U.S. patent application number 17/125275 was filed with the patent office on 2021-11-11 for multiple-variable dose regimen for treating tnfalpha-related disorders.
The applicant listed for this patent is ABBVIE BIOTECHNOLOGY LTD. Invention is credited to Elliot Keith Chartash, George Richard Granneman, Rebecca S. Hoffman, Susan K. Paulson, Joanna Z. Peng, Lori K. Taylor, Philip Yan.
Application Number | 20210347875 17/125275 |
Document ID | / |
Family ID | 1000005724737 |
Filed Date | 2021-11-11 |
United States Patent
Application |
20210347875 |
Kind Code |
A1 |
Hoffman; Rebecca S. ; et
al. |
November 11, 2021 |
MULTIPLE-VARIABLE DOSE REGIMEN FOR TREATING TNFalpha-RELATED
DISORDERS
Abstract
Multiple-variable dose methods for treating TNFa-related
disorders, including Crohn's disease and psoriasis, comprising
administering TNFa inhibitors, including TNFa antibodies, are
described. Multiple-variable dose methods include administration of
a TNF-inhibitor in an induction or loading phase followed by
administration of the agent in a maintenance or treatment phase,
wherein the TNF-inhibitor is administered in a higher dosage during
the induction phase.
Inventors: |
Hoffman; Rebecca S.;
(Wilmette, IL) ; Chartash; Elliot Keith;
(Randolph, NJ) ; Taylor; Lori K.; (Wadsworth,
IL) ; Granneman; George Richard; (Lindenhurst,
IL) ; Yan; Philip; (Vernon Hills, IL) ;
Paulson; Susan K.; (Downers Grove, IL) ; Peng; Joanna
Z.; (Deerfield, IL) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
ABBVIE BIOTECHNOLOGY LTD |
Hamilton |
|
BM |
|
|
Family ID: |
1000005724737 |
Appl. No.: |
17/125275 |
Filed: |
December 17, 2020 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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15915615 |
Mar 8, 2018 |
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17125275 |
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14745092 |
Jun 19, 2015 |
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15915615 |
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13433205 |
Mar 28, 2012 |
9061005 |
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14745092 |
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12008064 |
Jan 7, 2008 |
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13433205 |
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11804587 |
May 17, 2007 |
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12008064 |
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11104117 |
Apr 11, 2005 |
8889136 |
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11804587 |
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60569100 |
May 7, 2004 |
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60561710 |
Apr 12, 2004 |
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60561139 |
Apr 9, 2004 |
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60801584 |
May 17, 2006 |
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60849967 |
Oct 6, 2006 |
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60918174 |
Mar 14, 2007 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
C07K 2317/565 20130101;
C07K 2317/24 20130101; Y02A 50/30 20180101; A61K 39/3955 20130101;
C07K 16/241 20130101; C07K 2317/21 20130101; A61K 2039/505
20130101; C07K 2317/56 20130101; A61K 2039/545 20130101; A61K
31/519 20130101; A61K 9/0019 20130101; C07K 2317/76 20130101; C07K
2317/92 20130101 |
International
Class: |
C07K 16/24 20060101
C07K016/24; A61K 39/395 20060101 A61K039/395; A61K 9/00 20060101
A61K009/00; A61K 31/519 20060101 A61K031/519 |
Claims
1. A multiple-variable dose method for treating a disorder in which
TNF.alpha. activity is detrimental, comprising: administering to a
subject in need thereof at least one induction dose of a TNF.alpha.
inhibitor such that a threshold level of TNF.alpha. inhibitor is
achieved within an induction phase; and subsequently administering
to the subject at least one treatment dose of the TNF.alpha.
inhibitor within a treatment phase, such that treatment occurs.
2. The method of claim 1, wherein the TNF.alpha. inhibitor is a
human TNF.alpha. antibody, or antigen-binding fragment thereof.
3. The method of claim 1, wherein the TNF.alpha. inhibitor is a
recombinant human anti-TNF.alpha. antibody comprising: a heavy
chain comprising a CDR1 comprising the amino acid sequence of SEQ
ID NO:8; a CDR2 comprising the amino acid sequence of SEQ ID NO:6;
and a CDR3 comprising the amino acid sequence of SEQ ID NO:4; and a
light chain comprising a CDR1 comprising the amino acid sequence of
SEQ ID NO:7; a CDR2 comprising the amino acid sequence of SEQ ID
NO:5; and a CDR3 comprising the amino acid sequence of SEQ ID
NO:3.
4. The method of claim 3, wherein the heavy chain comprises a heavy
chain variable region comprising the amino acid sequence of SEQ ID
NO:2, and the light chain comprises a light chain variable region
comprising the amino acid sequence of SEQ ID NO:1.
5. The method of claim 4, wherein the heavy chain comprises an IgG1
heavy chain constant region and the light chain comprises a kappa
light chain constant region.
6. The method of claim 1, wherein the TNF.alpha. inhibitor is
adalimumab.
7. The method of claim 1, wherein the disorder is selected from the
group consisting of an autoimmune disease, an infectious disease,
transplant rejection or graft-versus-host disease, malignancy, a
pulmonary disorder, an intestinal disorder, a cardiac disorder,
sepsis, a spondyloarthropathy, a metabolic disorder, anemia, pain,
a hepatic disorder, a skin disorder, a nail disorder, and
vasculitis.
8. The method of claim 1, wherein the disorder is selected from the
group consisting of rheumatoid arthritis, psoriasis, psoriasis in
combination with psoriatic arthritis, ulcerative colitis, and
Crohn's disease.
9. The method of claim 1, wherein the treatment dose is 40-60% of
the induction dose.
10. The method of claim 1, wherein the induction dose ranges from
about 20 to about 200 mg.
11. The method of claim 1, wherein the treatment dose ranges from
about 20 to about 120 mg.
12. The method of claim 1, wherein the TNF.alpha. inhibitor is
administered subcutaneously.
13. (canceled)
14. (canceled)
15. The multiple-variable dose method of claim 1, wherein the
method induces remission of Crohn's disease or reduces psoriatic
plaques.
16. (canceled)
17. (canceled)
18. A method of treating Crohn's disease in a subject comprising
administering to the subject a TNF.alpha. inhibitor such that a
mean serum TNF.alpha. inhibitor trough level of about 12 .mu.g/mL
is achieved.
19. (canceled)
Description
RELATED APPLICATIONS
[0001] This application is a continuation of U.S. patent
application Ser. No. 15/915,615, filed Mar. 8, 2018 (pending),
which is a continuation application of U.S. patent application Ser.
No. 14/745,092 (abandoned), filed Jun. 19, 2015, which is a
divisional application of U.S. patent application Ser. No.
13/433,205, filed Mar. 28, 2012, now U.S. Pat. No. 9,061,005, which
is a continuation of U.S. patent application Ser. No. 12/008,064
(abandoned), filed Jan. 7, 2008, which is a continuation of U.S.
application Ser. No. 11/804,587 (abandoned), filed on May 17, 2007.
U.S. application Ser. No. 11/804,587 is a continuation-in-part of
U.S. application Ser. No. 11/104,117, filed on Apr. 11, 2005, now
U.S. Pat. No. 8,889,136. U.S. application Ser. No. 11/104,117
claims the benefit of priority to U.S. Provisional Application No.
60/561,139 (expired), filed Apr. 9, 2004; U.S. Provisional
Application No. 60/561,710 (expired), filed Apr. 12, 2004; and U.S.
Provisional Application No. 60/569,100 (expired), filed May 7,
2004. U.S. application Ser. No. 11/804,587 (abandoned) claims the
benefit of priority to U.S. Provisional Application No. 60/801,584
(expired), filed on May 17, 2006; U.S. Provisional Application No.
60/849,967 (expired), filed Oct. 6, 2006 and U.S. Provisional
Application No. 60/918,174 (expired), filed Mar. 14, 2007. The
entire contents of each of the foregoing patent applications are
hereby incorporated herein by reference.
SEQUENCE LISTING
[0002] The instant application contains a Sequence Listing which
has been submitted electronically as a text file in ASCII format
and is hereby incorporated by reference in its entirety. Said text
file, created on Dec. 16, 2020, is named
110222-0010-116-Sequence-Listing.txt and is 12,419 bytes in
size.
BACKGROUND OF THE INVENTION
[0003] Cytokines, such as interleukin-1 (IL-1) and tumor necrosis
factor (TNF) are molecules produced by a variety of cells, such as
monocytes and macrophages, which have been identified as mediators
of inflammatory processes. Cytokines, including TNF, regulate the
intensity and duration of the inflammatory response which occurs as
the result of an injury or infection. Elevated levels of TNF play
an important role in pathologic inflammation. TNF also referred to
as (TNF.alpha.) has been implicated in the pathophysiology of a
variety of human diseases and disorders, including sepsis,
infections, autoimmune diseases, transplant rejection and
graft-versus-host disease (see e.g., Moeller et al. (1990) Cytokine
2:162; U.S. Pat. No. 5,231,024 to Moeller et al.; European Patent
Publication No. 260 610 B1 by Moeller, A. et al.; Vasilli (1992)
Annu. Rev. Immunol. 10:411; Tracey and Cerami (1994) Annu. Rev.
Med. 45:491).
[0004] TNF has been implicated in psoriasis. Expression of
TNF-induced proteins and the presence of activated T lymphocytes in
psoriatic plaques but not uninvolved skin, suggest their
involvement in the pathogenesis of the disease. There are several
types of psoriasis according to cutaneous manifestations: plaque
psoriasis, guttate psoriasis, erythrodermic psoriasis, generalized
pustular and localized pustular psoriasis. Plaque psoriasis is the
most common type, however. Treatment of psoriasis depends on the
extent of the disease. Topical corticosteroids are commonly used
for mild to moderate localized cases. Keratolytic agents and coal
tar are also used as topical medications, and phototherapy is
commonly used for more widespread disease. Other systemic therapy,
such as methotrexate cyclosporine and synthetic retinoids are
effective, but are often administered in rotation due to their
possible cumulative toxic effect.
[0005] TNF has also been implicated in Crohn's disease. Crohn's is
diagnosed on the basis of clinical, endoscopic, radiographic, and
histologic criteria. The treatment of Crohn's disease is
challenging. Treatment is based on location, extent, and severity
of disease. Current compounds and regimens do not completely abate
the inflammatory process and have significant side effects.
SUMMARY OF THE INVENTION
[0006] There is a need to treat TNF.alpha.-related disorders, where
TNF.alpha. activity is detrimental, in a safe and effective manner.
The present invention includes multiple-variable dose methods for
improved treatment of TNF.alpha.-related disorders where TNF.alpha.
activity is detrimental.
[0007] The invention describes a multiple-variable dose method for
treating a disorder in which TNF.alpha. activity is detrimental,
comprising administering to a subject in need thereof at least one
induction dose of a TNF.alpha. inhibitor such that a threshold
level of TNF.alpha. inhibitor is achieved within an induction
phase; and subsequently administering to the subject at least one
treatment dose of the TNF.alpha. inhibitor within a treatment
phase, such that treatment occurs.
[0008] The invention also describes a multiple-variable dose method
for treating Crohn's disease, comprising administering to a subject
in need thereof at least one induction dose of a TNF.alpha.
inhibitor such that a threshold level of TNF.alpha. inhibitor is
achieved within an induction phase; and subsequently administering
to the subject at least one treatment dose of the TNF.alpha.
inhibitor within a treatment phase, such that treatment occurs. The
multiple-variable dose method of the invention can also be used to
treat ulcerative colitis or psoriasis. In another embodiment,
multiple-variable dose method of the invention is used to treat as
psoriasis in combination with psoriatic arthritis.
[0009] The invention includes a multiple-variable dose method of
inducing remission of Crohn's disease, comprising administering to
a subject in need thereof at least one induction dose of a
TNF.alpha. inhibitor such that a threshold level of TNF.alpha.
inhibitor is achieved within an induction phase; and subsequently
administering to the subject at least one treatment dose of the
TNF.alpha. inhibitor within a treatment phase, such that treatment
occurs.
[0010] In an additional embodiment, the invention includes a
multiple-variable dose method of reducing psoriatic plaques
comprising administering to a subject in need thereof at least one
induction dose of a TNF.alpha. inhibitor such that a threshold
level of TNF.alpha. inhibitor is achieved within an induction
phase; and subsequently administering to the subject at least one
treatment dose of the TNF.alpha. inhibitor within a treatment
phase, such that treatment occurs.
[0011] In one embodiment, the invention provides a method of
treating Crohn's disease in a subject comprising administering to
the subject a TNF.alpha. inhibitor, such as a TNF.alpha. antibody,
or an antigen-binding portion thereof, such that a mean serum
TNF.alpha. inhibitor trough level of about (approximately) 12
.mu.g/mL is achieved. In one embodiment, the mean serum trough
level of about 12 .mu.g/mL is achieved by administration of a
loading dose at week 0 followed by a second dose which comprises
half the amount of the loading dose at week 2. In one embodiment,
the mean serum trough level of about 12 .mu.g/mL is achieved at
week 2. In one embodiment, the mean serum trough level of about 12
.mu.g/mL is achieved at week 4.
[0012] In one embodiment, the invention provides a method of
treating Crohn's disease in a subject comprising subcutaneously
administering to the subject a TNF.alpha. inhibitor, such as a
TNF.alpha. antibody, or an antigen-binding portion thereof, on
multiple variable dosing regimen, wherein a therapeutic
concentration level of the TNF.alpha. inhibitor, e.g., antibody, or
an antigen-binding portion thereof, is achieved in the subject by
two weeks following the first administration of the TNF.alpha.
inhibitor, e.g., antibody, or antigen-binding portion thereof. In
one embodiment, the therapeutic concentration level of the
TNF.alpha. inhibitor, e.g., antibody, or an antigen-binding portion
thereof, is achieved in the subject by one week following the first
administration of the TNF.alpha. inhibitor, e.g., antibody, or
antigen-binding portion thereof.
[0013] The invention also includes a method of treating Crohn's
disease in a subject comprising subcutaneously administering to the
subject a TNF.alpha. inhibitor, e.g., antibody, or an
antigen-binding portion thereof, on a multiple variable dosing
regimen, wherein the serum concentration level of the TNF.alpha.
inhibitor, e.g., an antibody, or antigen-binding portion thereof,
in the subject is no less than about 1 to about 3 .mu.g/mL. In one
embodiment, the invention describes a method of treating Crohn's
disease in a subject comprising subcutaneously administering to the
subject a TNF.alpha. antibody, or an antigen-binding portion
thereof, on a multiple variable dosing regimen, wherein the serum
concentration level of the TNF.alpha. antibody, or antigen-binding
portion thereof, in the subject is about 2.7 to about 3.4 .mu.g/mL.
In one embodiment, the serum concentration level of the TNF.alpha.
inhibitor, e.g., an antibody, or antigen-binding portion thereof,
in the subject is about 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7,
1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3.0,
3.1, 3.2, 3.3, 3.4, 3.5. In one embodiment, the multiple variable
dosing regimen comprises an induction dose of about 40 mg and a
treatment dose of about 20 mg.
[0014] The invention also includes a method of treating Crohn's
disease in a subject comprising subcutaneously administering to the
subject a TNF.alpha. inhibitor, e.g., an antibody, or an
antigen-binding portion thereof, on a multiple variable dosing
regimen, wherein the serum concentration level of the TNF.alpha.
inhibitor, e.g., an antibody, or antigen-binding portion thereof,
in the subject is no less than about 3.15 .mu.g/mL. In one
embodiment, the serum concentration level of the TNF.alpha.
inhibitor, e.g., an antibody, or antigen-binding portion thereof,
in the subject is about 5.5 to about 7.0 .mu.g/mL. In one
embodiment, the serum concentration level of the TNF.alpha.
inhibitor, e.g., an antibody, or antigen-binding portion thereof,
in the subject is about 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3.0, 3.1,
3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4.0, 4.1, 4.2, 4.3, 4.4,
4.5, 4.6, 4.7, 4.8, 4.9, 5.0, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7,
5.8, 5.9, 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, and
7.0. In one embodiment, the multiple variable dosing regimen
comprises an induction dose of about 80 mg and a treatment dose of
about 40 mg.
[0015] In one embodiment, the invention provides a method of
treating Crohn's disease in a subject comprising subcutaneously
administering to the subject a TNF.alpha. inhibitor, e.g., an
antibody, or an antigen-binding portion thereof, on a multiple
variable dosing regimen, wherein the serum concentration level of
the TNF.alpha. inhibitor, e.g., an antibody, or antigen-binding
portion thereof, in the subject is no less than about 8.6 .mu.g/mL.
In one embodiment, the serum concentration level of the TNF.alpha.
inhibitor, e.g., an antibody, or antigen-binding portion thereof,
in the subject is about 12 to about 14 .mu.g/mL. In one embodiment,
the serum concentration level of the TNF.alpha. inhibitor, e.g., an
antibody, or antigen-binding portion thereof, in the subject is
about 3.6, 3.7, 3.8, 3.9, 4.0, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7,
4.8, 4.9, 5.0, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6.0,
6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7.0, 7.1, 7.2, 7.3,
7.4, 7.5, 7.6, 7.7, 7.8, 7.9, 8.0, 8.1, 8.2, 8.3, 8.4, 8.5, 8.6,
8.7, 8.8, 8.9, 9.0, 9.1, 9.2, 9.3, 9.4, 9.5, 9.6, 9.7, 9.8, 9.9,
10.0, 10.1, 10.2, 10.3, 10.4, 10.5, 10.6, 10.7, 10.8, 10.9, 11.0,
11.1, 11.2, 11.3, 11.4, 11.5, 11.6, 11.7, 11.8, 11.9, 12.0, 12.1,
12.2, 12.3, 12.4, 12.5, 12.6, and 12.7. In one embodiment, the
multiple variable dosing regimen comprises an induction dose of
about 160 mg and a treatment dose of about 80 mg.
[0016] In one embodiment, the TNF.alpha. inhibitor is etanercept or
infliximab.
[0017] In one embodiment of the invention, the TNF.alpha. inhibitor
is a TNF.alpha. antibody, or antigen-binding fragment thereof. In
another embodiment of the invention, the TNF.alpha. inhibitor is a
human TNF.alpha. antibody, or antigen-binding fragment thereof. In
one embodiment, the antibody is an isolated human antibody, or an
antigen-binding portion thereof, that dissociates from human
TNF.alpha. with a K.sub.d of 1.times.10.sup.-8M or less and a
K.sub.off rate constant of 1.times.10.sup.-3 s.sup.-1 or less, both
determined by surface plasmon resonance, and neutralizes human
TNF.alpha. cytotoxicity in a standard in vitro L929 assay with an
IC.sub.50 of 1.times.10.sup.-7M or less. In another embodiment, the
antibody has the following characteristics:
[0018] a) dissociates from human TNF.alpha. with a K.sub.off rate
constant of 1.times.10.sup.-3 s.sup.-1 or less, as determined by
surface plasmon resonance;
[0019] b) has a light chain CDR3 domain comprising the amino acid
sequence of SEQ ID NO: 3, or modified from SEQ ID NO: 3 by a single
alanine substitution at position 1, 4, 5, 7 or 8 or by one to five
conservative amino acid substitutions at positions 1, 3, 4, 6, 7, 8
and/or 9;
[0020] c) has a heavy chain CDR3 domain comprising the amino acid
sequence of SEQ ID NO: 4, or modified from SEQ ID NO: 4 by a single
alanine substitution at position 2, 3, 4, 5, 6, 8, 9, 10 or 11 or
by one to five conservative amino acid substitutions at positions
2, 3, 4, 5, 6, 8, 9, 10, 11 and/or 12.
[0021] In still another embodiment, the antibody has a light chain
variable region (LCVR) comprising the amino acid sequence of SEQ ID
NO:1 and a heavy chain variable region (HCVR) comprising the amino
acid sequence of SEQ ID NO:2. In a further embodiment, the antibody
is D2E7.
[0022] The methods of the invention can be used to treat a
TNF.alpha.-related disorder selected from the group consisting of
an autoimmune disease, an infectious disease, transplant rejection
or graft-versus-host disease, malignancy, a pulmonary disorder, an
intestinal disorder, a cardiac disorder, sepsis, a
spondyloarthropathy, a metabolic disorder, anemia, pain, a hepatic
disorder, a skin disorder, a nail disorder, and vasculitis. In one
embodiment, the autoimmune disorder is selected from the group
consisting of rheumatoid arthritis, rheumatoid spondylitis,
osteoarthritis, gouty arthritis, allergy, multiple sclerosis,
autoimmune diabetes, autoimmune uveitis, and nephrotic syndrome. In
another embodiment, the TNF.alpha.-related disorder is selected
from the group consisting of inflammatory bone disorders, bone
resorption disease, alcoholic hepatitis, viral hepatitis, fulminant
hepatitis, coagulation disturbances, burns, reperfusion injury,
keloid formation, scar tissue formation, pyrexia, periodontal
disease, obesity, and radiation toxicity. In still another
embodiment, the TNF.alpha.-related disorder is selected from the
group consisting of Behcet's disease, ankylosing spondylitis,
asthma, chronic obstructive pulmonary disorder (COPD), idiopathic
pulmonary fibrosis (IPF), restenosis, diabetes, anemia, pain, a
Crohn's disease-related disorder, juvenile rheumatoid arthritis
(JRA), a hepatitis C virus infection, psoriatic arthritis, and
chronic plaque psoriasis.
[0023] In one embodiment of the invention, the TNF.alpha.-related
disorder is Crohn's disease. In another embodiment, the disorder is
ulcerative colitis. In still another embodiment, the disorder is
psoriasis. In still another embodiment, the disorder is psoriasis
in combination with psoriatic arthritis (PsA). In still another
embodiment, the TNF.alpha.-related disorder is rheumatoid
arthritis.
[0024] In one embodiment, the treatment dose is 40-60% of the
induction dose.
[0025] In one embodiment, the induction dose used in the multiple
variable dose regimen of the invention ranges from about 20 to 200
mg. In another embodiment, the induction dose ranges from about 80
to 160 mg.
[0026] In one embodiment, the treatment dose used in the multiple
variable dose regimen of the invention ranges from about 20 to 120
mg. In another embodiment, the treatment dose ranges from about 40
to 80 mg.
[0027] In one embodiment of the invention, the induction dose
comprises about 160 mg. In another embodiment, the treatment dose
comprises about 80 mg.
[0028] In one embodiment of the invention, the induction dose
comprises about 80 mg. In still another embodiment, the treatment
dose comprises about 40 mg.
[0029] In one embodiment, the induction dose used in the multiple
variable dose regimen of the invention ranges from 20 to 200 mg. In
another embodiment, the induction dose ranges from 80 to 160 mg. In
one embodiment, the treatment dose used in the multiple variable
dose regimen of the invention ranges from 20 to 120 mg. In another
embodiment, the treatment dose ranges from 40 to 80 mg.
[0030] In still another embodiment of the invention, the induction
dose comprises 160 mg.
[0031] In yet another embodiment, the treatment dose comprises 80
mg.
[0032] In one embodiment of the invention, the induction dose
comprises 80 mg. In yet another embodiment, the treatment dose
comprises 40 mg.
[0033] In one embodiment, the treatment dose is administered about
2 weeks following the induction dose.
[0034] In one embodiment, the TNF.alpha. inhibitor is administered
subcutaneously. In another embodiment, the TNF.alpha. inhibitor is
administered in combination with methotrexate. The methotrexate can
be administered, for example, in a dose of between 2.5 mg and 30
mg.
[0035] In one embodiment, the threshold level of a multiple dose
method of treatment of Crohn's disease is determined by a reduction
in the subject's Crohn's Disease Activity Index (CDAI) score.
[0036] In one embodiment, the threshold level of a multiple dose
method of treatment of psoriasis is determined as a therapeutic
effect selected from the group consisting of a reduction in
psoriatic plaques, an improvement in the subject's Psoriatic Area
Severity Index (PAST), and an improvement in the subject's
Physician's Global Assessment (PGA) score.
[0037] In one embodiment, the subject has failed prior therapy with
infliximab.
[0038] The invention describes a multiple-variable dose method of
inducing remission of Crohn's disease, comprising administering to
a subject in need thereof at least one induction dose of D2E7 such
that a threshold level of TNF.alpha. inhibitor is achieved within
an induction phase; and subsequently administering to the subject
at least one treatment dose of D2E7 within a treatment phase, such
that treatment occurs.
[0039] The invention further provides a method of treating Crohn's
disease in a subject comprising administering to the subject a
TNF.alpha. inhibitor such that a mean serum TNF.alpha. inhibitor
trough level of about 12 .mu.g/mL is achieved. In one embodiment,
TNF.alpha. inhibitor is a human TNF.alpha. or antigen-binding
portion thereof, such as, but not limited to, adalimumab. In one
embodiment, the mean serum trough level of about 12 .mu.g/mL is
achieved by administration of a loading dose of the adalimumab at
week 0 followed by a second dose which comprises half the amount of
the loading dose at week 2. In one embodiment, the mean serum
trough level of about 12 .mu.g/mL is achieved at week 2. In one
embodiment, the mean serum trough level of about 12 .mu.g/mL is
achieved at week 4.
[0040] In another embodiment, the invention includes a
multiple-variable dose method of reducing psoriatic plaques
comprising: administering to a subject in need thereof at least one
induction dose of D2E7 such that a threshold level of TNF.alpha.
inhibitor is achieved within an induction phase; and subsequently
administering to the subject at least one treatment dose of the
D2E7 within a treatment phase, such that treatment occurs.
[0041] The invention provides a kit for the treatment of a disorder
in which TNF.alpha. activity is detrimental comprising: [0042] a)
at least one container comprising an induction dose of a TNF.alpha.
inhibitor; [0043] b) at least one container comprising a treatment
dose a TNF.alpha. inhibitor; and [0044] c) instructions for
administration of the induction dose within an induction phase and
the treatment dose of the TNF.alpha. inhibitor within a treatment
phase.
[0045] The invention also describes a kit for the treatment of a
disorder in which TNF.alpha. activity is detrimental, comprising at
least one container comprising an induction dose of a TNF.alpha.
inhibitor packaged with instructions for administration of the
induction dose within an induction phase.
[0046] The invention describes a kit for the treatment of a
disorder in which TNF.alpha. activity is detrimental, comprising at
least one container comprising a treatment dose of a TNF.alpha.
inhibitor packaged with instructions for administration of the
treatment dose within a treatment phase.
[0047] In one embodiment of the invention, the kit is used for the
treatment disorder is selected from the group consisting of an
autoimmune disease, an infectious disease, transplant rejection or
graft-versus-host disease, malignancy, a pulmonary disorder, an
intestinal disorder, a cardiac disorder, sepsis, a
spondyloarthropathy, a metabolic disorder, anemia, pain, a hepatic
disorder, a skin disorder, a nail disorder, and vasculitis. In one
embodiment, the autoimmune disorder is selected from the group
consisting of rheumatoid arthritis, rheumatoid spondylitis,
osteoarthritis, gouty arthritis, allergy, multiple sclerosis,
autoimmune diabetes, autoimmune uveitis, and nephrotic syndrome. In
still another embodiment, the TNF.alpha.-related disorder is
selected from the group consisting of Behcet's disease, ankylosing
spondylitis, asthma, chronic obstructive pulmonary disorder (COPD),
idiopathic pulmonary fibrosis (IPF), restenosis, diabetes, anemia,
pain, a Crohn's disease-related disorder, juvenile rheumatoid
arthritis (JRA), a hepatitis C virus infection, psoriatic
arthritis, and chronic plaque psoriasis.
[0048] In one embodiment of the invention, the kit is used for the
treatment disorder is selected from the group consisting of Crohn's
disease, ulcerative colitis, psoriasis in combination with
psoriatic arthritis, and psoriasis.
[0049] The invention provides compositions for use in treating
Crohn's disease with a TNF.alpha. inhibitor, e.g., a TNF.alpha.
antibody. In particular, the invention provides a printed material,
such as a label or packaging insert, which is used to inform a
reader, including a prospective purchaser and/or a subject who will
be administering the TNF.alpha. inhibitor for treatment, about the
TNF.alpha. inhibitor, e.g., a TNF.alpha. antibody such as
adalimumab. The label may contain important information regarding
adverse events, methods of administering, pharmacokinetic and
pharmacodynamic information, clinical trial information, etc.
[0050] In one embodiment, the label of the invention indicates that
the TNF.alpha. inhibitor, e.g., TNF.alpha. antibody, e.g.,
adalimumab, may be used to treat Crohn's disease in patients who
have had an inadequate response to conventional therapy and/or who
have lost response to or are intolerant to infliximab. In another
embodiment, the label of the invention indicates the TNF.alpha.
inhibitor is also indicated for treatment in adult patients with
moderately to severely active Crohn's disease who have lost
response to or are intolerant to infliximab. In another embodiment,
the label of the invention indicates that the TNF.alpha. inhibitor,
e.g., TNF.alpha. antibody, e.g., adalimumab, may be used for
reducing signs and symptoms and inducing remission in patients who
have lost response to or are intolerant to infliximab.
[0051] The label of the invention may also contain information
regarding the pharmacokinetics of the TNF.alpha. inhibitor. In one
embodiment, the label of the invention indicates that in patients
with Crohn's disease, the loading dose of 160 mg TNF.alpha.
inhibitor on week 0 followed by 80 mg TNF.alpha. inhibitor on week
2 achieves serum adalimumab trough levels of approximately 12
.mu.g/mL at week 2 and week 4.
[0052] In one embodiment, the invention includes an article of
manufacture comprising a TNF.alpha. inhibitor and a package insert,
wherein the package insert indicates that in patients with Crohn's
disease a loading dose at week 0 followed by a second dose which
about 40-60% of the loading dose on week 2 achieves a mean serum
TNF.alpha. inhibitor trough level of approximately 12 .mu.g/mL at
week 2 and week 4.
[0053] In one embodiment, the invention includes an article of
manufacture comprising a TNF.alpha. inhibitor and a package insert,
wherein the package insert indicates that in patients with Crohn's
disease a loading dose at week 0 followed by a second dose which
about 40-60% of the loading dose on week 2 achieves a mean serum
TNF.alpha. inhibitor trough level of approximately 12 .mu.g/mL at
week 2 and week 4.
[0054] In another embodiment, the TNF.alpha. inhibitor in the kit
is a TNF.alpha. antibody, or antigen-binding fragment thereof. In
one embodiment, the antibody is an isolated human antibody, or an
antigen-binding portion thereof, that dissociates from human
TNF.alpha. with a K.sub.d of 1.times.10.sup.-8M or less and a
K.sub.off rate constant of 1.times.10.sup.-3 s.sup.-1 or less, both
determined by surface plasmon resonance, and neutralizes human
TNF.alpha. cytotoxicity in a standard in vitro L929 assay with an
IC.sub.50 of 1.times.10.sup.-7 M or less. In another embodiment,
the antibody has the following characteristics:
[0055] a) dissociates from human TNF.alpha. with a K.sub.off rate
constant of 1.times.10.sup.-3 s.sup.-1 or less, as determined by
surface plasmon resonance;
[0056] b) has a light chain CDR3 domain comprising the amino acid
sequence of SEQ ID NO: 3, or modified from SEQ ID NO: 3 by a single
alanine substitution at position 1, 4, 5, 7 or 8 or by one to five
conservative amino acid substitutions at positions 1, 3, 4, 6, 7, 8
and/or 9;
[0057] c) has a heavy chain CDR3 domain comprising the amino acid
sequence of SEQ ID NO: 4, or modified from SEQ ID NO: 4 by a single
alanine substitution at position 2, 3, 4, 5, 6, 8, 9, 10 or 11 or
by one to five conservative amino acid substitutions at positions
2, 3, 4, 5, 6, 8, 9, 10, 11 and/or 12.
[0058] In still another embodiment, the antibody has a light chain
variable region (LCVR) comprising the amino acid sequence of SEQ ID
NO:1 and a heavy chain variable region (HCVR) comprising the amino
acid sequence of SEQ ID NO:2. In yet another embodiment, the
antibody is D2E7.
[0059] In one embodiment, the TNF.alpha. inhibitor of the kit of
the invention is etanercept or infliximab.
[0060] In one embodiment, the treatment dose provided in the kit is
40-60% of the induction dose.
[0061] In one embodiment, the induction dose provided in the kit
ranges from about 20 to 200 mg. In another embodiment, the
induction dose provided in the kit ranges from 80 to 160 mg.
[0062] In one embodiment, the treatment dose provided in the kit
ranges from about 20 to 120 mg. In another embodiment, the
treatment dose provided in the kit ranges from about 40 to 80
mg.
[0063] In one embodiment, the induction dose provided in the kit of
the invention comprises about 160 mg. In another embodiment, the
treatment dose comprises about 80 mg. In still another embodiment,
the induction dose comprises about 80 mg. In yet another
embodiment, the treatment dose comprises about 40 mg.
[0064] In one embodiment, the induction dose provided in the kit of
the invention comprises 160 mg. In another embodiment, the
treatment dose comprises 80 mg. In still another embodiment, the
induction dose comprises 80 mg. In yet another embodiment, the
treatment dose comprises 40 mg.
[0065] In yet another embodiment, the container is a pre-filled
syringe. In still another embodiment, the kit contains instructions
for administering the treatment dose 2 weeks following the
induction dose.
[0066] The invention also provides method for treating a disorder
in which TNF.alpha. activity is detrimental, comprising
administering to a subject in need thereof, a single dose of a
TNF.alpha. inhibitor such that the disorder is treated. In one
embodiment, the TNF.alpha. inhibitor is an anti-TNF.alpha.
antibody, or an antigen binding portion thereof. In another
embodiment, the TNF.alpha. inhibitor is a human anti-TNF.alpha.
antibody, or antigen binding portion thereof, including, for
example, a human antibody, or an antigen-binding portion thereof,
dissociates from human TNF.alpha. with a K.sub.d of
1.times.10.sup.-8M or less and a K.sub.off rate constant of
1.times.10.sup.-3 s.sup.-1 or less, both determined by surface
plasmon resonance, and neutralizes human TNF.alpha. cytotoxicity in
a standard in vitro L929 assay with an IC.sub.50 of
1.times.10.sup.-7 M or less. In one embodiment, said human
antibody, or antigen-binding portion thereof, dissociates from
human TNF.alpha. with a K.sub.off rate constant of
5.times.10.sup.-7 s.sup.-1 or less. In another embodiment, said
human antibody, or antigen-binding portion thereof, dissociates
from human TNF.alpha. with a K.sub.off rate constant of
1.times.10.sup.-4 s.sup.-1 or less. In still another embodiment,
said human antibody, or antigen-binding portion thereof,
neutralizes human TNF.alpha. cytotoxicity in a standard in vitro
L929 assay with an IC.sub.50 of 1.times.10.sup.-8M or less. In yet
another embodiment, said human antibody, or antigen-binding portion
thereof, neutralizes human TNF.alpha. cytotoxicity in a standard in
vitro L929 assay with an IC.sub.50 of 1.times.10.sup.-9M or less.
In a further embodiment, said human antibody, or antigen-binding
portion thereof, neutralizes human TNF.alpha. cytotoxicity in a
standard in vitro L929 assay with an IC.sub.50 of
1.times.10.sup.-10 M or less. The human antibody, or
antigen-binding portion thereof, can also be a recombinant
antibody, or recombinant antigen-binding portion thereof. In one
embodiment, said human antibody, or an antigen-binding portion
thereof, is D2E7. In another embodiment, the single dose is
selected from the group consisting of about 80 mg, 40, mg, and 20
mg. In still another embodiment, the administration is by
subcutaneous injection. In one embodiment of the invention, the
TNF.alpha.-related disorder is Crohn's disease. In another
embodiment, the disorder is ulcerative colitis. In still another
embodiment, the disorder is psoriasis. In still another embodiment,
the disorder is psoriasis in combination with psoriatic arthritis
(PsA). In still another embodiment, the TNF.alpha.-related disorder
is rheumatoid arthritis.
BRIEF DESCRIPTION OF THE DRAWINGS
[0067] FIG. 1 provides results demonstrating the percentage of
patient's with Crohn's disease remission (CDAI<150) over time
using the multiple-variable dose regimen.
[0068] FIG. 2 shows a graph of the decrease in the mean CDAI score
of Crohn's patients receiving the multiple variable dose regimens
over time.
[0069] FIGS. 3A and 3B show remission and clinical response in
Crohn's patients receiving multiple variable dose treatment. FIG.
3A graphically provides the percentage of patients with a
.gtoreq.70 point CDAI decrease at four weeks. The P-values
represent comparison with the placebo group. FIG. 3B provides a
graph of the percentage of patients with a CDAI decrease .gtoreq.70
over time; *p=0.015 vs. placebo and **p=0.008 vs. placebo.
[0070] FIGS. 4A and 4B show remission and clinical response in
Crohn's patients receiving multiple variable dose treatment. FIG.
4A graphically provides the percentage of patients with a
.gtoreq.100 point CDAI decrease at four weeks (p-values represent
comparison with the placebo group). FIG. 4B shows the percentage of
patients with a CDAI decrease .gtoreq.100 over time; *p=0.002 vs.
placebo.
[0071] FIG. 5 provides results showing the median CRP levels in
Crohn's patients receiving multiple-variable treatments versus the
placebo.
[0072] FIG. 6 provides results of the efficacy of the
multiple-variable dose regimen at treating Crohn's disease as
measured by the IBDQ score at four weeks (P-values represent
comparison with placebo group).
[0073] FIG. 7 shows the percentage of psoriasis patients with
.gtoreq.PASI 50/75/90 response at week 12 following treatment with
each multiple variable D2E7 dose and the placebo.
[0074] FIG. 8 provides results of the mean percentage PASI
(Psoriasis Area and Severity Index) improvement over a 12 week
treatment (eow=every other week; *=p<0.001 vs. placebo).
[0075] FIG. 9 shows a comparative graph of the efficacy response at
week 12 and week 24 for patients with psoriasis and PsA.
[0076] FIG. 10 shows a comparative graph of the efficacy response
at week 12 and week 24 for patients with psoriasis and without
PsA.
[0077] FIG. 11 graphically depicts the mean (SD) serum ADA
concentration in patients with Crohn's disease.
DETAILED DESCRIPTION OF THE INVENTION
Definitions
[0078] In order that the present invention may be more readily
understood, certain terms are first defined.
[0079] The term "human TNF.alpha." (abbreviated herein as
hTNF.alpha., or simply hTNF), as used herein, is intended to refer
to a human cytokine that exists as a 17 k.sub.D secreted form and a
26 k.sub.D membrane associated form, the biologically active form
of which is composed of a trimer of noncovalently bound 17 k.sub.D
molecules. The structure of hTNF.alpha. is described further in,
for example, Pennica, D., et al. (1984) Nature 312:724-729; Davis,
J. M., et al. (1987) Biochemistry 26:1322-1326; and Jones, E. Y.,
et al. (1989) Nature 338:225-228. The term human TNF.alpha. is
intended to include recombinant human TNF.alpha. (rhTNF.alpha.),
which can be prepared by standard recombinant expression methods or
purchased commercially (R & D Systems, Catalog No. 210-TA,
Minneapolis, Minn.). TNF.alpha. is also referred to as TNF.
