hgb, high platelets and elevated ESR. Bone marrow
analysis and an extensive infectious work up failed to yield a
specific diagnosis. The patient was treated with high dose IV
methylprednisolone, and symptoms improved. Over the next two years,
the patient presented flares and remissions. The last flare did not
respond to high dose steroids, and the patient developed swelling
over the radio-carpal joints bilaterally. Therapy with IL-1
antagonist Anakinra was initiated at a dose of 50 mg (0.5 cc) as a
subcutaneous daily injection. The day after the first subcutaneous
injection, the patient became asymptomatic, with the disappearance
of fever, rash, joint pain and swelling, and he remained free of
symptoms for over 3 months.
[0056] It will be understood that particular embodiments described
herein are shown by way of illustration and not as limitations of
the invention. The principal features of this invention can be
employed in various embodiments without departing from the scope of
the invention. Those skilled in the art will recognize, or be able
to ascertain using no more than routine experimentation, numerous
equivalents to the specific procedures described herein. Such
equivalents are considered to be within the scope of this invention
and are covered by the claims.
[0057] All publications and patent applications mentioned in the
specification are indicative of the level of skill of those skilled
in the art to which this invention pertains. All publications and
patent applications are herein incorporated by reference to the
same extent as if each individual publication or patent application
was specifically and individually indicated to be incorporated by
reference.
[0058] All of the compositions and/or methods disclosed and claimed
herein can be made and executed without undue experimentation in
light of the present disclosure. While the compositions and methods
of this invention have been described in terms of preferred
embodiments, it will be apparent to those of skill in the art that
variations may be applied to the compositions and/or methods and in
the steps or in the sequence of steps of the method described
herein without departing from the concept, spirit and scope of the
invention. More specifically, it will be apparent that certain
agents which are both chemically and physiologically related may be
substituted for the agents described herein while the same or
similar results would be achieved. All such similar substitutes and
modifications apparent to those skilled in the art are deemed to be
within the spirit, scope and concept of the invention as defined by
the appended claims.
* * * * *