[0080] The term "TNF.alpha. inhibitor" includes agents which
interfere with TNF.alpha. activity. Examples of TNF.alpha.
inhibitors include etanercept (Enbrel, Amgen), infliximab
(Remicade.RTM., Johnson and Johnson), human anti-TNF monoclonal
antibody (adalimumab/D2E7/HUIMIRA.RTM., Abbott Laboratories), CDP
571 (Celltech), and CDP 870 (Celltech), as well as other compounds
which inhibit TNF.alpha. activity, such that when administered to a
subject suffering from or at risk of suffering from a disorder in
which TNF.alpha. activity is detrimental, the disorder is treated.
The term also includes each of the anti-TNF.alpha. human antibodies
and antibody portions described herein as well as those described
in U.S. Pat. Nos. 6,090,382; 6,258,562; 6,509,015, and in U.S.
patent application Ser. Nos. 09/801,185 and 10/302,356, each
incorporated by reference herein.
[0081] The term "antibody", as used herein, is intended to refer to
immunoglobulin molecules comprised of four polypeptide chains, two
heavy (H) chains and two light (L) chains inter-connected by
disulfide bonds. Each heavy chain is comprised of a heavy chain
variable region (abbreviated herein as HCVR or VH) and a heavy
chain constant region. The heavy chain constant region is comprised
of three domains, CH1, CH2 and CH3. Each light chain is comprised
of a light chain variable region (abbreviated herein as LCVR or VL)
and a light chain constant region. The light chain constant region
is comprised of one domain, CL. The VH and VL regions can be
further subdivided into regions of hypervariability, termed
complementarity determining regions (CDR), interspersed with
regions that are more conserved, termed framework regions (FR).
Each VH and VL is composed of three CDRs and four FRs, arranged
from amino-terminus to carboxy-terminus in the following order:
FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4. The antibodies of the
invention are described in further detail in U.S. Pat. Nos.
6,090,382; 6,258,562; and 6,509,015, and in U.S. patent application
Ser. Nos. 09/801,185 and 10/302,356, each of which is incorporated
herein by reference in its entirety.
[0082] The term "antigen-binding portion" of an antibody (or simply
"antibody portion"), as used herein, refers to one or more
fragments of an antibody that retain the ability to specifically
bind to an antigen (e.g., hTNF.alpha.). It has been shown that the
antigen-binding function of an antibody can be performed by
fragments of a full-length antibody. Examples of binding fragments
encompassed within the term "antigen-binding portion" of an
antibody include (i) a Fab fragment, a monovalent fragment
consisting of the VL, VH, CL and CH1 domains; (ii) a F(ab')2
fragment, a bivalent fragment comprising two Fab fragments linked
by a disulfide bridge at the hinge region; (iii) a Fd fragment
consisting of the VH and CH1 domains; (iv) a Fv fragment consisting
of the VL and VH domains of a single arm of an antibody, (v) a dAb
fragment (Ward et al., (1989) Nature 341:544-546), which consists
of a VH domain; and (vi) an isolated complementarity determining
region (CDR). Furthermore, although the two domains of the Fv
fragment, VL and VH, are coded for by separate genes, they can be
joined, using recombinant methods, by a synthetic linker that
enables them to be made as a single protein chain in which the VL
and VH regions pair to form monovalent molecules (known as single
chain Fv (scFv); see e.g., Bird et al. (1988) Science 242:423-426;
and Huston et al. (1988) Proc. Natl. Acad. Sci. USA 85:5879-5883).
Such single chain antibodies are also intended to be encompassed
within the term "antigen-binding portion" of an antibody. Other
forms of single chain antibodies, such as diabodies are also
encompassed. Diabodies are bivalent, bispecific antibodies in which
VH and VL domains are expressed on a single polypeptide chain, but
using a linker that is too short to allow for pairing between the
two domains on the same chain, thereby forcing the domains to pair
with complementary domains of another chain and creating two
antigen binding sites (see e.g., Holliger, P., et al. (1993) Proc.
Natl. Acad. Sci. USA 90:6444-6448; Poljak, R. J., et al. (1994)
Structure 2:1121-1123). The antibody portions of the invention are
described in further detail in U.S. Pat. Nos. 6,090,382, 6,258,562,
6,509,015, and in U.S. patent application Ser. Nos. 09/801,185 and
10/302,356, each of which is incorporated herein by reference in
its entirety.
[0083] Binding fragments are produced by recombinant DNA
techniques, or by enzymatic or chemical cleavage of intact
immunoglobulins. Binding fragments include Fab, Fab', F(ab').sub.2,
Fabc, Fv, single chains, and single-chain antibodies. Other than
"bispecific" or "bifunctional" immunoglobulins or antibodies, an
immunoglobulin or antibody is understood to have each of its
binding sites identical. A "bispecific" or "bifunctional antibody"
is an artificial hybrid antibody having two different heavy/light
chain pairs and two different binding sites. Bispecific antibodies
can be produced by a variety of methods including fusion of
hybridomas or linking of Fab' fragments. See, e.g., Songsivilai
& Lachmann, Clin. Exp. Immunol. 79:315-321 (1990); Kostelny et
al., J. Immunol. 148, 1547-1553 (1992).
[0084] A "conservative amino acid substitution", as used herein, is
one in which one amino acid residue is replaced with another amino
acid residue having a similar side chain. Families of amino acid
residues having similar side chains have been defined in the art,
including basic side chains (e.g., lysine, arginine, histidine),
acidic side chains (e.g., aspartic acid, glutamic acid), uncharged
polar side chains (e.g., glycine, asparagine, glutamine, serine,
threonine, tyrosine, cysteine), nonpolar side chains (e.g.,
alanine, valine, leucine, isoleucine, proline, phenylalanine,
methionine, tryptophan), beta-branched side chains (e.g.,
threonine, valine, isoleucine) and aromatic side chains (e.g.,
tyrosine, phenylalanine, tryptophan, histidine).
[0085] The term "human antibody", as used herein, is intended to
include antibodies having variable and constant regions derived
from human germline immunoglobulin sequences. The human antibodies
of the invention may include amino acid residues not encoded by
human germline immunoglobulin sequences (e.g., mutations introduced
by random or site-specific mutagenesis in vitro or by somatic
mutation in vivo), for example in the CDRs and in particular CDR3.
However, the term "human antibody", as used herein, is not intended
to include antibodies in which CDR sequences derived from the
germline of another mammalian species, such as a mouse, have been
grafted onto human framework sequences.
[0086] The term "recombinant human antibody", as used herein, is
intended to include all human antibodies that are prepared,
expressed, created or isolated by recombinant means, such as
antibodies expressed using a recombinant expression vector
transfected into a host cell (described further below), antibodies
isolated from a recombinant, combinatorial human antibody library
(described further below), antibodies isolated from an animal
(e.g., a mouse) that is transgenic for human immunoglobulin genes
(see e.g., Taylor, L. D. et al. (1992) Nucl. Acids Res. 20:6287) or
antibodies prepared, expressed, created or isolated by any other
means that involves splicing of human immunoglobulin gene sequences
to other DNA sequences. Such recombinant human antibodies have
variable and constant regions derived from human germline
immunoglobulin sequences. In certain embodiments, however, such
recombinant human antibodies are subjected to in vitro mutagenesis
(or, when an animal transgenic for human Ig sequences is used, in
vivo somatic mutagenesis) and thus the amino acid sequences of the
VH and VL regions of the recombinant antibodies are sequences that,
while derived from and related to human germline VH and VL
sequences, may not naturally exist within the human antibody
germline repertoire in vivo.
[0087] An "isolated antibody", as used herein, is intended to refer
to an antibody that is substantially free of other antibodies
having different antigenic specificities (e.g., an isolated
antibody that specifically binds hTNF.alpha. is substantially free
of antibodies that specifically bind antigens other than
hTNF.alpha.). An isolated antibody that specifically binds
hTNF.alpha. may, however, have cross-reactivity to other antigens,
such as TNF.alpha. molecules from other species (discussed in
further detail below). Moreover, an isolated antibody may be
substantially free of other cellular material and/or chemicals.
[0088] A "neutralizing antibody", as used herein (or an "antibody
that neutralized hTNF.alpha. activity"), is intended to refer to an
antibody whose binding to hTNF.alpha. results in inhibition of the
biological activity of hTNF.alpha.. This inhibition of the
biological activity of hTNF.alpha. can be assessed by measuring one
or more indicators of hTNF.alpha. biological activity, such as
hTNF.alpha.-induced cytotoxicity (either in vitro or in vivo),
hTNF.alpha.-induced cellular activation and hTNF.alpha. binding to
hTNF.alpha. receptors. These indicators of hTNF.alpha. biological
activity can be assessed by one or more of several standard in
vitro or in vivo assays known in the art (see U.S. Pat. No.
6,090,382). Preferably, the ability of an antibody to neutralize
hTNF.alpha. activity is assessed by inhibition of
hTNF.alpha.-induced cytotoxicity of L929 cells. As an additional or
alternative parameter of hTNF.alpha. activity, the ability of an
antibody to inhibit hTNF.alpha.-induced expression of ELAM-1 on
HUVEC, as a measure of hTNF.alpha.-induced cellular activation, can
be assessed.
[0089] The term "surface plasmon resonance", as used herein, refers
to an optical phenomenon that allows for the analysis of real-time
biospecific interactions by detection of alterations in protein
concentrations within a biosensor matrix, for example using the
BIAcore system (Pharmacia Biosensor AB, Uppsala, Sweden and
Piscataway, N.J.). For further descriptions, see Example 1 of U.S.
Pat. No. 6,258,562 and Jonsson et al. (1993) Ann. Biol. Clin.
51:19; Jonsson et al. (1991) Biotechniques 11:620-627; Johnsson et
al. (1995) J. Mol. Recognit. 8:125; and Johnnson et al. (1991)
Anal. Biochem. 198:268.
[0090] The term "K.sub.off", as used herein, is intended to refer
to the off rate constant for dissociation of an antibody from the
antibody/antigen complex.
[0091] The term "K.sub.d", as used herein, is intended to refer to
the dissociation constant of a particular antibody-antigen
interaction.
[0092] The term "IC.sub.50" as used herein, is intended to refer to
the concentration of the inhibitor required to inhibit the
biological endpoint of interest, e.g., neutralize cytotoxicity
activity.
[0093] The term "nucleic acid molecule", as used herein, is
intended to include DNA molecules and RNA molecules. A nucleic acid
molecule may be single-stranded or double-stranded, but preferably
is double-stranded DNA.
[0094] The term "isolated nucleic acid molecule", as used herein in
reference to nucleic acids encoding antibodies or antibody portions
(e.g., VH, VL, CDR3) that bind hTNF.alpha., is intended to refer to
a nucleic acid molecule in which the nucleotide sequences encoding
the antibody or antibody portion are free of other nucleotide
sequences encoding antibodies or antibody portions that bind
antigens other than hTNF.alpha., which other sequences may
naturally flank the nucleic acid in human genomic DNA. Thus, for
example, an isolated nucleic acid of the invention encoding a VH
region of an anti-hTNF.alpha. antibody contains no other sequences
encoding other VH regions that bind antigens other than
hTNF.alpha..
[0095] The term "vector", as used herein, is intended to refer to a
nucleic acid molecule capable of transporting another nucleic acid
to which it has been linked. One type of vector is a "plasmid",
which refers to a circular double stranded DNA loop into which
additional DNA segments may be ligated. Another type of vector is a
viral vector, wherein additional DNA segments may be ligated into
the viral genome. Certain vectors are capable of autonomous
replication in a host cell into which they are introduced (e.g.,
bacterial vectors having a bacterial origin of replication and
episomal mammalian vectors). Other vectors (e.g., non-episomal
mammalian vectors) can be integrated into the genome of a host cell
upon introduction into the host cell, and thereby are replicated
along with the host genome. Moreover, certain vectors are capable
of directing the expression of genes to which they are operatively
linked. Such vectors are referred to herein as "recombinant
expression vectors" (or simply, "expression vectors"). In general,
expression vectors of utility in recombinant DNA techniques are
often in the form of plasmids. In the present specification,
"plasmid" and "vector" may be used interchangeably as the plasmid
is the most commonly used form of vector. However, the invention is
intended to include such other forms of expression vectors, such as
viral vectors (e.g., replication defective retroviruses,
adenoviruses and adeno-associated viruses), which serve equivalent
functions.
[0096] The term "recombinant host cell" (or simply "host cell"), as
used herein, is intended to refer to a cell into which a
recombinant expression vector has been introduced. It should be
understood that such terms are intended to refer not only to the
particular subject cell but to the progeny of such a cell. Because
certain modifications may occur in succeeding generations due to
either mutation or environmental influences, such progeny may not,
in fact, be identical to the parent cell, but are still included
within the scope of the term "host cell" as used herein.
[0097] The term "dose," as used herein, refers to an amount of
TNF.alpha. inhibitor which is administered to a subject.
[0098] The term "multiple-variable dose" includes different doses
of a TNF.alpha. inhibitor which are administered to a subject for
therapeutic treatment. "Multiple-variable dose regimen" or
"multiple-variable dose therapy" describe a treatment schedule
which is based on administering different amounts of TNF.alpha.
inhibitor at various time points throughout the course of
treatment. In one embodiment, the invention describes a
multiple-variable dose method of treatment comprising an induction
phase and a treatment phase, wherein a TNF.alpha. inhibitor is
administered at a higher dose during the induction phase than the
treatment phase.
[0099] The term "induction phase" or "loading phase", as used
herein, refers to a period of treatment comprising administration
of a TNF.alpha. inhibitor to a subject in order to attain a
threshold level. During the induction phase, at least one induction
dose of TNF.alpha. inhibitor is administered to a subject suffering
from a disorder in which TNF.alpha. is detrimental.
[0100] The term "threshold level", as used herein, refers to a
therapeutically effective level of a TNF.alpha. inhibitor in a
subject. A threshold level is achieved by administering at least
one induction dose during the induction phase of treatment. Any
number of induction doses may be administered to achieve a
threshold level of TNF.alpha. inhibitor. Once a threshold level is
achieved, the treatment phase is initiated.
[0101] The term "induction dose" or "loading dose," used
interchangeably herein, refers to the first dose of TNF.alpha.
inhibitor, which is larger in comparison to the maintenance or
treatment dose. The induction dose can be a single dose or,
alternatively, a set of doses. The induction dose is often used to
bring the drug in the body to a steady state amount, and may be
used to which to achieve maintenance drug levels quickly. An
induction dose is subsequently followed by administration of
smaller doses of TNF.alpha. inhibitor, i.e., the treatment dose.
The induction dose is administered during the induction phase of
therapy. In one embodiment of the invention, the induction dose is
at least twice the given amount of the treatment dose. In another
embodiment of the invention, the induction dose of D2E7 is 160 mg.
In another embodiment, the induction dose of D2E7 is 80 mg.
[0102] The term "treatment phase" or "maintenance phase", as used
herein, refers to a period of treatment comprising administration
of a TNF.alpha. inhibitor to a subject in order to maintain a
desired therapeutic effect. The treatment phase follows the
induction phase, and, therefore, is initiated once a threshold
level is achieved.
[0103] The term "treatment dose" or "maintenance dose" is the
amount of TNF.alpha. inhibit or taken by a subject to maintain or
continue a desired therapeutic effect. A treatment dose is
administered subsequent to the induction dose. A treatment dose can
be a single dose or, alternatively, a set of doses. A treatment
dose is administered during the treatment phase of therapy.
Treatment doses are smaller than the induction dose and can be
equal to each other when administered in succession. In one
embodiment, the invention describes at least one induction dose of
D2E7 of about 160 mg, followed by at least one treatment dose of
about 80 mg. In another embodiment, the invention describes at
least one induction dose of D2E7 of about 80 mg, followed by at
least one treatment dose of about 40 mg. In still another
embodiment, the treatment dose is administered at least two weeks
following the induction dose.
[0104] A "dosage regimen" or "dosing regimen" includes a treatment
regimen based on a determined set of doses. In one embodiment, the
invention describes a dosage regimen for the treatment of Crohn's
disease, wherein D2E7 is first administered as an induction dose
and then administered in treatment doses which are lower than that
of the induction dose.
[0105] The term "dosing", as used herein, refers to the
administration of a substance (e.g., an anti-TNF.alpha. antibody)
to achieve a therapeutic objective (e.g., the treatment of a
TNF.alpha.-associated disorder).
[0106] The terms "biweekly dosing regimen", "biweekly dosing", and
"biweekly administration", as used herein, refer to the time course
of administering a substance (e.g., an anti-TNF.alpha. antibody) to
a subject to achieve a therapeutic objective (e.g., the treatment
of a TNF.alpha.-associated disorder). The biweekly dosing regimen
is not intended to include a weekly dosing regimen. Preferably, the
substance is administered every 9-19 days, more preferably, every
11-17 days, even more preferably, every 13-15 days, and most
preferably, every 14 days.
[0107] The term "combination" as in the phrase "a first agent in
combination with a second agent" includes co administration of a
first agent and a second agent, which for example may be dissolved
or intermixed in the same pharmaceutically acceptable carrier, or
administration of a first agent, followed by the second agent, or
administration of the second agent, followed by the first agent.
The present invention, therefore, includes methods of combination
therapeutic treatment and combination pharmaceutical
compositions.
[0108] The term "concomitant" as in the phrase "concomitant
therapeutic treatment" includes administering an agent in the
presence of a second agent. A concomitant therapeutic treatment
method includes methods in which the first, second, third, or
additional agents are co-administered. A concomitant therapeutic
treatment method also includes methods in which the first or
additional agents are administered in the presence of a second or
additional agents, wherein the second or additional agents, for
example, may have been previously administered. A concomitant
therapeutic treatment method may be executed step-wise by different
actors. For example, one actor may administer to a subject a first
agent and a second actor may to administer to the subject a second
agent, and the administering steps may be executed at the same
time, or nearly the same time, or at distant times, so long as the
first agent (and additional agents) are after administration in the
presence of the second agent (and additional agents). The actor and
the subject may be the same entity (e.g., human).
[0109] The term "combination therapy", as used herein, refers to
the administration of two or more therapeutic substances, e.g., an
anti-TNF.alpha. antibody and another drug, such as a DMARD or
NSAID. The other drug(s) may be administered concomitant with,
prior to, or following the administration of an anti-TNF.alpha.
antibody.
[0110] The term "TNF.alpha.-mediated condition" or
"TNF.alpha.-related disorder" refers to a local and/or systemic
physiological disorder where TNF.alpha. is a primary mediator
leading to the manifestation of the disorder.
[0111] The term "kit" or "article of manufacture" as used herein
refers to a packaged product comprising components with which to
administer the TNF.alpha. antibody of the invention for treatment
of a TNF.alpha.-related disorder. The kit preferably comprises a
box or container that holds the components of the kit. The box or
container is affixed with a label or a Food and Drug Administration
approved protocol. The box or container holds components of the
invention which are preferably contained within plastic,
polyethylene, polypropylene, ethylene, or propylene vessels. The
vessels can be capped-tubes or bottles. The kit can also include
instructions for administering the TNF.alpha. antibody of the
invention. In one embodiment the kit of the invention includes the
formulation comprising the human antibody D2E7, as described in
PCT/I1303/04502 and U.S. application Ser. No. 10/222,140.
[0112] Various aspects of the invention are described in further
detail herein.
II. TNF.alpha. Inhibitors of the Invention
[0113] This invention provides a multiple-variable dose method of
treating a TNF.alpha.-related disorder in which the administration
of a TNF.alpha. inhibitor is beneficial. In one embodiment, these
methods include administration of isolated human antibodies, or
antigen-binding portions thereof, that bind to human TNF.alpha.
with high affinity and a low off rate, and have a high neutralizing
capacity. Preferably, the human antibodies of the invention are
recombinant, neutralizing human anti-hTNF.alpha. antibodies. The
most preferred recombinant, neutralizing antibody of the invention
is referred to herein as D2E7, also referred to as HUMIRA.RTM. and
adalimumab (the amino acid sequence of the D2E7 VL region is shown
in SEQ ID NO: 1; the amino acid sequence of the D2E7 VH region is
shown in SEQ ID NO: 2). The properties of D2E7 (HUIMIRA.RTM.) have
been described in Salfeld et al., U.S. Pat. Nos. 6,090,382,
6,258,562, and 6,509,015, which are each incorporated by reference
herein. Other examples of TNF.alpha. inhibitors include chimeric
and humanized murine anti-hTNF.alpha. antibodies which have
undergone clinical testing for treatment of rheumatoid arthritis
(see e.g., Elliott, M. J., et al. (1994) Lancet 344:1125-1127;
Elliot, M. J., et al. (1994) Lancet 344:1105-1110; Rankin, E. C.,
et al. (1995) Br. J. Rheumatol. 34:334-342).
[0114] In one embodiment, the multiple-variable dose method of the
invention includes the administration of D2E7 antibodies and
antibody portions, D2E7-related antibodies and antibody portions,
and other human antibodies and antibody portions with equivalent
properties to D2E7, such as high affinity binding to hTNF.alpha.
with low dissociation kinetics and high neutralizing capacity. In
one embodiment, the invention provides multiple-variable dose
treatment with an isolated human antibody, or an antigen-binding
portion thereof, that dissociates from human TNF.alpha. with a
K.sub.d of 1.times.10.sup.-8M or less and a K.sub.off rate constant
of 1.times.10.sup.-3 s.sup.-1 or less, both determined by surface
plasmon resonance, and neutralizes human TNF.alpha. cytotoxicity in
a standard in vitro L929 assay with an IC.sub.50 of
1.times.10.sup.-7M or less. More preferably, the isolated human
antibody, or antigen-binding portion thereof, dissociates from
human TNF.alpha. with a K.sub.off of 5.times.10.sup.-4 s.sup.-1 or
less, or even more preferably, with a K.sub.off of
1.times.10.sup.-8 s.sup.-1 or less. More preferably, the isolated
human antibody, or antigen-binding portion thereof, neutralizes
human TNF.alpha. cytotoxicity in a standard in vitro L929 assay
with an IC.sub.50 of 1.times.10.sup.-8M or less, even more
preferably with an IC.sub.50 of 1.times.10.sup.-9M or less and
still more preferably with an IC.sub.50 of 1.times.10.sup.-10 M or
less. In a preferred embodiment, the antibody is an isolated human
recombinant antibody, or an antigen-binding portion thereof.
[0115] It is well known in the art that antibody heavy and light
chain CDR3 domains play an important role in the binding
specificity/affinity of an antibody for an antigen. Accordingly, in
another aspect, the invention pertains to multiple-variable dose
methods of treating a TNF.alpha.-related disorder in which the
TNF.alpha. activity is detrimental by administering human
antibodies that have slow dissociation kinetics for association
with hTNF.alpha. and that have light and heavy chain CDR3 domains
that structurally are identical to or related to those of D2E7.
Position 9 of the D2E7 VL CDR3 can be occupied by Ala or Thr
without substantially affecting the K.sub.off. Accordingly, a
consensus motif for the D2E7 VL CDR3 comprises the amino acid
sequence: Q-R-Y-N-R-A-P-Y-(T/A) (SEQ ID NO: 3). Additionally,
position 12 of the D2E7 VH CDR3 can be occupied by Tyr or Asn,
without substantially affecting the K.sub.off. Accordingly, a
consensus motif for the D2E7 VH CDR3 comprises the amino acid
sequence: V-S-Y-L-S-T-A-S-S-L-D-(Y/N) (SEQ ID NO: 4). Moreover, as
demonstrated in Example 2 of U.S. Pat. No. 6,090,382, the CDR3
domain of the D2E7 heavy and light chains is amenable to
substitution with a single alanine residue (at position 1, 4, 5, 7
or 8 within the VL CDR3 or at position 2, 3, 4, 5, 6, 8, 9, 10 or
11 within the VH CDR3) without substantially affecting the
K.sub.off. Still further, the skilled artisan will appreciate that,
given the amenability of the D2E7 VL and VH CDR3 domains to
substitutions by alanine, substitution of other amino acids within
the CDR3 domains may be possible while still retaining the low off
rate constant of the antibody, in particular substitutions with
conservative amino acids. Preferably, no more than one to five
conservative amino acid substitutions are made within the D2E7 VL
and/or VH CDR3 domains. More preferably, no more than one to three
conservative amino acid substitutions are made within the D2E7 VL
and/or VH CDR3 domains. Additionally, conservative amino acid
substitutions should not be made at amino acid positions critical
for binding to hTNF.alpha.. Positions 2 and 5 of the D2E7 VL CDR3
and positions 1 and 7 of the D2E7 VH CDR3 appear to be critical for
interaction with hTNF.alpha. and thus, conservative amino acid
substitutions preferably are not made at these positions (although
an alanine substitution at position 5 of the D2E7 VL CDR3 is
acceptable, as described above) (see U.S. Pat. No. 6,090,382).
[0116] Accordingly, in another embodiment, the invention provides
multiple-variable dose methods of treating a TNF.alpha.-related
disorder by the administration of an isolated human antibody, or
antigen-binding portion thereof. The antibody or antigen-binding
portion thereof preferably contains the following
characteristics:
[0117] a) dissociates from human TNF.alpha. with a K.sub.off rate
constant of 1.times.10.sup.-3 s.sup.-1 or less, as determined by
surface plasmon resonance;
[0118] b) has a light chain CDR3 domain comprising the amino acid
sequence of SEQ ID NO: 3, or modified from SEQ ID NO: 3 by a single
alanine substitution at position 1, 4, 5, 7 or 8 or by one to five
conservative amino acid substitutions at positions 1, 3, 4, 6, 7, 8
and/or 9;
[0119] c) has a heavy chain CDR3 domain comprising the amino acid
sequence of SEQ ID NO: 4, or modified from SEQ ID NO: 4 by a single
alanine substitution at position 2, 3, 4, 5, 6, 8, 9, 10 or 11 or
by one to five conservative amino acid substitutions at positions
2, 3, 4, 5, 6, 8, 9, 10, 11 and/or 12.
[0120] More preferably, the antibody, or antigen-binding portion
thereof, dissociates from human TNF.alpha. with a K.sub.off of
5.times.10.sup.-4 s.sup.-1 or less. Even more preferably, the
antibody, or antigen-binding portion thereof, dissociates from
human TNF.alpha. with a K.sub.off of 1.times.10.sup.-4 s.sup.-1 or
less.
[0121] In yet another embodiment, the invention provides
multiple-variable dose methods of treating a TNF.alpha.-related
disorder by the administration of an isolated human antibody, or
antigen-binding portion thereof. The antibody or antigen-binding
portion thereof preferably contains a light chain variable region
(LCVR) having a CDR3 domain comprising the amino acid sequence of
SEQ ID NO: 3, or modified from SEQ ID NO: 3 by a single alanine
substitution at position 1, 4, 5, 7 or 8, and with a heavy chain
variable region (HCVR) having a CDR3 domain comprising the amino
acid sequence of SEQ ID NO: 4, or modified from SEQ ID NO: 4 by a
single alanine substitution at position 2, 3, 4, 5, 6, 8, 9, 10 or
11. Preferably, the LCVR further has a CDR2 domain comprising the
amino acid sequence of SEQ ID NO: 5 (i.e., the D2E7 VL CDR2) and
the HCVR further has a CDR2 domain comprising the amino acid
sequence of SEQ ID NO: 6 (i.e., the D2E7 VH CDR2). Even more
preferably, the LCVR further has CDR1 domain comprising the amino
acid sequence of SEQ ID NO: 7 (i.e., the D2E7 VL CDR1) and the HCVR
has a CDR1 domain comprising the amino acid sequence of SEQ ID NO:
8 (i.e., the D2E7 VH CDR1). The framework regions for VL preferably
are from the VKI human germline family, more preferably from the
A20 human germline Vk gene and most preferably from the D2E7 VL
framework sequences shown in FIGS. 1A and 1B of U.S. Pat. No.
6,090,382. The framework regions for VH preferably are from the
.sup.VH.sup.3 human germline family, more preferably from the DP-31
human germline VH gene and most preferably from the D2E7 VH
framework sequences shown in FIGS. 2A and 2B of U.S. Pat. No.
6,090,382.
[0122] Accordingly, in another embodiment, the invention provides
multiple-variable dose methods of treating a TNF.alpha.-related
disorder by the administration of an isolated human antibody, or
antigen-binding portion thereof. The antibody or antigen-binding
portion thereof preferably contains a light chain variable region
(LCVR) comprising the amino acid sequence of SEQ ID NO: 1 (i.e.,
the D2E7 VL) and a heavy chain variable region (HCVR) comprising
the amino acid sequence of SEQ ID NO: 2 (i.e., the D2E7 VH). In
certain embodiments, the antibody comprises a heavy chain constant
region, such as an IgG1, IgG2, IgG3, IgG4, IgA, IgE, IgM or IgD
constant region. Preferably, the heavy chain constant region is an
IgG1 heavy chain constant region or an IgG4 heavy chain constant
region. Furthermore, the antibody can comprise a light chain
constant region, either a kappa light chain constant region or a
lambda light chain constant region. Preferably, the antibody
comprises a kappa light chain constant region. Alternatively, the
antibody portion can be, for example, a Fab fragment or a single
chain Fv fragment.
[0123] In still other embodiments, the invention provides
multiple-variable dose methods of treating a TNF.alpha.-related
disorder in which the administration of an anti-TNF.alpha. antibody
is beneficial administration of an isolated human antibody, or an
antigen-binding portions thereof. The antibody or antigen-binding
portion thereof preferably contains D2E7-related VL and VH CDR3
domains, for example, antibodies, or antigen-binding portions
thereof, with a light chain variable region (LCVR) having a CDR3
domain comprising an amino acid sequence selected from the group
consisting of SEQ ID NO: 3, SEQ ID NO: 11, SEQ ID NO: 12, SEQ ID
NO: 13, SEQ ID NO: 14, SEQ ID NO: 15, SEQ ID NO: 16, SEQ ID NO: 17,
SEQ ID NO: 18, SEQ ID NO: 19, SEQ ID NO: 20, SEQ ID NO: 21, SEQ ID
NO: 22, SEQ ID NO: 23, SEQ ID NO: 24, SEQ ID NO: 25 and SEQ ID NO:
26 or with a heavy chain variable region (HCVR) having a CDR3
domain comprising an amino acid sequence selected from the group
consisting of SEQ ID NO: 4, SEQ ID NO: 27, SEQ ID NO: 28, SEQ ID
NO: 29, SEQ ID NO: 30, SEQ ID NO: 31, SEQ ID NO: 32, SEQ ID NO: 33,
SEQ ID NO: 34 and SEQ ID NO: 35.
[0124] In another embodiment, the TNF.alpha. inhibitor of the
invention is etanercept (described in WO 91/03553 and WO
09/406476), infliximab (described in U.S. Pat. No. 5,656,272),
CDP571 (a humanized monoclonal anti-TNF.alpha. IgG4 antibody), CDP
870 (a humanized monoclonal anti-TNF.alpha. antibody fragment),
D2E7 (a human anti-TNF mAb), soluble TNF receptor Type I, or a
pegylated soluble TNF receptor Type I (PEGs TNF-R1).
[0125] The TNF.alpha. antibody of the invention can be modified. In
some embodiments, the TNF.alpha. antibody or antigen binding
fragments thereof, is chemically modified to provide a desired
effect. For example, pegylation of antibodies and antibody
fragments of the invention may be carried out by any of the
pegylation reactions known in the art, as described, for example,
in the following references: Focus on Growth Factors 3:4-10 (1992);
EP 0 154 316; and EP 0 401 384 (each of which is incorporated by
reference herein in its entirety). Preferably, the pegylation is
carried out via an acylation reaction or an alkylation reaction
with a reactive polyethylene glycol molecule (or an analogous
reactive water-soluble polymer). A preferred water-soluble polymer
for pegylation of the antibodies and antibody fragments of the
invention is polyethylene glycol (PEG). As used herein,
"polyethylene glycol" is meant to encompass any of the forms of PEG
that have been used to derivatize other proteins, such as mono
(Cl-ClO) alkoxy- or aryloxy-polyethylene glycol.
[0126] Methods for preparing pegylated antibodies and antibody
fragments of the invention will generally comprise the steps of (a)
reacting the antibody or antibody fragment with polyethylene
glycol, such as a reactive ester or aldehyde derivative of PEG,
under conditions whereby the antibody or antibody fragment becomes
attached to one or more PEG groups, and (b) obtaining the reaction
products. It will be apparent to one of ordinary skill in the art
to select the optimal reaction conditions or the acylation
reactions based on known parameters and the desired result.
[0127] Pegylated antibodies and antibody fragments may generally be
used to treat TNF.alpha.-related disorders of the invention by
administration of the TNF.alpha. antibodies and antibody fragments
described herein. Generally the pegylated antibodies and antibody
fragments have increased half-life, as compared to the nonpegylated
antibodies and antibody fragments. The pegylated antibodies and
antibody fragments may be employed alone, together, or in
combination with other pharmaceutical compositions.
[0128] In yet another embodiment of the invention, TNF.alpha.
antibodies or fragments thereof can be altered wherein the constant
region of the antibody is modified to reduce at least one constant
region-mediated biological effector function relative to an
unmodified antibody. To modify an antibody of the invention such
that it exhibits reduced binding to the Fc receptor, the
immunoglobulin constant region segment of the antibody can be
mutated at particular regions necessary for Fc receptor (FcR)
interactions (see e.g., Canfield, S. M. and S. L. Morrison (1991)
J. Exp. Med. 173:1483-1491; and Lund, J. et al. (1991) J. of
Immunol. 147:2657-2662). Reduction in FcR binding ability of the
antibody may also reduce other effector functions which rely on FcR
interactions, such as opsonization and phagocytosis and
antigen-dependent cellular cytotoxicity.
[0129] An antibody or antibody portion of the invention can be
derivatized or linked to another functional molecule (e.g., another
peptide or protein). Accordingly, the antibodies and antibody
portions of the invention are intended to include derivatized and
otherwise modified forms of the human anti-hTNF.alpha. antibodies
described herein, including immunoadhesion molecules. For example,
an antibody or antibody portion of the invention can be
functionally linked (by chemical coupling, genetic fusion,
noncovalent association or otherwise) to one or more other
molecular entities, such as another antibody (e.g., a bispecific
antibody or a diabody), a detectable agent, a cytotoxic agent, a
pharmaceutical agent, and/or a protein or peptide that can mediate
associate of the antibody or antibody portion with another molecule
(such as a streptavidin core region or a polyhistidine tag).
[0130] One type of derivatized antibody is produced by crosslinking
two or more antibodies (of the same type or of different types,
e.g., to create bispecific antibodies). Suitable crosslinkers
include those that are heterobifunctional, having two distinctly
reactive groups separated by an appropriate spacer (e.g.,
m-maleimidobenzoyl-N-hydroxysuccinimide ester) or homobifunctional
(e.g., disuccinimidyl suberate). Such linkers are available from
Pierce Chemical Company, Rockford, Ill.
[0131] Useful detectable agents with which an antibody or antibody
portion of the invention may be derivatized include fluorescent
compounds. Exemplary fluorescent detectable agents include
fluorescein, fluorescein isothiocyanate, rhodamine,
5-dimethylamine-1-napthalenesulfonyl chloride, phycoerythrin and
the like. An antibody may also be derivatized with detectable
enzymes, such as alkaline phosphatase, horseradish peroxidase,
glucose oxidase and the like. When an antibody is derivatized with
a detectable enzyme, it is detected by adding additional reagents
that the enzyme uses to produce a detectable reaction product. For
example, when the detectable agent horseradish peroxidase is
present, the addition of hydrogen peroxide and diaminobenzidine
leads to a colored reaction product, which is detectable. An
antibody may also be derivatized with biotin, and detected through
indirect measurement of avidin or streptavidin binding.
[0132] An antibody, or antibody portion, of the invention can be
prepared by recombinant expression of immunoglobulin light and
heavy chain genes in a host cell. To express an antibody
recombinantly, a host cell is transfected with one or more
recombinant expression vectors carrying DNA fragments encoding the
immunoglobulin light and heavy chains of the antibody such that the
light and heavy chains are expressed in the host cell and,
preferably, secreted into the medium in which the host cells are
cultured, from which medium the antibodies can be recovered.
Standard recombinant DNA methodologies are used to obtain antibody
heavy and light chain genes, incorporate these genes into
recombinant expression vectors and introduce the vectors into host
cells, such as those described in Sambrook, Fritsch and Maniatis
(eds), Molecular Cloning; A Laboratory Manual, Second Edition, Cold
Spring Harbor, N.Y., (1989), Ausubel, F. M. et al. (eds.) Current
Protocols in Molecular Biology, Greene Publishing Associates,
(1989) and in U.S. Pat. No. 4,816,397 by Boss et al.
[0133] To express D2E7 or a D2E7-related antibody, DNA fragments
encoding the light and heavy chain variable regions are first
obtained. These DNAs can be obtained by amplification and
modification of germline light and heavy chain variable sequences
using the polymerase chain reaction (PCR). Germline DNA sequences
for human heavy and light chain variable region genes are known in
the art (see e.g., the "Vbase" human germline sequence database;
see also Kabat, E. A., et al. (1991) Sequences of Proteins of
Immunological Interest, Fifth Edition, U.S. Department of Health
and Human Services, NIH Publication No. 91-3242; Tomlinson, I. M.,
et al. (1992) "The Repertoire of Human Germline VH Sequences
Reveals about Fifty Groups of VH Segments with Different
Hypervariable Loops" J. Mol. Biol. 227:776-798; and Cox, J. P. L.
et al. (1994) "A Directory of Human Germ-line V.sub.78 Segments
Reveals a Strong Bias in their Usage" Eur. J. Immunol. 24:827-836;
the contents of each of which are expressly incorporated herein by
reference). To obtain a DNA fragment encoding the heavy chain
variable region of D2E7, or a D2E7-related antibody, a member of
the .sup.VH.sup.3 family of human germline VH genes is amplified by
standard PCR. Most preferably, the DP-31 VH germline sequence is
amplified. To obtain a DNA fragment encoding the light chain
variable region of D2E7, or a D2E7-related antibody, a member of
the VKI family of human germline VL genes is amplified by standard
PCR. Most preferably, the A20 VL germline sequence is amplified.
PCR primers suitable for use in amplifying the DP-31 germline VH
and A20 germline VL sequences can be designed based on the
nucleotide sequences disclosed in the references cited supra, using
standard methods.
[0134] Once the germline VH and VL fragments are obtained, these
sequences can be mutated to encode the D2E7 or D2E7-related amino
acid sequences disclosed herein. The amino acid sequences encoded
by the germline VH and VL DNA sequences are first compared to the
D2E7 or D2E7-related VH and VL amino acid sequences to identify
amino acid residues in the D2E7 or D2E7-related sequence that
differ from germline. Then, the appropriate nucleotides of the
germline DNA sequences are mutated such that the mutated germline
sequence encodes the D2E7 or D2E7-related amino acid sequence,
using the genetic code to determine which nucleotide changes should
be made. Mutagenesis of the germline sequences is carried out by
standard methods, such as PCR-mediated mutagenesis (in which the
mutated nucleotides are incorporated into the PCR primers such that
the PCR product contains the mutations) or site-directed
mutagenesis.
[0135] Once DNA fragments encoding D2E7 or D2E7-related VH and VL
segments are obtained (by amplification and mutagenesis of germline
VH and VL genes, as described above), these DNA fragments can be
further manipulated by standard recombinant DNA techniques, for
example to convert the variable region genes to full-length
antibody chain genes, to Fab fragment genes or to a scFv gene. In
these manipulations, a VL- or VH-encoding DNA fragment is
operatively linked to another DNA fragment encoding another
protein, such as an antibody constant region or a flexible linker.
The term "operatively linked", as used in this context, is intended
to mean that the two DNA fragments are joined such that the amino
acid sequences encoded by the two DNA fragments remain
in-frame.
[0136] The isolated DNA encoding the VH region can be converted to
a full-length heavy chain gene by operatively linking the
VH-encoding DNA to another DNA molecule encoding heavy chain
constant regions (CH1, CH2 and CH3). The sequences of human heavy
chain constant region genes are known in the art (see e.g., Kabat,
E. A., et al. (1991) Sequences of Proteins of Immunological
Interest, Fifth Edition, U.S. Department of Health and Human
Services, NIH Publication No. 91-3242) and DNA fragments
encompassing these regions can be obtained by standard PCR
amplification. The heavy chain constant region can be an IgG1,
IgG2, IgG3, IgG4, IgA, IgE, IgM or IgD constant region, but most
preferably is an IgG1 or IgG4 constant region. For a Fab fragment
heavy chain gene, the VH-encoding DNA can be operatively linked to
another DNA molecule encoding only the heavy chain CH1 constant
region.
[0137] The isolated DNA encoding the VL region can be converted to
a full-length light chain gene (as well as a Fab light chain gene)
by operatively linking the VL-encoding DNA to another DNA molecule
encoding the light chain constant region, CL. The sequences of
human light chain constant region genes are known in the art (see
e.g., Kabat, E. A., et al. (1991) Sequences of Proteins of
Immunological Interest, Fifth Edition, U.S. Department of Health
and Human Services, NIH Publication No. 91-3242) and DNA fragments
encompassing these regions can be obtained by standard PCR
amplification. The light chain constant region can be a kappa or
lambda constant region, but most preferably is a kappa constant
region.
[0138] To create a scFv gene, the VH- and VL-encoding DNA fragments
are operatively linked to another fragment encoding a flexible
linker, e.g., encoding the amino acid sequence (Gly4-Ser)3, such
that the VH and VL sequences can be expressed as a contiguous
single-chain protein, with the VL and VH regions joined by the
flexible linker (see e.g., Bird et al. (1988) Science 242:423-426;
Huston et al. (1988) Proc. Natl. Acad. Sci. USA 85:5879-5883;
McCafferty et al., Nature (1990) 348:552-554).
[0139] To express the antibodies, or antibody portions of the
invention, DNAs encoding partial or full-length light and heavy
chains, obtained as described above, are inserted into expression
vectors such that the genes are operatively linked to
transcriptional and translational control sequences. In this
context, the term "operatively linked" is intended to mean that an
antibody gene is ligated into a vector such that transcriptional
and translational control sequences within the vector serve their
intended function of regulating the transcription and translation
of the antibody gene. The expression vector and expression control
sequences are chosen to be compatible with the expression host cell
used. The antibody light chain gene and the antibody heavy chain
gene can be inserted into separate vector or, more typically, both
genes are inserted into the same expression vector. The antibody
genes are inserted into the expression vector by standard methods
(e.g., ligation of complementary restriction sites on the antibody
gene fragment and vector, or blunt end ligation if no restriction
sites are present). Prior to insertion of the D2E7 or D2E7-related
light or heavy chain sequences, the expression vector may already
carry antibody constant region sequences. For example, one approach
to converting the D2E7 or D2E7-related VH and VL sequences to
full-length antibody genes is to insert them into expression
vectors already encoding heavy chain constant and light chain
constant regions, respectively, such that the VH segment is
operatively linked to the CH segment(s) within the vector and the
VL segment is operatively linked to the CL segment within the
vector. Additionally or alternatively, the recombinant expression
vector can encode a signal peptide that facilitates secretion of
the antibody chain from a host cell. The antibody chain gene can be
cloned into the vector such that the signal peptide is linked
in-frame to the amino terminus of the antibody chain gene. The
signal peptide can be an immunoglobulin signal peptide or a
heterologous signal peptide (i.e., a signal peptide from a
non-immunoglobulin protein).
[0140] In addition to the antibody chain genes, the recombinant
expression vectors of the invention carry regulatory sequences that
control the expression of the antibody chain genes in a host cell.
The term "regulatory sequence" is intended to include promoters,
enhancers and other expression control elements (e.g.,
polyadenylation signals) that control the transcription or
translation of the antibody chain genes. Such regulatory sequences
are described, for example, in Goeddel; Gene Expression Technology:
Methods in Enzymology 185, Academic Press, San Diego, Calif.
(1990). It will be appreciated by those skilled in the art that the
design of the expression vector, including the selection of
regulatory sequences may depend on such factors as the choice of
the host cell to be transformed, the level of expression of protein
desired, etc. Preferred regulatory sequences for mammalian host
cell expression include viral elements that direct high levels of
protein expression in mammalian cells, such as promoters and/or
enhancers derived from cytomegalovirus (CMV) (such as the CMV
promoter/enhancer), Simian Virus 40 (SV40) (such as the SV40
promoter/enhancer), adenovirus, (e.g., the adenovirus major late
promoter (AdMLP)) and polyoma. For further description of viral
regulatory elements, and sequences thereof, see e.g., U.S. Pat. No.
5,168,062 by Stinski, U.S. Pat. No. 4,510,245 by Bell et al. and
U.S. Pat. No. 4,968,615 by Schaffner et al.
[0141] In addition to the antibody chain genes and regulatory
sequences, the recombinant expression vectors of the invention may
carry additional sequences, such as sequences that regulate
replication of the vector in host cells (e.g., origins of
replication) and selectable marker genes. The selectable marker
gene facilitates selection of host cells into which the vector has
been introduced (see e.g., U.S. Pat. Nos. 4,399,216, 4,634,665 and
5,179,017, all by Axel et al.). For example, typically the
selectable marker gene confers resistance to drugs, such as G418,
hygromycin or methotrexate, on a host cell into which the vector
has been introduced. Preferred selectable marker genes include the
dihydrofolate reductase (DHFR) gene (for use in dhfr-host cells
with methotrexate selection/amplification) and the neo gene (for
G418 selection).
[0142] For expression of the light and heavy chains, the expression
vector(s) encoding the heavy and light chains is transfected into a
host cell by standard techniques. The various forms of the term
"transfection" are intended to encompass a wide variety of
techniques commonly used for the introduction of exogenous DNA into
a prokaryotic or eukaryotic host cell, e.g., electroporation,
calcium-phosphate precipitation, DEAE-dextran transfection and the
like. Although it is theoretically possible to express the
antibodies of the invention in either prokaryotic or eukaryotic
host cells, expression of antibodies in eukaryotic cells, and most
preferably mammalian host cells, is the most preferred because such
eukaryotic cells, and in particular mammalian cells, are more
likely than prokaryotic cells to assemble and secrete a properly
folded and immunologically active antibody. Prokaryotic expression
of antibody genes has been reported to be ineffective for
production of high yields of active antibody (Boss, M. A. and Wood,
C. R. (1985) Immunology Today 6:12-13).
[0143] Preferred mammalian host cells for expressing the
recombinant antibodies of the invention include Chinese Hamster
Ovary (CHO cells) (including dhfr-CHO cells, described in Urlaub
and Chasin, (1980) Proc. Natl. Acad. Sci. USA 77:4216-4220, used
with a DHFR selectable marker, e.g., as described in R. J. Kaufman
and P. A. Sharp (1982) Mol. Biol. 159:601-621), NSO myeloma cells,
COS cells and SP2 cells. When recombinant expression vectors
encoding antibody genes are introduced into mammalian host cells,
the antibodies are produced by culturing the host cells for a
period of time sufficient to allow for expression of the antibody
in the host cells or, more preferably, secretion of the antibody
into the culture medium in which the host cells are grown.
Antibodies can be recovered from the culture medium using standard
protein purification methods.
[0144] Host cells can also be used to produce portions of intact
antibodies, such as Fab fragments or scFv molecules. It is
understood that variations on the above procedure are within the
scope of the present invention. For example, it may be desirable to
transfect a host cell with DNA encoding either the light chain or
the heavy chain (but not both) of an antibody of this invention.
Recombinant DNA technology may also be used to remove some or all
of the DNA encoding either or both of the light and heavy chains
that is not necessary for binding to hTNF.alpha.. The molecules
expressed from such truncated DNA molecules are also encompassed by
the antibodies of the invention. In addition, bifunctional
antibodies may be produced in which one heavy and one light chain
are an antibody of the invention and the other heavy and light
chain are specific for an antigen other than hTNF.alpha. by
crosslinking an antibody of the invention to a second antibody by
standard chemical crosslinking methods.
[0145] In a preferred system for recombinant expression of an
antibody, or antigen-binding portion thereof, of the invention, a
recombinant expression vector encoding both the antibody heavy
chain and the antibody light chain is introduced into dhfr-CHO
cells by calcium phosphate-mediated transfection. Within the
recombinant expression vector, the antibody heavy and light chain
genes are each operatively linked to CMV enhancer/AdMLP promoter
regulatory elements to drive high levels of transcription of the
genes. The recombinant expression vector also carries a DHFR gene,
which allows for selection of CHO cells that have been transfected
with the vector using methotrexate selection/amplification. The
selected transformant host cells are culture to allow for
expression of the antibody heavy and light chains and intact
antibody is recovered from the culture medium. Standard molecular
biology techniques are used to prepare the recombinant expression
vector, transfect the host cells, select for transformants, culture
the host cells and recover the antibody from the culture
medium.
[0146] Recombinant human antibodies of the invention in addition to
D2E7 or an antigen binding portion thereof, or D2E7-related
antibodies disclosed herein can be isolated by screening of a
recombinant combinatorial antibody library, preferably a scFv phage
display library, prepared using human VL and VH cDNAs prepared from
mRNA derived from human lymphocytes. Methodologies for preparing
and screening such libraries are known in the art. In addition to
commercially available kits for generating phage display libraries
(e.g., the Pharmacia Recombinant Phage Antibody System, catalog no.
27-9400-01; and the Stratagene SurfZAP.TM. phage display kit,
catalog no. 240612), examples of methods and reagents particularly
amenable for use in generating and screening antibody display
libraries can be found in, for example, Ladner et al. U.S. Pat. No.
5,223,409; Kang et al. PCT Publication No. WO 92/18619; Dower et
al. PCT Publication No. WO 91/17271; Winter et al. PCT Publication
No. WO 92/20791; Markland et al. PCT Publication No. WO 92/15679;
Breitling et al. PCT Publication No. WO 93/01288; McCafferty et al.
PCT Publication No. WO 92/01047; Garrard et al. PCT Publication No.
WO 92/09690; Fuchs et al. (1991) Bio/Technology 9:1370-1372; Hay et
al. (1992) Hum Antibod Hybridomas 3:81-85; Huse et al. (1989)
Science 246:1275-1281; McCafferty et al., Nature (1990)
348:552-554; Griffiths et al. (1993) EMBO J 12:725-734; Hawkins et
al. (1992) J Mol Biol 226:889-896; Clackson et al. (1991) Nature
352:624-628; Gram et al. (1992) PNAS 89:3576-3580; Garrard et al.
(1991) Bio/Technology 9:1373-1377; Hoogenboom et al. (1991) Nuc
Acid Res 19:4133-4137; and Barbas et al. (1991) PNAS
88:7978-7982.
[0147] In a preferred embodiment, to isolate human antibodies with
high affinity and a low off rate constant for hTNF.alpha., a murine
anti-hTNF.alpha. antibody having high affinity and a low off rate
constant for hTNF.alpha. (e.g., MAK 195, the hybridoma for which
has deposit number ECACC 87 050801) is first used to select human
heavy and light chain sequences having similar binding activity
toward hTNF.alpha., using the epitope imprinting methods described
in Hoogenboom et al., PCT Publication No. WO 93/06213. The antibody
libraries used in this method are preferably scFv libraries
prepared and screened as described in McCafferty et al., PCT
Publication No. WO 92/01047, McCafferty et al., Nature (1990)
348:552-554; and Griffiths et al., (1993) EMBO J 12:725-734. The
scFv antibody libraries preferably are screened using recombinant
human TNF.alpha. as the antigen.
[0148] Once initial human VL and VH segments are selected, "mix and
match" experiments, in which different pairs of the initially
selected VL and VH segments are screened for hTNF.alpha. binding,
are performed to select preferred VL/VH pair combinations.
Additionally, to further improve the affinity and/or lower the off
rate constant for hTNF.alpha. binding, the VL and VH segments of
the preferred VL/VH pair(s) can be randomly mutated, preferably
within the CDR3 region of VH and/or VL, in a process analogous to
the in vivo somatic mutation process responsible for affinity
maturation of antibodies during a natural immune response. This in
vitro affinity maturation can be accomplished by amplifying VH and
VL regions using PCR primers complimentary to the VH CDR3 or VL
CDR3, respectively, which primers have been "spiked" with a random
mixture of the four nucleotide bases at certain positions such that
the resultant PCR products encode VH and VL segments into which
random mutations have been introduced into the VH and/or VL CDR3
regions. These randomly mutated VH and VL segments can be
rescreened for binding to hTNF.alpha. and sequences that exhibit
high affinity and a low off rate for hTNF.alpha. binding can be
selected.
[0149] Following screening and isolation of an anti-hTNF.alpha.
antibody of the invention from a recombinant immunoglobulin display
library, nucleic acid encoding the selected antibody can be
recovered from the display package (e.g., from the phage genome)
and subcloned into other expression vectors by standard recombinant
DNA techniques. If desired, the nucleic acid can be further
manipulated to create other antibody forms of the invention (e.g.,
linked to nucleic acid encoding additional immunoglobulin domains,
such as additional constant regions). To express a recombinant
human antibody isolated by screening of a combinatorial library,
the DNA encoding the antibody is cloned into a recombinant
expression vector and introduced into a mammalian host cells, as
described in further detail in above.
[0150] Methods of isolating human antibodies with high affinity and
a low off rate constant for hTNF.alpha. are also described in U.S.
Pat. Nos. 6,090,382, 6,258,562, and 6,509,015, each of which is
incorporated by reference herein.
III. Uses of the TNF.alpha. Inhibitors of the Invention
[0151] The invention provides a multiple-variable dose method for
inhibiting TNF.alpha. activity in a subject suffering from a
disorder in which TNF.alpha. activity is detrimental. TNF.alpha.
has been implicated in the pathophysiology of a wide variety of
disorders (see e.g., Moeller, A., et al. (1990) Cytokine 2:162-169;
U.S. Pat. No. 5,231,024 to Moeller et al.; European Patent
Publication No. 260 610 B1 by Moeller, A.). TNF.alpha. has been
implicated in the pathophysiology of a wide variety of a
TNF.alpha.-related disorders including sepsis, infections,
autoimmune diseases, transplant rejection and graft-versus-host
disease (see e.g., Moeller, A., et al. (1990) Cytokine 2:162-169;
U.S. Pat. No. 5,231,024 to Moeller et al.; European Patent
Publication No. 260 610 B1 by Moeller, A., et al., Vasilli, P.
(1992) Annu. Rev. Immunol. 10:411-452; Tracey, K. J. and Cerami, A.
(1994) Annu. Rev. Med. 45:491-503). The invention provides
multiple-variable dose methods for inhibiting TNF.alpha. activity
in a subject suffering from a TNF.alpha.-related disorder, which
method comprises administering to a subject an initial induction
dose and subsequently administering a treatment dose of an
antibody, antibody portion, or other TNF.alpha. inhibitor, such
that TNF.alpha. activity is inhibited. Preferably, the TNF.alpha.
is human TNF.alpha. and the subject is a human subject. In one
embodiment, the TNF.alpha. inhibitor is D2E7, also referred to as
HUMIRA.RTM. (adalimumab).
[0152] As used herein, the term "a disorder in which TNF.alpha.
activity is detrimental" is intended to include diseases and other
disorders in which the presence of TNF.alpha. in a subject
suffering from the disorder has been shown to be or is suspected of
being either responsible for the pathophysiology of the disorder or
a factor that contributes to a worsening of the disorder.
Accordingly, a disorder in which TNF.alpha. activity is detrimental
is a disorder in which inhibition of TNF.alpha. activity is
expected to alleviate the symptoms and/or progression of the
disorder. Such disorders may be evidenced, for example, by an
increase in the concentration of TNF.alpha. in a biological fluid
of a subject suffering from the disorder (e.g., an increase in the
concentration of TNF.alpha. in serum, plasma, synovial fluid, etc.
of the subject), which can be detected, for example, using an
anti-TNF.alpha. antibody as described above. There are numerous
examples of disorders in which TNF.alpha. activity is detrimental.
The use of TNF.alpha. inhibitors, including antibodies and antibody
portions, of the invention in the treatment of specific disorders
using a multiple-variable dose therapy is discussed further
below:
[0153] A. Sepsis
[0154] Tumor necrosis factor has an established role in the
pathophysiology of sepsis, with biological effects that include
hypotension, myocardial suppression, vascular leakage syndrome,
organ necrosis, stimulation of the release of toxic secondary
mediators and activation of the clotting cascade (see e.g.,
Moeller, A., et al. (1990) Cytokine 2:162-169; U.S. Pat. No.
5,231,024 to Moeller et al.; European Patent Publication No. 260
610 B 1 by Moeller, A.; Tracey, K. J. and Cerami, A. (1994) Annu.
Rev. Med. 45:491-503; Russell, D and Thompson, R. C. (1993) Curr.
Opin. Biotech. 4:714-721). The multiple-variable dose methods of
the invention can be used to treat sepsis in any of its clinical
settings, including septic shock, endotoxic shock, gram negative
sepsis and toxic shock syndrome.
[0155] Furthermore, to treat sepsis, an anti-hTNF.alpha. antibody,
or antibody portion, of the invention can be coadministered with
one or more additional therapeutic agents that may further
alleviate sepsis, such as an interleukin-1 inhibitor (such as those
described in PCT Publication Nos. WO 92/16221 and WO 92/17583), the
cytokine interleukin-6 (see e.g., PCT Publication No. WO 93/11793)
or an antagonist of platelet activating factor (see e.g., European
Patent Application Publication No. EP 374 510). Other combination
therapies including multiple-variable dose therapies for the
treatment of sepsis are discussed further in subsection IV. In a
preferred embodiment, an anti-TNF.alpha. antibody or antibody
portion is administered to a human subject within a subgroup of
sepsis patients having a serum or plasma concentration of IL-6
above 500 pg/ml, and more preferably 1000 pg/ml, at the time of
treatment (see PCT Publication No. WO 95/20978 by Daum, L., et
al.).
[0156] B. Autoimmune Diseases
[0157] Tumor necrosis factor has been implicated in playing a role
in the pathophysiology of a variety of autoimmune diseases. For
example, TNF.alpha. has been implicated in activating tissue
inflammation and causing joint destruction in rheumatoid arthritis
(see e.g., Moeller, A., et al. (1990) Cytokine 2:162-169; U.S. Pat.
No. 5,231,024 to Moeller et al.; European Patent Publication No.
260 610 B1 by Moeller, A.; Tracey and Cerami, supra; Arend, W. P.
and Dayer, J-M. (1995) Arth. Rheum. 38:151-160; Fava, R. A., et al.
(1993) Clin. Exp. Immunol. 94:261-266). TNF.alpha. also has been
implicated in promoting the death of islet cells and in mediating
insulin resistance in diabetes (see e.g., Tracey and Cerami, supra;
PCT Publication No. WO 94/08609). TNF.alpha. also has been
implicated in mediating cytotoxicity to oligodendrocytes and
induction of inflammatory plaques in multiple sclerosis (see e.g.,
Tracey and Cerami, supra). TNF.alpha. also has been implicated in
mediating cytotoxicity to oligodendrocytes and induction of
inflammatory plaques in multiple sclerosis (see e.g., Tracey and
Cerami, supra). Chimeric and humanized murine anti-hTNF.alpha.
antibodies have undergone clinical testing for treatment of
rheumatoid arthritis (see e.g., Elliott, M. J., et al. (1994)
Lancet 344:1125-1127; Elliot, M. J., et al. (1994) Lancet
344:1105-1110; Rankin, E. C., et al. (1995) Br. J Rheumatol.
34:334-342).
[0158] TNF.alpha. inhibitors, including human antibodies, and
antibody portions such as D2E7, may be used in a multiple-variable
dose method to treat autoimmune diseases, in particular those
associated with inflammation. Examples of such autoimmune
conditions include rheumatoid arthritis, rheumatoid spondylitis,
osteoarthritis and gouty arthritis, allergy, multiple sclerosis,
autoimmune diabetes, autoimmune uveitis and nephrotic syndrome.
Other examples of autoimmune conditions include multisystem
autoimmune diseases and autoimmune hearing loss.
[0159] Typically, the antibody, or antibody portion, is
administered systemically, although for certain disorders, local
administration of the antibody or antibody portion at a site of
inflammation may be beneficial (e.g., local administration in the
joints in rheumatoid arthritis or topical application to diabetic
ulcers, alone or in combination with a cyclohexane-ylidene
derivative as described in PCT Publication No. WO 93/19751).
TNF.alpha. inhibitors, including human antibodies, and antibody
portions such as D2E7, also can be administered with one or more
additional therapeutic agents useful in the multiple-variable dose
treatment of autoimmune diseases, as discussed further in
subsection IV.
[0160] In one embodiment of the invention, a human TNF.alpha.
antibody is used in multiple-variable dose therapy to treat
autoimmune disorders such as lupus. Lupus is has been shown to be
associated with TNF activity (Shvidel et al. (2002) Hematol J.
3:32; Studnicka-Benke et al. (1996) Br J Rheumatol. 35:1067). The
term "lupus" as used herein refers to a chronic, inflammatory
autoimmune disorder called lupus erythematosus that may affect many
organ systems including the skin, joints and internal organs. Lupus
is a general term which includes a number of specific types of
lupus, including systemic lupus, lupus nephritis, and lupus
cerebritis. In systemic lupus (SLE), the body's natural defenses
are turned against the body and rogue immune cells attack the
body's tissues. Antibodies may be produced that can react against
the body's blood cells, organs, and tissues. This reaction leads to
immune cells attacking the affected systems, producing a chronic
disease. Lupus nephritis, also referred to as lupus glomerular
disease, is kidney disorder that is usually a complication of SLE,
and is characterized by damage to the glomerulus and progressive
loss of kidney function. Lupus cerebritis refers to another
complication of SLE, which is inflammation of the brain and/or
central nervous system.
[0161] Another autoimmune disease which can be treated using the
multiple-variable dose treatment of the invention is Crohn's
disease, which is described in more detail below in the Intestinal
Disorders Section.
[0162] C. Infectious Diseases
[0163] Tumor necrosis factor has been implicated in mediating
biological effects observed in a variety of infectious diseases.
For example, TNF.alpha. has been implicated in mediating brain
inflammation and capillary thrombosis and infarction in malaria.
TNF.alpha. also has been implicated in mediating brain
inflammation, inducing breakdown of the blood-brain barrier,
triggering septic shock syndrome and activating venous infarction
in meningitis. TNF.alpha. also has been implicated in inducing
cachexia, stimulating viral proliferation and mediating central
nervous system injury in acquired immune deficiency syndrome
(AIDS). Accordingly, antibodies, and antibody portions, directed
against TNF, can be used in multiple-variable dose treatment of
infectious diseases, including bacterial meningitis (see e.g.,
European Patent Application Publication No. EP 585 705), cerebral
malaria, AIDS and AIDS-related complex (ARC) (see e.g., European
Patent Application Publication No. EP 230 574), as well as
cytomegalovirus infection secondary to transplantation (see e.g.,
Fietze et al. (1994) Transplantation 58:675). The antibodies, and
antibody portions, of the invention, also can be used to alleviate
symptoms associated with infectious diseases, including fever and
myalgias due to infection (such as influenza) and cachexia
secondary to infection (e.g., secondary to AIDS or ARC).
[0164] D. Transplantation
[0165] Tumor necrosis factor has been implicated as a key mediator
of allograft rejection and graft versus host disease (GVHD) and in
mediating an adverse reaction that has been observed when the rat
antibody OKT3, directed against the T cell receptor CD3 complex, is
used to inhibit rejection of renal transplants (see e.g., Eason et
al. (1995) Transplantation 59:300; Suthanthiran and Strom (1994)
New Engl. J. Med. 331:365). Accordingly, the antibodies, and
antibody portions, of the invention, can be used to inhibit
transplant rejection using multiple-variable dose treatment,
including rejections of allografts and xenografts and to inhibit
GVHD. Although the antibody or antibody portion may be used alone,
more preferably it is used in combination with one or more other
agents that inhibit the immune response against the allograft or
inhibit GVHD. For example, in one embodiment, an antibody or
antibody portion of the invention is used in combination with OKT3
to inhibit OKT3-induced reactions. In another embodiment, an
antibody or antibody portion of the invention is used in
combination with one or more antibodies directed at other targets
involved in regulating immune responses, such as the cell surface
molecules CD25 (interleukin-2 receptor-.alpha.), CD11a (LFA-1),
CD54 (ICAM-1), CD4, CD45, CD28/CTLA4, CD80 (B7-1) and/or CD86
(B7-2). In yet another embodiment, an antibody or antibody portion
of the invention is used in combination with one or more general
immunosuppressive agents, such as cyclosporin A or FK506.
[0166] E. Malignancy
[0167] Tumor necrosis factor has been implicated in inducing
cachexia, stimulating tumor growth, enhancing metastatic potential
and mediating cytotoxicity in malignancies. Accordingly,
antibodies, and antibody portions, which directed against TNF, can
be used in the multiple-variable dose treatment of malignancies,
wherein treatment inhibits tumor growth or metastasis and/or
alleviates cachexia secondary to malignancy. The antibody, or
antibody portion, may be administered systemically or locally to
the tumor site.
[0168] F. Pulmonary Disorders
[0169] Tumor necrosis factor has been implicated in the
pathophysiology of adult respiratory distress syndrome (ARDS),
including stimulating leukocyte-endothelial activation, directing
cytotoxicity to pneumocytes and inducing vascular leakage syndrome.
The multiple-variable dose methods of the invention can be used to
treat various pulmonary disorders, including adult respiratory
distress syndrome, using multiple-variable dose treatment (see
e.g., PCT Publication No. WO 91/04054), shock lung, chronic
pulmonary inflammatory disease, pulmonary sarcoidosis, pulmonary
fibrosis and silicosis. The antibody, or antibody portion, may be
administered systemically or locally to the lung surface, for
example as an aerosol. An antibody, or antibody portion, also can
be administered with one or more additional therapeutic agents
useful in the multiple-variable dose treatment of pulmonary
disorders, as discussed further in subsection IV.
[0170] Other examples of pulmonary disorders in which TNF.alpha.
has been implicated in the pathophysiology include idiopathic
interstitial lung disease and chronic obstructive airway disorders
(see e.g., Piquet et al. (1989) J Exp Med. 170:655; Whyte et al.
(2000) Am J Respir Crit Care Med. 162:755; Anticevich et al. (1995)
Eur J Pharmacol. 284:221). The invention further provides methods
for treating TNF.alpha. activity in a subject suffering from such a
pulmonary disorder, which method comprises administering to the
subject an antibody, antibody portion, or other TNF.alpha.
inhibitor using a multiple variable dose regimen such that
TNF.alpha. activity in the subject suffering from idiopathic
interstitial lung disease or a chronic obstructive airway disorder
is inhibited. Examples of idiopathic interstitial lung diseases and
chronic obstructive airway disorders in which TNF.alpha. activity
is detrimental are discussed further below.
[0171] 1. Idiopathic Interstitial Lung Disease
[0172] In one embodiment, the TNF.alpha. antibody of the invention
is used in multiple-variable dose treatment regimen to treat
subjects who have an idiopathic interstitial lung disease. The term
"idiopathic pulmonary fibrosis" or "IPF" refers to a group of
disorders characterized by inflammation and eventually scarring of
the deep lung tissues, leading to shortness of breath. The scarring
of the alveoli (air sacs) and their supporting structures (the
interstitium) in IPF eventually leads to a loss of the functional
alveolar units and a reduction of the transfer of oxygen from air
to blood. IPF is also referred to as diffuse parenchymal lung
disease; alveolitis; cryptogenic fibrosing alveolitis (CFA);
idiopathic pulmonary pneumonitis (IPP); and usual interstitial
pneumonitis (UIP). IPF is often used synonymously with UIP
("IPF/UIP") because UIP is the most common cellular pattern seen in
the pathologic diagnosis of IPF.
[0173] Idiopathic interstitial lung diseases affect the lungs in
three ways: first, the lung tissue is damaged in some known or
unknown way; second, the walls of the air sacs in the lung become
inflamed; and finally, scarring (or fibrosis) begins in the
interstitium (or tissue between the air sacs), and the lung becomes
stiff. Examples of idiopathic interstitial lung diseases include
idiopathic pulmonary fibrosis (IPF). Tumor necrosis factor has been
implicated in the pathophysiology of idiopathic pulmonary fibrosis
(IPF) (see Piquet et al. (1989) J Exp Med. 170:655; Whyte et al.
(2000) Am J Respir Crit Care Med 162:755 Corbett et al. (2002) Am J
Respir Crit Care Med. 165:690). For example, it has been found that
IPF patients have increased levels of TNF expression in macrophages
and in type II epithelial cells (Piquet et al. (1993) Am J Pathol
143:651; Nash et al. (1993) Histopathology 22:343; Zhang et al.
(1993) J Immunol 150:4188). Certain genetic polymorphisms are also
associated with increased TNF expression, and are implicated in
playing a role in IPF and silicosis (Whyte et al., supra; Corbett
et al., supra).
[0174] Patients with IPF often exhibit certain symptoms, including
a dry cough, chest pain, and/or shortness of breath. Commonly used
drugs for the treatment of IPF are prednisone and cytoxan, although
only a fraction of patients improve with continued use of these
drugs (American Thoracic Society (2000) Am. J Respir. Crit. Care
Med. 161:646). Oxygen administration and transplantation of the
lung are other choices for treatment. In one embodiment, antibodies
used in the multiple-variable dose methods of the invention may be
used in combination with another therapeutic agent, for example
oxygen, for the treatment of idiopathic pulmonary fibrosis.
[0175] Examples of animal models used to study idiopathic
interstitial lung disease and chronic obstructive airway disorders
include ovalbumin (OVA) induced allergic asthma mice and cigarette
smoke induced chronic obstructive pulmonary disease mice (see
Hessel et al. (1995) Eur J Pharmacol. 293:401; Keast et al. (1981)
J. Pathol. 135:249).
[0176] 2. Chronic Obstructive Airway Disorder
[0177] In one embodiment, a TNF.alpha. antibody is used in
multiple-variable dose treatment regimen to treat a subject who has
a chronic obstructive airflow disorder. In these diseases, airflow
obstruction may be chronic and persistent or episodic and
recurrent. Airflow obstruction is usually determined by forced
expiratory spirometry, which is the recording of exhaled volume
against time during a maximal expiration. In a subject who does not
have an obstructed airflow, a full forced expiration usually takes
between 3 and 4 seconds. In a patient with chronic obstructive
airflow disorder, wherein airflow is obstructed, it usually takes
up to 15 to 20 seconds and may be limited by breath-holding time.
The normal forced expiratory volume in the first second of
expiration (FEV.sub.1) is easily measured and accurately predicted
on the basis of age, sex, and height. The ratio of FEV.sub.1 to
forced vital capacity (FEV.sub.1/FVC) normally exceeds 0.75.
Recording airflow against volume during forced expiration and a
subsequent forced inspiration--the flow-volume loop--is also
useful, mainly for distinguishing upper from lower airway
narrowing. Examples of chronic obstructive airway disorders are
described below.
[0178] a. Asthma
[0179] Tumor necrosis factor has been implicated in the
pathophysiology of asthma, (Anticevich et al. (1995) Eur J
Pharmacol. 284:221; Thomas et al. 1995. Am J Respir Crit Care Med.
152:76; Thomas and Heywood (2002) Thorax. 57:774). For example,
acute asthma attacks have been found to be associated with
pulmonary neutrophilia and elevated BAL TNF levels (Ordonez et al.
(2000) Am J Respir Crit Care Med 161:1185). It has been found that
the severity of asthma symptoms correlates with endotoxin levels in
house dust. In rats, anti-TNF antibodies reduced endotoxin-induced
airway changes (Kips et al. (1992) Am Rev Respir Dis 145:332).
[0180] The term "asthma" as used herein, refers to a disorder in
which inflammation of the airways causes airflow into and out of
the lungs to be restricted. Asthma is also referred to as bronchial
asthma, exercise induced asthma--bronchial, and reactive airways
disease (RAD). In some instances, asthma is associated with
allergies and/or is familial. Asthma includes a condition which is
characterized by widespread fluctuations in the diameter or caliber
of bronchial airways over short periods of time, resulting in
changes in lung function. The resulting increased resistance to air
flow produces symptoms in the affected subject, including
breathlessness (dyspnea), chest constriction or "tightness," and
wheezing.
[0181] Patients with asthma are characterized according to NIH
guidelines, are described as mild intermittent, mild persistent,
moderate persistent, and severe persistent (see NAEPP Expert Panel
Report Guidelines for the Diagnosis and Management of Asthma-Update
on Selected Topics 2002. JACI 2002; 110: S141-S209; Guidelines for
the Diagnosis and Management of Asthma. NIH Publication 97-4051,
July 1997). Patients diagnosed with moderate persistent asthma are
often treated with inhaled corticosteroids. Patients diagnosed with
severe persistent asthma are often treated with high dose inhaled
corticosteroids and p.o. corticosteroids.
[0182] b. Chronic Obstructive Pulmonary Disease (COPD)
[0183] Tumor necrosis factor has been implicated in the
pathophysiology of chronic obstructive pulmonary disease, (Keatings
(2000) Chest. 118:971; Sakao et al. (2001) Am J Respir Crit Care
Med. 163:420; Sakao et al. (2002) Chest. 122:416). The term
"chronic obstructive pulmonary disease" or "COPD" as used
interchangeably herein, refers to a group of lung diseases
characterized by limited airflow with variable degrees of air sack
enlargement and lung tissue destruction. The term COPD includes
chronic bronchitis (mucous hypersecretion with goblet cell
submucosal gland hyperplasia), chronic obstructive bronchitis, or
emphysema (destruction of airway parenchyma), or combinations of
these conditions. Emphysema and chronic bronchitis are the most
common forms of chronic obstructive pulmonary disease. COPD is
defined by irreversible airflow obstruction.
[0184] In COPD, chronic inflammation leads to fixed narrowing of
small airways and lung parenchyma and alveolar wall destruction
(emphysema). This is characterized by increased numbers of alveolar
macrophages, neutrophils, and cytotoxic T lymphocytes, and the
release of multiple inflammatory mediators (lipids, chemokines,
cytokines, growth factors). This inflammation leads to fibrosis
with a narrowing of the small airways and lung parenchymal
destruction. There is also a high level of oxidative stress, which
may amplify this inflammation.
[0185] G. Intestinal Disorders
[0186] Tumor necrosis factor has been implicated in the
pathophysiology of inflammatory bowel disorders including Crohn's
disease (see e.g., Tracy et al. (1986) Science 234:470; Sun et al.
(1988) J. Clin. Invest. 81:1328; MacDonald et al. (1990) Clin. Exp.
Immunol. 81:301). Chimeric murine anti-hTNF.alpha. antibodies have
undergone clinical testing for treatment of Crohn's disease (van
Dullemen et al. (1995) Gastroenterology 109:129). The invention
includes a multiple-variable dose regimen comprising administering
a TNF.alpha. inhibitor to treat intestinal disorders, such as
idiopathic inflammatory bowel disease, using human antibodies, or
antigen-binding fragments thereof. Idiopathic inflammatory bowel
disease includes two syndromes, Crohn's disease and ulcerative
colitis. In one embodiment, the multiple-variable dose regimen of
the invention is also used to treat disorders often associated with
IBD and Crohn's disease. The term "inflammatory bowel disorder
(IBD)-related disorder" or "Crohn's disease-related disorder," as
used interchangeably herein, is used to describe conditions and
complications commonly associated with IBD and Crohn's disease.
[0187] The invention includes a multiple-variable dose regimen
comprising administering a TNF.alpha. inhibitor to treat Crohn's
disease. The treatment of Crohn's disease is based on location,
extent, and severity of disease. Pharmacologic interventions
include anti-inflammatory agents (aminosalicylates and
corticosteroids) and immunomodulatory agents (azathioprine and
6-mercaptopurine [6-MP], cyclosporine, methotrexate [MTX],
antibiotic agents, and biologic agents). C-reactive protein (CRP)
and erythrocyte sedimentation rate (ESR) levels reflect
non-specific acute phase reactions. Endoscopy is a primary means of
diagnosing Crohn's disease. Radiologic features of Crohn's disease
are shown by barium examination includes mucosal edema, aphthous
and linear ulcerations, asymmetrical narrowing and strictures, and
separation of adjacent loops of bowel caused by mesenteric
thickening. Abnormalities are focal and asymmetric. The primary
histologic lesion is an aphthous ulcer. Subjects with Crohn's
disease can be evaluated using the Crohn's Disease Activity Index
(CDAI), which is a standard measure of the severity of the disease
with higher scores indicating more severe disease activity.
[0188] Examples of Crohn's disease-related disorders which can be
treated using the methods of the invention include fistulas in the
bladder, vagina, and skin; bowel obstructions; abscesses;
nutritional deficiencies; complications from corticosteroid use;
inflammation of the joints; erythem nodosum; pyoderma gangrenosum;
and lesions of the eye. Other disorders commonly associated with
Crohn's disease include Crohn's-related arthralgias, fistulizing
Crohn's, indeterminant colitis, and pouchitis.
[0189] H. Cardiac Disorders
[0190] The multiple-variable dose methods of the invention also can
be used to treat in of various cardiac or coronary disorders,
including ischemia of the heart (see e.g., European Patent
Application Publication No. EP 453 898) and heart insufficiency
(weakness of the heart muscle)(see e.g., PCT Publication No. WO
94/20139). TNF.alpha. has also been implicated in the
pathophysiology of restenosis (see e.g., Clausell et al. (1994),
supra; Medall et al. (1997) Heart 78:273).
[0191] As used herein, the term "a cardiac disorder in which
TNF.alpha. activity is detrimental" is intended to include coronary
and cardiovascular diseases in which the presence of TNF.alpha. in
a subject suffering from the disorder has been shown to be or is
suspected of being either responsible for the pathophysiology of
the disorder or a factor that contributes to a worsening of the
disorder, including cardiovascular disorders, e.g., restenosis. The
term "cardiovascular disorder" or "coronary disorder" as used
interchangeably herein, refers to any disease, disorder, or state
involving the cardiovascular system, e.g., the heart, the blood
vessels, and/or the blood. A coronary disorder is generally
characterized by a narrowing of the blood vessels that supply blood
and oxygen to the heart (coronary arteries). Coronary disease may
result from the build up of fatty material and plaque. As the
coronary arteries narrow, the flow of blood to the heart can slow
or stop. Coronary disorders of the invention can apply to any
abnormality of an artery, whether structural, histological,
biochemical or any other abnormality. An example of coronary heart
disease is restenosis. In one embodiment, a coronary disorder
refers to any disease, disorder, or state involving the
cardiovascular system excluding ischemia of the heart and heart
insufficiency.
[0192] Coronary disorders in which TNF.alpha. activity is
detrimental often result from a blockage in an artery. Such a
blockage can be caused by a clot, which usually forms in a coronary
artery that has been previously narrowed from changes usually
related to atherosclerosis. For example, if the atherosclerotic
plaque inside the arterial wall cracks, it can trigger the
formation of a thrombus, or clot. Such disorders may be evidenced,
for example, by an increase in the concentration of TNF.alpha. in a
biological fluid of a subject suffering from the disorder (e.g., an
increase in the concentration of TNF.alpha. in serum, plasma,
synovial fluid, etc. of the subject), which can be detected, for
example, using an anti-TNF.alpha. antibody as described above. A
coronary disorder can be also caused by an imbalance in arterial
pressure, a malfunction of the heart, or an occlusion of a blood
vessel, e.g., by a thrombus. Coronary disorders include both
coronary artery disease and peripheral vascular disease.
[0193] There are numerous examples of cardiac disorders in which
TNF.alpha. activity is detrimental, including restenosis. The use
of the antibodies, antibody portions, and other TNF.alpha.
inhibitors in multiple-variable dose regimens for treatment of
specific coronary disorders is discussed further below. In certain
embodiments, a antibody, antibody portion, or other TNF.alpha.
inhibitor is administered to the subject in combination with
another therapeutic agent, as described below.
[0194] The invention provides a multiple-variable dose method for
inhibiting TNF.alpha. activity in a subject with a cardiac
disorder. The invention provides multiple-variable dose methods for
inhibiting or decreasing TNF.alpha. activity in a subject with a
coronary disorder, comprising administering to the subject an
antibody, or antibody portion, or other TNF.alpha. inhibitor of the
invention such that TNF.alpha. activity in the subject is inhibited
or decreased. Preferably, the TNF.alpha. is human TNF.alpha. and
the subject is a human subject. Alternatively, the subject can be a
mammal expressing a TNF.alpha. with which an antibody of the
invention cross-reacts. Still further the subject can be a mammal
into which has been introduced hTNF.alpha. (e.g., by administration
of hTNF.alpha. or by expression of an hTNF.alpha. transgene). An
antibody of the invention can be administered to a human subject
for therapeutic purposes.
[0195] Moreover, an antibody of the invention can be administered
to a non-human mammal expressing a TNF.alpha. with which the
antibody cross-reacts (e.g., a primate, pig or mouse) for
veterinary purposes or as an animal model of human disease.
Regarding the latter, such animal models may be useful for
evaluating the multiple-variable dose therapeutic efficacy (e.g.,
testing of dosages and time courses of administration).
[0196] Commonly used animal models for studying coronary disorders,
including restenosis, include the rat or mouse carotid artery
ligation model and the carotid artery injury model (Ferns et al.
(1991) Science 253:1129; Clowes et al. (1983) Lab. Invest. 49:208;
Lindner et al. (1993) Circ Res. 73:792). In the carotid artery
ligation model, arterial blood flow is disrupted by ligation of the
vessel near the distal bifurnation. As described in Clowes et al.,
the carotid artery injury model is performed such that the common
carotid artery is denuded of endothelium by the intraluminal
passage of a balloon catheter introduced through the external
carotid artery. At 2 weeks, the carotid artery is markedly narrowed
due to smooth muscle cell constriction, but between 2 and 12 weeks
the intimal doubles in thickness leading to a decrease in luminal
size. Any of these models can be used to determine the potential
therapeutic action of the TNF.alpha. antibodies of the invention in
the prevention and treatment of restenosis in humans.
[0197] The invention includes multiple-variable dose regimen for
treatment of cardiovascular disorders in which TNF.alpha. activity
is detrimental, wherein inhibition of TNF.alpha. activity is
expected to alleviate the symptoms and/or progression of the
coronary disease or to prevent the coronary disease. Subjects
suffering from or at risk of developing coronary disorders can be
identified through clinical symptoms. Clinical symptoms in coronary
disease often include chest pain, shortness of breath, weakness,
fainting spells, alterations in consciousness, extremity pain,
paroxysmal nocturnal dyspnea, transient ischemic attacks and other
such phenomena experienced by the patient. Clinical signs of
coronary disease can also include EKG abnormalities, altered
peripheral pulses, arterial bruits, abnormal heart sounds, rates
and wheezes, jugular venous distention, neurological alterations
and other such findings discerned by the clinician. Coronary
disorders may also be evidenced, for example, by an increase in the
concentration of TNF.alpha. in a biological fluid of a subject
suffering from the disorder (e.g., an increase in the concentration
of TNF.alpha. in serum, plasma, synovial fluid, etc. of the
subject).
[0198] Examples of a cardiovascular disorder include, but are not
limited to, coronary artery disease, angina pectoris, myocardial
infarction, cardiovascular tissue damage caused by cardiac arrest,
cardiovascular tissue damage caused by cardiac bypass, cardiogenic
shock, and hypertension, atherosclerosis, coronary artery spasm,
coronary artery disease, valvular disease, arrhythmias, and
cardiomyopathies. The use of the antibodies, antibody portions, and
other TNF.alpha. inhibitors in multiple-variable dose regimens for
treatment of specific cardiovascular diseases are discussed further
below. In certain embodiments, the antibody, antibody portion, or
other TNF.alpha. inhibitor is administered to the subject in
combination with another therapeutic agent, as described below in
section IV.
[0199] 1. Restenosis
[0200] The term "restenosis" as used herein refers to the
recurrence of stenosis, which is the narrowing or constriction of
an artery. Restenosis often occurs as a preocclusive lesion that
develops following a reconstructive procedure in a diseased blood
vessel. The term is not only applied to the recurrence of a
pre-existing stenosis, but also to previously normal vessels that
become partially occluded following vascular bypass. In another
embodiment, the invention provides a method of treating restenosis
comprising administering the antibody, or antigen binding portion
thereof, of the invention to a subject who has or is at risk of
developing restenosis.
[0201] TNF.alpha. has been implicated in the pathophysiology of
restenosis (see Zhou et al. (2002) Atherosclerosis. 161:153; Javed
et al. (2002) Exp and Mol Pathol 73:104). For example, in the
murine wire carotid model, TNF -/- mice demonstrated a seven-fold
reduction in initial hyperplasia compared to wild type mice
(Zimmerman et al. (2002) Am J Phsiol Regul Integr Comp Physiol
283:R505). Restenosis can occur as the result of any type of
vascular reconstruction, whether in the coronary vasculature or in
the periphery (Colburn and Moore (1998) Myointimal Hyperplasia pp.
690-709 in Vascular Surgery: A Comprehensive Review Philadelphia:
Saunders). For example, studies have reported symptomatic
restenosis rates of 30-50% following coronary angioplasties (see
Berk and Harris (1995) Adv. Intern. Med. 40:455). After carotid
endarterectomies, as a further example, 20% of patients studied had
a luminal narrowing greater than 50% (Clagett et al. (1986) J.
Vasc. Surg. 3:10). Restenosis is evidenced in different degrees of
symptomatology which accompany preocclusive lesions in different
anatomical locations, due to a combination of factors including the
nature of the vessels involved, the extent of residual disease, and
local hemodynamics.
[0202] "Stenosis," as used herein refers to a narrowing of an
artery as seen in occlusive disorder or in restenosis. Stenosis can
be accompanied by those symptoms reflecting a decrease in blood
flow past the narrowed arterial segment, in which case the disorder
giving rise to the stenosis is termed a disease (i.e., occlusive
disease or restenosis disease). Stenosis can exist asymptomatically
in a vessel, to be detected only by a diagnostic intervention such
as an angiography or a vascular lab study.
[0203] The multiple-variable dose method of the invention can be
used to treat a subject suffering from or at risk of developing
restenosis. A subject at risk of developing restenosis includes a
subject who has undergone PTCA. The subject may have also had a
stent inserted to prevent restenosis. The TNF.alpha. antibody can
be used alone or in combination with a stent to prevent the
re-occurrence of stenosis in a subject suffering from
cardiovascular disease.
[0204] 2. Congestive Heart Failure
[0205] TNF.alpha. has been implicated in the pathophysiology of
congestive heart failure (see Zhou et al. (2002) Atherosclerosis
161:153). Serum levels of TNF.alpha. are elevated in patients with
congestive heart failure in a manner which is directly proportional
to the severity of the disease (Levine et al. (1990) N Engl J Med
323:236; Torre-Amione et al. (1996) J Am Coll Cardiol 27:1201). In
addition, inhibitors of TNF.alpha. have also been shown to improve
congestive heart failure symptoms (Chung et al. (2003) Circulation
107:3133).
[0206] As used herein, the term "congestive heart failure" includes
a condition characterized by a diminished capacity of the heart to
supply the oxygen demands of the body. Symptoms and signs of
congestive heart failure include diminished blood flow to the
various tissues of the body, accumulation of excess blood in the
various organs, e.g., when the heart is unable to pump out the
blood returned to it by the great veins, exertional dyspnea,
fatigue, and/or peripheral edema, e.g., peripheral edema resulting
from left ventricular dysfunction. Congestive heart failure may be
acute or chronic. The manifestation of congestive heart failure
usually occurs secondary to a variety of cardiac or systemic
disorders that share a temporal or permanent loss of cardiac
function. Examples of such disorders include hypertension, coronary
artery disease, valvular disease, and cardiomyopathies, e.g.,
hypertrophic, dilative, or restrictive cardiomyopathies.
[0207] A "subject who has or is suffering from congestive heart
failure" is a subject who has a disorder involving a clinical
syndrome of diverse etiologies linked by the common denominator of
impaired heart pumping in which the heart cannot pump blood
commensurate with the requirements of the metabolizing tissues, or
can do so only from an elevated filling pressure. A "subject at
risk of developing congestive heart failure" is a subject who has a
propensity of developing congestive heart failure because of
certain factors affecting the cardiovascular system of the subject.
It is desirable to reduce the risk of or prevent the development of
congestive heart failure in these subjects. The phrase "with
congestive heart failure" includes patients who are at risk of
suffering from this condition relative to the general population,
even though they may not have suffered from it yet, by virtue of
exhibiting risk factors. For example, a patient with untreated
hypertension may not have suffered from congestive heart failure,
but is at risk because of his or her hypertensive condition. In one
embodiment of the invention, the antibody D2E7 is used to treat a
subject at risk of developing congestive heart failure using
multiple-variable dose treatment.
[0208] 3. Acute Coronary Syndromes
[0209] TNF.alpha. has been implicated in the pathophysiology of
acute coronary syndromes (see Libby (1995) Circulation 91:2844).
Acute coronary syndromes include those disorders wherein the
subject experiences pain due to a blood flow restriction resulting
in not enough oxygen reaching the heart. Studies have found that
TNF.alpha. plays a role in acute coronary syndromes. For example,
in a novel rat heterotropic cardiac transplantation-coronary
ligation model capable of inducing myocardial infarction in the
absence of downstream hemodynamic effects, administration of
chimeric soluble TNF receptor (sTNFR) abolished transient LV
remodeling and dysfunction (Nakamura, et al. (2003) J. Cardiol.
41:41). It was also found that direct injection of an sTNFR
expression plasmid to the myocardium, resulted in a reduction in
the infarction size in acute myocardial infarction (AMI)
experimental rats (Sugano et al. (2002) FASEB J 16:1421).
[0210] In one embodiment, a TNF.alpha. antibody is used in a
multiple-variable dose method for the treatment or prevention of an
acute coronary syndrome in a subject, wherein the acute coronary
syndrome is a myocardial infarction or angina.
[0211] As used herein, the term "myocardial infarction" or "MI"
refers to a heart attack. A myocardial infarction involves the
necrosis or permanent damage of a region of the heart due to an
inadequate supply of oxygen to that area. This necrosis is
typically caused by an obstruction in a coronary artery from either
atherosclerosis or an embolis. MIs which are treated by the
TNF.alpha. antibody of the invention include both Q-wave and
non-Q-wave myocardial infarction. Most heart attacks are caused by
a clot that blocks one of the coronary arteries (the blood vessels
that bring blood and oxygen to the heart muscle). For example, a
clot in the coronary artery interrupts the flow of blood and oxygen
to the heart muscle, leading to the death of heart cells in that
area. The damaged heart muscle permanently loses its ability to
contract, and the remaining heart muscle needs to compensate for
it. An MI can also be caused by overwhelming stress in the
individual.
[0212] The term "angina" refers to spasmodic, choking, or
suffocative pain, and especially as denoting angina pectoris which
is a paroxysmal thoracic pain due, most often, to anoxia of the
myocardium. Angina includes both variant angina and exertional
angina. A subject having angina has ischemic heart disease which is
manifested by sudden, severe, pressing substemal pain that often
radiates to the left shoulder and along the left arm. TNF.alpha.
has been implicated in angina, as TNF.alpha. levels are upregulated
in patients with both MI and stable angina (Balbay et al. (2001)
Angiology 52109).
[0213] 4. Artherosclerosis
[0214] "Atherosclerosis" as used herein refers to a condition in
which fatty material is deposited along the walls of arteries. This
fatty material thickens, hardens, and may eventually block the
arteries. Atherosclerosis is also referred to arteriosclerosis,
hardening of the arteries, and arterial plaque buildup. Polyclonal
antibodies directed against TNF.alpha. have been shown to be
effective at neutralizing TNF.alpha. activity resulting in
inflammation and restenosis in the rabbit atherosclerotic model
(Zhou et al., supra). Accordingly, a TNF.alpha. antibody can be
used to treat or prevent subjects afflicted with or at risk of
having atherosclerosis using the multiple-variable dose method of
the invention.
[0215] 5. Cardiomyopathy
[0216] The term "cardiomyopathy" as used herein is used to define
diseases of the myocardium wherein the heart muscle or myocardium
is weakened, usually resulting in inadequate heart pumping.
Cardiomyopathy can be caused by viral infections, heart attacks,
alcoholism, long-term, severe hypertension (high blood pressure),
or by autoimmune causes.
[0217] In approximately 75-80% of heart failure patients coronary
artery disease is the underlying cause of the cardiomyopathy and is
designated "ischemic cardiomyopathy." Ischemic cardiomyopathy is
caused by heart attacks, which leave scars in the heart muscle or
myocardium. The affected myocardium is then unable to contribute to
the heart pumping function. The larger the scars or the more
numerous the heart attacks, the higher the chance there is of
developing ischemic cardiomyopathy.
[0218] Cardiomyopathies that are not attributed to underlying
coronary artery disease, and are designated "non-ischemic
cardiomyopathies." Non-ischemic cardiomyopathies include, but are
not limited to idiopathic cardiomyopathy, hypertrophic
cardiomyopathy, alcoholic cardiomyopathy, dilated cardiomyopathy,
peripartum cardiomyopathy, and restrictive cardiomyopathy.
[0219] I. Spondyloarthropathies
[0220] TNF.alpha. has been implicated in the pathophysiology of a
wide variety of disorders, including inflammatory diseases such as
spondyloarthopathies (see e.g., Moeller et al. (1990) Cytokine
2:162; U.S. Pat. No. 5,231,024; European Patent Publication No. 260
610). The invention provides multiple-variable dose methods for
inhibiting TNF.alpha. activity in a subject suffering from a
spondyloarthropathy, which method comprises administering to the
subject an antibody, antibody portion, or other TNF.alpha.
inhibitor initially in an induction dose, followed by a treatment
dose, such that TNF.alpha. activity in the subject suffering from a
spondyloarthropathy is inhibited.
[0221] As used herein, the term "spondyloarthropathy" or
"spondyloarthropathies" is used to refer to any one of several
diseases affecting the joints of the spine, wherein such diseases
share common clinical, radiological, and histological features. A
number of spondyloarthropathies share genetic characteristics, i.e.
they are associated with the HLA-B27 allele. In one embodiment, the
term spondyloarthropathy is used to refer to any one of several
diseases affecting the joints of the spine, excluding ankylosing
spondylitis, wherein such diseases share common clinical,
radiological, and histological features. Examples of
spondyloarthropathies include ankylosing spondylitis, psoriatic
arthritis/spondylitis, enteropathic arthritis, reactive arthritis
or Reiter's syndrome, and undifferentiated spondyloarthropathies.
Examples of animal models used to study spondyloarthropathies
include ank/ank transgenic mice, HLA-B27 transgenic rats (see
Taurog et al. (1998) The Spondylarthritides. Oxford: Oxford
University Press).
[0222] The multiple-variable dose methods of the invention can also
be used to treat subjects who are at risk of developing a
spondyloarthropathy using multiple-variable dose methods. Examples
of subjects who are at risk of having spondyloarthropathies include
humans suffering from arthritis. Spondyloarthropathies can be
associated with other forms of arthritis, including rheumatoid
arthritis. In one embodiment of the invention, antibodies are used
in multiple-variable dose methods to treat a subject who suffers
from a spondyloarthropathy associated with rheumatoid arthritis.
Examples of spondyloarthropathies which can be treated with a
TNF.alpha. antibody using the multiple-variable dose method of the
invention are described below:
[0223] 1. Ankylosing Spondylitis (AS)
[0224] Tumor necrosis factor has been implicated in the
pathophysiology of ankylosing spondylitis (see Verjans et al.
(1991) Arthritis Rheum. 34:486; Verjans et al. (1994) Clin Exp
Immunol. 97:45; Kaijtzel et al. (1999) Hum Immunol. 60:140).
Ankylosing spondylitis (AS) is an inflammatory disorder involving
inflammation of one or more vertebrae. AS is a chronic inflammatory
disease that affects the axial skeleton and/or peripheral joints,
including joints between the vertebrae of the spine and sacroiliac
joints and the joints between the spine and the pelvis. AS can
eventually cause the affected vertebrae to fuse or grow together.
Spondyarthropathies, including AS, can be associated with psoriatic
arthritis (PsA) and/or inflammatory bowel disease (IBD), including
ulcerative colitis and Crohn's disease.
[0225] Early manifestations of AS can be determined by radiographic
tests, including CT scans and Mill scans. Early manifestations of
AS often include scroiliitis and changes in the sacroliac joints as
evidenced by the blurring of the cortical margins of the
subchrondral bone, followed by erosions and sclerosis. Fatigue has
also been noted as a common symptom of AS (Duffy et al. (2002) ACR
66th Annual Scientific Meeting Abstract). Accordingly,
multiple-variable dose methods comprising administering an
antibody, or antigen-binding fragment thereof, of the invention can
be used to treat AS.
[0226] In one embodiment, the multiple-variable dose method of the
invention is used to treat a spondyloarthropathy associated with
IBD, including AS. AS is often treated with nonsteroidal
anti-inflammatory medications (NSAIDs), such as aspirin or
indomethacin. Accordingly, a TNF.alpha. antibody used in the
multiple-variable dose method of the invention may also be
administered in combination with agents commonly used to reduce
inflammation and pain commonly associated with ankylosing
spondylitis.
[0227] 2. Psoriatic Arthritis
[0228] Tumor necrosis factor has been implicated in the
pathophysiology of psoriatic arthritis (PsA) (Partsch et al. (1998)
Ann Rheum Dis. 57:691; Ritchlin et al. (1998) J Rheumatol.
25:1544). As referred to herein, psoriatic arthritis or psoriasis
associated with the skin, refers to chronic inflammatory arthritis
which is associated with psoriasis, which is a common chronic skin
condition that causes red patches on the body. About 1 in 20
individuals with psoriasis will develop arthritis along with the
skin condition, and in about 75% of cases, psoriasis precedes the
arthritis. PsA exhibits itself in a variety of ways, ranging from
mild to severe arthritis, wherein the arthritis usually affects the
fingers and the spine. When the spine is affected, the symptoms are
similar to those of ankylosing spondylitis, as described above. The
TNF.alpha. antibody, or antigen-binding fragment thereof, of the
invention can be used in multiple-variable dose treatment of
PsA.
[0229] PsA is sometimes associated with arthritis mutilans.
Arthritis mutilans refers to a disorder which is characterized by
excessive bone erosion resulting in a gross, erosive deformity
which mutilates the joint. In one embodiment, the multiple-variable
dose method of the invention can be used to treat arthritis
mutilans.
[0230] 3. Reactive Arthritis/Reiter's Syndrome
[0231] Tumor necrosis factor has been implicated in the
pathophysiology of reactive arthritis, which is also referred to as
Reiter's syndrome (Braun et al. (1999) Arthritis Rheum.
42(10):2039). Reactive arthritis (ReA) refers to arthritis which
complicates an infection elsewhere in the body, often following
enteric or urogenital infections. ReA is often characterized by
certain clinical symptoms, including inflammation of the joints
(arthritis), urethritis, conjunctivitis, and lesions of the skin
and mucous membranes. In addition, ReA can occurs following
infection with a sexually transmitted disease or dysenteric
infection, including Chlamydia, Campylobacter, Salmonella, or
Yersinia. Accordingly, the multiple-variable dose method of the
invention can be used to treat ReA using the multiple-variable dose
method of the invention.
[0232] 4. Undifferentiated Spondyloarthropathies
[0233] In one embodiment, multiple-variable dose methods of the
invention of the invention are used to treat subjects suffering
from undifferentiated spondyloarthropathies (see Zeidler et al.
(1992) Rheum Dis Clin North Am. 18:187). Other terms used to
describe undifferentiated spondyloarthropathies include
seronegative oligoarthritis and undifferentiated oligoarthritis.
Undifferentiated spondyloarthropathies, as used herein, refers to a
disorder wherein the subject demonstrates only some of the symptoms
associated with a spondyloarthropathy. This condition is usually
observed in young adults who do not have IBD, psoriasis, or the
classic symptoms of AS or Reiter's syndrome. In some instances,
undifferentiated spondyloarthropathies may be an early indication
of AS. In one embodiment, the multiple-variable dose method of the
invention comprises administering different doses of a TNF.alpha.
antibody, or antigen-binding fragment thereof, to treat
undifferentiated spondyloarthropathies.
[0234] J. Metabolic Disorders
[0235] TNF.alpha. has been implicated in the pathophysiology of a
wide variety of disorders, including metabolic disorders, such as
diabetes and obesity (Spiegelman and Hotamisligil (1993) Cell
73:625; Chu et al. (2000) Int J Obes Relat Metab Disord. 24:1085;
Ishii et al. (2000) Metabolism. 49:1616). The term "metabolic
disorder," as used herein, refers to diseases or disorders which
affect how the body processes substances needed to carry out
physiological functions. Examples of metabolic disorders include,
but are not limited to, diabetes and obesity. In one embodiment of
the invention, the term "metabolic disorder" is used to refer to
disorders which affect how the body processes substances needed to
carry out physiological functions, excluding autoimmune
diabetes.
[0236] The invention provides multiple-variable dose methods for
inhibiting TNF.alpha. activity in a subject suffering from such a
metabolic disorder, which method comprises administering to the
subject an induction dose followed by a treatment dose of an
antibody, antibody portion, or other TNF.alpha. inhibitor such that
TNF.alpha. activity in the subject suffering from a metabolic
disorder is inhibited. TNF.alpha. antibodies can also be used to
treat subjects who are at risk of developing a metabolic disorder
using the multiple-variable dose regimen of the invention.
[0237] Metabolic disorders are often associated with arthritis,
including rheumatoid arthritis. In one embodiment, a TNF.alpha.
inhibitor, such as an antibody, is used in a multiple-variable dose
regimen in a subject who suffers from a metabolic disorder
associated with rheumatoid arthritis. In another embodiment, the
multiple-variable dose treatment of the invention comprises
administering a TNF.alpha. antibody to treat disorders associated
with diabetes or obesity.
[0238] Examples of animal models for evaluating the efficacy of a
multiple-variable dose regimen using a TNF.alpha. antibody for the
treatment of a metabolic disorder include NOD transgenic mice,
Akita mice, NSY transgenic mice and ob/ob mice (see Baeder et al.
(1992) Clin Exp Immunol. 89:174; Haseyama et al. (2002) Tohoku J
Exp Med. 198:233; Makino et al. (1980): Exp. Anim. 29:1; Kolb
(1987) Diabetes/Metabolism Reviews 3:751; Hamada et al. (2001)
Metabolism. 50:1282; Coleman, (1978) Diabetologia, 14:141; Bailey
et al. (1982) Int. J Obesity 6:11). Examples of animal models used
to study vasculitis includes the mouse HSV model (Behcet's
disease), the mouse L. casei model (Kawasaki's disease), and the
mouse ANCA model (Kawasaki's disease). Other models of vasculitis
include the McH5-lpr/lpr strain (Nose et al. (1996) Am. J Path.
149:1763) and the SCG/Kj strain of mice (Kinjoh et al. (1993) Proc.
Natl. Acad. Sci., USA 90:3413). These mice strains spontaneously
develop crescentic glomerulonephritis and necrotizing vasculitis of
the small arteries and arterioles of the spleen, stomach, heart,
uterus and ovaries. These animals develop hypergammaglobulinemia
and ANCA autoantibodies that react with myeloperoxidase (MPO).
Additionally, immunization of rats with human MPO results in
ANCA-associated necrotizing crescentic glomerulonephritis (Brouwer
et al. (1993) J Exp. Med. 177:905).
[0239] Metabolic disorders affect how the body processes substances
needed to carry out physiological functions. A number of metabolic
disorders of the invention share certain characteristics, i.e. they
are associated the insulin resistance, lack of ability to regulate
blood sugar, weight gain, and increase in body mass index. Examples
of metabolic disorders include diabetes and obesity. Examples of
diabetes include type 1 diabetes mellitus, type 2 diabetes
mellitus, diabetic neuropathy, peripheral neuropathy, diabetic
retinopathy, diabetic ulcerations, retinopathy ulcerations,
diabetic macrovasculopathy, and obesity. Examples of metabolic
disorders which can be treated using multiple-variable dose methods
comprising administration of a TNF.alpha. antibody are described in
more detail below:
[0240] 1. Diabetes
[0241] Tumor necrosis factor has been implicated in the
pathophysiology of diabetes. (see e.g., Navarro et al. (2003) Am J
Kidney Dis. 42:53; Daimon et al. (2003) Diabetes Care. 26:2015;
Zhang et al. (1999) J Tongji Med Univ. 19:203; Barbieri et al.
(2003) Am J Hypertens. 16:537) For example, TNF.alpha. is
implicated in the pathophysiology for insulin resistance. It has
been found that serum TNF levels in patients with gastrointestinal
cancer correlates with insulin resistance (see e.g., McCall et al.
(1992) Br. J. Surg. 79:1361).
[0242] The term "diabetes" or "diabetic disorder" or "diabetes
mellitus," as used interchangeably herein, refers to a disease
which is marked by elevated levels of sugar (glucose) in the blood.
Diabetes can be caused by too little insulin (a chemical produced
by the pancreas to regulate blood sugar), resistance to insulin, or
both. Diabetes includes the two most common types of the disorder,
namely type I diabetes and type II diabetes, which both result from
the body's inability to regulate insulin. Insulin is a hormone
released by the pancreas in response to increased levels of blood
sugar (glucose) in the blood.
[0243] The term "type 1 diabetes," as used herein, refers to a
chronic disease that occurs when the pancreas produces too little
insulin to regulate blood sugar levels appropriately. Type 1
diabetes is also referred to as insulin-dependent diabetes
mellitus, IDMM, juvenile onset diabetes, and diabetes--type I. Type
1 diabetes represents is the result of a progressive autoimmune
destruction of the pancreatic .beta.-cells with subsequent insulin
deficiency.
[0244] The term "type 2 diabetes," refers to a chronic disease that
occurs when the pancreas does not make enough insulin to keep blood
glucose levels normal, often because the body does not respond well
to the insulin. Type 2 diabetes is also referred to as
noninsulin-dependent diabetes mellitus, NDDM, and diabetes--type
II
[0245] Diabetes is can be diagnosed by the administration of a
glucose tolerance test. Clinically, diabetes is often divided into
several basic categories. Primary examples of these categories
include, autoimmune diabetes mellitus, non-insulin-dependent
diabetes mellitus (type 1 NDDM), insulin-dependant diabetes
mellitus (type 2 IDDM), non-autoimmune diabetes mellitus,
non-insulin-dependant diabetes mellitus (type 2 NIDDM), and
maturity-onset diabetes of the young (MODY). A further category,
often referred to as secondary, refers to diabetes brought about by
some identifiable condition which causes or allows a diabetic
syndrome to develop. Examples of secondary categories include,
diabetes caused by pancreatic disease, hormonal abnormalities,
drug- or chemical-induced diabetes, diabetes caused by insulin
receptor abnormalities, diabetes associated with genetic syndromes,
and diabetes of other causes. (see e.g., Harrison's (1996) 14th
ed., New York, McGraw-Hill).
[0246] Diabetes is often treated with diet, insulin dosages, and
various medications described herein. Accordingly, a TNF.alpha.
antibody may also be administered in combination with agents
commonly used to treat metabolic disorders and pain commonly
associated with diabetes in the multiple-variable dose method of
the invention.
[0247] In addition, the phrase "disorders associated with
diabetes," as used herein, refers to conditions and other diseases
which are commonly associated with or related to diabetes. Example
of disorders associated with diabetes include, for example,
hyperglycemia, hyperinsulinaemia, hyperlipidaemia, insulin
resistance, impaired glucose metabolism, obesity, diabetic
retinopathy, macular degeneration, cataracts, diabetic nephropathy,
glomerulosclerosis, diabetic neuropathy, erectile dysfunction,
premenstrual syndrome, vascular restenosis, ulcerative colitis,
coronary heart disease, hypertension, angina pectoris, myocardial
infarction, stroke, skin and connective tissue disorders, foot
ulcerations, metabolic acidosis, arthritis, and osteoporosis. In
one embodiment the multiple-variable dose methods of the invention
can be used to treat disorders associated with diabetes.
[0248] Diabetes manifests itself in the foregoing categories and
can cause several complications that are discussed in the following
sections. Accordingly, the antibody, or antigen-binding fragment
thereof, of the invention can be used to treat diabetes. In one
embodiment, a TNF.alpha. antibody, or antigen-binding fragment
thereof, is used to treat diabetes associated with the above
identified categories using the multiple-variable dose method of
the invention. In another embodiment, the invention includes
multiple-variable dose regimens comprising administering a
TNF.alpha. antibody to treat disorders associated with diabetes.
Diabetes manifests itself in many complications and conditions
associated with diabetes, including the following categories:
[0249] a. Diabetic Neuropathy and Peripheral Neuropathy
[0250] Tumor necrosis factor has been implicated in the
pathophysiology of diabetic neuropathy and peripheral neuropathy.
(See Benjafield et al. (2001) Diabetes Care. 24:753; Qiang et al.
(1998) Diabetologia. 41: 1321; Pfeiffer et al. (1997) Horm Metab
Res. 29:111).
[0251] The term "neuropathy," also referred to as nerve
damage-diabetic, as used herein, refers to a common complication of
diabetes in which nerves are damaged as a result of hyperglycemia
(high blood sugar levels). A variety of diabetic neuropathies are
recognized, such as distal sensorimotror polyneuropathy, focal
motor neuropathy, and autonomic neuropathy.
[0252] The term "peripheral neuropathy," also known as peripheral
neuritis and diabetic neuropathy, as used herein, refers to the
failure of the nerves to carry information to and from the brain
and spinal cord. Peripheral neuropathy produces symptoms such as
pain, loss of sensation, and the inability to control muscles. In
some cases, the failure of nerves to control blood vessels,
intestinal function, and other organs results in abnormal blood
pressure, digestion, and loss of other basic involuntary processes.
Peripheral neuropathy may involve damage to a single nerve or nerve
group (mononeuropathy) or may affect multiple nerves
(polyneuropathy).
[0253] Neuropathies that affect small myelinated and unmyelinated
fibers of the sympathetic and parasympathetic nerves are known as
"peripheral neuropathies." Furthermore, the related disorder of
peripheral neuropathy, also known as peripheral neuritis and
diabetic neuropathy, refers to the failure of the nerves to carry
information to and from the brain and spinal cord. This produces
symptoms such as pain, loss of sensation, and the inability to
control muscles. In some cases, failure of nerves controlling blood
vessels, intestinal function, and other organs results in abnormal
blood pressure, digestion, and loss of other basic involuntary
processes. Peripheral neuropathy may involve damage to a single
nerve or nerve group (mononeuropathy) or may affect multiple nerves
(polyneuropathy).
[0254] The term "diabetic neuropathy" refers to a common
complication of diabetes in which nerves are damaged as a result of
hyperglycemia (high blood sugar levels). Diabetic neuropathy is
also referred to as neuropathy and nerve damage-diabetic. A variety
of diabetic neuropathies are recognized, such as distal
sensorimotror polyneuropathy, focal motor neuropathy, and autonomic
neuropathy.
[0255] b. Diabetic Retinopathy
[0256] Tumor necrosis factor has been implicated in the
pathophysiology of diabetic retinopthy (Scholz et al. (2003) Trends
Microbiol. 11:171). The term "diabetic retinopathy" as used herein,
refers to progressive damage to the eye's retina caused by
long-term diabetes. Diabetic retinopathy, includes proliferative
retinopathy. Proliferative neuropathy in turn includes
neovascularization, pertinal hemorrhage and retinal detachment.
[0257] In advanced retinopathy, small vessels proliferate on the
surface of the retina. These blood vessels are fragile, tend to
bleed and can cause peretinal hemorrhages. The hemorrhage can
obscure vision, and as the hemorrhage is resorbed fibrous tissue
forms predisposing to retinal detachments and loss of vision. In
addition, diabetic retinopathy includes prolferative retinopathy
which includes neovascularization, pertinal hemorrhage and retinal
detachment. Diabetic retinopathy also includes "background
retinopathy" which involves changes occurring with the layers of
the retina.
[0258] c. Diabetic Ulcerations and Retinopathy Ulcerations
[0259] Tumor necrosis factor has been implicated in the
pathophysiology of diabetic ulcerations, (see Lee et al. (2003) Hum
Immunol. 64:614; Navarro et al. (2003) Am J Kidney Dis. 42:53;
Daimon et al (2003) Diabetes Care. 26:2015; Zhang et al. (1999) J
Tongji Med Univ. 19:203; Barbieri et al. (2003) Am J Hypertens.
16:537; Venn et al. (1993) Arthritis Rheum. 36:819; Westacott et
al. (1994) J Rheumatol. 21:1710).
[0260] The term "diabetic ulcerations," as used herein, refers to
an ulcer which results as a complication of diabetes. An ulcer is a
crater-like lesion on the skin or mucous membrane caused by an
inflammatory, infectious, malignant condition, or metabolic
disorder. Typically diabetic ulcers can be found on limbs and
extremities, more typically the feet. These ulcers, caused by
diabetic conditions, such as neuropathy and a vascular
insufficiency, can lead to ischemia and poor wound healing. More
extensive ulcerations may progress to osteomyelitis. Once
osteomyelitis develops, it may be difficult to eradicate with
antibiotics alone and amputation maybe necessary.
[0261] The term "retinopathy ulcerations," as used herein refers to
an ulcer which causes or results in damages to the eye and the
eye's retina. Retinopathy ulcerations may include conditions such
has retinoathic hemorrhages.
[0262] d. Diabetic Macrovasculopathy
[0263] Tumor necrosis factor has been implicated in the
pathophysiology of diabetic macrovasculopathy (Devaraj et al.
(2000) Circulation. 102:191; Hattori et al. (2000) Cardiovasc Res.
46:188; Clausell et al. (1999) Cardiovasc Pathol. 8:145). The term
"diabetic macrovasculopathy," also referred to as "macrovascular
disease," as used herein, refers to a disease of the blood vessels
that results from diabetes. Diabetic macrovasculopathy complication
occurs when, for example, fat and blood clots build up in the large
blood vessels and stick to the vessel walls. Diabetic
macrovasculopathies include diseases such as coronary disease,
cerebrovascular disease, and peripheral vascular disease,
hyperglycaemia and cardiovascular disease, and strokes.
[0264] 2. Obesity
[0265] Tumor necrosis factor has been implicated in the
pathophysiology of obesity (see e.g., Pihlajamaki J et al. (2003)
Obes Res. 11:912; Barbieri et al. (2003) Am J Hypertens. 16:537;
Tsuda et al. (2003) J Nutr. 133:2125). The term "obesity" as used
herein, refers to a condition in which the subject has an excess of
body fat relative to lean body mass. In one embodiment, obesity
refers to a condition in which an individual weighs at least about
20% or more over the maximum desirable for their height. When an
adult is more than 100 pounds overweight, he or she is considered
to be "morbidly obese." In another embodiment, obesity is defined
as a BMI (body mass index) over 30 kg/m2. Obesity increases a
person's risk of illness and death due to diabetes, stroke,
coronary artery disease, hypertension, high cholesterol, and kidney
and gallbladder disorders. Obesity may also increase the risk for
some types of cancer, and may be a risk factor for the development
of osteoarthritis and sleep apnea. Obesity can be treated using the
multiple-variable dose methods of the invention.
[0266] K. Anemia
[0267] TNF.alpha. has been implicated in the pathophysiology of a
wide variety of anemias (see e.g., Jongen-Lavrencic et al. (1997)
J. Rheumatol. 24:1504; Demeter et al. (2002) Ann Hematol. 81:566;
DiCato (2003) The Oncologist 8 (suppl 1):19). The invention
provides multiple-variable dose methods for inhibiting TNF.alpha.
activity in a subject suffering from anemia, which method comprises
administering to the subject an induction dose followed by a
treatment dose of a TNF.alpha. inhibitor, wherein the TNF.alpha.
inhibitor is an antibody, antibody portion, such that TNF.alpha.
activity in the subject suffering from anemia is inhibited. In one
embodiment, the anemia is associated with rheumatoid arthritis.
[0268] The term "anemia" as used herein, refers to an abnormally
low number of circulating red cells or a decreased concentration of
hemoglobin in the blood. Examples of anemia related to rheumatoid
arthritis include, for example, anemia of chronic disease, iron
deficiency anemia, and autoimmune hemolytic anemia. In one
embodiment, the invention provides a method of treating anemias
related to, for example, anemias related to rheumatoid arthritis,
anemias of infection and chronic inflammatory diseases, iron
deficiency anemia, autoimmune hemolytic anemia, myelophthisic
anemia, aplastic anemia, hypoplastic anemia, pure red cell aplasia
and anemia associated with renal failure or endocrine disorders,
megaloblastic anemias, defects in heme or globin synthesis, anemia
caused by a structural defect in red blood cells, e.g., sickle-cell
anemia, and anemias of unknown origins such as sideroblastic
anemia, anemia associated with chronic infections such as malaria,
trypanosomiasis, HIV, hepatitis virus or other viruses, and
myelophthisic anemias caused by marrow deficiencies.
[0269] Examples of animal models used to study anemia include rats
inoculated with peptidolglycan-polysaccharide polymers (see Coccia
et al., (2001) Exp Hematology. 29:1201-1209). Examples of animal
models used to study pain are well known in the art, and include
the rat sciatic nerve ligation model, and the rat segmental spinal
nerve ligation model (see Bennett and Zie, (1988) Pain. 33:87-107;
Kim and Chung, (1992) Pain 50:355-363).
[0270] L. Pain
[0271] TNF.alpha. has been implicated in the pathophysiology of a
wide variety of pain syndromes (see e.g., Sorkin et al. (1997)
Neuroscience. 81:255; Huygen et al. (2002) Mediators Inflamm.
11:47; Parada et al. (2003) Eur J Neurosci. 17:1847). The term
"pain" as used herein, refers to all types of pain. The term shall
refer to acute and chronic pains, such as neuropathic pain and
post-operative pain, chronic lower back pain, cluster headaches,
herpes neuralgia, phantom limb pain, central pain, dental pain,
opioid-resistant pain, visceral pain, surgical pain, bone injury
pain, pain during labor and delivery, pain resulting from burns,
including sunburn, post partum pain, migraine, angina pain, and
genitourinary tract-related pain including cystitis. The term also
includes nociceptive pain or nociception.
[0272] The invention provides multiple-variable dose methods for
inhibiting TNF.alpha. activity in a subject suffering from such a
pain disorder, which method comprises administering to the subject
an induction dose followed by a treatment dose of an antibody,
antibody portion, or other TNF.alpha. inhibitor such that
TNF.alpha. activity in the subject suffering from pain is
inhibited. Pain has been defined in a variety of ways, including
nociceptive pain and neuropathic pain. The most commonly
experienced form of pain may be defined as the effect of a stimulus
on nerve endings, which results in the transmission of impulses to
the cerebrum. Pain is also commonly associated with inflammatory
disorders, including, for example, rheumatoid arthritis. In one
embodiment, the antibody of the invention is used to treat a
subject who suffers from pain associated with rheumatoid arthritis.
Examples of pain disorders in which TNF.alpha. activity is
detrimental are discussed further below.
[0273] 1. Neuropathic Pain
[0274] Tumor necrosis factor has been implicated in the
pathophysiology of neuropathic pain (see Sommer (1999) Schmerz.
13:315; Empl et al., (2001) Neurology. 56:1371; Schafers et al.
(2003) J Neurosci. 23:3028). As used herein the term "neuropathic
pain" refers to pain that results from injury to a nerve, spinal
cord, or brain, and often involves neural supersensitivity.
Examples of neuropathic pain include chronic lower back pain, pain
associated with arthritis, cancer-associated pain, herpes
neuralgia, phantom limb pain, central pain, opioid resistant
neuropathic pain, bone injury pain, and pain during labor and
delivery. Other examples of neuropathic pain include post-operative
pain, cluster headaches, dental pain, surgical pain, pain resulting
from severe, for example third degree, burns, post partum pain,
angina pain, genitourinary tract related pain, and including
cystitis.
[0275] Neuropathic pain is distinguished from nociceptive pain.
Pain involving a nociceptive mechanism usually is limited in
duration to the period of tissue repair and generally is alleviated
by available analgesic agents or opioids (Myers (1995) Regional
Anesthesia 20:173). Neuropathic pain typically is long-lasting or
chronic and often develops days or months following an initial
acute tissue injury. Neuropathic pain can involve persistent,
spontaneous pain as well as allodynia, which is a painful response
to a stimulus that normally is not painful. Neuropathic pain also
can be characterized by hyperalgesia, in which there is an
accentuated response to a painful stimulus that usually is trivial,
such as a pin prick. Unlike nociceptive pain, neuropathic pain
generally is resistant to opioid therapy (Myers, supra, 1995).
Accordingly, the multiple-variable dose methods of the invention
can be used to treat neuropathic pain.
[0276] 2. Nociceptive Pain
[0277] As used herein the term "nociceptive pain" refers to pain
that is transmitted across intact neuronal pathways, i.e., pain
caused by injury to the body. Nociceptive pain includes somatic
sensation and normal function of pain, and informs the subject of
impending tissue damage. The nociceptive pathway exists for
protection of the subject, e.g., the pain experienced in response
to a burn). Nociceptive pain includes bone pain, visceral pain, and
pain associated with soft tissue.
[0278] Tumor necrosis factor has been implicated in the
pathophysiology of visceral pain (see Coelho et al. (2000) Am J
Physiol Gastrointest Liver Physiol. 279:G781; Coelho et al. (2000)
Brain Res Bull. 52:223). Visceral pain is used to refer to
nociceptive pain that is mediated by receptors on A-delta and C
nerve fibers. A-delta and C-nerve fibers are which are located in
skin, bone, connective tissue, muscle and viscera. Visceral pain
can be vague in distribution, spasmodic in nature and is usually
described as deep, aching, squeezing and colicky in nature.
Examples of visceral pain include pain associated with a heart
attack, wherein the visceral pain can be felt in the arm, neck
and/or back, and liver capsule pain, wherein the visceral pain can
be felt in the back and/or right shoulder. Accordingly, the
multiple-variable dose methods of the invention can be used to
treat visceral pain.
[0279] M. Hepatic Disorders
[0280] TNF.alpha. has been implicated in the pathophysiology of a
wide variety of hepatic disorders (see e.g., Colletti et al. (1990)
J Clin Invest. 85:1936; Tiegs (1997) Acta Gastroenterol Belg.
60:176; Fernandez et al. (2000) J Endotoxin Res. 6:321). The
invention provides multiple-variable dose methods for inhibiting
TNF.alpha. activity in a subject suffering from such a hepatic
disorder.
[0281] As used herein, the term "a hepatic disorder in which
TNF.alpha. activity is detrimental" is intended to include diseases
and other disorders of the liver or conditions associated with
hepatocellular injury or a biliary tract disorders in which the
presence of TNF.alpha. in a subject suffering from the disorder has
been shown to be or is suspected of being either responsible for
the pathophysiology of the disorder or a factor that contributes to
a worsening of the disorder. Accordingly, a hepatic disorder in
which TNF.alpha. activity is detrimental is a disorder in which
inhibition of TNF.alpha. activity is expected to alleviate the
symptoms and/or progression of the hepatic disorder. In one
embodiment, hepatic disorders refers to a human liver disease or
condition associated with hepatocellular injury or a biliary tract
disorder excluding hepatitis, alcoholic hepatitis, and viral
hepatitis.
[0282] Examples of animal models used for evaluating the
therapeutic efficacy of an agent for treating a hepatic disorder
using multiple-variable dose methods include the chimpanzee
hepatitis C virus model (see Shimizu et al. (1990) Proc Natl Acad
Sci. USA 87:6441). Examples of animal models used to study skin and
nail disorder disorders include, for example, the severe combined
immunodeficient (SCID) mouse model (psoriasis) and the Smith line
(SL) chicken and depigmenting mouse (vitiligo) (see Nickoloff
(2000) Investig Dermatol Symp Proc 0.5:67; Austin et al. (1995) Am
J Pathol. 146:1529; Lerner et al. (1986) J Invest Dermatol.
87:299).
[0283] Hepatic disorders include many diseases and disorders
wherein the liver functions improperly or ceases to function.
Hepatocellular injuries can include alcoholic cirrhosis,
.quadrature.1 antitypsin deficiency, autoimmune cirrhosis,
cryptogenic cirrhosis, fulminant hepatitis, hepatitis B and C, and
steatohepatitis. Examples of biliary tract disorders include cystic
fibrosis, primary biliary cirrhosis, sclerosing cholangitis and
biliary obstruction (Wiesner (1996) "Current Indications, Contra
Indications and Timing for Liver Transplantation" in
Transplantation of the Liver, Saunders (publ.); Busuttil and
Klintmalm (eds.) Chapter 6; Klein (1998) Partial Hypertension: The
Role of Liver Transplantation, Musby (publ.) in Current Surgical
Therapy 6.sup.th Ed. Cameron, J. (ed).
[0284] The term "hepatitis" refers to inflammation of the liver.
Hepatitis can be caused by infections with various organisms,
including bacteria, viruses (Hepatitis A, B, C, etc.), or
parasites. Chemical toxins such as alcohol, drugs, or poisonous
mushrooms can also damage the liver and cause it to become
inflamed. A rare but extremely dangerous cause of hepatitis results
from overdose of acetaminophen (Tylenol), which can be deadly. In
addition, immune cells in the body may attack the liver and cause
autoimmune hepatitis. Hepatitis may resolve quickly (acute
hepatitis), or cause long-term disease (chronic hepatitis). In some
instances, progressive liver damage or liver failure may result.
The incidence and severity of hepatitis vary depending on many
factors, including the cause of the liver damage and any underlying
illnesses in a patient.
[0285] In one embodiment, the invention features multiple-variable
methods for treating a hepatic disorder in which TNF.alpha.
activity is detrimental, comprising administering to a subject an
effective amount of a TNF.alpha. inhibitor in an induction dose and
subsequently in a treatment dose, such that said disorder is
treated. In one embodiment, the hepatic disorder is selected from
the group consisting of hepatitis C virus, autoimmune hepatitis,
fatty-liver disease, hepatitis B virus, hepatotoxicity, and
non-alcoholic hepatitis, including non-alcoholic steatohepatitis
(NASH). Examples of hepatic disorders are further described
below.
[0286] 1. Hepatitis C Virus (HCV)
[0287] Tumor necrosis factor has been implicated in the
pathophysiology of the hepatitis C virus (see Gonzalez-Amaro.
(1994) J Exp Med. 179:841; Nelson et al. (1997) Dig Dis Sci
42:2487; Kallinowski et al. (1998) Clin Exp Immunol. 111:269). The
term "hepatitis C virus" or "HCV" is used to describe the hepatitis
virus which is the causative agent of non-A, non-B hepatitis.
Hepatitis C virus causes an inflammation of the liver. HCV
infection causes hepatitis C. Hepatitis C in the acute stage is, in
general, milder than hepatitis B, but a greater proportion of such
infections become chronic. HCV is a major cause of acute hepatitis
and chronic liver disease, including cirrhosis and liver cancer.
HCV is one of the viruses (A, B, C, D, and E), which together
account for the vast majority of cases of viral hepatitis. It is an
enveloped RNA virus in the flaviviridae family which appears to
have a narrow host range. An important feature of the virus is the
relative mutability of its genome, which in turn is probably
related to the high propensity (80%) of inducing chronic infection.
HCV is clustered into several distinct genotypes which may be
important in determining the severity of the disease and the
response to treatment. In one embodiment, the invention provides a
multiple-variable dose method for treating HCV.
[0288] 2. Autoimmune Hepatitis (AIH)
[0289] Tumor necrosis factor has been implicated in the
pathophysiology of autoimmune hepatitis (see Cookson et al., (1999)
Hepatology 30:851; Jazrawi et al., (2003) Liver Transpl. 9:377). As
used herein, "autoimmune hepatitis" refers to a hepatic disorder
characterized by inflammation of the liver caused by rogue immune
cells that mistake the liver's normal cells for a foreign tissue or
pathogen (disease-causing agent). Autoimmune hepatitis is often
responsible for a progressive destruction of the hepatic parenchyma
with a high mortality if left untreated (Johnson et al. (1993)
Hepatology, 18:998). One of the characteristics of autoimmune
hepatitis is the presence of circulating autoantibodies in almost
90% of patients' sera. Such antibodies can be used to identify
subjects who have autoimmune hepatitis.
[0290] Clinical and serological differences between patients have
lead to the classification of AIH into two types. Type 1 is
characterized by the presence of anti-smooth muscle (SMA) and/or
anti-nuclear antibodies (ANA) in patients' sera, while sera from
Type II patients show anti-liver kidney microsomal antibodies type
1 (LKM1) (Homberg et al., (1987) Hepatology, 7:1333; Maggiore et
al. (1993) J. Pediatr. Gastroenterol Nutr. 17:376). A serological
marker, anti-liver cytosol type I antibodies (LC1), has been
identified in 30% of patients with an AIH type II. In addition, LC1
proved to be the only serological marker in 10% of patients tested
(Martini et al. (1988) Hepatology, 8:1662). In one embodiment, the
multiple-variable dose method of the invention is used to treat
AIH.
[0291] 3. Fatty-Liver Disease
[0292] Tumor necrosis factor has been implicated in the
pathophysiology of fatty-liver disease (see Valenti et al., (2002)
Gastroenerology 122:274; Li et al., (2003) Hepatology 37:343).
Fatty-liver disease refers to a disease wherein fat (hepatocytes)
is excessively accumulated in the liver. Fatty liver disease is
believed to be caused by supernutrition, hyperingestion of alcohol,
diabetes and side effects due to administration of pharmaceuticals.
Fatty liver disease can cause severe diseases such as chronic
hepatitis and hepatic cirrhosis. In patients with fatty liver
disease, lipids, particularly neutral fat, accumulate in
hepatocytes to the extent that the amount exceeds the
physiologically permissible range. From a biochemical point of
view, a standard for judgment of fatty liver is that the weight of
neutral fat is about 10% (100 mg/g wet weight) or more of the wet
weight of hepatic tissue. In one embodiment, the multiple-variable
dose method of the invention is used to treat fatty liver
disease.
[0293] 4. Hepatitis B Virus (HBV)
[0294] Tumor necrosis factor has been implicated in the
pathophysiology of hepatitis B virus (see Kasahara et al., (2003) J
Virol. 77:2469; Wang (2003) World J Gastroenterol. 9:641; Biermer
et al. (2003) J Virol. 77:4033). The term "hepatitis B virus" (HBV)
is used to describe the virus (serum hepatitis virus) which
produces viral hepatitis type B in humans. This is a viral disease
with a long incubation period (about 50 to 160 days) in contrast to
hepatitis A virus (infectious hepatitis virus) which has a short
incubation period. The hepatitis B virus is usually transmitted by
injection of infected blood or blood derivatives or merely by use
of contaminated needles, lancets or other instruments. Clinically
and pathologically, the disease is similar to viral hepatitis type
A; however, there is no cross-protective immunity. Viral antigen
(HBAg) is found in the serum after infection.
[0295] Hepatitis B virus infects humans at a very high rate. Most
people who become infected with Hepatitis B get rid of the virus
within 6 months, wherein a short infection is known as an "acute"
case of Hepatitis B. It is estimated that at least about 300
million people are chronic carriers of HBV. Infection with the
virus results in a range of clinical symptoms including minor
flu-like symptoms to death. In one embodiment, the
multiple-variable dose method of the invention is used to treat HBV
infection.
[0296] 5. Hepatotoxicity
[0297] Tumor necrosis factor has been implicated in the
pathophysiology of hepatotoxicity (see Bruccoleri et al. (1997)
Hepatology 25:133; Luster et al. (2000) Ann NY Acad Sci. 919:214;
Simeonova et al. (2001) Toxicol Appl Pharmacol. 177:112). The term
hepatotoxicity refers to liver damage caused by medications and
other chemicals or drugs. The best indicator for identifying liver
toxicity in a subject is the elevation of certain enzyme
measurements in the blood, such as AST (aspartate
aminotransferase), ALT (alanine aminotransferase), and GOT
(glutamate oxalacetate transaminase).
[0298] Hepatotoxicity can cause permanent injury and death. Initial
symptoms of hepatotoxicity can include acute gastrointestinal
symptoms, e.g., severe diarrhea. The second phase of hepatotoxicity
is characterized by abatement of symptoms. During this apparent
subsidence, biochemical evidence of hepatic injury appears.
Oliguria (decreased urine output) is usual during the second phase.
The third phase, that of overt hepatic damage, becomes clinically
apparent 3 to 5 days after ingestion of the chemical, with the
appearance of jaundice. Renal failure may also occur. The symptoms
of chemically-induced (drug-induced) hepatitis are similar to that
of infectious hepatitis. In one embodiment, the multiple-variable
dose method of the invention is used to treat hepatotoxicity.
[0299] 6. Liver Failure (e.g. Chronic Liver Failure)
[0300] Tumor necrosis factor has been implicated in the
pathophysiology of liver failure (e.g. chronic liver failure) (see
Takenaka et al., (1998) Dig Dis Sci. 43:887; Nagaki et al. (1999) J
Hepatol. 31:997; Streetz et al., (2000) Gastroenterology. 119:446.
Liver failure, including chronic liver failure, usually develops
over a period of years and is caused by a repeated insult to the
liver (such as alcohol abuse or infection with hepatitis virus)
which slowly damages the organ. Less commonly, liver failure is
acute, and occurs over a period of days or weeks. Causes of acute
liver failure include hepatitis virus infections, drugs, pregnancy,
autoimmune disease, and sudden low blood flow to the liver. In one
embodiment, the multiple-variable dose method of the invention is
used to treat liver failure.
[0301] 7. Non-Alcoholic Hepatitis, Including NASH
[0302] Tumor necrosis factor has been implicated in the
pathophysiology of non-alcoholic hepatitis, including nonalcoholic
steatohepatitis (see Crespo et al., (2001) Hepatology. 34:1158;
Pessayre et al. (2002) 282(2):G193). The term "nonalcoholic
steatohepatitis" or "NASH" refers to the development of histologic
changes in the liver that are comparable to those induced by
excessive alcohol intake, but in the absence of alcohol abuse. NASH
is characterized by macrovesicular and/or microvesicular steatosis,
lobular and portal inflammation, and occasionally Mallory bodies
with fibrosis and cirrhosis. NASH is also commonly associated with
hyperlipidemia, obesity, and type II diabetes mellitus.
[0303] Additional clinical conditions which characterize hepatic
steatosis and inflammation include excessive fasting, jejunoileal
bypass, total parental nutrition, chronic hepatitis C, Wilson's
disease, and adverse drug effects such as those from
corticosteroids, calcium channel blockers, high dose synthetic
estrogens, methotrexate and amiodarone. Thus, the term
"nonalcoholic steatohepatitis" can be used to describe those
patients who exhibit these biopsy findings, coupled with the
absence of (a) significant alcohol consumption, (b) previous
surgery for weight loss, (c) history of drug use associated with
steatohepatitis, (d) evidence of genetic liver disease or (e)
chronic hepatitis C infection (see, e.g., Ludwig et al., (1980)
Mayo Clin. Proc. 55:434; Powell et al. (1990) Hepatol. 11:74). In
one embodiment, the multiple-variable dose method of the invention
is used to treat NASH.
[0304] N. Skin and Nail Disorders
[0305] Tumor necrosis factor has been implicated in the
pathophysiology of skin and nail disorders. In one embodiment, the
multiple-variable dose method of the invention comprising
administering an induction dose of a TNF.alpha. antibody followed
by a subsequent treatment dose, can be used to treat skin and nail
disorders. The term "skin disorder" or "skin disease" as used
interchangeably herein, refers to abnormalities, other than injury
wounds, of the skin which have induced a state of inflammation. In
one embodiment, the skin disorder of the invention is an
inflammatory skin disorder, wherein the skin is characterized by
capillary dilatation, leukocytic infiltration, redness, heat,
and/or pain. Examples of skin disorders include, but are not
limited to, psoriasis, pemphigus vulgaris, scleroderma, atopic
dermatitis, sarcoidosis, erythema nodosum, hidradenitis
suppurativa, lichen planus, Sweet's syndrome, and vitiligo. As used
herein, the term "skin and nail disorder in which TNF.alpha.
activity is detrimental" is intended to include skin and/or nail
disorders and other disorders in which the presence of TNF.alpha.
in a subject suffering from the disorder has been shown to be or is
suspected of being either responsible for the pathophysiology of
the disorder or a factor that contributes to a worsening of the
disorder, e.g., psoriasis. Accordingly, skin and nail disorders in
which TNF.alpha. activity is detrimental are disorders in which
inhibition of TNF.alpha. activity is expected to alleviate the
symptoms and/or progression of the disorder. The use of the
antibodies, antibody portions, and other TNF.alpha. inhibitors of
the invention in the treatment of specific skin and nail disorders
is discussed further below. In certain embodiments, the treatment
method of the invention is performed in combination with another
therapeutic agent, as described below in Section IV. In one
embodiment, the multiple-variable dose method of the invention
comprising administering a TNF.alpha. antibody in combination with
another therapeutic agent is used for the treatment of psoriasis
and the treatment of psoriasis associated with arthritis.
[0306] 1. Psoriasis
[0307] Tumor necrosis factor has been implicated in the
pathophysiology of psoriasis (Takematsu et al. (1989) Arch Dermatol
Res. 281:398; Victor and Gottlieb (2002) J Drugs Dermatol. 1:264).
The term "psoriasis" as used herein, refers to skin disorders
associated with epidermal hyperplasia. Example of psoriasis
include, but are not limited to, chronic plaque psoriasis, guttate
psoriasis, inverse psoriasis, pustular psoriasis, psoriasis
vulgaris, and erythrodermic psoriasis. Psoriasis can also be
associated with other inflammatory disorders, including
inflammatory bowel disease (IBD) and rheumatoid arthritis (RA).
[0308] Psoriasis is described as a skin inflammation (irritation
and redness) characterized by frequent episodes of redness,
itching, and thick, dry, silvery scales on the skin. In particular,
lesions are formed which involve primary and secondary alterations
in epidermal proliferation, inflammatory responses of the skin, and
an expression of regulatory molecules such as lymphokines and
inflammatory factors. Psoriatic skin is morphologically
characterized by an increased turnover of epidermal cells,
thickened epidermis, abnormal keratinization, inflammatory cell
infiltrates into the epidermis and polymorphonuclear leukocyte and
lymphocyte infiltration into the epidermis layer resulting in an
increase in the basal cell cycle. Psoriasis often involves the
nails, which frequently exhibit pitting, separation of the nail,
thickening, and discoloration. Psoriasis is often associated with
other inflammatory disorders, for example arthritis, including
rheumatoid arthritis, inflammatory bowel disease (IBD), and Crohn's
disease. Approximately one third of subjects with psoriasis also
have psoriatic arthritis (PsA) which, as described above, causes
stiffness, swelling of the joints, pain, and reduced range of
motion (Greaves et al. (1995) N. Eng. J. Med. 332:581).
[0309] Evidence of psoriasis is most commonly seen on the trunk,
elbows, knees, scalp, skin folds, or fingernails, but it may affect
any or all parts of the skin. Normally, it takes about a month for
new skin cells to move up from the lower layers to the surface. In
psoriasis, this process takes only a few days, resulting in a
build-up of dead skin cells and formation of thick scales. Symptoms
of psoriasis include: skin patches, that are dry or red, covered
with silvery scales, raised patches of skin, accompanied by red
borders, that may crack and become painful, and that are usually
located on the elbows, knees, trunk, scalp, and hands; skin
lesions, including pustules, cracking of the skin, and skin
redness; joint pain or aching which may be associated with of
arthritis, e.g., psoriatic arthritis.
[0310] Treatment for psoriasis often includes topical
corticosteroids, vitamin D analogs, and topical or oral retinoids,
or combinations thereof. In one embodiment, the TNF.alpha.
inhibitor of the invention is administered in combination with or
the presence of one of these common treatments. Additional
therapeutic agents which can also be combined with the TNF.alpha.
inhibitor of the invention for treatment of psoriasis are described
in more detail in Section IV.
[0311] The diagnosis of psoriasis is usually based on the
appearance of the skin. Additionally, a skin biopsy, or scraping
and culture of skin patches may be needed to rule out other skin
disorders. An x-ray may be used to check for psoriatic arthritis if
joint pain is present and persistent.
[0312] Improvements in psoriasis in a subject can be monitored by
the subject's Psoriasis Area and Severity Index Score (PAST). The
method for determining the PASI has been described in Fredriksson
and Pettersson (1978) Dermatologica 157:238 and Marks et al. (1989)
Arch Dermatol 125:235. Briefly, the index is based on evaluation of
four anatomic sites, including the head, upper extremities, trunk,
and lower extremities, for erythema, induration, and desquamation
using a 5 point scale (0=no symptoms; 1=slight; 2=moderate;
3=marked; 4=very marked). Based on the extent of lesions in a given
anatomic site, the area affected is assigned a numerical value
(0=0; 1=<10%; 2=10-29%; 3=30-49%; 4=50-69%; 5=70=89%;
6=90-100%). The PASI score is then calculated, wherein the possible
range of PASI score is 0.0 to 72.0 with the highest score
representing complete erythroderma of the severest degree.
[0313] In one embodiment of the invention, a TNF.alpha. inhibitor
is used in multiple-variable dose treatment for psoriasis,
including chronic plaque psoriasis, guttate psoriasis, inverse
psoriasis, pustular psoriasis, pemphigus vulgaris, erythrodermic
psoriasis, psoriasis associated with inflammatory bowel disease
(IBD), and psoriasis associated with rheumatoid arthritis (RA). In
another embodiment, a TNF.alpha. inhibitor, such as D2E7, is used
in a multiple variable dose regimen to treat subjects who have
psoriasis in combination with PsA. Specific types of psoriasis
included in the treatment methods of the invention are described in
detail below:
[0314] a. Chronic Plaque Psoriasis
[0315] Tumor necrosis factor has been implicated in the
pathophysiology of chronic plaque psoriasis (Asadullah et al.
(1999) Br J Dermatol.141:94). Chronic plaque psoriasis (also
referred to as psoriasis vulgaris) is the most common form of
psoriasis. Chronic plaque psoriasis is characterized by raised
reddened patches of skin, ranging from coin-sized to much larger.
In chronic plaque psoriasis, the plaques may be single or multiple,
they may vary in size from a few millimeters to several
centimeters. The plaques are usually red with a scaly surface, and
reflect light when gently scratched, creating a "silvery" effect.
Lesions (which are often symmetrical) from chronic plaque psoriasis
occur all over body, but with predilection for extensor surfaces,
including the knees, elbows, lumbosacral regions, scalp, and nails.
Occasionally chronic plaque psoriasis can occur on the penis, vulva
and flexures, but scaling is usually absent. Diagnosis of patients
with chronic plaque psoriasis is usually based on the clinical
features described above. In particular, the distribution, color
and typical silvery scaling of the lesion in chronic plaque
psoriasis are characteristic of chronic plaque psoriasis.
[0316] b. Guttate Psoriasis
[0317] Guttate psoriasis refers to a form of psoriasis with
characteristic water drop shaped scaly plaques. Flares of guttate
psoriasis generally follow an infection, most notably a
streptococcal throat infection. Diagnosis of guttate psoriasis is
usually based on the appearance of the skin, and the fact that
there is often a history of recent sore throat.
[0318] c. Inverse Psoriasis
[0319] Inverse psoriasis is a form of psoriasis in which the
patient has smooth, usually moist areas of skin that are red and
inflamed, which is unlike the scaling associated with plaque
psoriasis. Inverse psoriasis is also referred to as intertiginous
psoriasis or flexural psoriasis. Inverse psoriasis occurs mostly in
the armpits, groin, under the breasts and in other skin folds
around the genitals and buttocks, and, as a result of the locations
of presentation, rubbing and sweating can irritate the affected
areas.
[0320] d. Pustular Psoriasis
[0321] Pustular psoriasis, also referred to as palmar plantar
psoriasis, is a form of psoriasis that causes pus-filled blisters
that vary in size and location, but often occur on the hands and
feet. The blisters may be localized, or spread over large areas of
the body. Pustular psoriasis can be both tender and painful, can
cause fevers.
[0322] e. Other Psoriasis Disorders
[0323] Other examples of psoriatic disorders which can be treated
with the TNF.alpha. antibody of the invention include erythrodermic
psoriasis, vulgaris, psoriasis associated with IBD, and psoriasis
associated with arthritis, including rheumatoid arthritis.
[0324] 2. Pemphigus Vulgaris
[0325] Pemphigus vulgaris is a serious autoimmune systemic
dermatologic disease that often affects the oral mucous membrane
and skin. The pathogenesis of pemphigus vulgaris is thought to be
an autoimmune process that is directed at skin and oral mucous
membrane desmosomes. Consequentially, cells do not adhere to each
other. The disorder manifests as large fluid-filled, rupture-prone
bullae, and has a distinctive histologic appearance.
Anti-inflammatory agents are the only effective therapy for this
disease which has a high mortality rate. Complications that arise
in patients suffering from pemphigus vulgaris are intractable pain,
interference with nutrition and fluid loss, and infections.
[0326] 3. Atopic Dermatitis/Eczema
[0327] Atopic dermatitis (also referred to as eczema) is a chronic
skin disorder categorized by scaly and itching plaques. People with
eczema often have a family history of allergic conditions like
asthma, hay fever, or eczema. Atopic dermatitis is a
hypersensitivity reaction (similar to an allergy) which occurs in
the skin, causing chronic inflammation. The inflammation causes the
skin to become itchy and scaly. Chronic irritation and scratching
can cause the skin to thicken and become leathery-textured.
Exposure to environmental irritants can worsen symptoms, as can
dryness of the skin, exposure to water, temperature changes, and
stress.
[0328] Subjects with atopic dermatitis can be identified by certain
symptoms, which often include intense itching, blisters with oozing
and crusting, skin redness or inflammation around the blisters,
rash, dry, leathery skin areas, raw areas of the skin from
scratching, and ear discharges/bleeding.
[0329] 4. Sarcoidosis
[0330] Sarcoidosis is a disease in which granulomatous inflammation
occurs in the lymph nodes, lungs, liver, eyes, skin, and/or other
tissues. Sarcoidosis includes cutaneous sarcoidosis (sarcoidosis of
the skin) and nodular sarcoidosis (sarcoidosis of the lymph nodes).
Patients with sarcoidosis can be identified by the symptoms, which
often include general discomfort, uneasiness, or an ill feeling;
fever; skin lesions.
[0331] 5. Erythema Nodosum
[0332] Erythema nodosum refers to an inflammatory disorder that is
characterized by tender, red nodules under the skin, typically on
the anterior lower legs. Lesions associated with erythema nodosum
often begin as flat, but firm, hot red painful lumps (approximately
an inch across). Within a few days the lesions may become purplish,
and then over several weeks fade to a brownish flat patch.
[0333] In some instances, erythema nodosum may be associated with
infections including, Streptococcus, coccidioidomycosis,
tuberculosis, hepatitis B, syphilis, cat scratch disease,
tularemia, Yersinia, leptospirosis psittacosis, hi stoplasmosis,
mononucleosis (EBV). In other instances, erythema nodosum may be
associated with sensitivity to certain medications including, oral
contraceptives, penicillin, sulfonamides, sulfones, barbiturates,
hydantoin, phenacetin, salicylates, iodides, and progestin.
Erythema nodosum is often associated with other disorders
including, leukemia, sarcoidosis, rheumatic fever, and ulcerative
colitis.
[0334] Symptoms of erythema nodosum usually present themselves on
the shins, but lesions may also occur on other areas of the body,
including the buttocks, calves, ankles, thighs and upper
extremities. Other symptoms in subjects with erythema nodosum can
include fever and malaise.
[0335] 6. Hidradenitis Suppurativa
[0336] Hidradenitis suppurativa refers to a skin disorder in which
swollen, painful, inflamed lesions or lumps develop in the groin
and sometimes under the arms and under the breasts. Hidradenitis
suppurativa occurs when apocrine gland outlets become blocked by
perspiration or are unable to drain normally because of incomplete
gland development. Secretions trapped in the glands force
perspiration and bacteria into surrounding tissue, causing
subcutaneous induration, inflammation, and infection. Hidradenitis
suppurativa is confined to areas of the body that contain apocrine
glands. These areas are the axillae, areola of the nipple, groin,
perineum, circumanal, and periumbilical regions.
[0337] 7. Lichen Planus
[0338] Tumor necrosis factor has been implicated in the
pathophysiology of lichen planus (Sklavounou et al. (2000) J Oral
Pathol Med. 29:370). Lichen planus refers to a disorder of the skin
and the mucous membranes resulting in inflammation, itching, and
distinctive skin lesions. Lichen planus may be associated with
hepatitis C or certain medications.
[0339] 8. Sweet's Syndrome
[0340] Inflammatory cytokines, including tumor necrosis factor,
have been implicated in the pathophysiology of Sweet's syndrome
(Reuss-Borst et al. (1993) Br J Haematol. 84:356). Sweet's
syndrome, which was described by R. D. Sweet in 1964, is
characterized by the sudden onset of fever, leukocytosis, and
cutaneous eruption. The eruption consists of tender, erythematous,
well-demarcated papules and plaques which show dense neutrophilic
infiltrates microscopically. The lesions may appear anywhere, but
favor the upper body including the face. The individual lesions are
often described as pseudovesicular or pseudopustular, but may be
frankly pustular, bullous, or ulcerative. Oral and eye involvement
(conjunctivitis or episcleritis) have also been frequently reported
in patients with Sweet's syndrome. Leukemia has also been
associated with Sweet's syndrome.
[0341] 9. Vitiligo
[0342] Vitiligo refers to a skin condition in which there is loss
of pigment from areas of skin resulting in irregular white patches
with normal skin texture. Lesions characteristic of vitiligo appear
as flat depigmented areas. The edges of the lesions are sharply
defined but irregular. Frequently affected areas in subjects with
vitiligo include the face, elbows and knees, hands and feet, and
genitalia.
[0343] 10. Scleroderma
[0344] Tumor necrosis factor has been implicated in the
pathophysiology of scleroderma (Tutuncu et al. (2002) Clin Exp
Rheumatol. 20(6 Suppl 28): S146; Mackiewicz et al. (2003) Clin Exp
Rheumatol. 21:41; Murota et al. (2003) Arthritis Rheum. 48:1117).
Scleroderma refers to a diffuse connective tissue disease
characterized by changes in the skin, blood vessels, skeletal
muscles, and internal organs. Scleroderma is also referred to as
CREST syndrome or progressive systemic sclerosis, and usually
affects people between the ages 30-50. Women are affected more
often than men.
[0345] The cause of scleroderma is unknown. The disease may produce
local or systemic symptoms. The course and severity of the disease
varies widely in those affected. Excess collagen deposits in the
skin and other organs produce the symptoms. Damage to small blood
vessels within the skin and affected organs also occurs. In the
skin, ulceration, calcification, and changes in pigmentation may
occur. Systemic features may include fibrosis and degeneration of
the heart, lungs, kidneys and gastrointestinal tract.
[0346] Patients suffering from scleroderma exhibit certain clinical
features, including, blanching, blueness, or redness of fingers and
toes in response to heat and cold (Raynaud's phenomenon), pain,
stiffness, and swelling of fingers and joints, skin thickening and
shiny hands and forearm, esophageal reflux or heartburn, difficulty
swallowing, and shortness of breath. Other clinical symptoms used
to diagnose scleroderma include, an elevated erythrocyte
sedimentation rate (ESR), an elevated rheumatoid factor (RF), a
positive antinuclear antibody test, urinalysis that shows protein
and microscopic blood, a chest X-ray that may show fibrosis, and
pulmonary function studies that show restrictive lung disease.
[0347] 11. Nail Disorders
[0348] Nail disorders include any abnormality of the nail. The term
"nail disorder" or "nail disease" as used herein, refers to
conditions wherein the fingernails or toenails to abnormal color,
shape, texture, or thickness. Specific nail disorders include, but
are not limited to, pitting, koilonychia, Beau's lines, spoon
nails, onycholysis, yellow nails, pterygium (seen in lichen
planus), and leukonychia. Pitting is characterized by the presence
of small depressions on the nail surface. Ridges or linear
elevations can develop along the nail occurring in a "lengthwise"
or "crosswise" direction. Beau's lines are linear depressions that
occur "crosswise" (transverse) in the fingernail. Leukonychia
describes white streaks or spots on the nails. Koilonychia is an
abnormal shape of the fingernail where the nail has raised ridges
and is thin and concave Koilonychia is often associated with iron
deficiency.
[0349] Nail disorders which can be treated with the TNF.alpha.
antibody of the invention also include psoriatic nails. Psoriatic
nails include changes in nails which are attributable to psoriasis.
In some instances, psoriasis may occur only in the nails and
nowhere else on the body. Psoriatic changes in nails range from
mild to severe, generally reflecting the extent of psoriatic
involvement of the nail plate, nail matrix, i.e., tissue from which
the nail grows, nail bed, i.e., tissue under the nail, and skin at
the base of the nail. Damage to the nail bed by the pustular type
of psoriasis can result in loss of the nail. Nail changes in
psoriasis fall into general categories that may occur singly or all
together. In one category of psoriatic nails, the nail plate is
deeply pitted, probably due to defects in nail growth caused by
psoriasis. In another category, the nail has a yellow to
yellow-pink discoloration, probably due to psoriatic involvement of
the nail bed. A third subtype of psoriatic nails are characterized
by white areas which appear under the nail plate. The white areas
are actually air bubbles marking spots where the nail plate is
becoming detached from the nail bed. There may also be reddened
skin around the nail. A fourth category is evidenced by the nail
plate crumbling in yellowish patches, i.e., onychodystrophy,
probably due to psoriatic involvement in the nail matrix. A fifth
category is characterized by the loss of the nail in its entirety
due to psoriatic involvement of the nail matrix and nail bed.
[0350] The multiple-variable dose method of treatment of the
invention can also be used to treat nail disorders often associated
with lichen planus. Nails in subjects with lichen planus often show
thinning and surface roughness of the nail plate with longitudinal
ridges or pterygium.
[0351] The multiple-variable dose method of treatment of the
invention can be used to treat nail disorders, such as those
described herein. Often nail disorders are associated with skin
disorders. In one embodiment, the invention includes a
multiple-variable dose method of treatment for nail disorders using
a TNF.alpha. antibody. In another embodiment, the nail disorder is
associated with another disorder, including a skin disorder such as
psoriasis. In another embodiment, the disorder associated with a
nail disorder is arthritis, including psoriatic arthritis.
[0352] 12. Other Skin and Nail Disorders
[0353] The multiple-variable dose method of treatment of the
invention can be used to treat other skin and nail disorders, such
as chronic actinic dermatitis, bullous pemphigoid, and alopecia
areata. Chronic actinic dermatitis (CAD) is also referred to as
photosensitivity dermatitis/actinic reticuloid syndrome (PD/AR).
CAD is a condition in which the skin becomes inflamed, particularly
in areas that have been exposed to sunlight or artificial light.
Commonly, CAD patients have allergies to certain substances that
come into contact with their skin, particularly various flowers,
woods, perfumes, sunscreens and rubber compounds. Bullous
pemphigoid refers to a skin disorder characterized by the formation
of large blisters on the trunk and extremities. Alopecia areata
refers to hair loss characterized by round patches of complete
baldness in the scalp or beard.
[0354] O. Vasculitides
[0355] TNF.alpha. has been implicated in the pathophysiology of a
variety of vasculitides, (see e.g., Deguchi et al. (1989) Lancet.
2:745). In one embodiment, the invention provides a
multiple-variable dose method for inhibiting TNF.alpha. activity in
a subject suffering from a vasculitis in which TNF.alpha. activity
is detrimental.
[0356] The term "vasculitis" or "vasculitides" as used
interchangeably herein, refers to a group of disorders which are
characterized by the inflammation of blood vessels. Blood vessels
of all sizes may be affected, from the largest vessel in the body
(the aorta) to the smallest blood vessels in the skin
(capillaries). The size of blood vessel affected varies according
to the specific type of vasculitis. As used herein, the term "a
vasculitis in which TNF.alpha. activity is detrimental" is intended
to include vasculitis in which the presence of TNF.alpha. in a
subject suffering from the disorder has been shown to be or is
suspected of being either responsible for the pathophysiology of
the disorder or a factor that contributes to a worsening of the
disorder. Such disorders may be evidenced, for example, by an
increase in the concentration of TNF.alpha. in a biological fluid
of a subject suffering from the disorder (e.g., an increase in the
concentration of TNF.alpha. in serum, plasma, synovial fluid, etc.
of the subject), which can be detected, for example, using an
anti-TNF.alpha. antibody as described above.
[0357] There are numerous examples of vasculitides in which
TNF.alpha. activity is detrimental, including Behcet's disease. The
use of the antibodies, antibody portions, and other TNF.alpha.
inhibitors for multiple-variable dose treatment of the invention of
specific vasculitides is discussed further below. In certain
embodiments, the antibody, antibody portion, or other TNF.alpha.
inhibitor of the invention is administered to the subject in
combination with another therapeutic agent, as described below.
[0358] The multiple-variable dose regimen of the invention can be
used to treat vasculitis in which TNF.alpha. activity is
detrimental, wherein inhibition of TNF.alpha. activity is expected
to alleviate the symptoms and/or progression of the vasculitis or
to prevent the vasculitis. Subjects suffering from or at risk of
developing vasculitis can be identified through clinical symptoms
and tests. For example, subjects with vasculitides often develop
antibodies to certain proteins in the cytoplasm of neutrophils,
antineutrophil cytoplasmic antibodies (ANCA). Thus, in some
instances, vasculitides may be evidenced by tests (e.g., ELISA),
which measure ANCA presence.
[0359] Vasculitis and its consequences may be the sole
manifestation of disease or it may be a secondary component of
another primary disease. Vasculitis may be confined to a single
organ or it may simultaneously affect several organs. and depending
on the syndrome, arteries and veins of all sizes can be affected.
Vasculitis can affect any organ in the body.
[0360] In vasculitis, the vessel lumen is usually compromised,
which is associated with ischemia of the tissues supplied by the
involved vessel. The broad range of disorders that may result from
this process is due to the fact that any type, size and location of
vessel (e.g., artery, vein, arteriole, venule, capillary) can be
involved. Vasculitides are generally classified according to the
size of the affected vessels, as described below. It should be
noted that some small and large vessel vasculitides may involve
medium-sized arteries; but large and medium-sized vessel
vasculitides do not involve vessels smaller than arteries. Large
vessel disease includes, but is not limited to, giant cell
arteritis, also known as temporal arteritis or cranial arteritis,
polymyalgia rheumatica, and Takayasu's disease or arteritis, which
is also known as aortic arch syndrome, young female arteritis and
Pulseless disease. Medium vessel disease includes, but is not
limited to, classic polyarteritis nodosa and Kawasaki's disease,
also known as mucocutaneous lymph node syndrome. Non-limiting
examples of small vessel disease are Behcet's Syndrome, Wegner's
granulomatosis, microscopic polyangitis, hypersensitivity
vasculitis, also known as cutaneous vasculitis, small vessel
vasculitis, Henoch-Schonlein purpura, allergic granulamotosis and
vasculitis, also known as Churg Strauss syndrome. Other
vasculitides include, but are not limited to, isolated central
nervous system vasculitis, and thromboangitis obliterans, also
known as Buerger's disease. Classic Polyarteritis nodosa (PAN),
microscopic PAN, and allergic granulomatosis are also often grouped
together and are called the systemic necrotizing vasculitides. A
further description of vasculitis is described below:
[0361] 1. Large Vessel Vasculitis
[0362] In one embodiment, the TNF.alpha. antibody of the invention
is used to treat subjects who have large vessel vasculitis. The
term "large vessel(s)" as used herein, refers to the aorta and the
largest branches directed toward major body regions. Large vessels
include, for example, the aorta, and its branches and corresponding
veins, e.g., the subclavian artery; the brachiocephalic artery; the
common carotid artery; the innonimate vein; internal and external
jugular veins; the pulmonary arteries and veins; the venae cavae;
the renal arteries and veins; the femoral arteries and veins; and
the carotid arteries. Examples of large vessel vasculitides are
described below.
[0363] a. Giant Cell Arteritis (GCA)
[0364] Tumor necrosis factor has been implicated in the
pathophysiology of giant cell arteritis (Sneller (2002) Cleve.
Clin. J. Med. 69:SI140; Schett et al. (2002) Ann. Rheum. Dis.
61:463). Giant cell arteritis (GCA), refers to a vasculitis
involving inflammation and damage to blood vessels, particularly
the large or medium arteries that branch from the external carotid
artery of the neck. GCA is also referred to as temporal arteritis
or cranial arteritis, and is the most common primary vasculitis in
the elderly. It almost exclusively affects individuals over 50
years of age, however, there are well-documented cases of patients
40 years and younger. GCA usually affects extracranial arteries.
GCA can affect the branches of the carotid arteries, including the
temporal artery. GCA is also a systemic disease which can involve
arteries in multiple locations.
[0365] Histopathologically, GCA is a panarteritis with inflammatory
mononuclear cell infiltrates within the vessel wall with frequent
Langhans type giant cell formation. There is proliferation of the
intima, granulomatous inflammation and fragmentation of the
internal elastic lamina. The pathological findings in organs is the
result of ischemia related to the involved vessels.
[0366] Patients suffering from GCA exhibit certain clinical
symptoms, including fever, headache, anemia and high erythrocyte
sedimentation rate (ESR). Other typical indications of GCA include
jaw or tongue claudication, scalp tenderness, constitutional
symptoms, pale optic disc edema (particularly `chalky white` disc
edema), and vision disturbances. The diagnosis is confirmed by
temporal artery biopsy.
[0367] b. Polymyalgia Rheumatica
[0368] Tumor necrosis factor has been implicated in the
pathophysiology of polymyalgia rheumatica (Straub et al. (2002)
Rheumatology (Oxford) 41:423; Uddhammar et al. (1998) Br. J.
Rheumatol. 37:766). Polymyalgia rheumatica refers to a rheumatic
disorder that is associated with moderate to severe muscle pain and
stiffness in the neck, shoulder, and hip, most noticeable in the
morning. IL-6 and IL-1.beta. expression has also been detected in a
majority of the circulating monocytes in patients with the
polymyalgia rheumatica. Polymyalgia rheumatica may occur
independently, or it may coexist with or precede GCA, which is an
inflammation of blood vessels.
[0369] c. Takayasu's Arteritis
[0370] Tumor necrosis factor has been implicated in the
pathophysiology of Takayasu's arteritis (Kobayashi and Numano
(2002) Intern. Med. 41:44; Fraga and Medina (2002) Curr. Rheumatol.
Rep. 4:30). Takayasu's arteritis refers to a vasculitis
characterized by an inflammation of the aorta and its major
branches. Takayasu's arteritis (also known as Aortic arch syndrome,
young female arteritis and Pulseless disease) affects the thoracic
and abdominal aorta and its main branches or the pulmonary
arteries. Fibrotic thickening of the aortic wall and its branches
(e.g., carotid, inominate, and subclavian arteries) can lead to
reduction of lumen size of vessels that arise from the aortic arch.
This condition also typically affects the renal arteries.
[0371] Takayasu's arteritis primarily affects young women, usually
aged 20-40 years old, particularly of Asian descent, and may be
manifested by malaise, arthralgias and the gradual onset of
extremity claudication. Most patients have asymmetrically reduced
pulses, usually along with a blood pressure differential in the
arms. Coronary and/or renal artery stenosis may occur.
[0372] The clinical features of Takayasu's arteritis may be divided
into the features of the early inflammatory disease and the
features of the later disease. The clinical features of the early
inflammatory stage of Takayasu's disease are: malaise, low grade
fever, weight loss, myalgia, arthralgia, and erythema multiforme.
Later stages of Takayasu's disease are characterized by fibrotic
stenosis of arteries and thrombosis. The main resulting clinical
features are ischaemic phenomena, e.g. weak and asymmetrical
arterial pulses, blood pressure discrepancy between the arms,
visual disturbance, e.g. scotomata and hemianopia, other
neurological features including vertigo and syncope, hemiparesis or
stroke. The clinical features result from ischaemia due to arterial
stenosis and thrombosis.
[0373] 2. Medium Vessel Disease
[0374] In one embodiment, the TNF.alpha. antibody of the invention
is used to treat subjects who have medium vessel vasculitis. The
term "medium vessel(s)" is used to refer to those blood vessels
which are the main visceral arteries. Examples of medium vessels
include the mesenteric arteries and veins, the iliac arteries and
veins, and the maxillary arteries and veins. Examples of medium
vessel vasculitides are described below.
[0375] a. Polyarteritis Nodosa
[0376] Tumor necrosis factor has been implicated in the
pathophysiology of polyarteritis nodosa (DiGirolamo et al. (1997)
J. Leukoc. Biol. 61:667). Polyarteritis nodosa, or periarteritis
nodosa refers to vasculitis which is a serious blood vessel disease
in which small and medium-sized arteries become swollen and damaged
because they are attacked by rogue immune cells. Polyarteritis
nodosa usually affects adults more frequently than children. It
damages the tissues supplied by the affected arteries because they
don't receive enough oxygen and nourishment without a proper blood
supply.
[0377] Symptoms which are exhibited in patients with polyarteritis
nodosa generally result from damage to affected organs, often the
skin, heart, kidneys, and nervous system. Generalized symptoms of
polyarteritis nodosa include fever, fatigue, weakness, loss of
appetite, and weight loss. Muscle aches (myalgia) and joint
aches(arthralgia) are common. The skin of subjects with
polyarteritis nodosa may also show rashes, swelling, ulcers, and
lumps (nodular lesions).
[0378] Classic PAN (polyarteritis nodosa) is a systemic arteritis
of small to medium muscular arteritis in which involvement of renal
and visceral arteries is common. Abdominal vessels have aneurysms
or occlusions in 50% of PAN patients. Classic PAN does not involve
the pulmonary arteries although the bronchial vessels may be
involved. Granulomas, significant eosinophilia and an allergic
diathesis are not part of the syndrome. Although any organ system
may be involved, the most common manifestations include peripheral
neuropathy, mononeuritis multiplex, intestinal ischemia, renal
ischemia, testicular pain and livedo reticularis.
[0379] b. Kawasaki's Disease
[0380] Tumor necrosis factor has been implicated in the
pathophysiology of Kawasaki's disease (Sundel (2002) Curr.
Rheumatol. Rep. 4:474; Gedalia (2002) Curr. Rheumatol. Rep. 4:25).
Although the cause of Kawasaki's disease is unknown, it is
associated with acute inflammation of the coronary arteries,
suggesting that the tissue damage associated with this disease may
be mediated by proinflammatory agents such as TNF.alpha..
Kawasaki's disease refers to a vasculitis that affects the mucus
membranes, lymph nodes, lining of the blood vessels, and the heart.
Kawasaki's disease is also often referred to as mucocutaneous lymph
node syndrome, mucocutaneous lymph node disease, and infantile
polyarteritis. Subjects afflicted with Kawasaki's disease develop
vasculitis often involving the coronary arteries which can lead to
myocarditis and pericarditis. Often as the acute inflammation
diminishes, the coronary arteries may develop aneurysm, thrombosis,
and lead to myocardial infarction.
[0381] Kawasaki's disease is a febrile systemic vasculitis
associated with edema in the palms and the soles of the feet, with
enlargement of cervical lymph nodes, cracked lips and "strawberry
tongue". Although the inflammatory response is found in vessels
throughout the body, the most common site of end-organ damage is
the coronary arteries. Kawasaki's Disease predominantly affects
children under the age of 5. The highest incidence is in Japan but
is becoming increasingly recognized in the West and is now the
leading cause of acquired heart disease in US children. The most
serious complication of Kawasaki disease is coronary arteritis and
aneurysm formation that occurs in a third of untreated
patients.
[0382] 3. Small Vessel Disease
[0383] In one embodiment, the TNF.alpha. antibody of the invention
is used to treat subjects who have small vessel vasculitis. The
term "small vessel(s)" is used to refer to arterioles, venules and
capillaries. Arterioles are arteries that contain only 1 or 2
layers of sooth muscle cells and are terminal to and continuous
with the capillary network. Venules carry blood from the capillary
network to veins and capillaries connect arterioles and venules.
Examples of small vessel vasculitides are described below.
[0384] a. Behcet's Disease
[0385] Tumor necrosis factor has been implicated in the
pathophysiology of Behcet's disease (Sfikakis (2002) Ann. Rheum.
Dis. 61:ii51-3; Dogan and Farah (2002) Oftalmologia. 52:23).
Behcet's disease is a chronic disorder that involves inflammation
of blood vessels throughout the body. Behcet's disease may also
cause various types of skin lesions, arthritis, bowel inflammation,
and meningitis (inflammation of the membranes of the brain and
spinal cord). As a result of Behcet's disease, the subject with the
disorder may have inflammation in tissues and organs throughout the
body, including the gastrointestinal tract, central nervous system,
vascular system, lungs, and kidneys. Behcet's disease is three
times more common in males than females and is more common in the
eastern Mediterranean and Japan.
[0386] Subjects who have Behcet's disease may show clinical
symptoms including recurrent oral ulcers (resembling canker sores),
recurrent genital ulcers, and eye inflammation. Serum levels of
TNF.alpha., IL-8, IL-1, IL-6 INF-y and IL-12 are elevated in
Behcet's patients, and the production of these factors has been
shown to be elevated in the monocytes of Behcet's patients (see,
e.g., Inflammatory Disease of Blood Vessels (2001) Marcel Dekker,
Inc., eds. G. S. Hoffman and C. M. Weyand, p. 473).
[0387] b. Wegener's Granulomatosis
[0388] Tumor necrosis factor has been implicated in the
pathophysiology of Wegener's granulomatosis (Marquez et al. (2003)
Curr. Rheumatol. Rep. 5:128; Harman and Margo (1998) Surv.
Ophthalmol. 42:458). Wegener's granulomatosis refers to a
vasculitis that causes inflammation of blood vessels in the upper
respiratory tract (nose, sinuses, ears), lungs, and kidneys.
Wegener's granulomatosis is also referred to as midline
granulomatosis. Wegener's granulomatosis includes a granulomatous
inflammation involving the respiratory tract, and necrotizing
vasculitis affecting small to medium-sized vessels. Subjects who
have Wegener's granulomatosis often also have arthritis (joint
inflammation). Glomerulonephritis may also be present in affected
subjects, but virtually any organ may be involved.
[0389] Patients affected with Wegener's granulomatosis typically
show clinical symptoms comprising recurrent sinusitis or epistaxis,
mucosal ulcerations, otitis media, cough, hemoptysis and dyspnea.
The first symptoms of Wegener's granulomatosis frequently include
upper respiratory tract symptoms, joint pains, weakness, and
tiredness.
[0390] c. Churg-Strauss Syndrome
[0391] Tumor necrosis factor has been implicated in the
pathophysiology of Churg-Strauss syndrome (Gross (2002) Curr. Opin.
Rheumatol. 14:11; Churg (2001) Mod. Pathol. 14:1284). Churg-Strauss
syndrome refers to a vasculitis that is systemic and shows early
manifestation signs of asthma and eosinophilia. Churg-Strauss
syndrome is also referred to as allergic granulomatosis and
angiitis, and occurs in the setting of allergic rhinitis, asthma
and eosinophilia. Sinusitis and pulmonary infiltrates also occur in
Churg-Strauss syndrome, primarily affecting the lung and heart.
Peripheral neuropathy, coronary arteritis and gastrointestinal
involvement are common.
[0392] Patients afflicted with Churg-Strauss syndrome can be
diagnosed according to criteria established by the American College
of Rheumatology (ACR). These criteria were intended to distinguish
CSS from other forms of vasculitis. Not all patients meet every
criterion. Some, in fact, may have only 2 or 3 criteria, yet they
are still classified as Churg-Strauss syndrome. The ACR selected 6
disease features (criteria) as being those that best distinguished
Churg-Strauss syndrome from other vasculitides. These criteria
include: 1) asthma; 2) eosinophilia [>10% on differential WBC
count]; 3) mononeuropathy; 4) transient pulmonary infiltrates on
chest X-rays; 5) paranasal sinus abnormalities; and 6) biopsy
containing a blood vessel with extravascular eosinophils.
[0393] P. Other TNF.alpha.-Related Disorders
[0394] In one embodiment, the invention features a
multiple-variable dose method for treating a TNF.alpha.-related
disorder in which TNF.alpha. activity is detrimental, comprising
administering to a subject an induction dose of a TNF.alpha.
inhibitor and a subsequent treatment dose, such that said
TNF.alpha.-related disorder is treated. Examples of
TNF.alpha.-related disorders in which TNF.alpha. activity is
detrimental, are discussed further below.
[0395] 1. Juvenile Arthritis
[0396] Tumor necrosis factor has been implicated in the
pathophysiology of juvenile arthritis, including juvenile
rheumatoid arthritis (Grom et al. (1996) Arthritis Rheum. 39:1703;
Mangge et al. (1995) Arthritis Rheum. 8:211). In one embodiment,
the TNF.alpha. antibody of the invention is used to treat juvenile
rheumatoid arthritis.
[0397] The term "juvenile rheumatoid arthritis" or "JRA" as used
herein refers to a chronic, inflammatory disease which occurs
before age 16 that may cause joint or connective tissue damage. JRA
is also referred to as juvenile chronic polyarthritis and Still's
disease.
[0398] JRA causes joint inflammation and stiffness for more than 6
weeks in a child of 16 years of age or less. Inflammation causes
redness, swelling, warmth, and soreness in the joints. Any joint
can be affected and inflammation may limit the mobility of affected
joints. One type of JRA can also affect the internal organs.
[0399] JRA is often classified into three types by the number of
joints involved, the symptoms, and the presence or absence of
certain antibodies found by a blood test. These classifications
help the physician determine how the disease will progress and
whether the internal organs or skin is affected. The
classifications of JRA include the following
[0400] a. Pauciarticular JRA, wherein the patient has four or fewer
joints are affected. Pauciarticular is the most common form of JRA,
and typically affects large joints, such as the knees.
[0401] b. Polyarticular HRA, wherein five or more joints are
affected. The small joints, such as those in the hands and feet,
are most commonly involved, but the disease may also affect large
joints.
[0402] c. Systemic JRA is characterized by joint swelling, fever, a
light skin rash, and may also affect internal organs such as the
heart, liver, spleen, and lymph nodes. Systemic JRA is also
referred to as it Still's disease. A small percentage of these
children develop arthritis in many joints and can have severe
arthritis that continues into adulthood.
[0403] 2. Endometriosis
[0404] Tumor necrosis factor has been implicated in the
pathophysiology of endometriosis, as women with endometriosis have
elevated peritoneal levels of TNF (Eisermann et al. (1988) Fertil
Steril 50:573; Halme (1989) Am J Obstet Gynecol 161:1718; Mori et
al. (1991) Am J Reprod Immunol 26:62; Taketani et al. (1992) Am J
Obstet Gynecol 167:265; Overton et al. (1996) Hum Reprod 1996;
11:380). In one embodiment, the TNF.alpha. antibody of the
invention is used to treat endometriosis. The term "endometriosis"
as used herein refers to a condition in which the tissue that
normally lines the uterus (endometrium) grows in other areas of the
body, causing pain, irregular bleeding, and frequently
infertility.
[0405] 3. Prostatitis
[0406] Tumor necrosis factor has been implicated in the
pathophysiology of prostatitis, as men with chronic prostatitis and
chronic pelvic pain have significantly higher levels of TNF and
IL-1 in semen compared to controls (Alexander et al. (1998) Urology
52:744; Nadler et al. (2000) J Urol 164:214; Orhan et al. (2001)
Int J Urol 8:495)
[0407] Furthermore, in a rat model of prostatitis TNF levels were
also increased in comparison to controls (Asakawa et al. (2001)
Hinyokika Kiyo 47:459; Harris et al. (2000) Prostate 44:25). In one
embodiment, the TNF.alpha. antibody of the invention is used to
treat prostatitis.
[0408] The term "prostatitis" as used herein refers to an
inflammation of the prostate. Prostatitis is also referred to as
pelvic pain syndrome. Prostatitis manifests itself in a variety of
forms, including nonbacterial prostatitis, acute prostatitis,
bacterial prostatitis, and acute prostatitis. Acute prostatitis
refers to an inflammation of the prostate gland that develops
suddenly. Acute prostatitis is usually caused by a bacterial
infection of the prostate gland. Chronic prostatitis is an
inflammation of the prostate gland that develops gradually,
continues for a prolonged period, and typically has subtle
symptoms. Chronic prostatitis is also usually caused by a bacterial
infection.
[0409] 4. Choroidal Neovascularization
[0410] Tumor necrosis factor has been implicated in the
pathophysiology of choroidal neovascularization. For example, in
surgically excised choroidal neovascular membranes, neovascular
vessels stained positive for both TNF and IL-1 (Oh H et al. (1999)
Invest Ophthalmol Vis Sci 40:1891). In one embodiment, the
TNF.alpha. antibody of the invention is used to treat choroidal
neovascularization. The term "choroidal neovascularization" as used
herein refers to the growth of new blood vessels that originate
from the choroid through a break in the Bruch membrane into the
sub-retinal pigment epithelium (sub-RPE) or subretinal space.
Choroidal neovascularization (CNV) is a major cause of visual loss
in patients with the condition.
[0411] 5. Sciatica
[0412] Tumor necrosis factor has been implicated in the
pathophysiology of sciatica (Ozaktay et al. (2002) Eur Spine J.
11:467; Brisby et al. (2002) Eur Spine J. 11:62). In one
embodiment, the TNF.alpha. antibody of the invention is used to
treat sciatica. The term "sciatica" as used herein refers to a
condition involving impaired movement and/or sensation in the leg,
caused by damage to the sciatic nerve. Sciatica is also commonly
referred to as neuropathy of the sciatic nerve and sciatic nerve
dysfunction. Sciatica is a form of peripheral neuropathy. It occurs
when there is damage to the sciatic nerve, located in the back of
the leg. The sciatic nerve controls the muscles of the back of the
knee and lower leg and provides sensation to the back of the thigh,
part of the lower leg and the sole of the foot. Sciatica can be
indicative of another disorder, including a lumbar herniated disc,
spinal stenosis, degenerative disc disease, isthmic
spondyloisthesis and piniformis syndrome.
[0413] 6. Sjogren's syndrome
[0414] Tumor necrosis factor has been implicated in the
pathophysiology of Sjogren's syndrome (Koski et al. (2001) Clin Exp
Rheumatol. 19:131). In one embodiment, the TNF.alpha. antibody of
the invention is used to treat Sjogren's syndrome. The term
"Sjogren's syndrome" as used herein refers to a systemic
inflammatory disorder characterized by dry mouth, decreased
tearing, and other dry mucous membranes, and is often associated
with autoimmune rheumatic disorders, such as rheumatoid arthritis.
Dryness of the eyes and mouth are the most common symptoms of this
syndrome. The symptoms may occur alone, or with symptoms associated
with rheumatoid arthritis or other connective tissue diseases.
There may be an associated enlargement of the salivary glands.
Other organs may become affected. The syndrome may be associated
with rheumatoid arthritis, systemic lupus erythematosus,
scleroderma, polymyositis, and other diseases.
[0415] 7. Uveitis
[0416] Tumor necrosis factor has been implicated in the
pathophysiology of uveitis (Wakefield and Lloyd (1992) Cytokine
4:1; Woon et al. (1998) Curr Eye Res. 17:955). In one embodiment,
the TNF.alpha. antibody of the invention is used to treat uveitis.
The term "uveitis" as used herein refers to an inflammation of the
uvea, which is the layer between the sclera and the retina, which
includes the iris, ciliary body, and the choroid. Uveitis is also
commonly referred to as iritis, pars planitis, chroiditis,
chorioretinitis, anterior uveitis, and posterior uveitis. The most
common form of uveitis is anterior uveitis, which involves
inflammation in the front part of the eye, which is usually
isolated to the iris. This condition is often called iritis. In one
embodiment, the term uveitis refers to an inflammation of the uvea
which excludes inflammation associated with an autoimmune disease,
i.e., excludes autoimmune uveitis.
[0417] 8. Wet Macular Degeneration
[0418] Tumor necrosis factor has been implicated in the
pathophysiology of wet macular degeneration. In one embodiment, the
TNF.alpha. antibody of the invention is used to treat wet macular
degeneration. The term "wet macular degeneration" as used herein
refers to a disorder that affects the macula (the central part of
the retina of the eye) and causes decreased visual acuity and
possible loss of central vision. Patients with wet macular
degeneration develop new blood vessels under the retina, which
causes hemorrhage, swelling, and scar tissue.
[0419] 9. Osteoporosis
[0420] Tumor necrosis factor has been implicated in the
pathophysiology of osteoporosis, (Tsutsumimoto et al. (1999) J Bone
Miner Res. 14:1751). Osteoporosis is used to refer to a disorder
characterized by the progressive loss of bone density and thinning
of bone tissue. Osteoporosis occurs when the body fails to form
enough new bone, or when too much old bone is reabsorbed by the
body, or both. The TNF.alpha. antibody, or antigen-binding fragment
thereof, of the invention can be used to treat osteoporosis.
[0421] 10. Osteoarthritis
[0422] Tumor necrosis factor has been implicated in the
pathophysiology of osteoarthritis, (Venn et al. (1993) Arthritis
Rheum. 36:819; Westacott et al. (1994) J Rheumatol. 21:1710).
Osteoarthritis (OA) is also referred to as hypertrophic
osteoarthritis, osteoarthrosis, and degenerative joint disease. OA
is a chronic degenerative disease of skeletal joints, which affects
specific joints, commonly knees, hips, hand joints and spine, in
adults of all ages. OA is characterized by a number of the
following manifestations including degeneration and thinning of the
articular cartilage with associated development of "ulcers" or
craters, osteophyte formation, hypertrophy of bone at the margins,
and changes in the snyovial membrane and enlargement of affected
joints. Furthermore, osteoarthritis is accompanied by pain and
stiffness, particularly after prolonged activity. The antibody, or
antigen-binding fragment thereof, of the invention can be used to
treat osteoarthritis. Characteristic radiographic features of
osteoarthritis include joint space narrowing, subchondral
sclerosis, osteophytosis, subchondral cyst formation, loose osseous
body (or "joint mouse").
[0423] Medications used to treat osteoarthritis include a variety
of nonsteroidal, anti-inflammatory drugs (NSAIDs). In addition, COX
2 inhibitors, including Celebrex, Vioxx, and Bextra, and
Etoricoxib, are also used to treat OA. Steroids, which are injected
directly into the joint, may also be used to reduce inflammation
and pain. In one embodiment of the invention, TNF.alpha. antibodies
of the invention are administered in combination with a NSAIDs, a
COX2 inhibitor, and/or steroids.
[0424] 11. Other
[0425] The methods of the invention, also can be used to treat
various other disorders in which TNF.alpha. activity is
detrimental. Examples of other diseases and disorders in which
TNF.alpha. activity has been implicated in the pathophysiology, and
thus which can be treated using an antibody, or antibody portion,
of the invention, include inflammatory bone disorders, bone
resorption disease, coagulation disturbances, burns, reperfusion
injury, keloid formation, scar tissue formation, pyrexia,
periodontal disease, obesity, radiation toxicity, age-related
cachexia, Alzheimer's disease, brain edema, inflammatory brain
injury, cancer, chronic fatigue syndrome, dermatomyositis, drug
reactions, such as Stevens-Johnson syndrome and Jarisch-Herxheimer
reaction, edema in and/or around the spinal cord, familial periodic
fevers, Felty's syndrome, fibrosis, glomerulonephritides (e.g.
post-streptococcal glomerulonephritis or IgA nephropathy),
loosening of prostheses, microscopic polyangiitis, mixed connective
tissue disorder, multiple myeloma, cancer and cachexia, multiple
organ disorder, myelo dysplastic syndrome, orchitism osteolysis,
pancreatitis, including acute, chronic, and pancreatic abscess,
polymyositis, progressive renal failure, pseudogout, pyoderma
gangrenosum, relapsing polychondritis, rheumatic heart disease,
sarcoidosis, sclerosing cholangitis, stroke, thoracoabdominal
aortic aneurysm repair (TAAA), TNF receptor associated periodic
syndrome (TRAPS), symptoms related to Yellow Fever vaccination,
inflammatory diseases associated with the ear, chronic ear
inflammation, chronic otitis media with or without cholesteatoma,
pediatric ear inflammation, myotosis, ovarian cancer, colorectal
cancer, therapy associated with induced inflammatory syndrome
(e.g., syndromes following IL-2 administration), and a disorder
associated with a reperfussion injury.
[0426] It is understood that all of the above-mentioned
TNF.alpha.-related disorders include both the adult and juvenile
forms of the disease where appropriate. It is also understood that
all of the above-mentioned disorders include both chronic and acute
forms of the disease. In addition, the multiple-variable dose
methods of the invention can be used to treat each of the
above-mentioned TNF.alpha.-related disorders alone or in
combination with one another, e.g., a subject who is suffering from
uveitis and lupus.
IV. Pharmaceutical Compositions and Pharmaceutical
Administration
[0427] A. Compositions and Administration
[0428] Antibodies, antibody-portions, and other TNF.alpha.
inhibitors for use in the multiple-variable dose methods of the
invention, can be incorporated into pharmaceutical compositions
suitable for administration to a subject. Typically, the
pharmaceutical composition comprises an antibody, antibody portion,
or other TNF.alpha. inhibitor of the invention and a
pharmaceutically acceptable carrier. As used herein,
"pharmaceutically acceptable carrier" includes any and all
solvents, dispersion media, coatings, antibacterial and antifungal
agents, isotonic and absorption delaying agents, and the like that
are physiologically compatible. Examples of pharmaceutically
acceptable carriers include one or more of water, saline, phosphate
buffered saline, dextrose, glycerol, ethanol and the like, as well
as combinations thereof. In many cases, it is preferable to include
isotonic agents, for example, sugars, polyalcohols such as
mannitol, sorbitol, or sodium chloride in the composition.
Pharmaceutically acceptable carriers may further comprise minor
amounts of auxiliary substances such as wetting or emulsifying
agents, preservatives or buffers, which enhance the shelf life or
effectiveness of the antibody, antibody portion, or other
TNF.alpha. inhibitor.
[0429] The compositions for use in the methods of the invention may
be in a variety of forms. These include, for example, liquid,
semi-solid and solid dosage forms, such as liquid solutions (e.g.,
injectable and infusible solutions), dispersions or suspensions,
tablets, pills, powders, liposomes and suppositories. The preferred
form depends on the intended mode of administration and therapeutic
application. Typical preferred compositions are in the form of
injectable or infusible solutions, such as compositions similar to
those used for passive immunization of humans with other antibodies
or other TNF.alpha. inhibitors. The preferred mode of
administration is parenteral (e.g., intravenous, subcutaneous,
intraperitoneal, intramuscular). In a preferred embodiment, the
antibody or other TNF.alpha. inhibitor is administered by
intravenous infusion or injection. In another preferred embodiment,
the antibody or other TNF.alpha. inhibitor is administered by
intramuscular or subcutaneous injection.
[0430] Therapeutic compositions typically must be sterile and
stable under the conditions of manufacture and storage. The
composition can be formulated as a solution, microemulsion,
dispersion, liposome, or other ordered structure suitable to high
drug concentration. Sterile injectable solutions can be prepared by
incorporating the active compound (i.e., antibody, antibody
portion, or other TNF.alpha. inhibitor) in the required amount in
an appropriate solvent with one or a combination of ingredients
enumerated above, as required, followed by filtered sterilization.
Generally, dispersions are prepared by incorporating the active
compound into a sterile vehicle that contains a basic dispersion
medium and the required other ingredients from those enumerated
above. In the case of sterile powders for the preparation of
sterile injectable solutions, the preferred methods of preparation
are vacuum drying and freeze-drying that yields a powder of the
active ingredient plus any additional desired ingredient from a
previously sterile-filtered solution thereof. The proper fluidity
of a solution can be maintained, for example, by the use of a
coating such as lecithin, by the maintenance of the required
particle size in the case of dispersion and by the use of
surfactants. Prolonged absorption of injectable compositions can be
brought about by including in the composition an agent that delays
absorption, for example, monostearate salts and gelatin.
[0431] Supplementary active compounds can also be incorporated into
the compositions. In certain embodiments, an antibody or antibody
portion for use in the methods of the invention is coformulated
with and/or coadministered with one or more additional therapeutic
agents. For example, an anti-hTNF.alpha. antibody or antibody
portion of the invention may be coformulated and/or coadministered
with one or more DMARD or one or more NSAID or one or more
additional antibodies that bind other targets (e.g., antibodies
that bind other cytokines or that bind cell surface molecules), one
or more cytokines, soluble TNF.alpha. receptor (see e.g., PCT
Publication No. WO 94/06476) and/or one or more chemical agents
that inhibit hTNF.alpha. production or activity (such as
cyclohexane-ylidene derivatives as described in PCT Publication No.
WO 93/19751) or any combination thereof. Furthermore, one or more
antibodies of the invention may be used in combination with two or
more of the foregoing therapeutic agents. Such combination
therapies may advantageously utilize lower dosages of the
administered therapeutic agents, thus avoiding possible side
effects, complications or low level of response by the patient
associated with the various monotherapies.
[0432] In one embodiment, the invention includes pharmaceutical
compositions comprising an effective amount of a TNF.alpha.
inhibitor and a pharmaceutically acceptable carrier, wherein the
effective amount of the TNF.alpha. inhibitor may be effective to
treat a TNF.alpha.-related disorder, including, for example,
Crohn's disease, in a multiple variable dose regimen. In one
embodiment, the antibody or antibody portion for use in the
multiple variable dose methods of the invention is incorporated
into a pharmaceutical formulation as described in PCT/IB03/04502
and U.S. application Ser. No. 10/222,140, incorporated by reference
herein. This formulation includes a concentration 50 mg/ml of the
antibody D2E7, wherein one pre-filled syringe contains 40 mg of
antibody for subcutaneous injection.
[0433] The antibodies, antibody-portions, and other TNF.alpha.
inhibitors of the present invention can be administered by a
variety of methods known in the art within the scope of the
invention, although for many therapeutic applications, the
preferred route/mode of administration is subcutaneous injection.
In another embodiment, administration is via intravenous injection
or infusion. As will be appreciated by the skilled artisan, the
route and/or mode of administration will vary depending upon the
desired results, within the scope of the invention. In certain
embodiments, the active compound may be prepared with a carrier
that will protect the compound against rapid release, such as a
controlled release formulation, including implants, transdermal
patches, and microencapsulated delivery systems. Biodegradable,
biocompatible polymers can be used, such as ethylene vinyl acetate,
polyanhydrides, polyglycolic acid, collagen, polyorthoesters, and
polylactic acid. Many methods for the preparation of such
formulations are patented or generally known to those skilled in
the art. See, e.g., Sustained and Controlled Release Drug Delivery
Systems, J. R. Robinson, ed., Marcel Dekker, Inc., New York,
1978.
[0434] The TNF.alpha. antibodies of the invention can also be
administered in the form of protein crystal formulations which
include a combination of protein crystals encapsulated within a
polymeric carrier to form coated particles. The coated particles of
the protein crystal formulation may have a spherical morphology and
be microspheres of up to 500 micro meters in diameter or they may
have some other morphology and be microparticulates. The enhanced
concentration of protein crystals allows the antibody of the
invention to be delivered subcutaneously. In one embodiment, the
TNF.alpha. antibodies of the invention are delivered via a protein
delivery system, wherein one or more of a protein crystal
formulation or composition, is administered to a subject with a
TNF.alpha.-related disorder. Compositions and methods of preparing
stabilized formulations of whole antibody crystals or antibody
fragment crystals are also described in WO 02/072636, which is
incorporated by reference herein. In one embodiment, a formulation
comprising the crystallized antibody fragments described in
PCT/IB03/04502 and U.S. application Ser. No. 10/222,140,
incorporated by reference herein, are used to treat a
TNF.alpha.-related disorder using the multiple-variable dose
methods of the invention.
[0435] In certain embodiments, an antibody, antibody portion, or
other TNF.alpha. inhibitor of the invention may be orally
administered, for example, with an inert diluent or an assimilable
edible carrier. The compound (and other ingredients, if desired)
may also be enclosed in a hard or soft shell gelatin capsule,
compressed into tablets, or incorporated directly into the
subject's diet. For oral therapeutic administration, the compounds
may be incorporated with excipients and used in the form of
ingestible tablets, buccal tablets, troches, capsules, elixirs,
suspensions, syrups, wafers, and the like. To administer a compound
of the invention by other than parenteral administration, it may be
necessary to coat the compound with, or co-administer the compound
with, a material to prevent its inactivation.
[0436] The pharmaceutical compositions of the invention may include
a "therapeutically effective amount" or a "prophylactically
effective amount" of an antibody or antibody portion of the
invention. A "therapeutically effective amount" refers to an amount
effective, at dosages and for periods of time necessary, to achieve
the desired therapeutic result. A therapeutically effective amount
of the antibody, antibody portion, or other TNF.alpha. inhibitor
may vary according to factors such as the disease state, age, sex,
and weight of the individual, and the ability of the antibody,
antibody portion, other TNF.alpha. inhibitor to elicit a desired
response in the individual. A therapeutically effective amount is
also one in which any toxic or detrimental effects of the antibody,
antibody portion, or other TNF.alpha. inhibitor are outweighed by
the therapeutically beneficial effects. A "prophylactically
effective amount" refers to an amount effective, at dosages and for
periods of time necessary, to achieve the desired prophylactic
result. Typically, since a prophylactic dose is used in subjects
prior to or at an earlier stage of disease, the prophylactically
effective amount will be less than the therapeutically effective
amount.
[0437] Dosage regimens may be adjusted to provide the optimum
desired response (e.g., a therapeutic or prophylactic response)
within the scope of the invention. For example, a single bolus may
be administered, several divided doses may be administered over
time or the dose may be proportionally reduced or increased as
indicated by the exigencies of the therapeutic situation. It is
especially advantageous to formulate parenteral compositions in
dosage unit form for ease of administration and uniformity of
dosage. Dosage unit form as used herein refers to physically
discrete units suited as unitary dosages for the mammalian subjects
to be treated; each unit containing a predetermined quantity of
active compound calculated to produce the desired therapeutic
effect in association with the required pharmaceutical carrier. The
specification for the dosage unit forms of the invention are
dictated by and directly dependent on (a) the unique
characteristics of the active compound and the particular
therapeutic or prophylactic effect to be achieved, and (b) the
limitations inherent in the art of compounding such an active
compound for the treatment of sensitivity in individuals.
[0438] An exemplary, non-limiting range for a therapeutically or
prophylactically effective amount of an antibody or antibody
portion of the invention is 10 to 200 mg, more preferably 20 to 160
mg, more preferably 40 to 80 mg, and most preferably 80 mg. In one
embodiment, the therapeutically effective amount of an antibody or
portion thereof for use in the methods of the invention is about 20
mg. In another embodiment, the therapeutically effective amount of
an antibody or portion thereof for use in the methods of the
invention is about 40 mg. In still another embodiment, the
therapeutically effective amount of an antibody or portion thereof
for use in the methods of the invention is about 80 mg. In one
embodiment, the therapeutically effective amount of an antibody or
portion thereof for use in the methods of the invention is about
120 mg. In yet another embodiment, the therapeutically effective
amount of an antibody or portion thereof for use in the methods of
the invention is about 160 mg. Ranges intermediate to the above
recited dosages and those ranges described throughout, e.g. about
78.5 to about 81.5; about 15 to about 25; about 30 to about 50;
about 60 to about 100; about 90 to about 150; about 120 to about
200, are also intended to be part of this invention. For example,
ranges of values using a combination of any of the above recited
values as upper and/or lower limits are intended to be
included.
[0439] The invention provides a multiple-variable dose method for
treating a disorder in which TNF.alpha. activity is detrimental,
comprising administering to a subject in need thereof at least one
induction dose of a TNF.alpha. inhibitor, such as a human antibody,
such that a threshold level of TNF.alpha. inhibitor is achieved
within an induction phase, and subsequently administering to the
subject a treatment dose of the human antibody within a treatment
phase, such that treatment occurs.
[0440] The multiple-variable dose treatment method of the invention
comprises administering a therapeutic agent in an induction phase,
followed by a lower amount of the therapeutic agent during a
treatment phase. In one embodiment, the induction dose comprises
either 160 mg or 80 mg. In another embodiment, the induction dose
ranges from about 20 to about 200 mg of a TNF.alpha. inhibitor.
More preferably the induction dose ranges from about 40 to about
160 mg of a TNF.alpha. inhibitor. Most preferably the induction
dose ranges from about 80 to about 160 mg of a TNF.alpha. antibody.
The induction phase is complete once a threshold level of
therapeutic agent is reached. The induction phase can include a
single induction dose, or multiple induction doses wherein the same
or different amounts of therapeutic agent are used. More than one
induction dose may be administered during the induction phase,
wherein any determined amount of time interval may occur between
induction doses, including, for example, one hour apart, one day
apart, one week apart, two weeks apart, etc. Examples of induction
phase treatments of the invention used to achieve a threshold level
of TNF.alpha. inhibitor include, but are not limited to, the
following regimens: a 160 mg dose followed by an 80 mg dose; at
least one dose of 160 mg dose; at least one dose of 80 mg dose; at
least two doses of 80 mg dose; and two 80 mg induction doses at a
one week interval.
[0441] A threshold level is achieved once a pre-determined
therapeutic effect is reached. For example, the threshold level of
a TNF.alpha. inhibitor for the treatment of Crohn's disease may be
determined by monitoring a subject in the induction phase of
treatment for a reduction in their CDAI index. In another example,
the threshold level of a TNF.alpha. inhibitor for treatment of
psoriasis may be determined by a decrease in psoriatic plaques, an
improvement in the patient's Psoriasis Area Severity Index (PAST)
score, or an improved Physician's Global Assessment (PGA) score. In
still another example, the threshold level of a TNF.alpha.
inhibitor for treatment of a TNF.alpha.-related disorder is
determined by achievement of a stable blood plasma serum
concentration of the TNF.alpha. inhibitor.
[0442] Once a threshold level is achieved, the treatment phase is
initiated. At least one treatment dose is administered during the
treatment phase. More than one treatment dose may administered
during the treatment phase, wherein any determined amount of time
interval may occur between induction doses, including, for example,
one hour apart, one day apart, one week apart, two weeks apart,
etc. In one embodiment, the treatment dose ranges from about 20 to
about 120 mg of a TNF.alpha. inhibitor. Most preferably the
treatment dose ranges from about 40 to about 80 mg of a TNF.alpha.
inhibitor. In one embodiment, the treatment phase comprises
administering 40 mg of a TNF.alpha. inhibitor. In another
embodiment, the treatment phase comprises administering 80 mg of a
TNF.alpha. inhibitor.
[0443] The multiple-variable dose method described herein is based
on a treatment regimen which includes administration of at least
two different doses of a TNF.alpha. inhibitor. The induction dose
can be any multiple number greater than the treatment dose. For
example, the induction dose can be two times greater than the
treatment dose. In one embodiment of the invention, the induction
dose is 160 mg, and the treatment dose is 80 mg. In another
embodiment, the induction dose is 80 mg, and the treatment dose is
40 mg. In yet another embodiment, the induction dose is 70 mg, and
the treatment dose is 35 mg. In another example, the treatment dose
is 40% to 60% of the induction dose, e.g., the induction dose is
160 mg and the treatment dose ranges from 64 mg to 96 mg or the
induction dose ranges from 80 mg and the treatment dose is 32 mg to
48 mg.
[0444] In one embodiment, the invention provides a method of
treating Crohn's disease in a subject comprising administering to
the subject a TNF.alpha. inhibitor, such as a TNF.alpha. antibody,
or an antigen-binding portion thereof, such that a mean serum
TNF.alpha. inhibitor trough level of approximately 12 .mu.g/mL is
achieved. In one embodiment, the mean serum trough level of about
12 .mu.g/mL is achieved by administration of a loading dose at week
0 followed by a second dose which comprises half the amount of the
loading dose at week 2. In one embodiment, the mean serum trough
level of about 12 .mu.g/mL is achieved at week 2. In one
embodiment, the mean serum trough level of about 12 .mu.g/mL is
achieved at week 4.
[0445] It is to be noted that dosage values may vary with the type
and severity of the condition to be alleviated within the scope of
the invention. It is to be further understood that for any
particular subject, specific dosage regimens should be adjusted
over time according to the individual need and the professional
judgment of the person administering or supervising the
administration of the compositions, and that dosage ranges set
forth herein are exemplary only and are not intended to limit the
scope or practice of the claimed composition.
[0446] The invention also pertains to packaged pharmaceutical
compositions or kits for administering the multiple-variable dose
regimen of the invention. The kit or article of manufacture of the
invention contains materials useful for the treatment, prevention
and/or diagnosis of Crohn's disease. The kit or article of
manufacture may comprise a container and a label or package insert
or printed material on or associated with the container which
provides information regarding use of the TNF.alpha. inhibitor,
e.g., a TNF.alpha. antibody, for the treatment of Crohn's disease.
In one embodiment, the article of manufacture may comprise (a) a
first container with a composition contained therein, wherein the
composition comprises a TNF.alpha. antibody; and (b) a package
insert indicating that the TNF.alpha. antibody may be used to treat
Crohn's disease. In a preferred embodiment, the label or package
insert indicates that the TNF.alpha. inhibitor, e.g., a TNF.alpha.
antibody, is used for treating Crohn's disease.
[0447] Suitable containers for the TNF.alpha. inhibitor, e.g., a
TNF.alpha. antibody, include, for example, bottles, vials,
syringes, pens, etc. The containers may be formed from a variety of
materials such as glass or plastic. The container holds a
composition which is by itself or when combined with another
composition effective for treating, preventing and/or diagnosing
the condition and may have a sterile access port.
[0448] In one embodiment of the invention, the kit comprises a
TNF.alpha. inhibitor, such as an antibody, and administration
instructions according to the multiple-variable dose method for
treatment. In one embodiment, the kit of the invention comprises an
induction dose and/or a treatment dose for treatment of a
particular disorder in which TNF.alpha. activity is detrimental.
The kit may also include instructions relating to administration of
the induction and/or treatment doses. The instructions may describe
how, e.g., subcutaneously, and when, e.g., at week 0 and week 2,
the different doses of TNF.alpha. inhibitor shall be administered
to a subject for treatment. The instructions may also describe the
administration of the TNF.alpha. inhibitor during the induction and
the treatment phases of the multiple-variable dose treatment.
[0449] Kits to be used for the methods of the invention may include
individual doses of a TNF.alpha. inhibitor which can be used in
part, in whole, or in combination with one another to achieve the
multiple-variable dose regimen. For example, the kit may include a
number of prefilled syringes containing the TNF.alpha. antibody
D2E7, wherein each syringe contains a 40 mg dose of the TNF.alpha.
inhibitor. In one embodiment, multiple-variable dose therapy
includes administration of a 160 mg induction dose of D2E7,
followed by subsequent administration of an 80 mg dose of D2E7 at
least two weeks following administration of the induction dose for
the treatment of Crohn's disease. In such a case, the instructions
would describe administration of four syringes of D2E7 for the
induction dose, followed by administration of two syringes of D2E7
at least two weeks later. A kit of the invention for the treatment
of Crohn's may also include a dose or doses of methotrexate for
administration in combination with D2E7.
[0450] In another example, the kit of the invention may include
doses of D2E7 for multiple-variable dose treatment of psoriasis. In
one embodiment, the kit may contain at least one induction dose of
80 mg of D2E7, and at least one maintenance dose of 40 mg of D2E7.
Instructions for administration of D2E7 for the treatment of
psoriasis may include, for example, directions for administering
one 80 mg dose, a second 80 mg dose a week later, and a 40 mg dose
a week later and subsequently every other week. In another example,
the instructions may include directions for a single 80 mg dose of
D2E7, followed by a 40 mg treatment dose a week later and
subsequently every other week.
[0451] In one embodiment, the article of manufacture or kit
comprises a TNF.alpha. inhibitor, e.g., a TNF.alpha. antibody, and
a label which indicates to a subject who will be administering the
TNF.alpha. inhibitor about using the TNF.alpha. inhibitor for the
treatment of Crohn's disease. The label may be anywhere within or
on the article of manufacture. In one embodiment, the article of
manufacture comprises a container, such as a box, which comprises
the TNF.alpha. inhibitor and a package insert or label providing
information pertaining to use of the TNF.alpha. inhibitor for the
treatment of Crohn's disease. In another embodiment, the
information is printed on a label which is on the outside of the
article of manufacture, in a position which is visible to
prospective purchasers.
[0452] In one embodiment, the label of the invention informs a
reader, including a prospective purchaser and/or a subject who will
be administering the TNF.alpha. inhibitor for treatment, that the
TNF.alpha. inhibitor, e.g., a TNF.alpha. antibody such as
adalimumab, is an indicated treatment of Crohn's disease, including
treatment of moderately to severely active disease in adult
patients. The label may indicate that the TNF.alpha. antibody,
e.g., adalimumab, may be used to treat Crohn's disease in patients
who have had an inadequate response to conventional therapy and/or
who have lost response to or are intolerant to infliximab. In
another embodiment the label indicates that the TNF.alpha.
antibody, e.g., adalimumab, may be used for reducing signs and
symptoms and inducing clinical remission in patients with
moderately to severely active Crohn's disease who have lost
response to or are intolerant to infliximab.
[0453] In addition, the label of the invention may also contain
information regarding the pharmacokinetics of the TNF.alpha.
inhibitor, e.g., a TNF.alpha. antibody such as adalimumab. In one
embodiment, the label of the invention indicates that in patients
with Crohn's disease, the loading dose of 160 mg adalimumab on week
0 followed by 80 mg adalimumab on week 2 achieves serum adalimumab
trough concentrations of approximately 12 .mu.g/mL.
[0454] Another aspect of the invention pertains to kits containing
a pharmaceutical composition comprising an anti-TNF.alpha. antibody
and a pharmaceutically acceptable carrier and one or more
pharmaceutical compositions each comprising a drug useful for
treating a TNF.alpha.-related disorder and a pharmaceutically
acceptable carrier. Alternatively, the kit comprises a single
pharmaceutical composition comprising an anti-TNF.alpha. antibody,
one or more drugs useful for treating a TNF.alpha.-related disorder
and a pharmaceutically acceptable carrier. The kits contain
instructions for dosing of the pharmaceutical compositions for the
treatment of a TNF.alpha.-related disorder in which the
administration of an anti-TNF.alpha. antibody is beneficial, such
as Crohn's disease or psoriasis.
[0455] The package or kit alternatively can contain the TNF.alpha.
inhibitor and it can be promoted for use, either within the package
or through accompanying information, for the uses or treatment of
the disorders described herein. The packaged pharmaceuticals or
kits further can include a second agent (as described herein)
packaged with or copromoted with instructions for using the second
agent with a first agent (as described herein).
[0456] In one embodiment, the invention also provides a single dose
method for treating a disorder in which TNF.alpha. activity is
detrimental, comprising administering to a subject in need thereof
a single dose of a TNF.alpha. inhibitor, such as a human antibody.
In one embodiment, the TNF.alpha. inhibitor is the anti-TNF.alpha.
antibody D2E7. The single dose of TNF.alpha. inhibitor can be any
therapeutically or prophylactically effective amount. In one
embodiment, a subject is administered either about 20 mg, 40 mg, or
80 mg single dose of D2E7. The single dose may be administered
through any route, including, for example, subcutaneous
administration.
[0457] Ranges intermediate to the numerical ranges described
throughout are also intended to be part of this invention.
[0458] B. Additional Therapeutic Agents
[0459] The invention pertains to pharmaceutical compositions and
methods of use thereof for the treatment of a TNF.alpha.-related
disorder using a multiple-variable dose regimen. The pharmaceutical
compositions comprise a first agent that prevents or inhibits a
TNF.alpha.-related disorder. The pharmaceutical composition and
methods of use may comprise a second agent that is an active
pharmaceutical ingredient; that is, the second agent is therapeutic
and its function is beyond that of an inactive ingredient, such as
a pharmaceutical carrier, preservative, diluent, or buffer. The
second agent may be useful in treating or preventing
TNF.alpha.-related disorders. The second agent may diminish or
treat at least one symptom(s) associated with the targeted disease.
The first and second agents may exert their biological effects by
similar or unrelated mechanisms of action; or either one or both of
the first and second agents may exert their biological effects by a
multiplicity of mechanisms of action. A pharmaceutical composition
may also comprise a third compound, or even more yet, wherein the
third (and fourth, etc.) compound has the same characteristics of a
second agent.
[0460] It should be understood that the pharmaceutical compositions
described herein may have the first and second, third, or
additional agents in the same pharmaceutically acceptable carrier
or in a different pharmaceutically acceptable carrier for each
described embodiment. It further should be understood that the
first, second, third and additional agent may be administered
simultaneously or sequentially within described embodiments.
Alternatively, a first and second agent may be administered
simultaneously, and a third or additional agent may be administered
before or after the first two agents.
[0461] The combination of agents used within the methods and
pharmaceutical compositions described herein may have a therapeutic
additive or synergistic effect on the condition(s) or disease(s)
targeted for treatment. The combination of agents used within the
methods or pharmaceutical compositions described herein also may
reduce a detrimental effect associated with at least one of the
agents when administered alone or without the other agent(s) of the
particular pharmaceutical composition. For example, the toxicity of
side effects of one agent may be attenuated by another agent of the
composition, thus allowing a higher dosage, improving patient
compliance, and improving therapeutic outcome. The additive or
synergistic effects, benefits, and advantages of the compositions
apply to classes of therapeutic agents, either structural or
functional classes, or to individual compounds themselves.
[0462] Supplementary active compounds can also be incorporated into
the compositions. In certain embodiments, an antibody or antibody
portion of the invention is coformulated with and/or coadministered
with one or more additional therapeutic agents that are useful for
treating TNF.alpha.-related disorder in which TNF.alpha. activity
is detrimental. For example, an anti-hTNF.alpha.antibody, antibody
portion, or other TNF.alpha. inhibitor of the invention may be
coformulated and/or coadministered with one or more additional
antibodies that bind other targets (e.g., antibodies that bind
other cytokines or that bind cell surface molecules), one or more
cytokines, soluble TNF.alpha. receptor (see e.g., PCT Publication
No. WO 94/06476) and/or one or more chemical agents that inhibit
hTNF.alpha. production or activity (such as cyclohexane-ylidene
derivatives as described in PCT Publication No. WO 93/19751).
Furthermore, one or more antibodies or other TNF.alpha. inhibitors
of the invention may be used in combination with two or more of the
foregoing therapeutic agents. Such combination therapies may
advantageously utilize lower dosages of the administered
therapeutic agents, thus avoiding possible toxicities or
complications associated with the various monotherapies. Specific
therapeutic agent(s) are generally selected based on the particular
TNF.alpha.-related disorder being treated, as discussed below.
[0463] Nonlimiting examples of therapeutic agents with which an
antibody, antibody portion, or other TNF.alpha. inhibitor can be
combined in a multiple variable dose method of treatment of the
invention include the following: non-steroidal anti-inflammatory
drug(s) (NSAIDs); cytokine suppressive anti-inflammatory drug(s)
(CSAIDs); CDP-571/BAY-10-3356 (humanized anti-TNF.alpha. antibody;
Celltech/Bayer); cA2/infliximab (chimeric anti-TNF.alpha. antibody;
Centocor); 75 kdTNFR-IgG/etanercept (75 kD TNF receptor-IgG fusion
protein; Immunex; see e.g., Arthritis & Rheumatism (1994) Vol.
37, 5295; J. Invest. Med. (1996) Vol. 44, 235A); 55 kdTNF-IgG (55
kD TNF receptor-IgG fusion protein; Hoffmann-LaRoche);
IDEC-CE9.1/SB 210396 (non-depleting primatized anti-CD4 antibody;
IDEC/SmithKline; see e.g., Arthritis & Rheumatism (1995) Vol.
38, S185); DAB 486-IL-2 and/or DAB 389-IL-2 (IL-2 fusion proteins;
Seragen; see e.g., Arthritis & Rheumatism (1993) Vol. 36,
1223); Anti-Tac (humanized anti-IL-2Ra; Protein Design Labs/Roche);
IL-4 (anti-inflammatory cytokine; DNAX/Schering); IL-10 (SCH 52000;
recombinant IL-10, anti-inflammatory cytokine; DNAX/Schering);
IL-4; IL-10 and/or IL-4 agonists (e.g., agonist antibodies); IL-1RA
(IL-1 receptor antagonist; Synergen/Amgen); anakinra
(Kineret.RTM./Amgen); TNF-bp/s-TNF (soluble TNF binding protein;
see e.g., Arthritis & Rheumatism (1996) Vol. 39, No. 9
(supplement), 5284; Amer. J. Physiol.--Heart and Circulatory
Physiology (1995) Vol. 268, pp. 37-42); R973401 (phosphodiesterase
Type IV inhibitor; see e.g., Arthritis & Rheumatism (1996) Vol.
39, No. 9 (supplement), S282); MK-966 (COX-2 Inhibitor; see e.g.,
Arthritis & Rheumatism (1996) Vol. 39, No. 9 (supplement),
S81); Iloprost (see e.g., Arthritis & Rheumatism (1996) Vol.
39, No. 9 (supplement), S82); methotrexate; thalidomide (see e.g.,
Arthritis & Rheumatism (1996) Vol. 39, No. 9 (supplement),
5282) and thalidomide-related drugs (e.g., Celgen); leflunomide
(anti-inflammatory and cytokine inhibitor; see e.g., Arthritis
& Rheumatism (1996) Vol. 39, No. 9 (supplement), 5131;
Inflammation Research (1996) Vol. 45, pp. 103-107); tranexamic acid
(inhibitor of plasminogen activation; see e.g., Arthritis &
Rheumatism (1996) Vol. 39, No. 9 (supplement), S284); T-614
(cytokine inhibitor; see e.g., Arthritis & Rheumatism (1996)
Vol. 39, No. 9 (supplement), S282); prostaglandin E1 (see e.g.,
Arthritis & Rheumatism (1996) Vol. 39, No. 9 (supplement),
S282); Tenidap (non-steroidal anti-inflammatory drug; see e.g.,
Arthritis & Rheumatism (1996) Vol. 39, No. 9 (supplement),
S280); Naproxen (non-steroidal anti-inflammatory drug; see e.g.,
Neuro Report (1996) Vol. 7, pp. 1209-1213); Meloxicam
(non-steroidal anti-inflammatory drug); Ibuprofen (non-steroidal
anti-inflammatory drug); Piroxicam (non-steroidal anti-inflammatory
drug); Diclofenac (non-steroidal anti-inflammatory drug);
Indomethacin (non-steroidal anti-inflammatory drug); Sulfasalazine
(see e.g., Arthritis & Rheumatism (1996) Vol. 39, No. 9
(supplement), S281); Azathioprine (see e.g., Arthritis &
Rheumatism (1996) Vol. 39, No. 9 (supplement), S281); ICE inhibitor
(inhibitor of the enzyme interleukin-1.beta. converting enzyme);
zap-70 and/or lck inhibitor (inhibitor of the tyrosine kinase
zap-70 or lck); VEGF inhibitor and/or VEGF-R inhibitor (inhibitors
of vascular endothelial cell growth factor or vascular endothelial
cell growth factor receptor; inhibitors of angiogenesis);
corticosteroid anti-inflammatory drugs (e.g., SB203580);
TNF-convertase inhibitors; anti-IL-12 antibodies; anti-IL-18
antibodies; interleukin-11 (see e.g., Arthritis & Rheumatism
(1996) Vol. 39, No. 9 (supplement), S296); interleukin-13 (see
e.g., Arthritis & Rheumatism (1996) Vol. 39, No. 9
(supplement), S308); interleukin-17 inhibitors (see e.g., Arthritis
& Rheumatism (1996) Vol. 39, No. 9 (supplement), S120); gold;
penicillamine; chloroquine; hydroxychloroquine; chlorambucil;
cyclosporine; cyclophosphamide; total lymphoid irradiation;
anti-thymocyte globulin; anti-CD4 antibodies; CD5-toxins;
orally-administered peptides and collagen; lobenzarit disodium;
Cytokine Regulating Agents (CRAs) HP228 and HP466 (Houghten
Pharmaceuticals, Inc.); ICAM-1 antisense phosphorothioate
oligodeoxynucleotides (ISIS 2302; Isis Pharmaceuticals, Inc.);
soluble complement receptor 1 (TP10; T Cell Sciences, Inc.);
prednisone; orgotein; glycosaminoglycan polysulphate; minocycline;
anti-IL2R antibodies; marine and botanical lipids (fish and plant
seed fatty acids; see e.g., DeLuca et al. (1995) Rheum. Dis. Clin.
North Am. 21:759-777); auranofin; phenylbutazone; meclofenamic
acid; flufenamic acid; intravenous immune globulin; zileuton;
azaribine; mycophenolic acid (RS-61443); tacrolimus (FK-506);
sirolimus (rapamycin); amiprilose (therafectin); cladribine
(2-chlorodeoxyadenosine); methotrexate; antivirals; and immune
modulating agents. Any of the above-mentioned agents can be
administered in combination with the TNF.alpha. antibody of the
invention to treat an TNF.alpha.-related disorder using the
multiple variable dose or single dose method of treatments of the
invention.
[0464] In one embodiment, the TNF.alpha. antibody of the invention
is administered in combination with one of the following agents for
the treatment of rheumatoid arthritis using the multiple variable
dose method of treatment of the invention: small molecule inhibitor
of KDR (ABT-123), small molecule inhibitor of Tie-2; methotrexate;
prednisone; celecoxib; folic acid; hydroxychloroquine sulfate;
rofecoxib; etanercept; infliximab; anakinra (Kineret.RTM./Amgen);
leflunomide; naproxen; valdecoxib; sulfasalazine; ibuprofen;
methylprednisolone; meloxicam; methylprednisolone acetate; gold
sodium thiomalate; aspirin; azathioprine; triamcinolone acetonide;
propxyphene napsylate/apap; folate; nabumetone; diclofenac;
piroxicam; etodolac; diclofenac sodium; oxaprozin; oxycodone hcl;
hydrocodone bitartrate/apap; diclofenac sodium/misoprostol;
fentanyl; anakinra, human recombinant; tramadol hcl; salsalate;
sulindac; cyanocobalamin/fa/pyridoxine; acetaminophen; alendronate
sodium; prednisolone; morphine sulfate; lidocaine hydrochloride;
indomethacin; glucosamine sulfate/chondroitin; cyclosporine;
sulfadiazine; amitriptyline hcl; oxycodone hcl/acetaminophen;
olopatadine hcl; misoprostol; naproxen sodium; omeprazole;
mycophenolate mofetil; cyclophosphamide; rituximab; IL-1 TRAP; MRA;
CTLA4-IG; IL-18 BP; ABT-874; ABT-325 (anti-IL 18); anti-IL 15;
BIRB-796; SCIO-469; VX-702; AMG-548; VX-740; Roflumilast; IC-485;
CDC-801; and mesopram. In another embodiment, the TNF.alpha.
antibody of the invention is administered using a multiple-variable
dose method for the treatment of a TNF.alpha. related disorder in
combination with one of the above-mentioned agents for the
treatment of rheumatoid arthritis. In another embodiment, the
above-mentioned additional agents are used in combination with a
TNF.alpha. antibody in the single dose method of treatment of the
invention.
[0465] In one embodiment, the TNF.alpha. antibody of the invention
is administered using the multiple variable dose regimen in
combination with one of the following agents for the treatment of a
TNF.alpha.-related disorder in which TNF.alpha. activity is
detrimental: anti-IL12 antibody (ABT 874); anti-IL18 antibody (ABT
325); small molecule inhibitor of LCK; small molecule inhibitor of
COT; anti-IL1 antibody; small molecule inhibitor of MK2; anti-CD19
antibody; small molecule inhibitor of CXCR3; small molecule
inhibitor of CCR5; small molecule inhibitor of CCR11 anti-E/L
selectin antibody; small molecule inhibitor of P2X7; small molecule
inhibitor of IRAK-4; small molecule agonist of glucocorticoid
receptor; anti-05a receptor antibody; small molecule inhibitor of
C5a receptor; anti-CD32 antibody; and CD32 as a therapeutic
protein.
[0466] In yet another embodiment, the TNF.alpha. antibody of the
invention is administered using the multiple variable dose regimen
in combination with an antibiotic or antiinfective agent.
Antiinfective agents include those agents known in the art to treat
viral, fungal, parasitic or bacterial infections. The term,
"antibiotic," as used herein, refers to a chemical substance that
inhibits the growth of, or kills, microorganisms. Encompassed by
this term are antibiotic produced by a microorganism, as well as
synthetic antibiotics (e.g., analogs) known in the art. Antibiotics
include, but are not limited to, clarithromycin (Biaxin.RTM.),
ciprofloxacin (Cipro.RTM.), and metronidazole (Flagyl.RTM.).
[0467] In another embodiment, the TNF.alpha. antibody of the
invention is administered using the multiple variable dose regimen
in combination with an additional therapeutic agent to treat
sciatica or pain. Examples of agents which can be used to reduce or
inhibit the symptoms of sciatica or pain include hydrocodone
bitartrate/apap, rofecoxib, cyclobenzaprine hcl,
methylprednisolone, naproxen, ibuprofen, oxycodone
hcl/acetaminophen, celecoxib, valdecoxib, methylprednisolone
acetate, prednisone, codeine phosphate/apap, tramadol
hcl/acetaminophen, metaxalone, meloxicam, methocarbamol, lidocaine
hydrochloride, diclofenac sodium, gabapentin, dexamethasone,
carisoprodol, ketorolac tromethamine, indomethacin, acetaminophen,
diazepam, nabumetone, oxycodone hcl, tizanidine hcl, diclofenac
sodium/misoprostol, propoxyphene napsylate/apap,
asa/oxycod/oxycodone ter, ibuprofen/hydrocodone bit, tramadol hcl,
etodolac, propoxyphene hcl, amitriptyline hcl, carisoprodol/codeine
phos/asa, morphine sulfate, multivitamins, naproxen sodium,
orphenadrine citrate, and temazepam.
[0468] In yet another embodiment, the TNF.alpha.-related disorder
is treated using the multiple variable dose regimen with the
TNF.alpha. antibody of the invention in combination with
hemodialysis.
[0469] In another embodiment, a TNF.alpha. antibody of the
invention is used in combination with a drug used to treat Crohn's
disease or a Crohn's-related disorder in the multiple variable dose
regimen of the invention. Examples of therapeutic agents which can
be used to treat Crohn's include mesalamine, prednisone,
azathioprine, mercaptopurine, infliximab, budesonide,
sulfasalazine, methylprednisolone sod succ,
diphenoxylate/atropsulf, loperamide hydrochloride, methotrexate,
omeprazole, folate, ciprofloxacin/dextrose-water, hydrocodone
bitartrate/apap, tetracycline hydrochloride, fluocinonide,
metronidazole, thimerosal/boric acid, hyoscyamine sulfate,
cholestyramine/sucrose, ciprofloxacin hydrochloride, meperidine
hydrochloride, midazolam hydrochloride, oxycodone
hcl/acetaminophen, promethazine hydrochloride, sodium phosphate,
sulfamethoxazole/trimethoprim, celecoxib, polycarbophil,
propoxyphene napsylate, hydrocortisone, multivitamins, balsalazide
disodium, codeine phosphate/apap, colesevelam hcl, cyanocobalamin,
folic acid, levofloxacin, natalizumab, methylprednisolone,
interferon-gamma, and sargramostim (GM-CSF). In one embodiment,
methotrexate is administered for the treatment of Crohn's disease
at a dose of 2.5 mg to 30 mg per week.
[0470] In another embodiment, a TNF.alpha. antibody is administered
in combination with an additional therapeutic agent to treat asthma
in the multiple variable dose regimen of the invention. Examples of
agents which can be used to reduce or inhibit the symptoms of
asthma include the following: albuterol; salmeterol/fluticasone;
sodium; fluticasone propionate; budesonide; prednisone; salmeterol
xinafoate; levalbuterol hcl; sulfate/ipratropium; prednisolone
sodium phosphate; triamcinolone acetonide; beclomethasone
dipropionate; ipratropium bromide; Azithromycin; pirbuterol
acetate; prednisolone; theophylline anhydrous; zafirlukast;
methylprednisolone sod succ; clarithromycin; formoterol fumarate;
influenza virus vaccine; methylprednisolone; trihydrate; allergy
injection; cromolyn sodium; cefprozil; fexofenadine hydrochloride;
flunisolide/menthol; levofloxacin; amoxicillin/clavulanate, inhaler
assist device, guaifenesin, dexamethasone sod phosphate;
moxifloxacin hcl; hyclate; guaifenesin/d-methorphan; gatifloxacin;
pephedrine/cod/chlorphenir; cetirizine hydrochloride; mometasone
furoate; salmeterol xinafoate; benzonatate; cephalexin;
pe/hydrocodone/chlorphenir; cetirizine hcl/pseudoephed;
phenylephrine/cod/promethazine; codeine/promethazine; flunisolide;
dexamethasone; guaifenesin/pseudoephedrine;
chlorpheniramine/hydrocodone; nedocromil sodium; terbutaline
sulfate; epinephrine and methylprednisolone, metaproterenol
sulfate.
[0471] In another embodiment, the TNF.alpha. antibody of the
invention is administered in combination with an additional
therapeutic agent to treat COPD in the multiple variable dose
regimen of the invention. Examples of agents which can be used to
reduce or inhibit the symptoms of COPD include, albuterol
sulfate/ipratropium; ipratropium bromide; salmeterol/fluticasone;
albuterol; salmeterol; xinafoate; fluticasone propionate;
prednisone; theophylline anhydrous; levofloxacin;
methylprednisolone sod succ; montelukast sodium; budesonide;
formoterol fumarate; triamcinolone acetonide; guaifenesin;
azithromycin; beclomethasone; dipropionate; levalbuterol hcl;
flunisolide; sodium; trihydrate; gatifloxacin; zafirlukast;
furoate; amoxicillin/clavulanate; flunisolide/menthol;
chlorpheniramine/hydrocodone; metaproterenol sulfate;
methylprednisolone; ephedrine/cod/chlorphenir; pirbuterol acetate;
-ephedrine/loratadine; terbutaline sulfate; tiotropium bromide;
(R,R)-formoterol; TgAAT; Cilomilast and Roflumilast
[0472] In another embodiment, the TNF.alpha. antibody of the
invention is administered in combination with an additional
therapeutic agent to treat IPF in the multiple variable dose
regimen of the invention. Examples of agents which can be used to
reduce or inhibit the symptoms of IPF include prednisone;
azathioprine; albuterol; colchicines; sulfate; digoxin; gamma
interferon; methylprednisolone sod succ; furosemide; lisinopril;
nitroglycerin; spironolactone; cyclophosphamide; ipratropium
bromide; actinomycin d; alteplase; fluticasone propionate;
levofloxacin; metaproterenol sulfate; morphine sulfate; oxycodone
hcl; potassium chloride; triamcinolone acetonide; tacrolimus
anhydrous; calcium; interferon-alpha; methotrexate; mycophenolate
mofetil.
[0473] In one embodiment of the invention, a TNF.alpha. antibody is
administered in combination with an agent which is commonly used to
treat spondyloarthropathies in the multiple variable dose regimen
of the invention. Examples of such agents include nonsteroidal,
anti-inflammatory drugs (NSAIDs), COX 2 inhibitors, including
Celebrex.RTM., Vioxx.RTM., and Bextra.RTM., and etoricoxib.
Physiotherapy is also commonly used to treat spondyloarthropathies,
usually in conjunction with non-steoidal inflammatory drugs.
[0474] In another embodiment, the TNF.alpha. antibody of the
invention is administered in combination with an additional
therapeutic agent to treat ankylosing spondylitis in the multiple
variable dose regimen of the invention. Examples of agents which
can be used to reduce or inhibit the symptoms of ankylosing
spondylitis include ibuprofen, diclofenac and misoprostol,
naproxen, meloxicam, indomethacin, diclofenac, celecoxib,
rofecoxib, sulfasalazine, prednisone, methotrexate, azathioprine,
minocyclin, prednisone, etanercept, and infliximab.
[0475] In another embodiment, the TNF.alpha. antibody of the
invention is administered in combination with an additional
therapeutic agent to treat psoriatic arthritis in the multiple
variable dose regimen of the invention. Examples of agents which
can be used to reduce or inhibit the symptoms of psoriatic
arthritis include methotrexate; etanercept; rofecoxib; celecoxib;
folic acid; sulfasalazine; naproxen; leflunomide;
methylprednisolone acetate; indomethacin; hydroxychloroquine
sulfate; sulindac; prednisone; betamethasone diprop augmented;
infliximab; methotrexate; folate; triamcinolone acetonide;
diclofenac; dimethylsulfoxide; piroxicam; diclofenac sodium;
ketoprofen; meloxicam; prednisone; methylprednisolone; nabumetone;
tolmetin sodium; calcipotriene; cyclosporine; diclofenac;
sodium/misoprostol; fluocinonide; glucosamine sulfate; gold sodium
thiomalate; hydrocodone; bitartrate/apap; ibuprofen; risedronate
sodium; sulfadiazine; thioguanine; valdecoxib; alefacept; and
efalizumab.
[0476] In one embodiment the TNF.alpha. inhibitor is administered
following an initial procedure for treating coronary heart disease
in the multiple variable dose regimen of the invention. Examples of
such procedures include, but are not limited to coronary artery
bypass grafting (CABG) and Percutaneous transluminal coronary
balloon angioplasty (PTCA) or angioplasty. In one embodiment, the
TNF.alpha. inhibitor is administered in order to prevent stenosis
from re-occurring. In another embodiment of the invention, the
TNF.alpha. inhibitor is administered in order to prevent or treat
restenosis. The invention also provides a method of treatment,
wherein the TNF.alpha. inhibitor is administered prior to, in
conjunction with, or following the insertion of a stent in the
artery of a subject receiving a procedure for treating coronary
heart disease. In one embodiment the stent is administered
following CABG or PTCA.
[0477] A wide variety of stent grafts may be utilized within the
context of the present invention, depending on the site and nature
of treatment desired. Stent grafts may be, for example, bifurcated
or tube grafts, cylindrical or tapered, self-expandable or
balloon-expandable, unibody, or, modular. Moreover, the stent graft
may be adapted to release the drug at only the distal ends, or
along the entire body of the stent graft. The TNF.alpha. inhibitor
of the invention can also be administered on a stent. In one
embodiment, the TNF.alpha. antibody of the invention, including,
for example, D2E7/HUIMIRA.RTM. is administered by a drug-eluting
stent.
[0478] The TNF.alpha. antibody can be administered in combination
with an additional therapeutic agent to treat restenosis in the
multiple variable dose regimen of the invention. Examples of agents
which can be used to treat or prevent restenosis include sirolimus,
paclitaxel, everolimus, tacrolimus, ABT-578, and acetaminophen.
[0479] The TNF.alpha. antibody of the invention can be administered
in combination with an additional therapeutic agent to treat
myocardial infarction in the multiple variable dose regimen of the
invention. Examples of agents which can be used to treat or prevent
myocardial infarction include aspirin, nitroglycerin, metoprolol
tartrate, enoxaparin sodium, heparin sodium, clopidogrel bisulfate,
carvedilol, atenolol, morphine sulfate, metoprolol succinate,
warfarin sodium, lisinopril, isosorbide mononitrate, digoxin,
furosemide, simvastatin, ramipril, tenecteplase, enalapril maleate,
torsemide, retavase, losartan potassium, quinapril hcl/mag carb,
bumetanide, alteplase, enalaprilat, amiodarone hydrochloride,
tirofiban hcl m-hydrate, diltiazem hydrochloride, captopril,
irbesartan, valsartan, propranolol hydrochloride, fosinopril
sodium, lidocaine hydrochloride, eptifibatide, cefazolin sodium,
atropine sulfate, aminocaproic acid, spironolactone, interferon,
sotalol hydrochloride, potassium chloride, docusate sodium,
dobutamine hcl, alprazolam, pravastatin sodium, atorvastatin
calcium, midazolam hydrochloride, meperidine hydrochloride,
isosorbide dinitrate, epinephrine, dopamine hydrochloride,
bivalirudin, rosuvastatin, ezetimibe/simvastatin, avasimibe,
abciximab, and cariporide.
[0480] The TNF.alpha. antibody of the invention can be administered
in combination with an additional therapeutic agent to treat angina
in the multiple variable dose regimen of the invention. Examples of
agents which can be used to treat or prevent angina include:
aspirin; nitroglycerin; isosorbide mononitrate; atenolol;
metoprolol succinate; metoprolol tartrate; amlodipine besylate;
digoxin; dilitiazem hydropchloride; isosorbide dinitrate;
clopidogrel bisulfate; nifedipine; atorvastatin calcium; potassium
chloride; simvastatin; verapamil hcl; furosemide; propranolol hcl;
carvedilo; lisinopril; sprionolactone; hydrochlorothiazide;
enalapril maleate; madolol; ramipril; enoxaparin sodium; heparin
sodium; valsartan; sotalol hydrochloride; fenofibrate; ezetimibe;
bumetanide; losartan potassium; lisinopril/hydrochlorothiazide;
felodipine; captopril; and bisoprolol fumarate.
[0481] In one embodiment of the invention, a TNF.alpha. antibody is
administered in combination with an agent which is commonly used to
treat hepatitis C virus in the multiple variable dose regimen of
the invention. Examples of such agents include Interferon-aplha-2a,
Interferon.alpha.-2b, Interferon.alpha. coni, Interfero-aopha-n1,
Pegylated interferon.alpha.-2a, Pegylated interferon.alpha.-2b,
Ribavirin, Peginterferon alfa-2b and ribavirin, Ursodeoxycholic
Acid, Glycyrrhizic Acid, Thymalfasin, Maxamine, and VX-497.
[0482] The TNF.alpha. antibody of the invention is administered in
combination with topical corticosteroids, vitamin D analogs, and
topical or oral retinoids, or combinations thereof, for the
treatment of psoriasis in the multiple variable dose regimen of the
invention. In addition, the TNF.alpha. antibody of the invention is
administered in combination with one of the following agents for
the treatment of psoriasis: small molecule inhibitor of KDR
(ABT-123), small molecule inhibitor of Tie-2, calcipotriene,
clobetasol propionate, triamcinolone acetonide, halobetasol
propionate, tazarotene, methotrexate, fluocinonide, betamethasone
diprop augmented, fluocinolone, acetonide, acitretin, tar shampoo,
betamethasone valerate, mometasone furoate, ketoconazole,
pramoxine/fluocinolone, hydrocortisone valerate, flurandrenolide,
urea, betamethasone, clobetasol propionate/emoll, fluticasone
propionate, azithromycin, hydrocortisone, moisturizing formula,
folic acid, desonide, coal tar, diflorasone diacetate, etanercept,
folate, lactic acid, methoxsalen, hc/bismuth subgal/znox/resor,
methylprednisolone acetate, prednisone, sunscreen, salicylic acid,
halcinonide, anthralin, clocortolone pivalate, coal extract, coal
tar/salicylic acid, coal tar/salicylic acid/sulfur, desoximetasone,
diazepam, emollient, pimecrolimus emollient,
fluocinonide/emollient, mineral oil/castor oil/na lact, mineral
oil/peanut oil, petroleum/isopropyl myristate, psoralen, salicylic
acid, soap/tribromsalan, thimerosal/boric acid, celecoxib,
infliximab, alefacept, efalizumab, tacrolimus, pimecrolimus, PUVA,
UVB and other phototherapy, and sulfasalazine.
[0483] An antibody, antibody portion, or other TNF.alpha. inhibitor
of the invention can be used in combination with other agents to
treat skin conditions in the multiple variable dose regimen of the
invention. For example, an antibody, antibody portion, or other
TNF.alpha. inhibitor of the invention is combined with PUVA
therapy. PUVA is a combination of psoralen (P) and long-wave
ultraviolet radiation (UVA) that is used to treat many different
skin conditions. The antibodies, antibody portions, or other
TNF.alpha. inhibitors of the invention can also be combined with
pimecrolimus. In another embodiment, the antibodies of the
invention are used to treat psoriasis, wherein the antibodies are
administered in combination with tacrolimus. In a further
embodiment, tacrolimus and TNF.alpha. inhibitors are administered
in combination with methotrexate and/or cyclosporine. In still
another embodiment, the TNF.alpha. inhibitor of the invention is
administered with excimer laser treatment for treating
psoriasis.
[0484] Nonlimiting examples of other therapeutic agents with which
a TNF.alpha. inhibitor can be combined to treat a skin or nail
disorder include UVA and UVB phototherapy in the multiple variable
dose regimen of the invention. Other nonlimiting examples which can
be used in combination with a TNF.alpha. inhibitor include
anti-IL-12 and anti-IL-18 therapeutic agents, including
antibodies.
[0485] In one embodiment, the TNF.alpha. antibody of the invention
is administered in combination with an additional therapeutic agent
in the treatment of Behcet's disease in the multiple variable dose
regimen of the invention. Additional therapeutic agents which can
be used to treat Behcet's disease include, but are not limited to,
prednisone, cyclophosphamide (Cytoxan), Azathioprine (also called
imuran, methotrexate, timethoprim/sulfamethoxazole (also called
bactrim or septra) and folic acid.
[0486] Any one of the above-mentioned therapeutic agents, alone or
in combination therewith, can be administered to a subject
suffering from a TNF.alpha.-related disorder in which TNF.alpha. is
detrimental, in combination with the TNF.alpha. antibody using a
multiple variable dose treatment regimen of the invention. In one
embodiment, any one of the above-mentioned therapeutic agents,
alone or in combination therewith, can be administered to a subject
suffering from Crohn's disease or psoriasis, in addition to a
TNF.alpha. antibody to treat a TNF.alpha.-related disorder. It
should be understood that the additional therapeutic agents can be
used in combination therapy as described above, but also may be
used in other indications described herein wherein a beneficial
effect is desired.
[0487] It also is understood that the above-mentioned additional
agents can also be used in combination with a TNF.alpha. inhibitor,
e.g., a TNF.alpha. antibody, to treat a TNF.alpha.-related disorder
using the single dose treatment method of the invention.
[0488] This invention is further illustrated by the following
examples which should not be construed as limiting. The contents of
all references, patents and published patent applications cited
throughout this application are incorporated herein by
reference
Examples
Example 1: Study of Efficacy of Multiple-Dose Therapy for Treatment
of Crohn's Disease
[0489] Multiple-Variable Dose Treatment of Crohn's Disease (CD)
with D2E7 (Adalimumab)
[0490] Studies were performed to determine the efficacy of a
multiple-variable dose regimen of a TNF.alpha. inhibitor, namely
D2E7 (also referred to as adalimumab and Humira), for treating
Crohn's disease (CD). Efficacy and tolerability of D2E7 in the
treatment of patients with active Crohn's disease were evaluated in
the following randomized, double-blind, placebo-controlled,
multicenter study. Another objective of the following study was to
assess the pharmacokinetics of adalimumab (ADA or D2E7), a fully
human monoclonal antibody recognizing TNF, following subcutaneous
(sc) administration in patients with Crohn's disease. To assess the
pharmacokinetics of adalimumab was determined, a fully human
monoclonal antibody TNF antagonist, following subcutaneous (sc)
administration over 4 weeks in patients with CD who participated in
this study.
[0491] In this study, two hundred ninety-nine patients without
previous exposure to TNF-antagonists and with active Crohn's
Disease were selected. The initial screening period lasted up to 14
days. Crohn's disease in each patient was confirmed by endoscopic
or radiologic evaluation. Subjects were randomized equally to one
of four treatment groups (three treatment groups and one placebo
group). The three treatment groups included a 40 mg dose at
baseline (week 0) followed by a 20 mg dose at week 2 (n=74); an 80
mg dose at baseline followed by a 40 mg dose at week 2 (n=75); and
a 160 mg dose at baseline followed by an 80 mg dose at week 2
(n=76). The placebo group had 74 participants. Eligible subjects
included men and women between 18 and 75 years of age having a
diagnosis of Crohn's disease for more than four months. In
addition, selected patients had moderate to severely active Crohn's
disease, defined as a Crohn's Disease Activity Index (CDAI) score
of 220 to 450 points. Baseline characteristics were similar across
treatment groups. CDAI was equivalent across treatment groups and
was representative of moderate to severely active CD.
[0492] At baseline (Week 0), subjects received a loading dose of
D2E7 followed by a treatment dose at Week 2, wherein the treatment
dose was lower than the initial loading dose. Patients received one
of the following multiple variable dose treatment regimens at Week
0 (baseline) and Week 2 (Week 0/Week 2): 160 mg/80 mg D2E7; 80
mg/40 mg D2E7; 40 mg/20 mg D2E7; or placebo/placebo. Patients were
administered D2E7 or placebo treatment subcutaneously.
[0493] Blood samples for determination of serum ADA concentrations
were collected prior to dose at Week 0 and Week 2, and at the same
time of the day as study drug had previously been administered at
Week 1 and Week 4. Serum ADA concentrations were determined using a
validated ELISA assay. Based on PK modeling, higher dosing at Week
0 was expected to produce serum concentrations equivalent to values
shown to be efficacious in the treatment of rheumatoid
arthritis.
[0494] The study was conducted for up to ten weeks, including an
initial two week screening period, a four week treatment period
(Weeks 0 to 4), and a four week follow-up period. Participants were
evaluated for induction of clinical remission of Crohn's disease,
defined as a CDAI score of <150 at week 4. Clinical response,
defined as a decrease in CDAI compared to the CDAI baseline reading
of >70 [A70] or >100 points [A100]), was also assessed in the
participants. Serum adalimumab concentrations, were determined
using a validated ELISA assay.
[0495] Efficacy of the multiple-variable dose regimen was further
measured according to improvements in the patient''s Inflammatory
Bowel Disease Questionnaire (IBDQ) score, and improvements or
remission of draining fistulas. Fistula remission was defined as
closure of all fistulas that were draining at baseline for at least
two consecutive visits. Fistula improvement was defined as a
decrease of .gtoreq.50% in the number of draining fistula for at
least two consecutive visits. C-reactive protein (CRP) levels were
also measured, as CRP levels are reflective of inflammation in the
body.
[0496] Statistical analysis was determined using chi-square tests,
which were used for overall comparison of efficacy (remission and
clinical response) among the three treatment groups (two higher
adalimumab doses and placebo) and pair-wise comparisons were used
to compare each adalimumab dose and placebo. Descriptive statistics
for serum adalimumab concentration data were also calculated.
[0497] A total of 299 patients entered the study and were
randomized. 284 (95%) completed the trial (patients shown in Table
1).
TABLE-US-00001 TABLE 1 Patient Disposition Adalimumab Placebo 40/20
mg 80/40 mg 160/80 mg N = 74 N = 74 N = 75 N = 76 Completed 68 72
70 74 Withdrawn 6 2 5 2 Reason AE 2 1 1 0 Protocol violation 1 1 3
0 Lack of efficacy 1 1 1 1 Withdrew consent 1 0 0 1 Other 1 0 0
0
[0498] Results from the study show that multiple, variable D2E7
dosage treatments were effective at inducing Crohn's disease
remission. Table 2 shows the percentage of patients with clinical
remission (CDAI<150) at week 4 of the dosing regimen. As shown
below in Table 2, thirty percent of patients who received 80/40 mg
or 160/80 mg of D2E7 achieved clinical remission compared with 12%
who received placebo (p=0.004.) Patients in the highest dose group,
160/80 mg, achieved a statistically significant remission rate of
36% versus a placebo rate of 12%. (p=0.001). In addition, the 80/40
mg dose group trended toward statistical significance with 24% of
patients in remission by Week 4 vs. 12% placebo (p=0.06).
TABLE-US-00002 TABLE 2 D2E7 induces clinical remission in treatment
groups at Week 4 Placebo 40/20 mg 80/40 mg 160/80 mg CDAI < 150
12% 18% 24% 36%* (*denotes p = 0.001) (Placebo n = 74; 20 mg n =
74; 40 mg n = 75; 80 mg n = 76)
[0499] Results of remission of Crohn's disease (measured
CDAI<150) from each dosage group are also shown in FIG. 1 (note
dosage references in FIG. 1, as well as FIGS. 2-6 refer to the
treatment dose, i.e., 40 mg refers to the 80/40 treatment
regimen).
[0500] The median 4-week changes in the CDAI index for each dose
group (points with data at both baseline and week 4) were as
follows: placebo, .DELTA.-47 (n=67); 20 mg, .DELTA.-73 (n=70); 40
mg, .DELTA.-90 (n=70); and 80 mg, .DELTA.-101 (n=73). The decrease
in the CDAI index for patients who received the multiple variable
dose treatment of D2E7 is also shown in FIG. 2.
[0501] Clinical response results of CDAI.gtoreq.70 point and
.gtoreq.100 point decrease from baseline at four weeks are shown in
FIGS. 3 and 4, respectively. Significant increases in clinical
response (CDAI decrease of at least 70 or 100 points) were also
observed, as shown in FIGS. 3A, 3B, 4A and 4B. All adalimumab
treatment groups had a statistically significant clinical response
of decreased CDAI scores from Baseline .gtoreq.70 points compared
to placebo by Week 4 (FIGS. 3A and 3B). About 50% of patients in
the 160/80 mg treatment arm achieved a decrease in CDAI score from
Baseline .gtoreq.100 points compared to 25% of placebo patients at
Week 4 (FIGS. 4A and 4B).
[0502] Thus, patients who received multiple, variable doses of
D2E7, especially Crohn's patients receiving 80/40 mg and 160/80 mg,
showed a decrease in the CDAI index indicating remission of Crohn's
disease.
[0503] In addition, as shown in FIG. 5, patients receiving the
160/80 mg dosing regimen showed the greatest decrease in CRP
levels, with the placebo group showing the least decrease. Patients
also showed an overall improvement in their IBDQ score, as shown in
FIG. 6.
[0504] In addition, sustained serum D2E7 concentrations were
achieved early in treatment as a result of the multiple variable
dose regimen. Serum ADA concentrations were available from 211
patients. Serum ADA concentrations increased proportionally with
dose. Serum ADA concentrations were similar at Weeks 2 and 4 for
each treatment indicating that the initial dose brings ADA
concentrations to stable levels by Week 2 (see Table 3 and FIG.
11). Mean.+-.SD serum ADA concentrations (.mu.g/mL) at Weeks 1, 2,
and 4 among the 3 treatment arms were: (40/20 mg arm) 3.42.+-.1.37
(n=64), 2.95.+-.1.08 (n=69), 2.79.+-.1.48 (n=66); (80/40 mg)
7.00.+-.2.89 (n=68), 5.57.+-.2.42 (n=68), 5.65.+-.3.06 (n=65); and
(160/80 mg) 14.26.+-.4.92 (n=66), 12.34.+-.3.68 (n=68),
12.61.+-.5.25 (n=67), respectively.
TABLE-US-00003 TABLE 3 Serum Adalimumab Concentrations (.mu.g/mL)
Over 4 Weeks Mean .+-. SD serum adalimumab concentrations
(.mu.g/mL) Treatment Week 1 Week 2 Week 4 40/20 mg 3.42 .+-. 1.37
2.95 .+-. 1.08 2.79 .+-. 1.48 (n = 64) (n = 69) (n = 66) 80/40 mg
7.00 .+-. 2.89 5.57 .+-. 2.42 5.65 .+-. 3.06 (n = 68) (n = 68) (n =
65) 160/80 mg 14.26 .+-. 4.92 12.34 .+-. 3.68 12.61 .+-. 5.25 (n =
66) (n = 68) (n = 67)
[0505] The overall incidence of adverse events (AE) was low and did
not differ among groups. The most common AE were injection site
reactions, most of which were mild. Statistically significant
results were not dependent on baseline CRP concentration.
[0506] In sum, multiple, variable doses of D2E7 significantly
increased the frequency of remission of disease and clinical
response in Crohn's disease subjects. In combination, 30% of
subjects receiving D2E7 doses of 80/40 mg and 160/80 mg achieved
remission in comparison to only 12% of placebo subjects. There was
also a significant increase in the clinical response (a decrease in
the CDAI index of >70 points) and IBDQ scores of the 40 mg and
80 mg treatment doses every other week compared to the placebo. In
the treatment group receiving an 80 mg D2E7 treatment dose every
other week, 49% of the subjects achieved a clinical response (a
decrease in the CDAI of .gtoreq.100 points). Sustained serum
adalimumab concentrations were achieved early in treatment due to
the loading doses administered. Interestingly, serum adalimumab
concentrations in Crohn's patients administered the multiple
variable dose regimen were comparable to levels shown to be
efficacious in rheumatoid arthritis.
Example 2: Additional Study of Efficacy of Multiple-Dose Therapy
for Treatment of Crohn's Disease
[0507] Multiple-Variable Dose Treatment of Crohn's Disease with
D2E7
[0508] A study was performed to assess the tolerability and
clinical benefit of a multiple-variable dose treatment using a
TNF.alpha. inhibitor, specifically D2E7, in adult patients with
Crohn's disease who had previously received and responded to a
different TNF.alpha. inhibitor. The study included patients who had
previously received the chimeric anti-TNF antibody infliximab, but
who no longer have a sustained response and/or tolerance to
infliximab.
[0509] Patients who had lost responsiveness or developed
intolerance (acute or delayed infusion reactions) were treated with
D2E7 80 mg at week 0 and 40 mg at week 2. All treatments were
subcutaneous. Antibodies to infliximab (ATI) were determined at
baseline (Prometheus Laboratories, San Diego, Calif.). Crohn's
disease activity index (CDAI) scores, presence of fistulas, and
C-reactive protein (CRP) concentration were determined at weeks 0
and 4. Clinical response (decrease in CDAI of >/=100 points),
clinical remission (CDAI </=150 points), fistula improvement
(closure >/=50% of open fistulas), complete fistula closure, and
acute and delayed hypersensitivity reactions were recorded
throughout the study.
[0510] Twenty-four patients were enrolled and completed 4 weeks of
the multiple-variable dose therapy. Four of 16 patients (25%) were
positive for ATI. Of 13 patients with week 0 CDAI scores >/=220,
6 (46%) achieved clinical response and 1 (8%) achieved remission at
week 4. Of 6 patients with perianal and/or rectovaginal fistulas, 4
(67%) had fistula improvement and 3 (50%) had complete fistula
closure at week 4. Only 6 patients (38%) had CRP values above the
normal range. Among all patients, the mean+/-SD CRP concentrations
decreased from 17.0+/-29.3 mg/L at week 0 to 11.3+/-17.3 mg/L at
week 4. No patients experienced acute or delayed hypersensitivity
reactions during treatment with D2E7 (including 8 who previously
experienced treatment-limiting acute hypersensitivity reactions and
3 who previously experienced delayed hypersensitivity reactions
with infliximab).
[0511] In sum, multiple-variable dose treatment using D2E7 was well
tolerated and was clinically beneficial in patients with Crohn's
disease who had previously received and responded to infliximab,
but who no longer had a sustained response to or could not tolerate
infliximab.
Example 3: Efficacy of Multiple-Dose Therapy Using TNF.alpha.
Inhibitor for Treatment of Psoriasis
[0512] Multiple-Variable Dose Treatment of Psoriasis with D2E7
[0513] A study was performed to determine the efficacy of a
multiple-variable dose regimen of D2E7 for treating psoriasis.
Efficacy and tolerability of D2E7 in the treatment of patients with
moderate to severe chronic plaque psoriasis were evaluated in a
randomized, double-blind, placebo-controlled multicenter study.
[0514] In this study, one hundred forty-eight adult patients with a
diagnosis of moderate to severe psoriasis for at least one year
were selected to receive multiple-variable dose treatment. Patients
were also selected based on an affected body surface area (BSA) of
.gtoreq.5%. Subjects were randomized equally to one of three groups
(two treatment groups and one placebo).
[0515] At baseline (Week 0) patients in both treatment groups
received an induction dose of 80 mg of D2E7. Patients in the first
treatment group subsequently received a treatment dose of 40 mg of
D2E7 at week 1 followed by 40 mg every other week (eow) starting at
week 3. Subjects in the second treatment group received an
induction dose of 80 mg dose of D2E7 at Week 1 (following the
initial 80 mg dose at Week 0) followed by a treatment dose of 40 mg
of D2E7 weekly starting at week 2. The placebo group received only
the placebo weekly starting at baseline. All treatment was
administered subcutaneously (sc) with pre-filled syringes. A
summary of the different regimens are described below in Table
4:
TABLE-US-00004 TABLE 4 Psoriasis study regimens Regimen Detailed
description A D2E7 80 mg sc administered at Week 0 (baseline); D2E7
40 mg sc every other week administered starting at Week 1 through
Week 11, with placebo administered on alternate weeks B D2E7 80 mg
sc administered starting at Week 0 (baseline) and at Week 1
(80/80); D2E7 40 mg sc weekly administered starting at Week 2
through Week 11 C Placebo sc will be administered at baseline and
then weekly through Week 11, with two injections given at Week 1
and Week 1
[0516] In order to maintain the blind study, all subjects received
a total of 2 injections at baseline and week 1. During the
remaining period of the study (weeks 2 through 12), subjects
received one injection per week. The treatment dose per injection
correlated to the dose regimen randomly assigned to each
subject.
[0517] The PASI of the participants of the multiple-variable dose
regimen was determined according to standard methods (see
Fredriksson and Pettersson, supra and Marls et al., supra). The
primary efficacy endpoint of the study was the percentage of
subjects achieving a clinical response as defined by at least a 75%
reduction in the PASI score (>PAST 75) at Week 12.
[0518] Secondary efficacy measures included a static Physician's
Global Assessment (PGA) of "clear" or "almost clear" at Week 12.
PGA was determined according to a seven point scale used to measure
the severity of psoriasis at the time of the physician's
evaluation. Descriptions of the disease used included the
following: severe=very marked plaque elevation, scaling, and/or
erythema; moderate to severe=marked plaque elevation, scaling,
and/or erythema; moderate=moderate plaque elevation, scaling,
and/or erythema; mild to moderate=intermediate between moderate and
mild; mild=slight plaque elevation, scaling, and/or erythema;
almost clear=intermediate between mild and clear; and clear=no
signs of psoriasis.
[0519] The results show that at Week 12, statistically
significantly greater percentages of patients achieved a PASI 75
response or better on D2E7 than those on a placebo treatment. For
patients receiving 40 mg treatment dose of D2E7 eow, 53%
demonstrated a PASI of 75 or higher. In addition, 80% of patients
receiving a 40 mg treatment dose of D2E7 weekly showed a PASI 75 or
higher, compared to only 4% of the placebo treatment group
(p<0.001 vs. placebo). Response rates at Week 12 for both dosing
regimens of D2E7 were statistically significantly greater than for
placebo, as shown in FIG. 7.
[0520] Overall, the mean percentage changes in PASI score for
patients on D2E7 multiple-variable dose therapy were statistically
significantly greater than placebo. The changes were evident as
early as Week 1 after the initial dose, as shown in FIG. 8. At Week
12, 49% of patients on D2E7 receiving 40 mg eow and 76% of patients
receiving 40 mg of D2E7 weekly achieved a PGA of "clear" or "almost
clear," compared with 2% of placebo patients.
[0521] Of the one hundred forty-eight adult patients enrolled in
the study, 29% also had a medical history of psoriatic arthritis
(PsA). Both doses of D2E7 were effective in the treatment of
psoriasis in both patients with and without PsA. Patients with PsA
had a similar efficacy response to D2E7 as those without PsA. For
both PsA and without PsA subgroups, the percentages of patients
achieving a PASI 75 response or better at week 12 was statistically
significant for the eow (with PsA, 47%; without PsA, 57%) and
weekly treatment arms (with PsA, 58%; without PsA, 87%) compared
with placebo. Continued improvements in efficacy were seen through
week 24 in the eow arm (with PsA, 53%; without PsA, 70%). Efficacy
responses in patients with and without PsA at weeks 12 and 24 are
shown in FIGS. 9 and 10, respectively.
[0522] In conclusion, D2E7 administered for 12 weeks was effective
in the treatment of moderate to severe chronic plaque psoriasis.
53% of patients on 40 mg eow achieved >PASI 75, compared with 4%
on placebo. 80% of patients on 40 mg weekly achieved >PASI 75.
49% and 76% of patients on D2E7 40 mg eow and 40 mg weekly,
respectively, were "clear" or "almost clear" of their psoriasis. In
addition, D2E7 was equally effective at treating psoriasis patients
with and without PsA.
Example 4: Efficacy of Single Dose Treatment of D2E7
[0523] A study was performed to determine the efficacy of a single
dose regimen of D2E7 for treating rheumatoid arthritis (RA). The
objective of the study was to determine and compare the single-dose
safety and efficacy of 3 subcutaneous (sc) doses (20, 40, or 80 mg)
of D2E7 in Japanese and Caucasian subjects with RA.
[0524] D2E7 was administered as single sc doses (20, 40, or 80 mg)
in 40 Japanese (in Japan) and 36 Caucasian (in US) subjects with
RA, well-matched for moderate-to-severe baseline disease severity,
in 2 separate clinical studies of similar design--open-label,
parallel group. On Study Days 1, 15 and 29, safety evaluations
included physical examinations, vital signs, and laboratory
assessments to determine adverse events (AEs), and efficacy
evaluations included CRP, Physician's and Subject's Assessment of
Disease Activity, Subject's Assessment of Pain, Disability Index of
the Health Assessment Questionnaire (DIHAQ), and tender and swollen
joint counts.
[0525] Results from the study showed that all Japanese treatment
groups had statistically significant improvements of all ACR
components (except DIHAQ) on Day 15 and on Day 29 compared to Day
1. In the 3 Caucasian treatment groups, only the 80-mg treatment
group exhibited a statistically significant improvement at Day 29
in all individual ACR components with the exception of the DIHAQ
score. Although the study duration was only 29 days, ACR20
responses were achieved in 47.5% (19/40) of the Japanese patients
and in 30.6% (11/36) of the Caucasian patients. In addition, the
difference in frequency of subjects reporting AEs between treatment
groups was not clinically relevant within each study.
Interestingly, there was an increased incidence of AEs in Japanese
subjects which may reflect racial differences or investigator
cultural tendency to report.
[0526] The results demonstrate an improvement of comparable
magnitude in RA signs and symptoms in both groups in this
short-term study using a single dose treatment. These results also
suggest similar safety of single-dose sc administration of ADA in
Japanese and Caucasian subjects.
[0527] This application is related to U.S. Pat. Nos. 6,090,382,
6,258,562, and 6,509,015. This application is also related to U.S.
patent application Ser. No. 09/801,185, filed Mar. 7, 2001; U.S.
patent application Ser. No. 10/302,356, filed Nov. 22, 2002; U.S.
patent application Ser. No. 10/163,657, filed Jun. 5, 2002; U.S.
patent application Ser. No. 10/133,715, filed Apr. 26, 2002; U.S.
patent application Ser. No. 10/222,140, filed Aug. 16, 2002; U.S.
patent application Ser. No. 10/693,233, filed Oct. 24, 2003; U.S.
patent application Ser. No. 10/622,932, filed Jul. 18, 2003; U.S.
patent application Ser. No. 10/623,039, filed Jul. 18, 2003; U.S.
patent application Ser. No. 10/623,076, filed Jul. 18, 2003; U.S.
patent application Ser. No. 10/623,065, filed Jul. 18, 2003; U.S.
patent application Ser. No. 10/622,928, filed Jul. 18, 2003; U.S.
patent application Ser. No. 10/623,075, filed Jul. 18, 2003; U.S.
patent application Ser. No. 10/623,035, filed Jul. 18, 2003; U.S.
patent application Ser. No. 10/622,683, filed Jul. 18, 2003; U.S.
patent application Ser. No. 10/622,205, filed Jul. 18, 2003; U.S.
patent application Ser. No. 10/622,210, filed Jul. 18, 2003; U.S.
patent application Ser. No. 10/623,318, filed Jul. 18, 2003; and
U.S. patent application Ser. No. 10/422,287, filed Apr. 24, 2003.
The entire contents of each of these patents and patent
applications are hereby incorporated herein by reference. Forming
part of the present disclosure is the appended Sequence Listing,
the contents of which are summarized in the table below:
TABLE-US-00005 SEQ ANTIBODY SEQUENCE ID NO: CHAIN REGION TYPE 1
D2E7 VL amino acid 2 D2E7 VH amino acid 3 D2E7 VL CDR3 amino acid 4
D2E7 VH CDR3 amino acid 5 D2E7 VL CDR2 amino acid 6 D2E7 VH CDR2
amino acid 7 D2E7 VL CDR1 amino acid 8 D2E7 VH CDR1 amino acid 9
2SD4 VL amino acid 10 2SD4 VH amino acid 11 2SD4 VL CDR3 amino acid
12 EP B12 VL CDR3 amino acid 13 VL10E4 VL CDR3 amino acid 14
VL100A9 VL CDR3 amino acid 15 VLL100D2 VL CDR3 amino acid 16 VLL0F4
VL CDR3 amino acid 17 LOE5 VL CDR3 amino acid 18 VLLOG7 VL CDR3
amino acid 19 VLLOG9 VL CDR3 amino acid 20 VLLOH1 VL CDR3 amino
acid 21 VLLOH10 VL CDR3 amino acid 22 VL1B7 VL CDR3 amino acid 23
VL1C1 VL CDR3 amino acid 24 VL0.1F4 VL CDR3 amino acid 25 VL0.1H8
VL CDR3 amino acid 26 LOE7.A VL CDR3 amino acid 27 2SD4 VH CDR3
amino acid 28 VH1B11 VH CDR3 amino acid 29 VH1D8 VH CDR3 amino acid
30 VH1A11 VH CDR3 amino acid 31 VH1B12 VH CDR3 amino acid 32 VH1E4
VH CDR3 amino acid 33 VH1F6 VH CDR3 amino acid 34 3C-H2 VH CDR3
amino acid 35 VH1-D2.N VH CDR3 amino acid 36 D2E7 VL nucleic acid
37 D2E7 VH nucleic acid
EQUIVALENTS
[0528] Those skilled in the art will recognize, or be able to
ascertain using no more than routine experimentation, many
equivalents to the specific embodiments of the invention described
herein. Such equivalents are intended to be encompassed by the
following claims.
Sequence CWU 1
1
371107PRTArtificial SequenceD2E7 light chain variable region 1Asp
Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly1 5 10
15Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Ile Arg Asn Tyr
20 25 30Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu
Ile 35 40 45Tyr Ala Ala Ser Thr Leu Gln Ser Gly Val Pro Ser Arg Phe
Ser Gly 50 55 60Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser
Leu Gln Pro65 70 75 80Glu Asp Val Ala Thr Tyr Tyr Cys Gln Arg Tyr
Asn Arg Ala Pro Tyr 85 90 95Thr Phe Gly Gln Gly Thr Lys Val Glu Ile
Lys 100 1052121PRTArtificial SequenceD2E7 heavy chain variable
region 2Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly
Arg1 5 10 15Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asp
Asp Tyr 20 25 30Ala Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu
Glu Trp Val 35 40 45Ser Ala Ile Thr Trp Asn Ser Gly His Ile Asp Tyr
Ala Asp Ser Val 50 55 60Glu Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala
Lys Asn Ser Leu Tyr65 70 75 80Leu Gln Met Asn Ser Leu Arg Ala Glu
Asp Thr Ala Val Tyr Tyr Cys 85 90 95Ala Lys Val Ser Tyr Leu Ser Thr
Ala Ser Ser Leu Asp Tyr Trp Gly 100 105 110Gln Gly Thr Leu Val Thr
Val Ser Ser 115 12039PRTArtificialD2E7 light chain variable region
CDR3VARIANT9Xaa = Any Amino Acid 3Gln Arg Tyr Asn Arg Ala Pro Tyr
Xaa1 5412PRTArtificialD2E7 heavy chain variable region
CDR3VARIANT12Xaa = Any Amino Acid 4Val Ser Tyr Leu Ser Thr Ala Ser
Ser Leu Asp Xaa1 5 1057PRTArtificialD2E7 light chain variable
region CDR2 5Ala Ala Ser Thr Leu Gln Ser1 5617PRTArtificialD2E7
heavy chain variable region CDR2 6Ala Ile Thr Trp Asn Ser Gly His
Ile Asp Tyr Ala Asp Ser Val Glu1 5 10 15Gly711PRTArtificialD2E7
light chain variable region CDR1 7Arg Ala Ser Gln Gly Ile Arg Asn
Tyr Leu Ala1 5 1085PRTArtificialD2E7 heavy chain variable region
CDR1 8Asp Tyr Ala Met His1 59107PRTArtificial2SD4 light chain
variable region 9Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser
Ala Ser Ile Gly1 5 10 15Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln
Gly Ile Arg Asn Tyr 20 25 30Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys
Ala Pro Lys Leu Leu Ile 35 40 45Tyr Ala Ala Ser Thr Leu Gln Ser Gly
Val Pro Ser Arg Phe Ser Gly 50 55 60Ser Gly Ser Gly Thr Asp Phe Thr
Leu Thr Ile Ser Ser Leu Gln Pro65 70 75 80Glu Asp Val Ala Thr Tyr
Tyr Cys Gln Lys Tyr Asn Ser Ala Pro Tyr 85 90 95Ala Phe Gly Gln Gly
Thr Lys Val Glu Ile Lys 100 10510121PRTArtificial2SD4 heavy chain
variable region 10Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val
Gln Pro Gly Arg1 5 10 15Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe
Thr Phe Asp Asp Tyr 20 25 30Ala Met His Trp Val Arg Gln Ala Pro Gly
Lys Gly Leu Asp Trp Val 35 40 45Ser Ala Ile Thr Trp Asn Ser Gly His
Ile Asp Tyr Ala Asp Ser Val 50 55 60Glu Gly Arg Phe Ala Val Ser Arg
Asp Asn Ala Lys Asn Ala Leu Tyr65 70 75 80Leu Gln Met Asn Ser Leu
Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95Thr Lys Ala Ser Tyr
Leu Ser Thr Ser Ser Ser Leu Asp Asn Trp Gly 100 105 110Gln Gly Thr
Leu Val Thr Val Ser Ser 115 120119PRTArtificial2SD4 light chain
variable region CDR3 11Gln Lys Tyr Asn Ser Ala Pro Tyr Ala1
5129PRTArtificialEP B12 light chain variable region CDR3 12Gln Lys
Tyr Asn Arg Ala Pro Tyr Ala1 5139PRTArtificialVL10E4 light chain
variable region CDR3 13Gln Lys Tyr Gln Arg Ala Pro Tyr Thr1
5149PRTArtificialVL100A9 light chain variable region CDR3 14Gln Lys
Tyr Ser Ser Ala Pro Tyr Thr1 5159PRTArtificialVLL100D2 light chain
variable region CDR3 15Gln Lys Tyr Asn Ser Ala Pro Tyr Thr1
5169PRTArtificialVLL0F4 light chain variable region CDR3 16Gln Lys
Tyr Asn Arg Ala Pro Tyr Thr1 5179PRTArtificialLOE5 light chain
variable region CDR3 17Gln Lys Tyr Asn Ser Ala Pro Tyr Tyr1
5189PRTArtificialVLLOG7 light chain variable region CDR3 18Gln Lys
Tyr Asn Ser Ala Pro Tyr Asn1 5199PRTArtificialVLLOG9 light chain
variable region CDR3 19Gln Lys Tyr Thr Ser Ala Pro Tyr Thr1
5209PRTArtificialVLLOH1 light chain variable region CDR3 20Gln Lys
Tyr Asn Arg Ala Pro Tyr Asn1 5219PRTArtificialVLLOH10 light chain
variable region CDR3 21Gln Lys Tyr Asn Ser Ala Ala Tyr Ser1
5229PRTArtificialVL1B7 light chain variable region CDR3 22Gln Gln
Tyr Asn Ser Ala Pro Asp Thr1 5239PRTArtificialVL1C1 light chain
variable region CDR3 23Gln Lys Tyr Asn Ser Asp Pro Tyr Thr1
5249PRTArtificialVL0.1F4 light chain variable region CDR3 24Gln Lys
Tyr Ile Ser Ala Pro Tyr Thr1 5259PRTArtificialVL0.1H8 light chain
variable region CDR3 25Gln Lys Tyr Asn Arg Pro Pro Tyr Thr1
5269PRTArtificialLOE7.A light chain variable region CDR3 26Gln Arg
Tyr Asn Arg Ala Pro Tyr Ala1 52712PRTArtificial2SD4 heavy chain
variable region CDR3 27Ala Ser Tyr Leu Ser Thr Ser Ser Ser Leu Asp
Asn1 5 102812PRTArtificialVH1B11 heavy chain variable region CDR3
28Ala Ser Tyr Leu Ser Thr Ser Ser Ser Leu Asp Lys1 5
102912PRTArtificialVH1D8 heavy chain variable region CDR3 29Ala Ser
Tyr Leu Ser Thr Ser Ser Ser Leu Asp Tyr1 5
103012PRTArtificialVH1A11 heavy chain variable region CDR3 30Ala
Ser Tyr Leu Ser Thr Ser Ser Ser Leu Asp Asp1 5
103112PRTArtificialVH1B12 heavy chain variable region CDR3 31Ala
Ser Tyr Leu Ser Thr Ser Phe Ser Leu Asp Tyr1 5
103212PRTArtificialVH1E4 heavy chain variable region CDR3 32Ala Ser
Tyr Leu Ser Thr Ser Ser Ser Leu His Tyr1 5 103312PRTArtificialVH1F6
heavy chain variable region CDR3 33Ala Ser Phe Leu Ser Thr Ser Ser
Ser Leu Glu Tyr1 5 103412PRTArtificial3C-H2 heavy chain variable
region CDR3 34Ala Ser Tyr Leu Ser Thr Ala Ser Ser Leu Glu Tyr1 5
103512PRTArtificialVH1-D2.N heavy chain variable region CDR3 35Val
Ser Tyr Leu Ser Thr Ala Ser Ser Leu Asp Asn1 5
1036321DNAArtificialD2E7 light chain variable region 36gacatccaga
tgacccagtc tccatcctcc ctgtctgcat ctgtagggga cagagtcacc 60atcacttgtc
gggcaagtca gggcatcaga aattacttag cctggtatca gcaaaaacca
120gggaaagccc ctaagctcct gatctatgct gcatccactt tgcaatcagg
ggtcccatct 180cggttcagtg gcagtggatc tgggacagat ttcactctca
ccatcagcag cctacagcct 240gaagatgttg caacttatta ctgtcaaagg
tataaccgtg caccgtatac ttttggccag 300gggaccaagg tggaaatcaa a
32137363DNAArtificialD2E7 heavy chain variable region 37gaggtgcagc
tggtggagtc tgggggaggc ttggtacagc ccggcaggtc cctgagactc 60tcctgtgcgg
cctctggatt cacctttgat gattatgcca tgcactgggt ccggcaagct
120ccagggaagg gcctggaatg ggtctcagct atcacttgga atagtggtca
catagactat 180gcggactctg tggagggccg attcaccatc tccagagaca
acgccaagaa ctccctgtat 240ctgcaaatga acagtctgag agctgaggat
acggccgtat attactgtgc gaaagtctcg 300taccttagca ccgcgtcctc
ccttgactat tggggccaag gtaccctggt caccgtctcg 360agt 363
* * * * *